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WO 2020/0951S3 A1 14 May 2020 (14.05.2020) I 4 P Cl I P C T

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WO 2020/0951S3 A1 14 May 2020 (14.05.2020) I 4 P Cl I P C T (12) INTERNATIONAL APPLICATION PI;BLISHED I. NDER THE PATENT COOPERATION TREATY (PCT) (19) World intellectual Propertv Organraation llIIlIIlllIlIlllIlIllIllIllIIIIIIIIIIIIIIIIIIIIIIllIlIlIlIllIlllIIllIlIIllllIIIIIIIIIIIIIIIIIII International Bureau (10) International Publication Number (43) International Publication Date WO 2020/0951S3 A1 14 May 2020 (14.05.2020) I 4 P Cl I P C T (51) International Patent Classification: MC. MK, MT. M., NO, PL, PT, RO, RS. SE. SI. SK. SM, A6JK3J/4166 (2006.01) A6/K&/5/t)6 (200G 01) TR). OAPI (BF, BJ, CF, CG, CI. CYI. GA, GN, GQ. GW. AGJK39/00(2006 01) C07K/6/28 (2006 01) KM,:vIL. MR, NE. SN, TD, TG) A6JP35/00(200G 01) AGJK38/68 (2019 Ol) Published: (21) International Application tiumber: »iili nrternatinrral seair 6 repurt 14rt 2113&i PCT/IB2019/059459 m Alar/ and &ilnte, the mternat»rrral app/icramn as fihrl (22) International Filing Date: crmiamerl en/«i rrr grevscale a&irl is rivrnhihiefur d«ii nlrrarl 04 November 2019 (04,11.2019) /rum P) TES"/;ST'OPE (25) Filing Langurrge: Enghsh (26) Public&stion Language: Enghsh (30) Priority Data: (&2/755.944 05 Not en&ber 2018105.11 20)8) US (i2/882.424 02 Auknrst 2019 (02 08.2019) US (71) Applicants: PFIZER INC. [US/L S], 233 East 42nd Street. Neve York. Ncw York 10017 (US). MERCK PATENT GMBH [DE/DE], Frankfurter Strasse 250, G4293 Dmm- stadi (DE) NEKTAR THERAPEUTICS [US/US]. 435 Nlission Ba) Boulmard South. Suite 100. San Francis- co, California 94158 (US). ASTELLAS PHARMA INC. f JP/JP], 2-5-1. Nihonbashi-Honcho, Chuo-Ku, Tokv o (JP) (72) Inventors: BOSHOFF, Christoffel Hendrik; c/o PFIZER INC, 235 East 42nd Street Neu York. Nevv York 10017 (US) CESARI, Rossano. c/o PI'IZER ITALIA SRL. 113 Via Valbondionc. 00188 Room (IT). MASSACESI, Crist- ian. 68 West End Avenue. Srunnut. Ncvv Jersc) 07901 (US). CHARYCH, Dcbondr, 909 Ta) lor Street. Albany. Califor- rua 94706 (US). (74) Agent: ZI ELINSKI, Br)an Cn Pfraer inc., 235 East 42nd Street, MS 235/9/S20, Yevv York, Yevv York 10017 (US) (81) Designated States ln&iles& «ther» me»idir:nted, fi&r every Dnd of natin»al protection avm/able&: AE. AG, AL, AM, AO, AT. AU. AZ, BA, B B, BG, BI I, BY,. BR, B W. BY, BZ. CA. CI I, CL, CN. CO, CR, CU. CZ. DE, DJ, DK. DVI, DO, DZ, EC. EE, EG, ES. Fl, GB. GD. GE, Gl I, GVI, GT, I IY» I IR. I IU, ID, IL. IN, IR, IS, JO, JP, KE, KG, Kl I, KY., KP, KR, KW, KZ, LA. LC, LK. LR, LS, LU. LY, MA, MD, ME. VIG. MK, MN, VIW, VIX, MY. MZ, YA, NG. Yl, YO, NZ, OVI, PA, PE, PG. Pl I, PL. PT. QA, RO, RS. RU. RW. SA. SC, SD, SE. SG, SK. SL, SNI, ST. SV SY Tll, TJ, TM, TY,, TR, TT. TZ, UA. UG. US, UZ, VC, VN, ZA. ZM, ZW (84) Designated States l»»less r&ihere ise urdicated, for ever) ln»d r f regir&nal prntecnn&i availahlei'RIPO (BW. GII. GVL KE, LR, LS, MW, NIZ, NA, RW, SD. SL. ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM. AZ, BY, KG. KZ. RU, TJ. 00 TM), European (AL, AT, BE. BG, Cl I. CY, CZ. DE, DK, EE. ES. FR, IE. LT, LL', LV. I/i FI, GB, GR, IIR, IIU, IS, IT, Ch CO (54) Title: COVIBINATION FOR TREATING CAYCER CO (57) Abstract& Provided hcrcin arc methods and combinations for treating a subject having cancer by administering to thc subject a 0 PD-I/PD-L I axis inlubitor, a CD-122-biased- c) tokiuc agonist, and an antiiandrogcn or a Phanmrccutically acccptablc salt thcrcof WO 2020/095103 PCT/IB2019/059459 COMBINATION FOR TREATING CANCER FIELD The instant application relates to cancer therapy. Certain embodiments relate to the treatment of an individual having cancer by administering to the individual a 5 combination of a PD-1 axis binding antagonist with a CD-122-biased cytokine agonist, and an anti-androgen, or a pharmaceutically acceptable salt thereof. BACKGROUND PD-L1 is overexpressed in many cancers and is often associated with poor prognosis (Okazaki T et al., Intern. Immun. 2007 19(7):813) (Thompson RH et al., 10 Cancer Res 2006, 66(7):3381) Interestingly, the majority of tumor infiltrating T lymphocytes predominantly express PD-1, in contrast to T lymphocytes in normal tissues and peripheral blood. PD-1 on tumor-reactive T cells can contribute to impaired antitumor immune responses (Ahmadzadeh et al, Blood 2009 1 14(8): 1537). This may be due to exploitation of PD-L1 signaling mediated by PD-L1 expressing tumor cells 15 interacting with PD-1 expressing T cells to result in attenuation of T cell activation and evasion of immune surveillance (Sharpe et al., Nat Rev 2002) (Keir ME et al., 2008 Annu. Rev. Immunol. 