Molecular Targets in Bladder Cancer: PD-1 and Beyond

Transcription

1 Molecular Targets in Bladder Cancer: PD-1 and Beyond Sumanta Kumar Pal, M.D. Assistant Professor, Department of Medical Oncology & Experimental Therapeutics Co-Director, Kidney Cancer Program City of Hope Comprehensive Cancer Center August 20, 2016

2 Disclosures Consulting: Pfizer, Novartis, Genentech, GSK, Astellas, Medivation Honoraria: Genentech

3 Developments in Prostate Cancer Docetaxel Cabazitaxel Enzalutamide Abiraterone Sipuleucel-T Radium-223

4 Developments in Renal Cell Carcinoma Sorafenib Temsirolimus Bevacizumab Axitinib Cabozantinib Sunitinib Everolimus Pazopanib Nivolumab Lenvatinib

5 Developments in Bladder Cancer Cisplatin Atezolizumab

6 Overview Disease Bladder Cancer Nature of Treatment Immune Targeted Topic MOA PD-1- Directed Therapy MOA FGFR and HER2 inhibition

7 Overview Disease Bladder Cancer Nature of Treatment Immune Targeted Topic MOA PD-1- Directed Therapy MOA FGFR and HER2 inhibition

8 BCG was FDA Approved in 1990 Internalized BCG in tumor epithelial cell Proposed BCG mechanism of action Immune cell recruitment Cytokine production Immune-mediated cytotoxicity Adapted from: Redelman-Sidi G, et al. Nat Rev Urol. 2014;11:

9 PD-1 and PD-L1 inhibition: The next generation T-cell Antigen Presenting Cell Adapted from: Pal SK et al Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm. Mol Cancer Ther 2012 Feb 17.

10 Genomic diversity in bladder cancer Lawrence MS et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature /11/print;499(7457):214-8.

11 FDA approved the use of atezolizumab

12 Imvigor 210 Study Design Locally advanced or metastatic urothelial carcinoma. Predominantly urothelial histology Tumor tissue for PD-L1 testing Cohort 1 (N=119) 11 Cisplatin Ineligible Cohort 2 (N-310) Platinum-treated nuc Cohort 1 to be shown later Median follow-up: 17.5 months (range, 0.2 to mo) Atezolizumab 1200 mg IV q3w until Loss of Benefit Co-primary endpoints: ORR (confirmed) per RECIST v1.1 by central review ORR per immune-modified RECIST by investigator Key secondary endpoints DOR, PFS, OS, safety Key exploratory endpoints Intratumoral biomarkers Cohort 2-Specific Inclusion Criteria Progression during/following platinum (no restrictions on # prior lines of therapy) ECOG PS 0-1 CrCl 30 ml/min Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated muc. ASCO 2016

13 Atezolizumab Response Rates (by PD-L1 status) IC2/3 n = 100 IC1/2/3 n = 207 All a N = 310 IC1 n = 107 IC0 n = 103 ORR: confirmed IRF RECIST v1.1 (95% CI) 28% (19, 38) 19% (14, 25) 16% (12, 20) 11% (6, 19) 9% (4, 16) CR rate: confirmed IRF RECIST v1.1 (95% CI) 15% (9, 24) 9% (6, 14) 7% (4, 10) 4% (1, 9) 2% (0, 7) Responses were seen in all IC subgroups, but ORR was enriched with higher PD-L1 status Complete responses accounted for nearly half of the observed responses CRs were observed in all PD-L1 subgroups, with the highest rate in IC2/3 patients a Includes 46 patients with missing/unevaluable responses. b CR + PR + SD 24-wk rate per IRF RECIST v1.1. Treated patients had measurable disease at baseline per investigator-assessed RECIST v1.1. Data cutoff: Mar. 14, Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated muc. ASCO 2016

14 SLD Change From Baseline, % Duration of Response to Atezolizumab Patients with CR or PR per IRF RECIST v IC2/3 IC1 IC Data cutoff: September 14, Time on Study, weeks Responses were durable, with mdor not reached in any PD-L1 subgroup (range, 2.0+ to mo) Ongoing responses were seen in 38 of 45 responding patients (84%) Median follow-up time: 11.7 mo (range, 0.2+ to 15.2 mo) Discontinued New lesion Hoffman-Censits et al. GU ASCO Abstr 355.

15 SLD Change From Baseline, % Stable Disease with Atezolizumab Patients with stable disease per IRF RECIST v IC2/3 IC1 IC Data cutoff: September 14, Time on study, weeks Discontinued New lesion Many non-responding patients experienced SD, suggesting that atezolizumab may provide clinical benefit to these patients Disease control rate (CR + PR + SD 24-wk rate): 35% (IC2/3), 21% (IC1) and 19% (IC0) Hoffman-Censits et al. GU ASCO Abstr 355.

