BR112021011699A2 - COMBINATION THERAPY WITH A RAF INHIBITOR AND A CDK4/6 INHIBITOR FOR USE IN CANCER TREATMENT - Google Patents

Abstract

combination therapy with a raf inhibitor and a cdk4/6 inhibitor for use in cancer treatment. the present invention relates to a pharmaceutical combination comprising (a) a raf inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and (b) an inhibitor of ckd4/6, particularly ribociclib particularly for use in treating a proliferative disease, preferably melanoma or pancreatic ductal adenocarcinoma.

Description

Invention Patent Descriptive Report for "TERA-

COMBINATION SINK WITH A RAF INHIBITOR AND A CDK4/6 INHIBITOR FOR USE IN THE TREATMENT OF CANCER".

FIELD OF THE INVENTION

[001] The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, particularly ribociclib or a pharmaceutically acceptable salt thereof.

[002] This invention also relates to such combinations for use in the treatment of cancer; uses of such combinations for the preparation of a drug for the treatment of cancer; methods of treating cancer, in a subject in need thereof comprising administering to said subject a conjointly therapeutically effective amount of said combinations; use of such combinations for the treatment of cancer; and pharmaceutical compositions comprising such combinations.

[003] This invention also relates to the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, for use in a combination therapy with a CDK4/6 inhibitor, particularly ribociclib or a pharmaceutically acceptable salt. acceptable of the same. Also provided herein is a CDK4/6 inhibitor, particularly ribociclib or a pharmaceutically acceptable salt thereof, for use in a combination therapy with the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt of the same. same.

BACKGROUND OF THE INVENTION

[004] More than 30% of human cancers harbor mutations in the Mitogen-Activated Protein Kinase (MAPK) pathway, of which the most prevalent are RAS or BRAF mutations. The MAPK way

(also known as the RAS/RAF/CDK4/6/ERK pathway) is a key signaling cascade that directs cell proliferation, differentiation, and survival. Deregulation of this pathway forms the basis of many cases of tumorigenesis including melanoma (Kirkwood et al., Clin Cancer Res 18(2):555 to 567, 2012). This pathway is composed of RAS small guanidine triphosphatase (GTPase) which, when activated, promotes the activation of RAF family proteins (ARAF, BRAF and CRAF, also known as RAF1). Activated RAF proteins lead to phosphorylation and activation of CDK4/61/2 proteins that subsequently phosphorylate and activate extracellular signal-regulated kinases (ERKs). ERKs phosphorylate a variety of substrates, including multiple transcription factors, and regulate several key cellular activities, including proliferation, differentiation, migration, survival, and angiogenesis. Furthermore, RAS or BRAF mutations constitutively activate the Cyclin D-CDK4/6 complex, where they cooperate with CDK4 activation and lead to tumor progression (Chudnovsky Y et al. 2005; Monahan KB et al. 2010).

[005] There is a high frequency of activating mutations in proteins of the MAPK pathway in melanoma. RAS mutant melanoma shows aggressive behavior, with a high rate of liver and brain metastases already present at initial diagnosis (Bergamasco et al., Value in Health Journal 19 A347 to A766, 2016) and therefore poor prognosis . The response to standard chemotherapy treatment is very limited. A Phase 3 study demonstrated some benefits of the CDK4/6 inhibitor binimetinib compared to standard of care chemotherapy with dacarbazine, eg improved overall response rate of 15 vs. 7%. 402 patients were randomly assigned in a 2:1 fashion. A median PFS of 2.8 (95% CI: 2.8-3.6) vs. 1.5 (1.5-1.7), HR 0.62 (0.47-0.80) in favor of binimetinib was observed. However, the rate of discontinuation as a result of adverse events suspected to be related to study drug was high (20% vs. 5%), and the benefit in PFS did not transfer to improvements in overall survival (11.0 (95% CI: 8.9-13.6) vs. 10.1 (7.0-16.5) months (Dummer et al., Lancet Oncol 18(4):435 to 445, 2017 ).

[006] The NRAS gene is mutated in 15 to 20% of melanomas—a relatively common subtype of melanoma. In melanoma, most activating variants in NRAS occur at codon 61, with variants at codons 12 and 13 occurring less frequently (Gao et al., Sci Signal, 2013; van Elsas, Recent Results Cancer Res, 1995). The presence of NRAS mutations in melanoma causes a shift in MAPK signaling from BRAF to CRAF, initiating deregulated cAMP signaling that allows CRAF to signal to CDK4/6 (Dumaz 2006). Mutations in NRAS are unique to alterations in PTEN, implying that mutations in NRAS alone can activate signaling along the MAPK and PI3K pathways (Goel et al., J Invest Dermatol 6(269):pl1, 2006, Davies et al. al., Clin Cancer Res 15(24): 7538-46 2009 Compared to other melanoma subtypes, melanomas with NRAS mutations are associated with a worse prognosis (Devitt et al., Pigment Cell Melanoma Res. 24(4): 666 to 672, 2011), and responses to standard chemotherapy of care are very limited.

[007] KRAS mutations are frequently found in pancreatic cancer (di Magliano MP & Logsdon CD, Gastroenterology 2013; 144(6): 1220 to 1229). A study of samples from patients with PDAC showed that 93% of all samples had KRAS mutations (Biankin et al. Nature 2012; 491, 399 to 405). KRAS has the same downstream effectors as NRAS. However, there remains a major unmet medical need in NRAS and KRAS mutant cancers.

[008] The selective pharmacological inhibition of NRAS remains technically challenging because its GTPase activity has, so far, eluded the successful design of specific small molecule antagonists. Muñoz-Couselo E, et. al., Onco Targets and Therapy, 2017:10 Pages 3941 to 3947 suggests that combinations with MEK inhibitors and immunotherapy are the most promising strategy. However, the effectiveness of current approaches has not yet been established.

[009] It was recently reported that LY3009120, a pan-Raf inhibitor in combination with abemaciclib, a CDK4/6 inhibitor, inhibited the proliferation of certain tumor cells with KRAS or BRAF mutations (Chen SH et al., Oncogene, 2018, 37, 821 to 832). However, LY3009120 inhibits several other kinases, including those that have important roles in cancer, such as Ephrine receptors, JNK family members and SRC, potentially leading to off-target toxicities.

[0010] Effective therapies that target RAS mutant cancers, including NRAS mutant melanoma and KRAS pancreatic duct adenocarcinoma (PDAC), therefore remain an unmet medical need.

SUMMARY OF THE INVENTION

[0011] It was found that CDK4/6 inhibitor ribociclib in combination with a selective Raf inhibitor, such as a Compound of formula (I) synergistically inhibited tumor cells in vitro. The combination also led to significant tumor regression in patient-derived melanoma xenografts, particularly NRAS mutant melanoma xenografts, and increased median percent survival in preclinical models.

[0012] Combination treatment of Compound of formula (I) and ribociclib was well tolerated and led to increased antitumor activity compared to single agents in tumor-derived xenografts.

of patients. These data indicate that the combination activity of Compound of formula (I) and ribociclib can elicit greater and more durable responses in patients suffering from RAS mutant cancer (such as melanoma) in particular NRAS mutant cancer, more specifically NRAS mutant melanoma. It is important to note that the same doses that evoke very little effect when Compound of formula (I) and ribociclib are used as single agents, evoke a greater effect when the agents are combined.

[0013] Thus, the combination of the Compound of formula (I) and a CDK4/6 inhibitor, particularly ribociclib, or a pharmaceutically active salt thereof, may elicit greater and more durable responses in patients with the Activated MAPK, in particular, NRAS mutant cancer such as NRAS mutant melanoma or KRAS mutant cancer such as KRAS mutant pancreatic duct adenocarcinoma (PDAC). Combination therapy may also provide few side effects and/or be more tolerable for patients in need of it.

[0014] Compound of formula (I), a selective Raf inhibitor, with the CDK4/6 inhibitor ribociclib, may also optimize suppression of MAPK signaling in NRAS mutant melanoma. Compound of formula (I) and ribociclib in combination may also help prevent the emergence of resistance to the combination inhibitors of BRAF and CDK4/6 (mitogen activated protein kinase kinase) in NRAS mutant melanoma or KRAS mutant PDAC.

[0015] No targeted therapy is currently available outside of clinical studies for patients with NRAS mutant melanomas. The synergistic combination of a Raf inhibitor and a CDK4/6 inhibitor may exert a strong clinical benefit in patients suffering from NRAS mutant cancer and, in particular, NRAS mutant melanoma.

[0016] The invention therefore provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is the Compound of formula (I), (I) or a pharmaceutically acceptable salt. the same.

[0017] In another aspect, the invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the invention provides a pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein (i) the Raf inhibitor is the Compound of formula (I) or a pharmaceutically acceptable salt of the same; and (ii) the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the invention provides these pharmaceutical combinations for use in the treatment of cancer.

[0020] The present invention is particularly related to the combination of the invention for use in the treatment of a cancer that is characterized by activating mutations in the MAPK pathway and, in particular, by one or more mutations in NRAS or KRAS. In particular, the combination of the invention may be useful for the treatment of melanoma, particularly NRAS mutant melanoma. Furthermore, the combination of the invention may be useful for the treatment of pancreatic cancer, particularly KRAS mutant PDAC.

[0021] The present invention provides the Compound of formula (I) for

for use in the treatment of cancer by co-administration with a CDK4/6 inhibitor, eg ribociclib or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides ribociclib or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by co-administration with the Compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, the invention provides the use of the pharmaceutical combination of a Raf inhibitor which is Compound of formula (I) and a CDK4/6 inhibitor for the preparation of a medicament for the treatment of of cancer.

[0024] In another aspect, the invention provides a method of treating cancer in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination of a Raf inhibitor which is the Compound of formula (I) and a CDK4/6 inhibitor.

[0025] The present invention also provides a method of treating a cancer comprising simultaneously, separately or sequentially administering to a subject in need thereof a combination of the invention in an amount that is together therapeutically effective against said cancer.

[0026] The present invention also provides a pharmaceutical composition or combination preparation comprising an amount of the combination of the invention, which is together therapeutically effective against a cancer, and, optionally, at least one pharmaceutically acceptable carrier.