26:677). Therefore, inhibition of the PD-L1 /PD-1 interaction may enhance CD8+ T cell-mediated killing of tumors. The inhibition of PD-1 axis signaling through its direct ligands (e.g., PD-L1, PD- 20 L2) has been proposed as a means to enhance T cell immunity for the treatment of cancer (e.g., tumor immunity). Moreover, similar enhancements to T cell immunity have been observed by inhibiting the binding of PD-L1 to the binding partner B7-1. There are currently at least five PD-1 axis binding antagonists approved by the FDA in more than 10 cancer indications (A Ribas et al, Science, 359, 1350-1355, 2018). 25 Among these, nivolumab (OPDIVO ), and pembrolizumab (KEYTRUDA ) are each anti-PD-1 antibodies, while avelumab (BAVENCIO ), atezolizumab (TECENTRIQ )) and durvalumab (IMFINZI )) are each anti-PD-L1 antibodies. The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to the 30 IL-2 cytokine. The IL-2 receptor is made up of 3 subunits - IL-2Ra, IL-2RI3, and IL-2Ry, with each of IL-2Ra and IL-2RI3 having binding affinity for IL-2 while IL-2RY alone has no appreciable affinity. Theze et al. (1994) Immunol. Today 17(10).481-486. Further, WO 2020/095103 PCT/IS2019/059459 the IL-2Raj3 heterodimer has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. Liparoto et al. J. Mol. Recognit.12(5):316- 321. CD8+ memory T-cells, which are responsible for enhancing the immune 5 response, preferentially express the IL-2Rj3 form of the IL-2R (this form of the IL-2R is also known as CD-122). Thus, administration of compounds that are CD-122-biased cytokine agonists can be expected to enhance the immune response (by, e g., increasing the proliferation of CD8+ memory T-cells). Thus, the art recognizes the potential of administration of IL-2RP-selective 10 agonists (also known as CD-122-biased cytokine agonists) in the treatment of patients suffering from cancer. Androgen receptor (AR) is a member of the nuclear hormone receptor family activated by androgens such as dihydrotestosterone (DHT). AR is a prime therapeutic target for treating prostate cancer. Several compounds have been developed as 15 chemotherapy for prostate cancer However, these compounds bind AR with affinities comparable to or less than the endogenous hormone and over time patients develop resistance to these drugs. Higher affinity and/or slower off-rate ligands (e.g. covalent ligands) are needed to provide more effective therapies. Anti-androgens are thought to suppress androgen activity by a number of 20 different mechanisms. One example of an anti-androgen approved for the treatment of metastatic castration-resistant prostate cancer and metastatic high risk castration sensitive prostate cancer is abiraterone acetate (marketed as Zytiga™), a steroidal CY17A1 inhibitor which is dosed in conjunction with prednisone. One specific class of anti-androgens are androgen receptor inhibitors, also known as androgen receptor 25 antagonists, which are thought to compete with endogenous ligands, androgens, for the androgen receptor When an antagonist binds to an androgen receptor it is thought to induce a conformational change in the receptor itself that impedes transcription of key androgen regulated genes and therefore inhibits the biological effects of the androgens themselves, such as testosterone and dihydrotestosterone. Current drugs for prostate 30 cancer include flutamide, bicalutamide, nilutamide, enzalutamide and apalutamide However, despite treatment with anti-androgens, for some subjects, their cancer will relapse or the subjects may develop therapeutic resistance. The mechanisms that underlie such resistance are, to date, not yet fully understood WO 2020/095183 PCT/IS2019/059459 -3- The combination therapy of a PD-1 axis binding antagonist with one or more anti-cancer agents has been investigated, with the first, and the only, new clinical trial started in 2009 New clinical trials directed to such combinations have increased dramatically since then with 467 new tnals registered in 2017 (C. Schmidt, Nature, Vol 5 552, 21/28 December 2017). While the combination therapy of nivolumab and ipilimumab to treat melanoma, and the combination therapy of pemborlizumab with chemotherapy to treat non-small cell lung cancer were approved by the FDA in 2015 and 2017, respectively, there is a continued need of finding optimal therapies that combine a PD-1 axis binding antagonist with one or more other anti-cancer agents, for 10 treating, stabilizing, preventing, and/or delaying development of various cancers. SUMMARY Each of the embodiments descnbed below can be combined with any other embodiment described herein not inconsistent with the embodiment with which it is combined. Furthermore, each of the embodiments described herein envisions within its 15 scope pharmaceutically acceptable salts of the compounds described herein Accordingly, the phrase "or a pharmaceutically acceptable salt thereof's implicit in the description of all compounds described herein.
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