Immunotherapy in uro oncolgy

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1. Immunotherapy and Uro -Oncology Dr Alok Gupta MD, DM, Consultant Medical Oncologist Max Super Speciality Hospital, Saket Ex-Asst. Professor, AIIMS, New Delhi

2. Outli n e 2 Immunotherapy in Bladder Cancer Immunotherapy in Kidney Cancer Immunotherapy in Prostate cancer

3. Role of immune system in advanced Bladder Cancer Martincorena I, Campbell PJ. Science. 2015;349:1483-9 High mutational load may correlate with immunogenicity, and provides valuable prognostic information 3

4. FDA-Approved Checkpoint Inhibitors for UC 1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017. 3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018. 5. Pembrolizumab [package insert]. June 2018. Agent Target Schedule FDA Approval Type by Setting Post-Platinum Frontline Cisplatin Ineligible Atezolizumab [1] PD-L1 Q3W Accelerated Accelerated Avelumab [2] PD-L1 Q2W Accelerated -- Durvalumab [3] PD-L1 Q2W Accelerated -- Nivolumab [4] PD-1 Q4W Accelerated -- Pembrolizumab [5] PD-1 Q3W Level 1 Accelerated

5. Post-Platinum Urothelial Carcinoma: ORR CT: ~ 10% 1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124 . 3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. Atezolizumab [1] ORR (%, 95% CI) Data from separate studies. Not head-to-head comparisons. 13.4 18.2 17.8 19.6 21.1 10 20 30 40 50 60 70 Pembrolizumab [5] Nivolumab [4] Durvalumab [3] Avelumab [2]

6. Post-Platinum Urothelial Carcinoma: OS at 12 Mos 1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124 . 3. O’Donnell P, et al. AACR 2018. Abstract CT031. 4. Sharma P, et al. AACR 2018. Abstract CT178. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. CT: ~ 26% Atezolizumab [1] OS (%, 95% CI) Data from separate studies. Not head-to-head comparisons. 39.2 54.3 46.6 40.3 43.9 10 20 30 40 50 60 70 Pembrolizumab [5] Nivolumab [4] Durvalumab [3] Avelumab [2]

7. IMvigor 210: Study Design Single-arm phase II study with 2 cohorts Pts with inoperable advanced or metastatic UC, predominantly TCC histology, evaluable tumor tissue for PD-L1 testing Cohort 1 Previously untreated , cisplatin ineligible Cohort 2 Prior platinum treatment Atezolizumab 1200 mg IV Q3W until PD Atezolizumab 1200 mg IV Q3W until loss of benefit Rosenberg JE, et al. Lancet. 2016;387:1909-1920 Primary endpoints : confirmed ORR by RECIST v1.1 (per central review), ORR per immune- modified RECIST (per investigator) Secondary endpoints : DoR, PFS, OS, safety 7

8. Cohort 1 : Cisplatin ineligible – Survival No clear difference in OS between PD-L1 subgroups Median OS was not reached in patients with no risk factors 13·4 months in patients with one risk factor (either visceral metastases or ECOG 2) 6·2 months in patients with two risk factors 19·1 months median OS reported in the stable disease subgroup 8

9. Cohort 2: Post platinum – Responses Responses seen in all PD-L1 IC subgroups; higher response seen with higher PD-L1 status After a median follow-up of 11·7 months, the median duration of response was not yet reached in any of the PD-L1 subgroups (range 2·0–13·7 months) At the time of the updated data cutoff, ongoing responses were reported in 38 (84%) of the 45 responding patients The median time to response was 2·1 months (95% CI 2·0–2·2) 9