[0027] The present invention also provides a combined preparation comprising (a) one or more dosage units of a Raf inhibitor selected from the group consisting of (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof and ( b) one or more dosage units of a CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0028] The present invention also provides a commercial package comprising, as active ingredients, a combination of the invention and instructions for simultaneous, separate or sequential administration of a combination of the invention to a patient in need thereof for use in the medical field. treatment of a cancer, such as melanoma, and, in particular, NRAS mutant melanoma or pancreatic cancer, such as KRAS mutant PDAC.

[0029] Various aspects of the invention are described in more detail below. Additional definitions are presented throughout the descriptive report.

BRIEF DESCRIPTION OF THE FIGURES

[0030] Compound of formula (I) is also referred to herein as "LXH254" or as "NVP-LXH254". Ribociclib is referred to herein as "LEE011" or "NVP-LEE011". FIGURE 1: Effect of a combination of Compound of formula (I) and ribociclib on antiproliferative effects and phophorb suppression relative to single treatments in the sk-mel-30 melanoma cell line

[0031] Shown in (FIGURE 1a, FIGURE 1b, FIGURE 1c) combination matrices for inhibition of proliferation (FIGURE 1a), excessive Loewe inhibition (ADD) (FIGURE 1b) and Inhibition of Growth (GI) ( FIGURE 1c) for ribociclib in combination with the Compound of formula (I) as measured by the CyQUANT® Direct Cell Proliferation Assay in the melanoma cell line SK-MEL-30 that contains coincident mutations in NRAS (Q61K) and BRAF (D287H ). In all cases, increasing concentrations of ribociclib are shown along the bottom row from left to right and increasing concentrations of Compound of formula (I) along the leftmost column from bottom to top.

All remaining points on the grid display the percent inhibition that results from a combination of the two inhibitors that correspond to the single agent concentrations denoted on the two axes.

The excessive inhibition matrix shows the excessive percent inhibition of the experimental values (left grid) over the predicted values of the Loewe dose additivity model, which predicts inhibition due to dose additivity alone (Lehar et al. , 2009). Positive numbers represent areas of increasing synergy and negative numbers represent regions of antagonism.

The Growth Inhibition (GI) measurement is based on normalizing experimental inhibition measurements using an additional zero time vehicle reference level (time of drug addition). The measured GI results in effect values at two different linear normalization scale portions with a 'break point' at zero time level (i.e., at GI=100%). GI values will be > 100% if the stasis point is exceeded (Lehar et.

Al. 2009). (FIGURE 1d) Western blot analysis of phosphorylated RB1, CDK4/61/2, ERK1/2 and RSK3 after single agent or combination treatments with ribociclib and the Compound of formula (I) in SK-MEL-20 cells. Drug treatments, including nanomolar (nM) concentrations, are seen above Western blot images.

The duration of drug treatment for all samples was 48 hours.

The specific proteins being probed are seen to the right of each set of panels.

FIGURE 2: The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative effects and phopho-rb suppression over single treatments in the ipc-298 melanoma cell line

[0032] Antiproliferative effects (FIGURE 2a, FIGURE 2b, FIGURE 2c) and western analysis of key signaling protein (FIGURE 2d) are shown in the NRAS mutant melanoma cell line IPC298 (NRASQ61L). The experimental protocols and data points in FIGURE 2a, FIGURE 2b, FIGURE 2c are as described for FIGURE 1 above. FIGURE 3: The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative effects and phophor-rb suppression over single treatments in the meljuso melanoma cell line

[0033] Antiproliferative effects (FIGURE 3a, FIGURE 3b and FIGURE 3c) and western analysis of key signaling protein (FIGURE 3d) in the NRAS mutant melanoma Meljuso cell line (NRASQ61L) are shown. The experimental protocols and data points in FIGURE 3a, FIGURE 3b and FIGURE 3c are as described for FIGURE 1 above. FIGURE 4: The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative effects and phophor-rb suppression over single treatments in the meljuso melanoma cell line

[0034] Shown are the antiproliferative effects (FIGURE 4a, FIGURE 4b and FIGURE 4c) and Western analysis of the key signaling protein (FIGURE 4d) on the NRAS mutant melanoma cell line SK-MEL-2 ( NRASQ61R). The experimental protocols and data points in FIGURE 4a, FIGURE 4b and FIGURE 4c are as described for FIGURE 1 above. FIGURE 5: Anti-tumor activity of Compound of formula (I) and ribociclib on nine mouse patient-derived nrasmut melanoma tumor xenograft models.

[0035] Each bar represents the best response obtained by each treatment (plotted as the average of 3-5 mice/treatment) in an individual patient-derived xenograft model (PDX). The models for each treatment are plotted from left to right in the following order: HMEX20864, HMEX20744, HMEX4339, HMEX5727, HMEX21124, HMEX3486, HMEX20667, HMEX20585, and HMEX2921. FIGURE 6: Graph of Kaplan-Meier time at which tumors reached a size of 700 mm3 during daily treatment of single agents of the compound of formula (I) and ribociclib or a combination of both

[0036] Treatment was initiated when the mean tumor size of each model was around 350 mm3, and all animals received continuous daily drug treatments for the duration of the study. The study was terminated when the animals were treated for >/=90 days or reached a tumor size of >/=700 mm3. The combination group survival curves were statistically significant [*p<0.05 Log-rank (Mantel-Cox test)] when compared with each individual agent or untreated controls.

DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention provides a pharmaceutical combination comprising (a) a Raf inhibitor which is a Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CDK4/6 inhibitor, particularly for use in the treatment of cancer.

[0038] As used herein, the term "Raf inhibitor" refers to a competitive adenosine triphosphate (ATP) inhibitor of B-Raf protein kinase (also referred to herein as b-RAF, BRAF or b-Raf) and protein kinase C-Raf (also referred to herein as c-RAF, CRAF or c-Raf). The Raf inhibitor preferentially inhibits Raf monomers and Raf dimers.

[0039] The compound of formula (I) has the following structure: (I).

[0040] For convenience, the group of the compound and its salts is collectively referred to as "Compound of formula (I)" or "Compound (I)", meaning that reference to "Compound of formula (I)" or " Compound (I)" will refer to any of the Compounds or a pharmaceutically acceptable salt thereof in alternative form.

[0041] The Raf inhibitor Compound of formula (I) and its pharmaceutically acceptable salts are described in WO2014/151616 , which is hereby incorporated by reference in its entirety, and methods for its preparation have been described, for example , in Example 1156 therein. Compound of formula (I) is a potent and selective inhibitor that targets BRAF and CRAF kinases with sub-nM inhibition concentration values of 50% (IC50) in biochemical assays, while inhibiting the binding of only 2 (the receptor for the tyrosine kinase 1 (DDR1) discoid domain and platelet-derived growth factor receptor, polypeptide beta (PDGFRβ)) of 456 kinases to a similar degree. Compound of formula (I) has demonstrated efficacy in a wide range of human cancer cell lines driven by the MAPK pathway and tumor xenografts in vivo, including models harboring activation lesions in KRAS, NRAS and BRAF oncogenes. For example, Compound of formula (I) exhibits activity in the low µM range in human pancreatic cancer cell lines that express KRAS mutations (see WO/2018/203219 A1, Example 1B, Table 2).

[0042] The pharmaceutical combinations of the present invention com-

further comprise a CDK4/6 inhibitor. The D-cyclin-CDK4/6-RB1 axis is an important downstream effector pathway of MAPK signaling that controls the transition of cells from the G1-to-S phase of the cell cycle.

[0043] CDK4/6 inhibitors suitable for use in the present invention include ribociclib or a pharmaceutically acceptable salt thereof, and palbociclib or a pharmaceutically acceptable salt thereof.

[0044] A CDK4/6 inhibitor useful in the pharmaceutical combinations of the invention includes ribociclib or palbociclib.

[0045] Ribociclib (Kisqali®) is an orally bioavailable and highly selective small molecule inhibitor with highly specific inhibitory activity against CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complexes. A particularly useful salt of ribociclib is the succinate salt thereof.

[0046] The present invention further relates to a pharmaceutical combination comprising (a) a Raf inhibitor which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, particularly for simultaneous, separate or sequential use in the treatment of cancer.

[0047] Certain terms are defined below and throughout the order. Compounds of the present invention are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The following general definitions shall apply in this descriptive report, unless otherwise specified.

[0048] As used herein, the term "combination of the invention" refers to the pharmaceutical combination of (a) a Raf inhibitor which is the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) an inhibitor of CDK4/6, preferably ribociclib or a pharmaceutically acceptable salt thereof. As used herein, the term "combination of the invention" also refers to the co-administration or combined administration of (a) a Raf inhibitor which is the Compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) an inhibitor of Raf. CDK4/6, preferably ribociclib or a pharmaceutically acceptable salt thereof. The Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof, can be used in combination according to the invention by the simultaneous administration in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each including the Raf inhibitor and a CDK4/6 inhibitor in a sequential manner in which, for example, the Raf inhibitor or a CDK4/6 inhibitor is administered. first and the other later. Such sequential administration may be close in time (eg, simultaneous) or remote in time.

[0049] As used herein, the terms "a" and "an" and "the" and "the" and similar terms in the context of describing the invention are to be interpreted as embracing the singular and the plural, unless otherwise indicated in this document or clearly contradicted by the context. When the plural form is used for compounds, salts and the like, it should be interpreted to also mean a single compound, salt or the like.

[0050] The term "or" is used herein to mean, and is used interchangeably with, the term "and/or", unless the context clearly indicates otherwise.

[0051] "About" and "approximately" generally mean an acceptable degree of error for the measured quantity given the nature or accuracy of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values. When a dosage is described herein as "about" a specified amount, the actual dosage may vary by up to 10% from the stated amount: this use of "about" recognizes that the precise amount in a A given dosage form may differ slightly from a desired amount for various reasons without materially affecting the in vivo effect of the administered compound.

[0052] When a dosage is described herein as a specified amount, i.e. without the term "about", the actual dosage may vary by up to 10% (preferably up to 5%) of the stated amount: this usage recognizes that the precise amount in a given dosage form may differ slightly from an intended amount for various reasons without materially affecting the in vivo effect of the administered compound.

[0053] The terms "comprising" and "including" are used herein in their open and non-limiting sense unless otherwise indicated.

