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(12) Patent Application Publication (10) Pub. No.: US 2016/0022680 A1 SUN Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0022680 A1 SUN Et Al US 2016.0022680A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0022680 A1 SUN et al. (43) Pub. Date: Jan. 28, 2016 (54) COMBINATIONS FOR TREATMENT OF Publication Classification CANCER (51) Int. Cl. (71) Applicant: STICHTING HET NEDERLANDS KANKER INSTITUUT ANTON VAN A 6LX3/57 (2006.01) LEEUWENHOEK ZIEKENHUIS, A6II 45/06 (2006.01) Amsterdam (NL) A63/66 (2006.01) (52) U.S. Cl. (72) Inventors: Chong SUN, AMSTERDAM (NL); CPC ............. A6 IK3I/517 (2013.01); A61 K3I/I66 Rene BERNARDS, AMSTERDAM (2013.01); A61K 45/06 (2013.01) (NL) Appl. No.: 14/775,009 (21) (57) ABSTRACT (22) PCT Fled: Mar. 12, 2014 (86) PCT NO.: PCT/NL2014/05O148 The current disclosure relates to pharmaceutical combina S371 (c)(1), tions and compositions useful in the treatment of certain types Sep. 11, 2015 of cancer. The disclosure also relates to method of treatment (2) Date: these certain types of cancer. In particular, the disclosure (30) Foreign Application Priority Data relates to the combined use of inhibitors of MEK, EGFR and ERBB2 in the treatment of KRAS-mutant lung cancer, and Mar. 12, 2013 (NL) ...................................... 2O10440 KRAS-mutant colon cancer. Patent Application Publication Jan. 28, 2016 Sheet 1 of 3 US 2016/002268.0 A1 Figure 1 Selumetinib Patent Application Publication Jan. 28, 2016 Sheet 2 of 3 US 2016/002268.0 A1 Figure 2 Seitetility 8is is i is 2s * Dacoratinib (c.stas SSS Patent Application Publication Jan. 28, 2016 Sheet 3 of 3 US 2016/002268.0 A1 Figure 3 Selumetinib(uM) -la. +Gefitinib (1M) Š +CP724714 (2M) S $ +Afatinib (1M) +Dacomitinib (0.5uM) SW837 US 2016/002268.0 A1 Jan. 28, 2016 COMBINATIONS FOR TREATMENT OF well as to provide for products and therapeutically pharma CANCER ceutical combinations for use in these KRAS-mutant cancers. FIELD OF THE INVENTION DESCRIPTION OF THE DRAWINGS 0001. The current disclosure relates to pharmaceutical 0007 FIG. 1 Suppression of ERBB3 by shRNA enhances combinations and compositions useful in the treatment of response to MEK inhibitor. H358 KRAS mutant (Non-Small certain types of cancer. The disclosure also relates to method Cell Lung Cancer (NSCLC) cells were infected with two of treatment of these certain types of cancer. In particular, the independent shRNAs targeting ERBB3 as indicated. pKO disclosure relates to the combined use of inhibitors of MEK, vector serves as a control vector. After puromycin selection, EGFR and ERBB2 in the treatment of KRAS-mutant lung cells were cultured in the absence or presence of 1 uM selu cancer, and KRAS-mutant colon cancer. metinib for 20 days. 0008 FIG. 2 SW837 colorectal cancer (CRC) cells were PRIOR ART cultured in increasing concentration of MEK inhibitor selu metinib alone, EGFR inhibitor gefitinib alone, ERBB2 0002 Cancer is one of the leading causes of death in the inhibitor CP724714 alone, EGFR/ERBB2 dual inhibitor afa Europe and the United States. Despite recent advances in tinib, EGFR/ERBB2 dual inhibitor dacomitinib alone or their understanding mechanisms involved in cancer and in diagno combinations as indicated. Cells were harvested, fixed and sis and treatment, drug therapies for metastatic disease are stained after 21 days. often palliative in nature. Drug therapies seldom offer along 0009 FIG. 3 H538 lung cancer cells were cultured in term cure. There is a constant need for new methods of treat increasing concentration of MEK inhibitor selumetinib ment, either in the form of monotherapy or in the form of alone, EGFR inhibitor gefitinib alone, ERBB2 inhibitor combination treatment, combining different new or known CP724714 alone, EGFR/ERBB2 dual inhibitor afatinib, drugs as first line therapy, and as second line therapies in EGFR/ERBB2 dual inhibitor dacomitinib alone or their com treatment of resistant tumors. binations as indicated. 0003 Cancer cells are by definition heterogeneous. For example, multiple mutational mechanisms may lead to the DESCRIPTION development of cancer and mutational mechanisms associ ated with Some cancers may differ between one tissue type Definitions and another; it is therefore often difficult to predict whether a 0010 Unless defined otherwise, technical and scientific specific cancer will respond to a specific chemotherapeutic terms used herein have the same meaning as commonly (Cancer Medicine, 5th edition, Bast et al. B. C. Decker Inc., understood by one of ordinary skill in the art to which this Hamilton, Ontario). disclosure belongs. One skilled in the art will recognize many 0004. The treatment of cancer is gradually changing from methods and materials similar or equivalent to those an organ-centered to a pathway-centered approach. Cancer described herein, which could be used in the practice of the cells often have an addiction to the signals that are generated present invention. Indeed, the present invention is in no way by the cancer-causing genes. Consequently, targeted cancer limited to the methods and