10. Was the accelerated approval too early? 10

11. IMvigor211 Study Design Primary endpoint OS, tested hierarchically in pre-specified populations A t e z o l i z u mab 1200 mg q3w R 1:1 No crossover permitted per protocol Survival f ol l o w - up Loss of clinical benefit RECIST v1.1 progression Key Eligibility Criteria mUC with progression during or following platinum-based chemotherapy – ≤ 2 prior lines of therapy Measurable disease per RECIST v1.1 ECOG PS 0-1 Evaluable sample for PD-L1 testing TCC histology as primary component (N = 931) Stratification Factors No. of risk factors a (0 vs. 1/2/3) Liver metastases (yes vs. no) PD-L1 status (0/1 vs. 2/3) Chemotherapy (vinflunine vs. taxanes) Additional endpoints Efficacy: RECIST v1.1 ORR, PFS and DOR Safety PROs: EORTC QLQ-C30 Chemotherapy (investigator’s choice) 11 Vinflunine q3w Docetaxel q3w Paclitaxel q3w a Defined by time from prior chemotherapy < 3 mo, ECOG performance status > and hemoglobin < 10 g/dL.

12. OS Analysis: IC2/3 Population 20 Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56) Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50) 10 12 14 16 18 20 8 HR = 0.87 (95% CI: 0.63, 1.21) P = 0.41 0 2 4 6 24 22 100 Overall Survival 80 60 40 20 No. at Risk Mo n t h s A te z oli z u m ab 116 100 85 77 71 58 51 39 27 19 11 6 Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1 12

13. IMvigor211 – Conclusion 13 The primary endpoint of OS was not met in the IC2/3 population Due to delayed separation of the Kaplan-Meier curves, the differences in mOS and HR do not fully reflect the clinical activity achieved with atezolizumab The safety data showed no new safety signals and demonstrated a more favorable safety profile for atezolizumab than for chemotherapy

14. KEYNOTE-045: Study Design International, randomized, open-label phase III study Primary endpoints: OS, PFS Secondary endpoints: ORR, DoR, safety Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. Adult patients with predominantly transitional cell UC of the renal pelvis, ureter, bladder, or urethra; PD after 1-2 lines of platinum-based CT or recurrence < 12 mos after perioperative platinum-based CT; ECOG PS 0-2(N = 542) Treatment continued for 2 yrs or until PD, unacceptable toxicity, or withdrawal of consent Pembrolizumab 200 mg IV Q3W (n = 270) Paclitaxel 175 mg/m 2 IV Q3W or Docetaxel 75 mg/m 2 IV Q3W or Vinflunine 320 mg/m 2 IV Q3W (n = 272) Stratified by ECOG PS (0/1 vs 2), Hg (< 10 vs ≥ 10 g/dL), liver mets (yes vs no), and time since last CT (< vs ≥ 3 mos)

15. Pembrolizumab Chemotherapy KEYNOTE-045: OS 270 194 147 116 98 67 23 272 171 109 73 58 35 13 44.4% 30.3% 33.2% 19.7% Median OS, Mos (95% CI) 10.3 (8.0-12.3) 7.4 (6.3-8.3) 4 8 12 16 20 24 28 32 20 40 60 80 OS (%) Mos 100 Patients at Risk, n de Wit R, et al. ESMO 2017. Abstract LBA37_PR. Data cutoff: May 19, 2017 HR: 0.70 (0.57-0.86; P = .0003)

16. FDA-Approved Checkpoint Inhibitors for UC 1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017. 3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018. 5. Pembrolizumab [package insert]. June 2018. Agent Target Schedule FDA Approval Type by Setting Post-Platinum Frontline Cisplatin Ineligible Atezolizumab [1] PD-L1 Q3W Accelerated Accelerated Avelumab [2] PD-L1 Q2W Accelerated -- Durvalumab [3] PD-L1 Q2W Accelerated -- Nivolumab [4] PD-1 Q4W Accelerated -- Pembrolizumab [5] PD-1 Q3W Level 1 Accelerated

17. First-line Therapy for Metastatic UC: What We Know Chemotherapy is active in this space Cisplatin-eligible patients should get cisplatin FDA and EMA warn of decreased survival with first-line atezolizumab or pembrolizumab in cisplatin-ineligible patients with low PD-L1, as assessed by an appropriate companion diagnostic test Access to such diagnostic tests is variable, limited at many institutions