[0054] By "a combination" or "in combination with" or "co-administration", it is not intended to imply that the therapy or therapeutic agents must be physically mixed or administered at the same time and/or formulated for joint release, although these release methods fall within the scope described here. A therapeutic agent in such combinations can be administered concurrently with, prior to, or subsequent to one or more additional therapies or therapeutic agents. Therapeutic agents may be administered in any order. In general, each agent will be administered at a dose and/or time schedule determined for that agent. It will be further appreciated that the additional therapeutic agent used in this combination may be administered together in a single composition or administered separately in different compositions. In general, additional therapeutic agents used in combination are expected to be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than those used as single agent therapeutics.

[0055] The combinations of the invention have therapeutic or protective functions or both. For example, these molecules can be administered to a human subject to treat and/or prevent a variety of disorders, such as cancers, as described herein.

[0056] The terms "combination", "therapeutic combination", or "pharmaceutical combination", as used herein, refer to a fixed combination in a unit dosage form, or non-fixed combination, or a kit of parts for combined administration (co-administration) where two or more therapeutic agents can be administered together, independently at the same time or separately within time intervals, especially where these time intervals allow the combination partners to show an effect cooperative, for example, synergistic.

[0057] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation that has a fixed ratio of active ingredients or in separate formulations (e.g., capsules and/or intravenous formulations) for each active ingredient. Furthermore, such administration and co-administration also encompasses the use of each type of therapeutic agent in a sequential or separate manner, at approximately the same time or at different times. Regardless of whether the active ingredients are administered as a single formulation or in separate formulations, the drugs are administered to the same patient as part of the same therapy cycle. In any event, the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.

[0058] By simultaneous therapeutic use, within the meaning of the present invention, is meant an administration of at least two active ingredients by the same route and at the same time or substantially at the same time.

[0059] By separate use, within the meaning of the present invention, is meant, in particular, an administration of at least two active ingredients at the same time or substantially at the same time by different routes.

[0060] By sequential therapeutic use is meant the administration of at least two active ingredients at different times, the route of administration being identical or different. More particularly, by a method of administration is meant according to which the total administration of one of the active ingredients is carried out before starting the administration of the other or others.

[0061] The terms "fixed combination", "fixed dose" and "single formulation" as used herein refer to a single carrier or vehicle or dosage form formulated for the administration of an amount, which is jointly therapeutically effective for the treatment of cancer, of both therapeutic agents to a patient. The single vehicle is intended for the administration of an amount of each of the agents together with any pharmaceutically acceptable carriers or excipients. In some modalities

the carrier is a tablet, capsule, pill or patch. In other embodiments, the vehicle is a solution or suspension.

[0062] The term "non-fixed combination" or "kit of parts" means that the combination therapeutic agents of the invention are both administered to a patient as separate entities simultaneously, concurrently, or sequentially without any time limit. specific, wherein such administration provides therapeutically effective levels of the two compounds in the body of a subject in need thereof. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0063] The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of good medical judgment, suitable for contact with the tissues of a subject, eg, a mammal or human, without toxicity, irritation or excessive allergic response or other problems or complications, consistent with a reasonable benefit/risk ratio.

[0064] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g. antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, dyes and like and combinations thereof, as would be known to those skilled in the art. Except to the extent that any conventional carrier is incompatible with the active ingredient, its use in therapeutic and pharmaceutical compositions is contemplated.

[0065] The term "pharmaceutical composition" is defined herein as referring to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to or treat a disease. or particular condition affecting the subject.

The present pharmaceutical combinations may be formulated into pharmaceutical compositions suitable for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules.

Unless otherwise indicated, they are prepared in a manner known per se, for example by means of various conventional processes of mixing, comminution, direct compression, granulation, sugar coating, dissolution, lyophilization or fabrication techniques readily apparent to those skilled in the art.

It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not itself constitute an effective amount as the required effective amount can be achieved by administering a plurality of dosage units. .

The pharmaceutical composition may contain from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of the therapeutic agent(s). . One of ordinary skill in the art can select one or more of the previously mentioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without unnecessary burden.

The amount of each of the carriers used may vary within ranges conventional in the art.

The following references disclose techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These additional conventional carriers op-

Drugs may be incorporated into the oral dosage form by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination. of agents in the oral dosage form. In the latter embodiment, the blended mixture may be further mixed, e.g. by means of a V-blender, and subsequently compressed or molded into a tablet, e.g. a monolithic tablet, encapsulated by a capsule or placed in a sachet.

[0066] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. In certain embodiments, the unit dose includes one or more carriers such that each carrier includes an effective amount of at least one of the therapeutic agents together with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, injections, infusions, patches or the like, administered to the patient at the same time. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those which contain a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the art of pharmacy.

[0067] Pharmaceutical compositions of the invention may include a "therapeutically effective amount" or an "effective amount" of a compound of the invention. The term "pharmaceutically effective amount", "therapeutically effective amount" or "clinically-effective amount"

"effectively" of a combination of therapeutic agents is an amount sufficient, in dosages and for periods of time necessary, to provide clinically significant or observable improvement above the baseline of clinically observable signs and symptoms of the disorders treated with the combination. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual. A therapeutically effective amount is also one in which any toxic or harmful effects of the agents therapeutics are offset by therapeutically beneficial effects. A "therapeutically effective dosage" preferentially modulates a measurable parameter, such as the rate of tumor growth or disease progression in a desired manner. The ability of a compound to modulate a measurable parameter can be evaluated in an animal model system predictive of efficacy in human tumors to help establish appropriate dosage levels and schedules. Alternatively, this property of a composition can be assessed by examining the Compound's ability to modulate an undesired parameter using in vitro assays known to the skilled artisan.

[0068] The term "joint therapeutically active" or "joint therapeutic effect" as used herein means that the therapeutic agents may be delivered together, separately or sequentially at preferred time intervals so that the subject , especially human being, to be treated, still shows an interaction (joint therapeutic effect) (preferably synergistic). Whether this is the case can be determined, among other things, by monitoring the blood levels of the compounds, showing that both compounds are present in the blood of the human being treated at least during certain time intervals.

[0069] As used herein, the term "agent" is understood to mean a substance that produces a desired effect on a tissue, system, animal, mammal, human or other subject. It is also to be understood that an "agent" can be a single compound or a combination or composition of two or more compounds.

[0070] The term "cancer" is preferably a cancer.

[0071] As used herein, the term "cancer" refers to a disease characterized by the unwanted and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. As used herein, the term "cancer" or "tumor" includes pre-malignant as well as malignant cancers and tumors. The term "cancer" is used herein to mean a broad spectrum of tumors, including all solid and hematologic malignancies.

[0072] The terms "proliferative disease" or "proliferative disorder" also refer to cancer in general or to a cancer as defined herein.

[0073] An "oral dosage form" includes a unit dosage form prescribed or intended for oral administration.

[0074] As used herein, the terms "treating", "treatment" and "treating" refer to reducing or ameliorating the progression, severity and/or duration of a disorder, for example, a proliferative disorder, or the amelioration of one or more symptoms, suitably one or more discernable symptoms, of the disorder resulting from the administration of one or more therapies. In specific modalities, the terms "treat", "treatment" and "treating" refer to the improvement of at least one measurable physical parameter of a proliferative disorder, such as tumor growth, not necessarily dis-

credible by the patient. In other embodiments, the terms "treat", "treatment" and "treating" refer to inhibiting the progression of a proliferative disorder, either physically by, for example, stabilizing a discernible symptom, physiologically by, by for example, stabilization of a physical parameter or both. In other embodiments, the terms "treat", "treatment" and "treating" refer to the reduction or stabilization of tumor size or cancer cell count.

[0075] The terms "treat", "treatment" and "treating" include reducing the incidence and severity of adverse events (AEs) and serious AEs (SAEs) including changes in laboratory values, vital signs and electrocardiograms ( ECGs) in a patient or patient population.

[0076] The terms "treat", "treatment" and "treating" include an improvement in the Overall Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR), Prophylaxis Free Survival. - regression (PFS), for example, as per Response Assessment Criteria in Solid Tumors (RECIST) version 1.1, in a patient or a population of patients.

[0077] Within the meaning of the present disclosure, the term "treat" also denotes stopping, delaying the onset (i.e., the period before the clinical manifestation of a disease) and/or reducing the risk of development or worsening. of an illness. The term "protect" is used herein to mean preventing, delaying or treating, or all, as appropriate, the development, continuation or worsening of a disease in a subject, for example, a mammal or human.

[0078] The term "subject" or "patient" as used herein is intended to include animals, which are capable of suffering from or being affected by a cancer or any disorder involving, directly or indirectly, a cancer. Examples of subjects include mammals, e.g. humans, apes, monkeys, dogs, cows, goats.

vase, pigs, sheep, goats, cats, mice, rabbits, rats and non-human transgenic animals. In a preferred embodiment, the subject is a human, for example, a human suffering from, at risk of suffering from, or potentially capable of suffering from a cancer, such as cancer.

[0079] The term "inhibition", "inhibitor" or "antagonist" includes a reduction in a certain parameter, eg an activity, of a given molecule or pathway. For example, inhibition of a targeted kinase activity (Raf or CDK4/6) by 5%, 10%, 20%, 30%, 40% or more is included by this term. Thus, inhibition can be, but need not be, 100%.

[0080] As used herein, "salts" (meaning "or salts thereof" or "or a salt thereof"), may be present alone or in admixture with free compounds of the combination of the invention, for example, compound of formula (I) Raf inhibitor or CDK4/6 inhibitor, preferably ribociclib, and are preferably pharmaceutically acceptable salts. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of the combination of the invention with a basic nitrogen atom, especially the pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts which retain the biological efficacy and properties of the compound and which are typically not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group.

[0081] A list of suitable salts can be found in "Remington's Pharmaceuticals Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); new version: "Remington: the science and practice of pharmacy", 22nd ed., Pharmaceutical Press, London (2012); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and

Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2011).

[0082] For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, eg picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (when applicable in the form of pharmaceutical preparations), and these are therefore preferred. In view of the close relationship between novel compounds in the free form and those in the form of their salts, including those salts which can be used as intermediates, for example, in the purification or identification of novel compounds, any reference to the compounds free shall be understood to refer also to the corresponding salts, as appropriate and expedient. Salts of compounds used in the combination of the invention are preferably pharmaceutically acceptable salts; suitable counterions forming pharmaceutically acceptable salts are known in the art. Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination provided herein includes both the free base of the compounds and all pharmaceutically acceptable salts of the compounds.