materials described. drugs that selectively inhibit the products of activated onco 0011 For purposes of the present invention, the following genes can have dramatic effects on cancer cell viability. This terms are defined below. approach has yielded significant clinical results for Non 0012. As used herein, the singular forms “a” an and “the Small Cell Lung Cancer (NSCLC) having activating muta include plural referents unless the context clearly dictates tions in EGFR or translocations of the ALK kinase and for otherwise. For example, a method for administrating a drug melanoma patients having a BRAF mutant tumor. However, includes the administrating of a plurality of molecules (e.g. this approach has not been Successful in all type of cancers, in 10’s, 100's, 1000s, 10's of thousands, 100's of thousands, particular in cancers characterized by oncogenic mutations in millions, or more molecules). one of the members of the RAS gene family, in particular 0013. As used herein, the term “and/or indicates that one KRAS. or more of the stated cases may occur, alone or in combination 0005. On the other hand, it has been reported that whereas with at least one of the stated cases, up to with all of the stated melanoma patients with a specific activating mutation in CaSCS. BRaf(V600E) benefit from treatment with Vemurafenib, an 0014. As used herein, with “At least a particular value inhibitor that was designed specifically against this mutant means that particular value or more. For example, “at least 2' form of BRaf, a significant subset of colorectal carcinoma is understood to be the same as “2 or more' i.e., 2, 3, 4, 5, 6, patients having the same mutant fail to respond to treatment 7, 8, 9, 10, 11, 12, 13, 14, 15, etc. with that same drug. The reason why is that in colorectal 0015. As used herein "cancer and "cancerous”, refer to or cancer cells a feedback mechanism is present through which describe the physiological condition in mammals that is typi a signaling blockade at the BRaf level can be circumvented. cally characterized by unregulated cell growth. Examples of This feedback mechanism is not present in melanoma cells cancer include, but are not limited to, colon cancer and lung (Prahallad A, et al Nature. 2012 Jan. 26: 483 (7387): 100-3). cancer. Cancer is also referred to as malignant neoplasm. This suggests in cancer treatment, pathway information from 0016. As used herein, “incombination with is intended to one type of organ can not directly be transferred to any other refer to all forms of administration that provide a first drug Organ. together with a further (second, third) drug. The drugs may be 0006. It is a goal of the current invention to provide for new administered simultaneous, separate or sequential and in any and improved methods of treatment of KRAS-mutant cancer, order. Drugs administered in combination have biological in particular colon cancer and KRAS-mutant lung cancer, as activity in the subject to which the drugs are delivered. US 2016/002268.0 A1 Jan. 28, 2016 0017. As used herein, “colon cancer', or “colorectal can claimed combination works particularly well in those cells cer elates to a cancer from uncontrolled cell growth in the that are relatively insensitive to inhibition by MEK-inhibitors colon or rectum, or in the appendix. alone. 0018. As used herein, “to comprise' and its conjugations 0023 The inventors of the present invention have demon is used in its non-limiting sense to mean that items following strated via experiments, that the combination of a MEK the word are included, but items not specifically mentioned inhibitor, an EGFR-inhibitor and an ERBB2-inhibitor mani are not excluded. It also encompasses the more limiting “to fests an unexpected and strong synergistic, therapeutic effect consist or on the treatment of KRAS-mutant lung cancer and KRAS mutant colon cancer. Based on experimental data, the present 0019. A used herein “compositions”, “products” or “com inventors believe (without being bound by theory) that spe binations’ useful in the methods of the present disclosure cifically in KRAS mutant lung cancer and KRAS mutant include those suitable for various routes of administration, colon cancer, MEK inhibition leads to the MYC-dependent including, but not limited to, intravenous, Subcutaneous, formation of kinase-active EGFR-ERBB3 and ERBB2 intradermal, Subdermal, intranodal, intratumoral, intramus ERBB3 heterodimeric complexes which can be inhibited to cular, intraperitoneal, oral, nasal, topical (including buccal enable the colon cancer or lung cancer cells to respond to and Sublingual), rectal, vaginal, aerosol and/or parenteral or MEK inhibition. mucosal application. The compositions, formulations, and 0024. The combination disclosed herein exhibits thera products according to the disclosure invention normally com peutic synergy. Therapeutic synergy may be demonstrated by prise the drugs (alone or in combination) and one or more the showing that the combination is Superior to one or other of Suitable pharmaceutically acceptable excipients.
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