18. Characteristic Pembrolizumab (n = 43) [1] Atezolizumab (n = 68) [2] Eligibility criteria T2-T3b; N1 allowed T2-T4a; N0 only Cisplatin eligible, % 100 Received neoadjuvant CT, % 12 Duration of neoadjuvant checkpoint inhibition 3 cycles (9 wks) 2 cycles (6 wks) Safe Yes Yes Pathological CR (pT0), % 40 29 Available biomarker data Yes Yes Neoadjuvant Checkpoint Inhibition in Bladder Cancer: Early Results of Phase II Trials 1. Necchi A, et al. ASCO 2018. Abstract 4507. 2. Powles T, et al. ASCO 2018. Abstract 4506. Encouraging results; long-term outcomes needed before clinical use pT0 Rates W ith CT: Gem/Cis, 15% to 32% DD MVAC, 26% to 43%

19. Sum m ary 19 We have 5 IO drugs with some data for use in mUC but only one with phase III trial data to support its use (Pembrolizumab) Biomarker studies seem to show a relationship but not clear Accelerated approval does not guarantee phase 3 trial success More IO drugs and combination trials are ongoing Cost will play a big role in its usage and access in non reimbursable markets

20. Outli n e 20 Immunotherapy in Bladder Cancer Immunotherapy in Kidney Cancer Immunotherapy in Prostate cancer

21. IMDC Prognostic score

22. Role of immune system in Kidney Cancer Martincorena I, Campbell PJ. Science. 2015;349:1483-9 High mutational load may correlate with immunogenicity, and provides valuable prognostic information 23

23. Immunotherapy in Advanced RCC: A Renewed Level of Interest? Level of Research < 1980s 1992 2000 2009 2015 High-dose IL-2 IFN- α and IL-2–based regimens Rise of the targeted therapies Bevacizumab + IFN- α Checkpoint inhibitors Vaccines* Recombinant T-cell receptors* Bispecific T-cell engagers * *Not approved for metastatic RCC as of January 2016. Slide credit: clinicaloptions.com McDermott DF, et al. Semin Oncol. 2013;40:492-498. Figure adapted from L Harshman, MD

24. 46 NCCN 2017

25. CheckMate-025: Nivolumab in Previously Treated Metastatic RCC Primary endpoint: OS Secondary endpoints: PFS, ORR, OR duration, Safety Motzer R, et al. N Engl J Med. 2015;373:1803-1813. Nivolumab 3 mg/kg IV every 2 wks Everolimus 10 mg PO daily Metastatic RCC with ≤ 2 prior antiangiogenic therapies and ≤ 3 total prior systemic regimens ( N = 821 ) Slide credit: clinicaloptions.com

26. CheckMate-025: OS Median OS, Mos (95% CI) Nivolumab (n = 410) 25.0 (21.8-NE) Everolimus (n = 411) 19.6 (17.6-23.1) HR: 0.73 (98.5% CI: 0.57-0.93; P = .0018) 3 6 12 9 15 Mos 18 21 24 27 30 33 Pts at Risk, n Nivolumab 410 389 359 337 305 275 213 139 73 29 3 411 366 324 287 265 241 187 115 61 20 2 Everolimus 30 10 20 40 50 60 70 80 90 100 OS (%) Nivolumab Everolimus Motzer R, et al. N Engl J Med. 2015;373:1803-1813. Slide credit: clinicaloptions.com