[0083] The term "synergistic effect" as used herein refers to the action of two agents, such as, for example, the Raf inhibitor Compound (I) or a pharmaceutically acceptable salt thereof, and an inhibitor of CDK4/6, preferably ribociclib or a pharmaceutically acceptable salt thereof, to produce an effect, e.g., slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered in yes.

[0084] In one embodiment, the combination of the invention comprises (a) a Raf inhibitor which is the Compound of formula (I)

(I), or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor.

[0085] In one embodiment, the combination of the invention comprises (a) a Raf inhibitor Compound of formula (I) (I), or a pharmaceutically acceptable salt thereof, and (b) a selected CDK4/6 inhibitor of ribociclib and palbociclib, and pharmaceutically acceptable salts thereof. The CDK4/6 inhibitor is preferably ribociclib or a pharmaceutically acceptable salt thereof.

[0086] The combinations of the invention have demonstrated greater depth and durability of tumor response compared to single agent therapy in cell lines and human xenograft models, (see Examples) and may therefore be effective for the treatment of cancer. Accordingly, the invention provides compositions and methods using a Raf inhibitor which is the Compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor and, in particular, with ribociclib or a pharmaceutically acceptable salt thereof to treat solid tumors, particularly tumors harboring one or more MAPK pathway alterations, eg NRAS mutant cancers and KRAS mutant cancers.

[0087] Preferably, such therapeutic agents are administered in therapeutically effective dosages which, when combined, provide a beneficial effect. The present invention particularly relates to a combination of the invention useful for separate, simultaneous or sequential administration to a subject in need thereof to treat a cancer. Alternatively stated, the present invention particularly relates to a combination of the invention for use in the treatment of a cancer.

[0088] The nature of cancer is multifactorial. Under certain circumstances, therapeutic agents with different mechanisms of action may be combined. However, just considering any combination of therapeutic agents having different modes of action does not necessarily lead to combinations with advantageous effects and does not necessarily translate into clinical benefit for patients suffering from certain cancers.

[0089] In the present invention, it is expected that administration of the combination of the invention will result in a more beneficial effect, e.g., an improved synergistic or antiproliferative effect, e.g. with respect to delaying the progression or inhibiting the cancer or its symptoms, and may also provide additional beneficial effects, such as any one or more of the following: few side effects, such as skin-related toxicity (e.g., rash) and gastrointestinal toxicity (e.g., diarrhea), improved tolerability, improved quality of life, and decreased morbidity, as compared with any prior art therapy or with monotherapy with any of the combination partners.

[0090] The combination therapeutic agents of the invention may be administered separately, simultaneously or sequentially to a subject in need thereof. Preferably, such therapeutic agents are administered in therapeutically effective dosages which, when combined, provide a beneficial effect. Thus, in one embodiment of the present invention, the combination of the invention is for use in the treatment of cancer, particularly a cancer as described herein.

[0091] The term "cancer" is used herein to mean a broad spectrum of tumors, including all solid and hematologic malignancies. The cancer can be at an early, intermediate, or late stage. The cancer can be locally advanced or metastatic.

[0092] The cancer to be treated by the combination therapy described herein may have progressed past the standard of care or be one for which no effective standard therapy exists.

[0093] In one embodiment, the cancer is melanoma.

[0094] The combination of the invention is particularly useful for the treatment of a cancer, such as a cancer that contains one or more alterations of the mitogen-activated protein kinase (MAPK) pathway, such as an NRAS mutant tumor, and in in particular, a tumor that expresses at least one Ras gain-of-function mutation, as described herein, and/or at least one Raf gain-of-function mutation, as described herein.

[0095] NRAS mutant cancers or tumors are included. NRAS mutations of interest can be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. The term "NRAS mutant" tumor or cancer includes any tumor that exhibits a mutated NRAS protein, in particular NRAS gain-of-function mutation; especially any NRAS mutant tumor of G13R, Q61K, Q61L and Q61R. Therefore, NRAS mutant melanoma includes melanoma that has at least one corresponding NRAS mutation.

considering Q61K, Q61L or Q61R. The cancer may be melanoma with an NRAS QG13R mutation. Also included are cancers or mutant KRAS tumors. KRAS mutations of interest can be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. The term "mutant KRAS" tumor or cancer includes any tumor that exhibits a mutated KRAS protein. The cancer can be at an early, intermediate, or late stage. The cancer can be locally advanced or metastatic.

[0096] In another modality, the cancer is resistant or refractory to the standard of care.

[0097] In another modality, the cancer is resistant or refractory to the standard of care with dacarzabine.

[0098] In another embodiment, the cancer is resistant or refractory to treatment with a MEK inhibitor.

[0099] In another embodiment, the cancer is resistant or refractory to treatment with immunotherapy treatment including therapy with one or more immune screening inhibitors.

[00100] In another embodiment, the cancer is resistant or refractory to treatment with a cytotoxic agent, such as a nitrosourea and/or mitomycin C.

[00101] In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising NRAS proteins.

[00102] In one embodiment, the cancer is characterized by an NRAS mutation.

[00103] In one embodiment, the combination of the invention relates to a method of treating a cancer, particularly a melanoma.

[00104] The combination of the invention may be especially useful in the treatment of NRAS mutant melanoma.

[00105] In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising KRAS proteins.

[00106] In one embodiment, the cancer is characterized by a KRAS mutation.

[00107] In one embodiment, the combination of the invention relates to a method of treating a cancer, particularly a pancreatic cancer.

[00108] The combination of the invention may be especially useful in the treatment of KRAS mutant PDAC.

[00109] In one embodiment, provided herein is a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical combination of the invention comprising (a) a Raf inhibitor which is Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CDK4/6 inhibitor. In a preferred embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[00110] In one embodiment, provided herein is a method of treating cancer in a subject in need thereof comprising simultaneously, separately or sequentially administering to a subject in need thereof a combination of the invention in an amount that is together therapeutically effective. against said cancer wherein the combination of the invention comprises (a) an inhibitor of Raf which is the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof and (b) an inhibitor of CDK4/6. In a preferred embodiment, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.

[00111] In a further embodiment, the present invention particularly relates to a method of treating a cancer harboring one or more alterations in the mitogen-activated protein kinase (MAPK) pathway. In one embodiment, the present invention relates to a method of treating a cancer that is characterized by at least one mutation in NRAS. In another embodiment, the present invention relates to a method of treating a cancer that is characterized by at least one mutation in KRAS. In one embodiment, the present invention relates to the use of the combination of the invention for the preparation of a medicament for the treatment of cancer, particularly a cancer as described herein. In one embodiment, the combination of the invention is for use in the preparation of a medicament for the treatment of cancer.

[00112] In a further embodiment, the present invention relates to the use of the combination of the invention for the preparation of a medicament for the treatment of a cancer characterized by a gain-of-function mutation in the MAPK pathway.

[00113] In one embodiment, the combination or composition, or both, provided herein exhibits a synergistic effect.

[00114] Accordingly, in one aspect, the invention may provide a method of enhancing the effectiveness of an anti-cancer compound using it in combination with another anti-cancer compound, particularly a method using a Raf inhibitor which is the Raf Compound. formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, together with a CDK4/6 inhibitor, suitably ribociclib, or a pharmaceutically acceptable salt, thereof to provide enhanced efficacy that is not achievable by administration of similar doses of the Compound of formula (I) or a pharmaceutically acceptable salt thereof, or the CDK4/6 inhibitor as a single agent (monotherapy).

[00115] A further benefit provided by the invention may be that lower doses of the inventive combination therapeutic agents may be used, for example, such that dosages may not only be often lower, but may also be applied less frequently. frequently or can be used to decrease the incidence of side effects seen with one of the combination partners alone.

[00116] In some embodiments, the Compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, and/or the CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof, may be administered at a therapeutic or less than therapeutic dose relative to a single agent dose level. In certain embodiments, the concentration or dosage of the therapeutic agent that is required to achieve inhibition, for example, inhibition of tumor growth or shrinkage, is lower when the other therapeutic agent is used or administered in combination with the first. therapeutic agent than when each therapeutic agent is administered individually. In certain modalities, in a combination therapy, the concentration or dosage of a therapeutic agent that is required to achieve inhibition, e.g., growth inhibition, is lower than the therapeutic dose as a monotherapy, e.g., 10 to 20%, 20 to 30%, 30 to 40%, 40 to 50%, 50 to 60%, 60 to 70%, 70 to 80% or 80 to 90% lower.

[00117] In determining a synergistic interaction between one or more components, the optimal range for effect and absolute dose ranges of each component for effect can be definitively measured by administering the components at different doses and ranges of p ratios. /pa patients requiring treatment. In the case of human beings, the complexity and cost of carrying out clinical studies in patients can make the use of this form of evaluation as a primary model of synergy impractical. However, the ob-

The observation of synergy in certain experiments can be predictive of the effect in another species, and existing animal models can be used to further quantify a synergistic effect. The observation of synergy in one species can predict the effect in other species and with the use of animal models, as described in the present document, a synergistic effect can be measured and the results of such studies can also be used to predict ranges of occurrence. effective dose ratios and the absolute doses and plasma concentrations required in other species by the application of pharmacokinetic/pharmacodynamic (FC/FD) methods. Correlations established between tumor models and effects observed in man suggest that the synergy in animals can be demonstrated, for example, by xenograft models or in appropriate cell lines. It can be demonstrated by established test models that a combination of the invention results in the beneficial effects described in the present document. The person skilled in the art is fully capable of selecting a relevant test model to prove such beneficial effects. The pharmacological activity of the combination of the invention may, for example, be demonstrated in a clinical study or in an in vivo or in vitro test procedure as essentially described herein.

[00118] Administration of the combination, (in other words, administration of one therapeutic agent with the other combination partner, ie, "co-administration") includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The individual combination partners of the inventive combination may be administered separately at different times during the therapy cycle, either sequentially in any order or simultaneously in single or divided combination forms, e.g. simultaneously or in conjointly therapeutically effective amounts, preferably in synergistically effective amounts, for example, in daily or intermittent (i.e., non-daily) dosages corresponding to the amounts described herein.

[00119] The Compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the methods, treatments, combinations and compositions disclosed herein is a potent inhibitor of BRAF and CRAF. In some embodiments, the Compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally. In one embodiment, the Compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in a total daily dose of about 200 to 1200 mg, about 300 to 1000 mg, about 400 to 800 mg, or about 500 to 600 mg (for example, once a day). The Compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in a total daily dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950mg, about 1000mg, about 1050mg, about 1100mg, about 1150mg, or about 1200mg. In a preferred embodiment, the Compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in a total daily dose selected from about 200mg, 400mg, 600mg, 800mg and 1200mg.