16 Overall Survival with Atezolizumab Median OS (95% CI) Subgroup All pts (N = 310) IC2/3 IC0/1 All 11.9 mo (9.0, 17.9) 6.7 mo (5.4, 8.0) 7.9 mo (6.7, 9.3) 12-mo OS (95% CI) Subgroup All pts (N = 310) IC2/3 IC0/1 All 50% (40, 60) 31% (24, 37) 37% (31, 42) Median follow-up (range): All Pts: 17.5 mo (0.2 to mo) Longer OS observed in patients with higher PD-L1 IC status mpfs (2.1 mo per RECIST v1.1; 2.6 mo per imrecist) underscores a disconnect between PFS and OS NE, not estimable. Data cutoff: Mar. 14, Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated muc. ASCO 2016

17 Immune-mediated Adverse Events AE (N = 310) a All Grade Grade 3-4 Pneumonitis 2% 1% AST increased 2% 1% Dyspnea 1% 1% ALT increased 1% < 1% Blood bilirubin increased 1% < 1% Rash 1% < 1% Hyperglycemia 1% 0% Colitis 1% 1% Diarrhea 1% < 1% Transaminases increased 1% < 1% Dry skin 1% 0% Pruritus 1% 0% Pyrexia 1% 0% 30% of patients received steroids for any purpose Immune-mediated AEs (imaes) were observed at frequencies of 10% (all Grade) and 6% (G3-4) No patients were treated with non-corticosteroids immunomodulatory agents for imaes (e.g. infliximab, tocilizumab, rituximab, IL-2) a Occurring in 2 patients (all Grade). Additional G3-4 events (n = 1 each): Autoimmune hepatitis, Cytokine release syndrome, hepatitis, paraplegia, pericardial effusion, blood alkaline phosphatase increased, chronic kidney disease, hypotension, musculoskeletal pain, sepsis. Data cutoff: March 14, Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated muc. ASCO 2016

18 Overall Response Rates of PD-1/PD-L1 Antibodies in Post- Platinum Setting Slide courtesy of Betsy Plimack from ASCO 2016 Discussion

19 Genomic diversity in bladder cancer Lawrence MS et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature /11/print;499(7457):214-8.

20 Atezolizumab in bladder cancer Rosenberg JE et al Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm,

21 PD-L1 status as a Biomarker for Metastatic Urothelial Cancer Author Phase Drug Setting Balar ASCO 16 Dreicer ASCO 16 Sharma ASCO 16 Massard ASCO 16 Plimack ASCO 15 Apolo GUASCO 2016 Petrylak ASCO 15 Total n Definition of PDL1 + % of patients PDL1 "high" or "positive" ORR in favorable biomarker group ORR - all II Atezolizumab First line cis ineligible 119 IC 2/3 27% 28% 24% II Atezolizumab Post platinum 310 IC 2/3 32% 28% 16% I basket Nivolumab Post platinum 78 >=1% TC 37% 24% 24% I basket Durvalumab Post platinum 42 I basket Pembrolizumab Post platinum 29 I basket Avelumab Post platinum 44 >25% in TC or IC 1% tumor or stroma 5% tumor cells* 67% 46% 31% 100% 28% 28% 16% 40% 16% I basket Atezolizumab pre/post platinum 87 IC 2/3 45% 50% 34% Slide courtesy of Betsy Plimack from ASCO 2016 Discussion

22 Imvigor 210 Study Design Locally advanced or metastatic urothelial carcinoma. Predominantly urothelial histology Tumor tissue for PD-L1 testing Cohort 1 (N=119) 11 Cisplatin Ineligible Cohort 2 (N-310) Platinum-treated nuc Cohort 1 to be shown later Median follow-up: 17.5 months (range, 0.2 to mo) Atezolizumab 1200 mg IV q3w until Loss of Benefit Co-primary endpoints: ORR (confirmed) per RECIST v1.1 by central review ORR per immune-modified RECIST by investigator Key secondary endpoints DOR, PFS, OS, safety Key exploratory endpoints Intratumoral biomarkers Cohort 2-Specific Inclusion Criteria Progression during/following platinum (no restrictions on # prior lines of therapy) ECOG PS 0-1 CrCl 30 ml/min Dreicer R et al. IMvigor210: Atezolizumab in platinum-treated muc. ASCO 2016