27. CheckMate-025: OS by PD-L1 Expression PD-L1 < 1% (n = 575/756, 76%) Median OS, Mos (95% CI) Nivolumab 21.8 (16.5-28.1) Everolimus 18.8 (11.9-19.9) Pts at Risk, n Nivolumab 94 86 79 73 66 58 45 31 18 4 1 Everolimus 97 77 68 59 52 47 40 19 9 4 1 Nivolumab Everolimus PD-L1 ≥ 1% (n = 181/756, 24%) Median OS, Mos (95% CI) Nivolumab 27.4 (21.4-NE) Everolimus 21.2 (17.7–26.2) 276 265 245 233 210 189 145 94 48 22 2 299 267 238 214 200 192 137 92 51 16 1 Nivolumab Everolimus HR: 0.78 (95% CI: 0.53-1.16) HR: 0.76 (95% CI: 0.60-0.97) Motzer R, et al. N Engl J Med. 2015;373:1803-1813. Slide credit: clinicaloptions.com 3 6 12 9 15 Mos 18 21 24 27 30 33 30 10 20 40 50 60 70 80 90 100 OS (%) 3 6 12 9 15 Mos 18 21 24 27 30 33 30 10 20 40 50 60 70 80 90 100

28. Recent updates in the treatment of mRCC 2015 2016 Nivolumab November 2015 Second Line April 2016 Cabozantinib Second Line M ay 2016 Lenvatinib Second Line CABOSUN trial ESMO 2016 Phase II Trial of Cabozantinib vs Sunitinib for Patients with Previously Untreated a RCC S-TRAC trial ESMO 2016 Sunitinib in Adjuvant setting 2017 Check Mate 214 ESMO 2017 Nivo+Ipi vs Sunitinib for Treatment-Naïve mRCC IMmotion trial ASCO GU 2017 atezolizumab as monotherapy or in combination with bevacizumab vs sunitinib in patients with previously untreated mRCC 2018 Nivolumab + Ipilumab FDA approval for first line intermediate and poor risk mRCC

29. Treatment Patients Randomise 1:1 CheckMate 214: Study design IMDC, International Metastatic RCC Database Consortium; KPS, Karnofsky performance status; PD-L1, programmed cell death ligand 1 ; Q2W , every 2 weeks; Q3W, every 3 weeks. Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017. Treatment-naïve advanced or metastatic clear-cell RCC Measurable disease KPS ≥70% Tumour tissue available for PD-L1 testing Treatment until progression or unacceptable toxicity Arm A 3 mg/kg nivolumab IV + 1 mg/kg ipilimumab IV Q3W for four doses, then 3 mg/kg nivolumab IV Q2W Arm B 50 mg sunitinib orally once daily for 4 weeks (6-week cycles) Stratified by IMDC prognostic score (0 vs 1–2 vs 3–6) Region (US vs Canada / Europe vs Rest of World) NCT02231749 Co-primary endpoints In IMDC intermediate- and poor-risk patients ORR (per IRRC) PFS (per IRRC) OS Statistical analyses Overall alpha is 0.05, split among the three co-primary endpoints 0.001 for ORR, 0.009 for PFS, and 0.04 for OS

30. Significantly improved ORR and CR rates (both P < .0001) with nivo + ipi vs sun in IMDC intermediate-/poor-risk pts ORR most improved in pts with tumor PD-L1 ≥ 1% (58% vs 22%; P < .0001) Escudier B, et al. ESMO 2017. Abstract LBA5. Response per IRRC,* % Nivo + Ipi (n = 425) Sunitinib (n = 422) ORR 42 27 CR 9 1 PR 32 25 SD 31 45 PD 20 17 NR/unable to determine 8 12 CheckMate 214: ORR in IMDC Poor-/Intermediate-Risk Patients

31. 3 6 9 12 15 18 21 24 27 30 Progression-Free Survival (Probability) 425 304 233 187 163 149 118 46 17 3 422 282 191 139 107 86 57 33 11 1 No. at Risk NIVO + IPI SUN Months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Co-primary endpoint PFS per IRRC: IMDC intermediate/poor risk Hazard ratio (99.1% CI), 0.82 (0.64–1.05) P =0.0331 Median PFS, months (95% CI) NIVO + IPI 11.6 (8.7–15.5) SUN 8.4 (7.0–10.8) CI, confidence interval; IMDC, International Metastatic RCC Database Consortium; IPI, ipilimumab ; NIVO, nivolumab; IRRC, independent radiology review committee; NE, not estimable; NR, not reported; OS, overall survival; SUN, sunitinib . Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017. NCT02231749