[00120] The total dose of the Compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered once daily, or may be divided into two and each dose of the Compound of formula (I) administered twice daily, with the actual dosage and time of administration determined by criteria such as the patient's age, weight, and gender; the extent and severity of the cancer to be treated; and the judgment of an attending physician. Preferably, the total dose of the Compound of formula (I) is administered once daily. In another preferred embodiment, the total dose of Compound of formula (I) is administered twice daily.

[00121] The CDK4/6 inhibitor as part of the combination according to the present invention is administered to a subject in need thereof in a therapeutically effective amount.

[00122] In a preferred embodiment, the total daily dose of CDK4/6 inhibitor ribociclib or a pharmaceutically acceptable salt thereof, administered daily as part of the combination in accordance with the present invention to a subject in need thereof will be an amount selected from about 100 mg to about 600 mg per day; suitably, the amount will be selected from about 200 mg to about 400 mg per day. In a preferred embodiment, ribociclib or a pharmaceutically acceptable salt thereof is administered at a daily dose selected from about 100, about 200 mg, about 400 mg, and about 600 mg. Alternatively, the total dose can be divided into two doses, which are given twice daily.

[00123] In particular, the following daily doses can be considered: Daily dose of Com- Daily dose of ribociclib post of formula (I) 200 mg 100 mg, 200 mg, 400 mg, 600 mg, or 900 mg 400 mg 100mg, 200mg, 400mg, 600mg, or 900mg 600mg 100mg, 200mg, 400mg, 600mg, or 900mg 800mg 100mg, 200mg, 400mg, 600mg, or 900mg 1200 mg 100mg, 200mg, 400mg, 600mg, or 900mg 1600mg 100mg, 200mg, 400mg, 600mg, or 900mg

[00124] When doses or dosages are mentioned herein, the amount mentioned refers to the amount of the therapeutic agent. For example, when a dose of 200 mg of ribociclib is administered, and ribociclib is administered in a tablet containing ribociclib succinate, the tablet will contain ribociclib succinate equivalent to 200 mg of ribociclib.

[00125] In some embodiments, ribociclib or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, ribociclib is prepared for administration via oral delivery, and can be used in a salt form, eg the succinate salt form. In some embodiments, the compound is prepared in tablet form for oral administration. Tablets can be produced in a variety of strengths for flexible administration.

[00126] The dose of ribociclib or a pharmaceutically acceptable salt thereof can be administered once a day, or twice a day, or three times a day, or four times a day. The total daily dose of ribociclib, or a pharmaceutically acceptable salt thereof, can be administered once or twice daily.

[00127] For example, as part of combination therapy, the Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in a total daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1200 mg, and ribociclib, for example, in the succinate salt form, can be administered in a total daily dose selected from about 100 mg, about 200 mg, about 400 mg, and about of 600 mg. The daily dose of Compound of formula (1) may be administered once or twice daily. Accordingly, a dose of about 200 mg of the Compound of formula (I) can be administered twice daily (total daily dose about 400 mg) and a dose of about 100 mg or about 200 mg of ribociclib can be administered once a day. Alternatively, a dose of about 200 mg of the Compound of formula (I) can be administered twice daily and (total daily dose about 400 mg) and a dose of about 100 mg or about 200 mg of ribociclib can be administered twice a day.

[00128] Alternatively, the Compound of formula (I) may be administered 600 mg twice daily (b.i.d or BID) and ribociclib administered 600 mg once daily. The Compound of formula (I) can also be administered 400 mg twice daily (BID) and ribociclib administered 200 mg once daily.

[00129] The Compound of formula (I) is preferably administered continuously, i.e., without a drug break.

[00130] The CDK4/6 inhibitor can be administered continuously, i.e., without a break during the treatment period, or with a drug break.

[00131] For example, the CDK4/6 inhibitor, for example ribociclib or a pharmaceutically acceptable salt thereof, can be administered every 3 weeks and 1 week, or 2 weeks and 2 weeks off; preferably 3 weeks yes and 1 week no. In particular, the following regimens can be used in accordance with the present invention. Regime Regime Regime Regime Regime 1 2 3 4 5 6 Compound bid, bid, bid, qd, con- qd, con- qd, con- of formula continuously- continuously- continuously- (I) continuously mind mind mind Inhibitor of qd, 3 qd, con- qd, 2 qd, 3 qd, con- qd, 2 CKD4/6, weeks on-weeks weeks-on-weeks for example, 1 mind yes, 2 yes, 1 mind yes, 2 plo, riboci- week weeks week weeks clib no no no no bid or BID: twice a day qd or qd: once a day

[00132] For example, the Compound of formula (I) can be provided without a once or twice daily drug break and the CDK4/6 inhibitor (e.g. ribociclib or a pharmaceutically acceptable salt thereof) can be administered three weeks yes and one week no.

[00133] In the drug regimens considered, the total daily doses of the Compound of formula (I) and the CDK4/6 inhibitor are as described above and throughout the description.

[00134] For example, a 400 mg or 600 mg dose of Compound of formula (I) may be given once or twice daily, preferably twice daily, and a 200 mg dose of ribociclib may be given. be provided once a day, three weeks on and one week off.

[00135] For example, a 600 mg dose of Compound of formula (I) may be given once or twice daily, preferably twice daily, and a 600 mg dose of ribociclib may be given once a day. once a day, three weeks on and one week off.

[00136] The Compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof can be used together in accordance with the methods disclosed herein . The two compounds may be administered together or separately, depending on the desired dosage amount and frequency of administration, as it is contemplated that treatments of the invention may be continued for 2 days, 3 days, 4 days, 5 days. , 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks or longer than 4 weeks, as deemed appropriate by the treating physician and further as directed using methods described herein for determining a dosage and frequency of appropriate administration. The frequency of dosing may vary depending on the

station used and the particular condition to be treated. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred and can be determined by criteria such as the patient's age, weight, and sex; the extent and severity of the cancer being treated; and evaluation by an attending physician. Patients can generally be monitored for therapeutic efficacy using assays appropriate for the condition being treated, which will be familiar to those of ordinary skill in the art.

[00137] The ideal ratios, individual and combined dosages and concentrations of the combination partners of the combination of the invention, (ie, Compound of formula (I), or a pharmaceutically acceptable salt thereof, and a CDK4/ 6, suitably ribociclib, or a pharmaceutically acceptable salt thereof, that produces efficacy without toxicity are based on the kinetics of availability of the therapeutic agents to target sites and a variety of factors, including, but not limited to, the degree of progression of the disease. ; to the age, body weight, general health, sex and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages can be established using routine tests and procedures that are well known. For example, a single bolus can be administered, multiple divided doses can be administered over time, or the dose can be proportionately reduced or increased as indicated by the requirements. of the therapeutic situation.

[00138] The combination therapeutic agents of the invention may be administered by any appropriate route. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the site of cancer being treated. It will also be appreciated that each of the therapeutic agents can be administered by the same route or different routes and that the therapeutic agents, for example, the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4 inhibitor/ 6, suitably ribociclib or a pharmaceutically acceptable salt thereof, can be combined in a pharmaceutical composition.

[00139] The Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, can be used together as disclosed herein. The two therapeutic agents of the inventive combination can be administered together (simultaneously), sequentially or separately.

[00140] Furthermore, it does not matter whether the compounds are administered in the same dosage form, for example, one compound can be administered topically and the other compound can be administered orally. Suitably, both therapeutic agents are administered orally. The compounds may be administered in the same or different dosage form.

[00141] Thus, in one embodiment, one or more doses of the Compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially, or separately with one or more doses of a CDK4 inhibitor/ 6, suitably ribociclib or a pharmaceutically acceptable salt thereof.

[00142] In one embodiment, multiple doses of the Compound of formula (I) or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or separately with multiple doses of a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt. acceptable of the same.

[00143] In one embodiment, several doses of the Compound of formula (I) or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or separately with a dose of a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt. acceptable of the same.

[00144] In one embodiment, a dose of the Compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with various doses of a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof.

[00145] In one embodiment, a dose of the Compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with a dose of a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutical salt. - skeptically acceptable of the same.

[00146] In all of the above embodiments, the Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered first or the CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof may be administered first.

[00147] In one embodiment, provided herein is a pharmaceutical composition comprising (a) the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt the same for use in the methods of the invention. In one embodiment, the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable diluents, excipients or carriers. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not harmful to the recipient thereof. Such elements of the pharmaceutical compositions used may be presented in separate pharmaceutical combinations or formulated together in a pharmaceutical composition. The combinations disclosed herein may be administered

treated together in a single composition or administered separately in two or more different compositions, e.g. compositions or dosage forms as described and the components may be administered as the same formulation or as separate formulations alone , for example, as indicated above, or in combination with one or more pharmaceutically acceptable carriers by any suitable route.

[00148] Dosage unit forms as used herein refer to physically distinct units suitable as unitary dosages for the subjects to be treated; each unit contains a predetermined amount of active compound (e.g. the Compound of formula (I) or a pharmaceutically acceptable salt thereof, or the CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier The unit dosage form can also be a fixed combination.

[00149] Effective dosing of each of the combination partners may require more frequent administration of one of the therapeutic agents compared to the other therapeutic agent in the combination. Therefore, in order to allow for proper dosing, packaged pharmaceuticals may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the inventive combination therapeutic agents, but not the other therapeutic agent of the combination of the invention.

[00150] When the combination partners, which are employed in the combination of the invention, are applied in the form as marketed as a single drug, their dosage and mode of administration may be in accordance with the information provided in the package insert.

package of the respective marketed drug, unless stated otherwise.

[00151] Therefore, in order to allow for proper dosing, packaged pharmaceuticals may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the therapeutic agents in the combination. - nation, but not the other therapeutic agent in the combination.

[00152] Also within the scope of the invention is a combination kit comprising, as therapeutic agents, the inventive combination for simultaneous, separate or sequential administration as described herein, together with one or more additional elements : instructions for use; other reagents for use with the inventive combination; devices or other materials for preparing the compound for administration, such as a mixing vessel; pharmaceutically acceptable carriers; and devices or other materials for administration to a subject, such as a syringe.