23 Imvigor 210 Cohort 1 Data from ASCO IC2/3 (n = 32) IC1/2/3 (n = 80) All Patients (N = 119) IC1 (n = 48) IC0 (n = 39) ORR a (95% CI) 28% (14, 47) 25% (16, 36) 24% (16, 32) 23% (12, 37) 21% (9, 36) CR 6% 6% 7% 6% 8% PR 22% 19% 17% 17% 13% Subgroup ORR a 95% CI Demographics and prior treatment Age 80 years (n = 25) 28% 12, 49 Perioperative chemo b (n = 22) 36% 17, 59 Primary tumor sites Bladder/urethra (n = 85) 17% 9, 26 Upper tract (n = 33) 42% 25, 61 Metastatic sites at baseline Lymph node only (n = 31) 32% 17, 51 Visceral c (n = 78) 15% 8, 25 Liver (n = 25) 12% 3, 31 Key Demographics 28% with upper tract disease 70% with Cr Cl % ECOG 2 Cisplatin ineligibility criteria Impaired renal function (n = 83) 27% 17, 37 ECOG PS2 (n = 24) 25% 10, 47 Renal impairment and ECOG PS2 (n = 8) 25% 3, 65 Balar AV et al. ASCO 2016; LBA4500.

24 PD-1/PD-L1 inhibition in earlier settings? Courtesy of Peter Black, MD.

25 Bladder Cancer Diagnostics: The Pre-Metastatic Niche There is an environment in the lymph nodes around the bladder that cultivates the spread of cancer. Diagnostic: Features of the pre-metastatic niche could serve as a personalized prognostic factor

26 Bladder Cancer Diagnostics: The Pre-Metastatic Niche Neutrophil infiltration and pstat3 in benign lymph nodes predict OS Pal SK, Pham A, Vuong W, Liu X, Lin Y, Ruel N, Yuh BE, Chan K, Wilson T, Lerner SP, McConkey D, Jove R, Liang W. Prognostic Significance of Neutrophilic Infiltration in Benign Lymph Nodes in Patients with Muscle-invasive Bladder Cancer. Euroepan Urology Focus. 2016;16:S

27 Bladder Cancer Diagnostics: The Pre-Metastatic Niche SWOG Coltman Award: Validation of findings in S1011 Tissues will be send to the Lee lab at City of Hope

28 Overview Disease Bladder Cancer Nature of Treatment Immune Targeted Topic MOA PD-1- Directed Therapy MOA FGFR and HER2 inhibition

29 Bladder Cancer Diagnostics: Defining Landscape Characterizing Frequent Mutations in Advanced Bladder Cancer More advanced population than TCGA High frequency of FGFR3 alterations High frequency of HER2 alterations Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, Nazeer T, Elvin JA, Palma N, Yelensky R, Lipson D, Miller VA, Stephens PJ, Subbiah V, Pal SK. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer Dec 9.

30 Bladder Cancer Diagnostics: Defining Landscape Upper Tract versus Lower Tract Disease Parameter UCB UTUC Number of Patients Genomic Alterations/sample Short Variants 61% 76% Copy Number Changes 22% 37% Rearrangements 2% 2% Clinically Relevant GA/sample Most Frequent Clinically Relevant GA ERBB2 short variant mutation frequency in micropapillary variant of UC FGFR3 (21%) PIK3CA (20%) ERBB2 (16%) FGFR3 (28%) PIK3CA(16%) CCND1 (12%) MDM2 (11%) TSC1 (11%) ERBB2 (11%) 40% 43% Pal SK, Ali SM, Elvin JA, Frampton GM, Vergilio J-A, Suh J, Gunuganti V, Mian B, Fisher HAG, Nazeer T, Miller VA, Stephens PJ, Ross JS. Comparison of upper tract urothelial carcinoma and urothelial carcinoma of the bladder to reveal key differences in mutational profile and load. ASCO Meeting Abstracts. 2016;34(15_suppl):4522.

31 Bladder Cancer Diagnostics: Defining Landscape Smoking vs Non-Smoking Never, current and ex-smokers have a distinct genomic profile GAs in NSD1 were more frequent in CS as compared to other groups (P < 0.001) Joshi M, Vasekar M, Grivas P, Emamekhoo H, Hsu J, Miller VA, Stephens PJ, Ali SM, Ross JS, Zhu J, Warrick J, Drabick JJ, Holder SL, Kaag M, Li M, Pal SK. Relationship of smoking status to genomic profile, chemotherapy response and clinical outcome in patients with advanced urothelial carcinoma. Oncotarget May 18.

32 Bladder Cancer Diagnostics: Setting Guidelines There is a dearth of available therapies Even immunotherapy approaches are non-curative Broader use of genomic profiling will facilitate studies of targeted therapy in this disease Pal SK, Agarwal N, Boorjian SA, Hahn NM, Siefker-Radtke AO, Clark PE, Plimack ER. National Comprehensive Cancer Network Recommendations on Molecular Profiling of Advanced Bladder Cancer. J Clin Oncol Jul 25.