[00153] By the term "combination kit" or "part kit" as used herein is meant the pharmaceutical composition or compositions which are used in accordance with the invention. When both compounds are administered simultaneously, the combination kit may contain the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor, suitably ribociclib or a pharmaceutically acceptable salt thereof in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the inhibitor of CDK4/6, suitably ribociclib or a pharmaceutically acceptable salt thereof, and the inhibitor

CDK4/6 pain, suitably ribociclib or a pharmaceutically acceptable salt thereof are not administered simultaneously, the combination kit will contain the Compound of formula (I) or a pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor 6, suitably ribociclib or a pharmaceutically acceptable salt thereof in separate pharmaceutical compositions in a single pack or in separate pharmaceutical compositions in separate packs.

[00154] In one embodiment of the invention, the kit of parts comprising the following components: (a) a Raf inhibitor compound selected from the group consisting of (i) the Compound of formula (I) or a pharmaceutically acceptable salt thereof same, in association with pharmaceutically acceptable excipients, diluents and/or carriers, and (b) a CDK4/6 inhibitor, preferably ribociclib or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipients, diluents or carriers , wherein the components are provided in a form that is suitable for sequential, separate and/or simultaneous administration. The combination kit may also be provided with instructions, such as instructions regarding dosage and administration. Such instructions regarding dosage and administration may be of the type that is provided to a physician, for example, by a drug product label, or they may be of the type that is provided by a physician, such as instructions for a physician. patient.

[00155] Other features, objects and advantages of the invention will be evident from the description and drawings and from the claims.

[00156] The following Examples illustrate the invention described above; are not, however, intended to limit the scope of the invention in any way. The beneficial effects of the pharmaceutical combination of the present invention can also be determined by other test models known as such to the person skilled in the relevant art.

EXAMPLES EXAMPLE 1: Enhanced Combination Effects of RAF Inhibition with CDK4/CDK6 Inhibition in NRAS Mutant Melanoma Cell Lines Method

[00157] Compound of formula (I) (NVP-LXH254) and ribociclib (NVP-ribociclib) were synthesized and stocks of ribociclib compound were prepared in DMSO to a final concentration of 10 mM. For combination plots, working stocks were serially diluted in the appropriate cell culture medium in 3-fold increments (2-fold increments for ribociclib) to obtain final assay concentrations ranging from 10 μM to 1 .5 nM for NVP-LXH254 and 10 µM to 39 nM for NVP-ribociclib (as the succinate salt).

[00158] SK-MEL-2 cells were purchased from the American Type Culture Collection (ATCC), MEL-JUSO cells were purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), MM415 cells were purchased from Cell Bank Australia and IPC-298 and SK-MEL-30 cells were purchased from GNF. IPC-298, MEL-JUSO, MM415 and SK-MEL-30 cells were cultured in RPMI medium (ATCC) and SK-MEL-2 cells were cultured in EMEM medium (ATCC), both supplemented with 10% fetal serum. beef (Gibco) and incubated at 37°C/5% CO2. For the combination activity, cells were seeded in 80 µl of medium in 96-well plates (Corning #3904) at 5000 cells per well and incubated overnight prior to compound addition. Compound stock (10x) was freshly prepared in the appropriate culture medium and manually added to the plates by electronic multichannel pipette to create a complete 10x10 combination matrix grid. In a minimum of three

Replicated samples, the number and viability of cells at the time of compound addition, as well as the quantification of combination effects after 72 hours, were evaluated by the fluorescence-based DNA binding proliferation assay, CyQUANT® Direct (Ther - mo #C35011) according to the manufacturer's protocol. Analysis of combined data was performed using Novartis' in-house software, Combination Analysis Module. The application used Loewe's dose additivity model to calculate a weighted synergy score on each dose matrix that adjusts for sampling and dose coverage, and weights to favor combination effects at high levels. inhibition (Lehar et al., 2009).

[00159] Cells were plated in 6-well plates (#3506, Corning, NY) at a density of 0.5x10 6 cells per well. One day after plating, the lines were treated with single agent ribociclib at 200, 400 and 800 nM and with the combination of Compound of formula (I) (300 nM) for 48 hours. Cells were harvested in RIPA lysis buffer (#89900, Thermo Fisher, Waltham, MA) containing protease inhibitors (#87785, Thermo Fisher, Waltham, MA) and phosphatase inhibitors (#78420, Thermo Fisher, Waltham, MA) BAD). Proteins were separated on a 4-12% Bis-Tris NuPAGE SDS gel (#WG1403Bx10, Life Technologies, Carlsbad, CA) and transferred to nitrocellulose using the Trans-Blot Turbo System (Bio-Rad, Hercules, CA) . Proteins were detected with 1:1000 dilutions of antibodies recognizing pRB (#8516, Cell Signaling Technology, Beverly, MA), pCDK4/61/2 (#9154, Cell Signaling Technology, Beverly, MA), pERK1/2 (#4730, Cell Signaling Technology, Beverly, MA) and pRSK (#9348, Cell Signaling Technology, Beverly, MA) and 1:5000 dilution of an antibody that recognizes β-actin (#AM4302, Life Technologies, Carlsbad, CA) . Protein levels were detected using anti-mouse-HRP or anti-rabbit-HRP secondary antibodies and de-

developed with SuperSignal West Femto (#34096, Thermo Scientific, Waltham, MA) or Dura chemiluminescent substrate (#34076, Thermo Scientific, Waltham, MA) on a GE Image Quant LAS 4000 imaging system (GE Healthcare, Woburn, MA) ). Results

[00160] The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative and phopho-Rb suppressing effects over single treatments in the SK-MEL-30 melanoma cell line (FIGURE 1). The SK-MEL-30 melanoma cell line harbors coincident mutations in NRAS (Q61K) and BRAF (D287H).

[00161] The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative and phopho-Rb suppression effects over single treatments in the IPC-298 melanoma cell line (FIGURE 2). The IPC-298 melanoma cell line harbors an NRAS mutation (NRASQ61L).

[00162] The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative suppression and phopho-Rb effects over single treatments in the Meljuso melanoma cell line (FIGURE 3). The Meljuso melanoma cell line harbors an NRAS mutation (NRASQ61L).

[00163] The combination of Compound of formula (I) and ribociclib demonstrated improved antiproliferative suppression and phopho-Rb effects over single treatments in the Meljuso melanoma cell line (FIGURE 4). EXAMPLE 2: Efficacy of combination of Compound of formula (I) and ribociclib in xenografts derived from patient with NRAS mutant melanoma

[00164] The effect of inhibiting RAF and selective double CDK4/6 in vivo was investigated by the combination of Compound of formula (I) and ribocytosis.

clib in nine melanoma xenografts derived from NRAS mutant patients. methods

[00165] Animals and maintenance conditions: Unbred athymic (nu/nu) female mice (Athymic Nu-nu") (Charles River, Indianapolis) were allowed to acclimate at the Novartis NIBR animal facility with access to food and water ad libitum for at least 3 days before handling (Table 1) Table 1 Characteristics Animals Study Species Lineage Category Seller Gender Age HMEX5727 HMEX3486 HMEX20667 HMEX2921 Camun- Charles dongo Athymic 8 to 10 sec- HMEX20585 Mutant River, In- Female (Mus Mus - nu-nu manas HMEX20864 dianapolis culus) HMEX21124 HMEX4339 HMEX20744 Animal Welfare Statement: Animals were handled in accordance with Novartis NIBR ACUC regulations and guidelines.

[00166] Test compound and formulations: The compound of formula (I) (free base form) was dosed p.o. (orally) in MEPC4 vehicle (Cremophor RH40 45% + PEG400 27% + Corn Oil Glycerides 18% + ethanol 10%). Compound of formula (I) was formulated at 5 mg/ml. The ribociclib succinate salt was dosed p.o. (orally) in a 0.5% methylcellulose vehicle; ribociclib was formulated at 7.5 mg/ml. Development of a patient derivative xenograft (PDX) model in nude mice

[00167] The patient-derived tumor xenografts (PDX) HMEX5727, HMEX3486, HMEX20667, HMEX2921, HMEX20864, HMEX20585, HMEX4339, HMEX20744 and HMEX21124 were

by serial passage of tumor paste in nude mice. Briefly, fresh tumor fragments from a previous passage were homogenized using Soft MACS Dissociator (MACS (Miltenyi Biotec, #120-005-331), passed through a tissue shredder (Chemglass lifeSciences #CLS-5020-085), diluted in PBS and mixed with an equal volume of Matrigel™ Matrix (Corning #354234) Then 200 µl of tumor paste was implanted subcutaneously into the right flank of female nude mice. - side using a modified ellipsoidal formula, where tumor volume (Vt) (mm3) = (lx w2)/2, where l is the longest axis of the tumor and w is perpendicular to L. Mice were monitored for cres - Tumor cement, body weight and body condition twice/week Efficacy study project in PDX models

[00168] Efficacy study design for all models is described in Table 2. Test agents were dosed at a dose volume of 10 ml/kg, which was adjusted according to body weight. Tumor dimensions and body weights were collected at the time of randomization and twice weekly thereafter during the study. Mice were randomized into treatment groups (n = 3-5/group) when the mean tumor volume was approximately 350 mm3, and treatments were performed until tumor growth (tumor volume >/=700 mm3) or approximately 90 days. The percent change in tumor volume was determined for all models by comparing the change in tumor volume at time t with its baseline value. The best response was the minimum value of percent change in tumor volume for t ≥ 10 days. At the time the untreated control mice were sacrificed, 2 mice from each group were also sacrificed.

and tumors collected for future pharmacodynamic (PD) analysis. Efficacy was performed with 3 mice/group beyond this point. Table 2 Treatment groups for efficacy studies Group Number of Compound Dose Via Chrono-mice (mg/kg) gram 1 3-5 Untreated - p.o. - 2 3-5 LXH254 50 p.o. bid 3 3-5 ribociclib 75 p.o. qd 4 3-5 LXH254+ribociclib 50+75 p.o. bid+qd p.o.: per os (oral gavage) qd: once a day bid: twice a day Data Analysis

[00169] Body Weight: The percent change in body weight was calculated as (BW current-BWinitial)/(BWinitial) x 100%. Data were presented as mean percent change in body weight from the day of treatment initiation ± SEM.

[00170] Tumor volume: Percent change in tumor volume was determined by comparing the change in tumor volume at time t with its baseline value using the following formula: % change in tumor volume = ΔVt = 100% x (( Vt-Vinitial)/Vinitial). The best answer was the minimum value of ΔVt for t ≥ 10 days.

[00171] Where: ΔVt = change in tumor volume Vt = tumor volume of the drug-treated (or untreated) group on a given study day; Vinitial = tumor volume of the drug-treated (or untreated) group on the initial day of dosing. Best response >/= -30% was considered tumor regression.

[00172] Kaplan-Meier survival graph was generated using GraphPad Prism software for individual mice that reached an endpoint of tumor size >/=700 mm3. Statistical analysis for significance between groups was performed using the Log-rank test (Mantel-Cox). p <0.05 was considered significant. Results: Combination Efficacy of Compound of formula (I) and ribociclib in patient-derived NRAS mutant melanoma xenograft models in nude mice

[00173] The antitumor efficacy of Compound of formula (I) when combined with ribociclib was determined using nine NRAS mutant patient-derived melanoma xenograft models in nude mice: HMEX5727 (NRASQ61K), HMEX3486 (NRASQ61K), HMEX20667 (NRASQ61R) , HMEX2921 (NRASQ61R), HMEX20585 (NRASQ61R), HMEX20864 (NRASQ61R), HMEX21124 (NRASQ61H), HMEX20744 (NRASQ61K) and HMEX4339 (NRASQ61R). Mice were treated for approximately 90 to 100 days or until the tumor size in each group reached >/=700 mm3. Percent change in tumor volume (best response), percentage change in body weight, and survival are reported in Table 3, FIGURE 5, and FIGURE 6.

[00174] The combined activity of Compound of formula (I) + ribociclib dosed at 50 mg/kg bid and Compound of formula (I)) + 75 mg/kg qd (ribociclib) led to tumor regression by 44% of the tested models. In comparison, neither the single agent Compound of formula (I) dosed at 50 mg/kg bid nor the single agent ribociclib dosed at 75 mg/kg qd achieved tumor regression in any of the models tested (Table 3 and FIGURE 5). Furthermore, the combination of Compound of formula (I) + ribociclib led to a significant increase in median survival, compared with either single agent or untreated controls (FIGURE 6).

[00175] Both single agents and combination treatments were very well tolerated, as assessed by the lack of body weight loss among the models. A mouse treated with Compound of formula (I) was sacrificed at an earlier time point due to loss of body weight. Table 3: Antitumor efficacy and tolerability of Compound of formula (I) and ribociclib in nine NRAS mutant melanoma tumor xenograft models derived from patients in mice % change in volume % change in weight Days after tumor treatment Mean+/ SEM corporeal Mean+/SEM Days after implant Survival Dose (mg/kg) Drug Model Vehicle 40 12 204.23± 70.46 2.50 ± 1.52 3/3 LXH254 50 bid 40 12 60.20± 34.18 2.30 ± 1.26 3/3

HMEX ribociclib 75 qd 40 12 120.55± 4.43 1.99 ± 1.74 3/3 20585 LXH254+ 50 bid+ 40 12 23.93± 17.42 -1.02 ± 1.50 3/3 ribociclib 75 qd Vehicle 35 11 223.97 ± 22.49 6.30 ± 0.48 5/5 LXH254 50 bid 35 11 118.78 ± 23.65 2.04 ± 1.48 5/5

HMEX ribociclib 75 qd 35 11 142.57 ± 15.02 2.27 ± 0.99 5/5 20677 50 bid+ LXH254 38 14 5.42 ± 15.11 3.33 ± 1.74 5/5 75 qd Vehicle 20 7* 372.45± 79.63 -1.64 ± 0.80 5/5 LXH254 50 bid 20 7* 161.18± 34.37 -5.11 ± 1.35 5/5

HMEX ribociclib 75 qd 20 7* 350.51 ± 67.22 -6.01 ± 1.55 5/5 5727 LXH254+ 50 bid+ 48 35 -46.41 ± 25.25 4.68 ± 1.10 3/3 ribociclib 75 when

% change in volume % change in weight Days after tumor treatment Mean+/SEM body Mean+/SEM Days after implant Survival Dose (mg/kg) Drug Model Vehicle 45 12 303.57± 78.08 3.13 ± 0.84 3/3 LXH254 50 bid 45 12 148.85± 16.77 -6.79 ± 1.48 3/3

HMEX ribociclib 75 qd 45 12 240.32± 72.55 4.21 ± 1.71 3/3 2921 LXH254+ 50 bid+ 45 12 41.35± 13.22 2.84 ± 2.57 3/3 ribociclib 75 qd Vehicle 22 8* 358.71± 99.83 1.60 ± 1.75 5/5 LXH254 50 bid 26 12 146.22 ± 27.86 2.52 ± 1.14 5/5

HMEX ribociclib 75 qd 26 12 287.09 ± 52.45 -1.07 ± 1.10 5/5 3486 LXH254+ 50 bid+ 40 26 -7.82 ± 25.94 7.45 ± 1.27 3/3 ribociclib 75 qd 278.81 ± Vehicle 30 11 -0.07 ± 1.23 5/5 34.23 LXH254 50 bid 30 11 96.72 ± 27.35 -0.42 ± 2.28 5/5

HMEX 216.16 ± 20864 ribociclib 75 qd 30 11 -0.25 ± 2.16 5/5 46.98 LXH254+ 50 bid+ 68 49 -87.38 ± 0.71 8.02 ± 2.17 3/3 ribociclib 75 qd 112.05 ± Vehicle 55 10 -0.30 ± 1.27 5/5 31.69 HMEX LXH254 50 bid 55 10 31.99 ± 32.74 -3.36 ± 0.75 5/5 21124 ribociclib 75 qd 55 10 57.84 ± 19.83 2.85 ± 1.26 5/5 LXH254+ 50 bid+ 55 10 -15.84 ± 7.64 -0.10 ± 2.00 5/5 ribociclib 75 qd

% change in volume % change in weight Days after tumor treatment Mean+/SEM body Mean+/SEM Days after implant Survival Dose (mg/kg) Drug Model Vehicle 70 11 159.94 ± 26.2 2.74 ± 1.52 3/3 LXH254 50 bid 83 24 -6.14 ± 24.14 6.14 ± 3.50 3/3 ribociclib 75 qd 70 11 57.50 ± 13.94 4.84 ± 1.58 3/ 3

HMEX 186.05 ± 20744 Vehicle# 55 10 5.67 ± 0.68 3/3 40.04 LXH254# 50 bid+ 10.62 ± 83 38 -83.90 ± 3.10 3/3 +ribociclib 75qd 0.07 Vehicle 48 10 93.41 ± 7.92 -3.66 ± 0.86 3/3 LXH254 50 bid 48 10 9.35 ± 16.00 6.28 ± 4.04 3/3

HMEX ribociclib 75 qd 48 10 65.18 ± 9.67 5.96 ± 1.97 3/3 4339 LXH254+ 50 bid+ 10.99 ± 91 53 -50.90 ± 8.57 3/3 ribociclib 75 qd 2.14 *indicates the last day of treatment (tumor size >/=700 mm3) #group conducted in a separate experiment Conclusion and discussion

[00176] The in vivo activity of the combination of Compound of formula (I) + ribociclib in NRAS mutant melanoma was plotted on a panel of nine melanoma xenografts derived from NRAS mutant patients. The combined activity of Compound of formula (I) + ribociclib dosed at 50 mg/kg bid (the Compound of formula (I)) + 75 mg/kg qd (ribociclib) led to tumor regression in 44% of the models tested. In comparison, neither the single agent Compound of formula (I) dosed at 50 mg/kg bid nor the single agent ribociclib dosed at 50 mg/kg bid.

75 mg/kg qd achieved tumor regression in any of the models tested. In addition, the combination of Compound (I) + ribociclib was well tolerated and led to a significant increase in median percent survival compared with either single agent or untreated controls. A strong synergy of the CDK4/6 inhibitor ribociclib with the Compound of formula (I) was observed in melanoma xenografts derived from NRAS mutant patients, leading to significant tumor regression and increased mean percent survival in models. preclinical. Collectively, these data indicate that the combination of Compound of formula (I) + ribociclib can achieve greater and more durable responses in patients with NRAS mutant melanoma. EXAMPLE 3: A Phase Ib, open-label, multicenter study of Compound of formula (I) in combination with ribociclib in patients with NRAS mutant melanoma

[00177] The purpose of the study is to characterize the safety and tolerability of the dual combination of Compound of formula (I) and ribociclib in patients with NRAS mutant melanoma and to identify a recommended dose.

[00178] Primary endpoints are (1) safety: incidence and severity of adverse events (AEs) and serious AEs (SAEs), including changes in laboratory values, vital signs and electrocardiograms (ECGs), incidence and nature of limiting toxicities (DLTs) during the first cycle (dose escalation only), (2) tolerability: dose interruptions, dose reductions and intensity.

[00179] Objectives and secondary endpoints are: (a) To assess the preliminary antitumor activity of Compound of formula (I) in combination with ribociclib. Overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to Solid Tumor Response Assessment Criteria (RECIST) version

1.1. For dose expansion part only: overall survival (OS), plasma concentrations and derived PK parameters (b) To characterize the pharmacokinetic (PK) profile of Compound of formula (I) and ribociclib in combination. Changes from baseline of the PD marker DUSP6 in tumor tissue. (c) To assess the pharmacodynamic effect (PD) of the Compound of formula (I) and ribociclib in combination on the tumor (DUSP6)

[00180] Exploratory goals and endpoints are: (a) To assess genetic changes in various cancer-related genes in tumor samples (tumor and plasma (free circulating DNA (cfDNA)) to assess their relationship to clinical/developmental outcomes of resistance. Genetic changes in multiple cancer-related genes found in tumor samples at baseline and post-dose, including disease progression, and their relationship to clinical outcome endpoints. (b) To further assess the effect of the PD of the Compound of formula (I) in combination with ribociclib. Changes from the baseline value of PD markers in the blood (eg, DUSP6) (c) To assess the drug-drug interaction (DDI) between the Compound of formula (I) and ribociclib Compound of formula (I) and plasma concentrations of ribociclib and derived PK parameters (d) To investigate how cfDNA changes reflect the genetic alteration of archived tumor samples (when available) and newly obtained. Differences in genetic changes measured in tumor and plasma samples as a surrogate tissue from the same patient at certain time points (pre-dose and post-dose).