33 Everolimus: Retrospectively Assessing Extreme Responders Iyer G Science 2012

34 Everolimus: Applying FM Results to an Individual Case Author Timing of Genomic Profiling mtor Pathway Alternations Other Genomic Alterations Iyer et al Retrospective after treatment TSC1/NF2 Unknown Wagle et al Retrospective after treatment MTOR E2014k, E2419K CTNNB1, TP53 Ali et al Prospective and guided treatment NF2 TP53, ATRX, ATM Ali S (Submitted)

35 Targets To Explore Pal SK, Milowsky MI, Plimack ER. Optimizing systemic therapy for bladder cancer. Journal of the National Comprehensive Cancer Network : JNCCN 2013 Jul 1;11(7):

36 Dovitinib Stratification / Study Entry Treatment with Dovitinib 500 mg p.o. 5 days on / 2 days off, cycle: 28 days FGFR3 mut FGFR3 WT Stage 1 Stage 2 Group 1: FGFR3 mut ~20 patients Group 1: FGFR3 mut ~ 20 patients Group 2: FGFR3 WT ~20 patients Group 2: FGFR3 WT ~ 20 patients Study Endpoints Primary: ORR (CR, PR) Secondary: PFS, DCR, Safety, PK Profile Milowsky ASCO GU 2013

37 Dovitinib Milowsky ASCO GU 2013

38 BGJ398: A more potent dovitinib? Sequist AACR 2014

39 Bladder Cancer Therapeutics: Targeted Therapies FGFR3 inhibition in bladder cancer Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, Nazeer T, Elvin JA, Palma N, Yelensky R, Lipson D, Miller VA, Stephens PJ, Subbiah V, Pal SK. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer Dec 9.

40 Bladder Cancer Therapeutics: Targeted Therapies FGFR3 inhibition in bladder cancer Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, Hoffman-Censits JH, Quinn D, van der Noll R, Burris HA, Galsky MD, Gravis G, Lee J-L, Medioni J, Mortazavi A, Maroto P, Parker K, Chen X, Isaacs R, Bajorin DF. Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (muc) with FGFR3 alterations. ASCO Meeting Abstracts. 2016;34(15_suppl):4517.

41 Bladder Cancer Therapeutics: Targeted Therapies FGFR3 inhibition with BGJ398 Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, Hoffman-Censits JH, Quinn D, van der Noll R, Burris HA, Galsky MD, Gravis G, Lee J-L, Medioni J, Mortazavi A, Maroto P, Parker K, Chen X, Isaacs R, Bajorin DF. Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (muc) with FGFR3 alterations. ASCO Meeting Abstracts. 2016;34(15_suppl):4517.

42 Bladder Cancer Therapeutics: Targeted Therapies FGFR3 inhibition with BGJ398 Pal SK, Rosenberg JE, Keam B, Wolf J, Berger R, Dittrich C, Hoffman-Censits JH, Quinn D, van der Noll R, Burris HA, Galsky MD, Gravis G, Lee J-L, Medioni J, Mortazavi A, Maroto P, Parker K, Chen X, Isaacs R, Bajorin DF. Efficacy of BGJ398, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, in patients (pts) with previously treated advanced/metastatic urothelial carcinoma (muc) with FGFR3 alterations. ASCO Meeting Abstracts. 2016;34(15_suppl):4517.

43 Bladder Cancer Therapeutics: Targeted Therapies DNA Repair Pathways Remain Essential in Bladder Cancer VX-970 is a first-in-class ATR inhibitor and may synergize with cisplatin Adapted from Jackson SP, Bartek J. The DNA- damage response in human biology and disease Nature (2009) 461, 1071

44 1:1 Randomization Bladder Cancer Therapeutics: Targeted Therapies NCI Project Team Member: VX-970 First-in-class ATR inhibitor Metastatic urothelial carcinoma No prior systemic therapy for metastatic disease At least 12 months elapsed since platinum-based perioperative treatment KPS 70 CrCl > 50 ml/min CG CG + VX- 970* Primary Endpoint: Progression-free survival Secondary Endpoints: Overall survival Response rate Safety Biomarker assessments Total Enrollment: N=90

45 Bladder Cancer Therapeutics: Chemo as targeted therapy?

46 1:1 Randomization Bladder Cancer Therapeutics: Targeted Therapies COXEN Led by Tom Flaig, MD (U. Colorado) Muscle-invasive bladder cancer No prior systemic therapy f Candidates for platinumbased chemotherapy KPS 70 CrCl > 60 ml/min CG ddmvac Primary Endpoint: To characterize the relationship of DDMVACand Gemcitabine-Cisplatin (GC)-specific COXEN scores by pt0 rate at cystectomy in patients treated with neoadjuvant chemotherapy