[00181] This is an open-label, multicenter, Phase Ib dose escalation study followed by a dose expansion portion. Compound of formula (I) in combination with ribociclib will be administered to melanoma patients carrying NRAS mutations. Study treatment will be performed until the patient experiences unacceptable toxicity, progressive disease, and/or treatment is discontinued at the investigator's or patient's discretion or due to withdrawal of consent. A cycle is defined as 28 days.

[00182] Inclusion Criteria: Adult patients (18 years and older) with melanoma diagnosed with locally advanced or metastatic NRAS-mutated melanoma who have progressed following standard of care or for whom no effective standard therapy exists, are tolerated, appropriate or considered equivalent to the treatment of the study will be eligible to participate in this study. The presence of NRAS mutation in tumor tissue pre-dates study treatment, as determined by a local laboratory or a Novartis-designated central laboratory, or written documentation of the KRAS, BRAF, or NRAS mutation. The ECOG (Eastern Cooperative Oncology Group) performance status is ≤ 2. Patients must have a biopsy-proven disease site and must be willing to undergo a re-biopsy of the tumor at baseline and during treatment accordingly. with the guidelines and requirements of the treatment institution itself for such procedure. The presence of at least one measurable lesion according to RECIST v1.1 is required.

[00183] Exclusion criteria: (a) Previous treatment with an RAF inhibitor (including any BRAF inhibitor and Raf inhibitor) or CDK4/6 inhibitor. (b) Treatment with any of the following anticancer therapies prior to the first dose of study treatment within the established timeframes:

(i) ≤4 weeks for radiation therapy or ≤2 weeks for limited field radiation for palliation prior to the first dose of study treatment. (ii) ≤4 weeks or ≤5 half-life (whichever is shorter) for chemotherapy or biological therapy (except immunotherapy) or continuous or intermittent small molecule therapeutics or any other investigational agent. (iii) ≤4 weeks for any immunotherapy treatment including immune checkpoint inhibitors. (iv) ≤6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and mitomycin C. (c) History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes). (d) Any medical condition that, in the investigator's judgment, prevents the patient from participating in the clinical trial due to safety concerns or compliance with clinical trial procedures.

Any serious, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with participation in the study or the administration of study treatment or that may interfere with the interpretation of study results and, in the judgment of the investigator, would render the patient inappropriate for the study. (e) Patients receiving treatment with drugs that are known to be strong inhibitors and/or inducers of CYP3A and CYP2C8; UGT2B7 inhibitor or inducers; UGT1A1 substrates and inhibitors; CYP2C8, CYP2C9 and CYP3A substrates with a narrow therapeutic index; and sensitive substrates of CYP3A, herbal medicines known to cause liver toxicity.

ca, which cannot be discontinued 7 days before the start of study treatment and during the study. (f) Patients receiving proton pump inhibitors (PPI) who cannot be discontinued 3 days prior to the start of study treatment and during the study. (g) Patients with malignancy other than the one being treated in this study. Exceptions to this exclusion criterion include the following: malignancies that were curatively treated and did not recur in the 2 years prior to study treatment; completely resected basal and squamous cell skin cancers; and completely resected in situ carcinoma of any type.

[00184] Clinical efficacy will be assessed by measuring overall response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) according to RECIST version 1.1 and overall survival (OS) (dose expansion part only).

[00185] Data from a dose fractionation efficacy study on Calu-6 xenografts demonstrated that at different dosage levels, Compound of formula (I) dosed QD (qd) and fractionated twice daily (BID) showed levels similar anti-tumor activity. These results support exploration of QD or BID dose regimens in the clinic.

[00186] Assessment of possible signs of clinical efficacy will be performed, which includes assessments of ORR, PFS and OS.

[00187] All patients enrolled during the dose escalation portion of the study will be assigned to receive Compound of formula (I) in combination with ribociclib to assess the safety and tolerability of the combinations.

[00188] Dose escalation for each regimen tested will be guided by a Bayesian Logistic Regression (BLRM) model based on data from the first cycle of DLT.

[00189] BLRM/BHLRM is a well-established method for estimating MTD in cancer patients. The adaptive BLRM/BHLRM will be guided by the principle of escalation with overdose control (EWOC) to control the risk of DLT in future study patients. The use of adaptive Bayesian response models for small datasets has been accepted by the EMEA ("Guideline on clinical trials in small populations", 13 February 2007) and endorsed by numerous publications (Babb et al 1998, Neuenschwander et al 2008, Neuenschwander et al 2010), and their development and proper use are an aspect of the FDA's Critical Path Initiative.

[00190] Patients enrolled in this expansion part will be treated on the recommended dose combination (in MTD or lower dose combination) of Compound of formula (I) and ribociclib.

[00191] The safety (including dose-DLT relationship) and tolerability of the combination will be evaluated; dose(s) and regimen(s) will be identified for use in dose expansion based on the review of these data. The recommended dose for expansion will also be guided by available information on PK, PD and preliminary antitumor activity. Treatment

[00192] Study treatment will be administered in 28-day fasting dosing cycles.

[00193] Tablet and capsule for oral use, dose as designated, daily dose for 28-day cycles.

[00194] The investigator or responsible site personnel must instruct the patient to take the study drug exactly as prescribed to promote adherence.

[00195] Patients should inform the research center staff

information about any missed or delayed doses.

[00196] Patients may be discontinued from study treatment early due to unacceptable toxicity, progressive disease, if treatment is discontinued at the discretion of the investigator or patient, and/or if the patient withdraws consent.

[00197] The following table describes the starting doses and interim dose levels of the individual investigational drugs (not the combination) that can be evaluated during this trial. Suggested dose levels of combination of Compound of formula (I) and ribociclib Dose Level Proposed Daily Dose for Compound of Formula (I)* -2 400 mg -1** 600 mg 1 800 mg (initial dose) 2 1200 mg 3 1600 mg Dose level Proposed daily dose for ribociclib* -1** 100 mg 1 200 mg (initial dose) 2 400 mg 3 600 mg *Additional and/or intermediate dose levels may be added during the course of the study, including doses outside the interim dose range shown in this table and not exceeding the recommended dose (RD) for either single agent. Cohorts can be added at any dose level below the maximum tolerated dose (MTD) of the combination to better understand safety, PK or PD. **DL-1 represents treatment doses for patients who require a dose reduction from the starting dose level and/or the potential starting dose, depending on safety information from FIH studies.

[00198] MTD(s) for any combination are defined as the highest dose combination for that combination that is unlikely (<25% later probability) to cause DLTs in 33% or more of patients treated in first cycle of treatment with the Compound of formula (I) and ribociclib during the escalation part of the study.

[00199] The RD will be a dose that is less than or equal to the MTD and has, in the opinion of the investigators and Novartis study staff, the most appropriate risk-benefit assessment based on the safety and tolerability review , PK, PD and activity information. Note that MTD may not be achieved in some situations.

[00200] The CDK4/6 inhibitor can be administered continuously, i.e., without a break during the treatment period, or with a vacation period.

[00201] For example, the CDK4/6 inhibitor, eg ribociclib or a pharmaceutically acceptable salt thereof, can be administered every 3 weeks and 1 week, or 2 weeks and 2 weeks off; preferably 3 weeks yes and 1 week no. In particular, the following regimens can be used in accordance with the present invention. Regime Regime Regime Regime Regime 1 2 3 4 5 6 Compound bid, bid, bid, qd, con- qd, con- qd, con- of formula continuously- continuously- continuously- (I) continuously mind mind mind Inhibitor of qd, 3 qd, con- qd, 2 qd, 3 qd, con- qd, 2 CKD4/6, weeks on-weeks weeks-on-weeks eg 1 mind yes, 2 yes, 1 mind yes, 2 plo, riboci- week weeks week weeks clib no no no no bid or BID: twice a day qd or qd: once a day

Claims (15)

1. Pharmaceutical combination of a Raf inhibitor and a CDK4/6 inhibitor characterized in that the Raf inhibitor is the Compound of formula (I), (I) or a pharmaceutically acceptable salt thereof. 2. Pharmaceutical combination according to claim 1, characterized in that the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof. 3. Pharmaceutical combination according to claim 1 or 2, characterized in that it is intended for use in the treatment of cancer. A pharmaceutical combination for use according to claim 3, characterized in that the cancer has an NRAS mutation or a KRAS mutation. Pharmaceutical combination for use according to claim 3 or 4, characterized in that the cancer is melanoma, wherein the melanoma optionally expresses at least one mutation selected from the group consisting of the NRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. A pharmaceutical combination for use according to claim 3 or 4, characterized in that the cancer is pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC)), wherein the cancer is optionally a PDAC expressing at least one mutation selected from the group consisting of the mutations tions of KRAS G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. A pharmaceutical combination for use according to any one of claims 3 to 6, characterized in that the two compounds, or pharmaceutically acceptable salts thereof, are administered separately, simultaneously or sequentially. A pharmaceutical combination for use according to any one of claims 3 to 7, characterized in that the Raf inhibitor, or a pharmaceutically acceptable salt thereof, is administered in a total daily dose of approximately 100 mg, 200 mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg or 1600mg. A pharmaceutical combination for use according to any one of claims 3 to 8, wherein the Raf inhibitor is administered once a day or twice a day. A pharmaceutical combination for use according to any one of claims 3 to 9, characterized in that the Raf inhibitor is administered continuously during the treatment period. A pharmaceutical combination for use according to any one of claims 3 to 10, characterized in that the CDK4/6 inhibitor is ribociclib, or a pharmaceutically acceptable salt thereof, and is administered in a total daily dose of approximately 100 µg. mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg or 600mg. A pharmaceutical combination for use according to claim 11, wherein the CDK4/6 inhibitor is administered once a day or twice a day. A pharmaceutical combination for use according to claim 11 or 12, characterized in that the CDK4/6 inhibitor is administered with a period of temporary drug withdrawal, for example, three weeks of administration and one week of no administration. 14. A compound characterized by having formula (I) (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer by means of co-administration with ribociclib or a pharmaceutically acceptable salt thereof, wherein the cancer is, optionally, NRAS mutant melanoma. 15. Ribociclib, or a pharmaceutically acceptable salt thereof, characterized in that it is intended for use in the treatment of cancer by means of co-administration with the Compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer is optionally , NRAS mutant melanoma.