32. Hazard ratio (99.8% CI), 0.63 (0.44–0.89) P <0.0001 Median OS, months (95% CI) NIVO + IPI NR (28.2–NE) SUN 26.0 (22.1–NE) Overall survival (probability) 425 399 372 348 332 318 300 241 119 44 2 422 387 352 315 288 253 225 179 89 34 3 Months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 18 21 24 27 30 33 15 12 9 6 3 Co-primary endpoint OS: IMDC intermediate/poor risk CI, confidence interval; IPI, ipilimumab ; NIVO, nivolumab; NE, not estimable; NR, not reported; OS, overall survival; SUN, sunitinib . Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017. NCT02231749 No. at Risk NIVO + IPI SUN

33. N=249 a Outcome NIVO + IPI n=125 SUN n=124 Confirmed ORR, b % (95% CI) 29 (21–38) 52 (43–61) P=0.0002 PFS, c median (95% CI), months 15.3 (9.7–20.3) 25.1 (20.9–NE) HR (99.1% CI) 2.18 (1.29–3.68) P <0.0001 Exploratory endpoint ORR and PFS: IMDC favourable risk a 11% of patients in both arms had tumour PD-L1 expression ≥1%; b IRRC -assessed by RECIST v1.1; c IRRC -assessed. CI, confidence interval; IMDC, International Metastatic RCC Database Consortium; HR, hazard ratio; IPI, ipilimumab ; NIVO, nivolumab; NE, not estimable; NR, not reported; ORR, objective response rate; PFS, progression-free survival; SUN, sunitinib . Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017. NCT02231749

34. NIVO + IPI n=547 SUN n=535 Event, % Any grade Grade 3–5 Any grade Grade 3–5 a Treatment-related adverse events in ≥25% of patients 93 46 97 63 Fatigue 37 4 49 9 Pruritus 28 <1 9 Diarrhoea 27 4 52 5 Nausea 20 2 38 1 Hypothyroidism 16 <1 25 <1 Decreased appetite 14 1 25 1 Dysgeusia 6 33 <1 Stomatitis 4 28 3 Hypertension 2 <1 40 16 Mucosal inflammation 2 28 3 Palmar-plantar erythrodysesthesia syndrome 1 43 9 Treatment-related AEs leading to discontinuation, % 22 15 12 7 Treatment-related deaths n=7 b n=4 c Treatment-related adverse events: All treated patients NCT02231749 a Two patients had grade 5 cardiac arrest. b Pneumonitis , immune-mediated bronchitis, lower GI haemorrhage, hemophagocytic syndrome, sudden death, liver toxicity, lung infection. c Cardiac arrest (n=2), heart failure, multiple organ failure. AE, adverse event; IPI, ipilimumab ; NIVO, nivolumab; SUN, sunitinib. Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017.

35. NIVO + IPI n=547 Category, % Any grade Grade 3–4 Rash 17 3 Diarrhoea /colitis 10 5 Hepatitis 7 6 Nephritis and renal dysfunction 5 2 Pneumonitis 4 2 Hypersensitivity/infusion reaction 1 Hypothyroidism 19 <1 Hyperthyroidism 12 <1 Adrenal insufficiency 8 3 Hypophysitis 5 3 Thyroiditis 3 <1 Diabetes mellitus 3 1 Immune-mediated adverse events: All treated patients 60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event Secondary immunosupression with infliximab (3%) and mycophenolic acid (1%) was reported NCT02231749 Immune-mediated AE analyses included events, regardless of causality, occurring <100 days of the last dose. These analyses were limited to patients who received immune modulating medication for treatment of the event, except endocrine events that were included in the analysis regardless of treatment since these events are often managed without immunosuppression IPI, ipilimumab ; NIVO, nivolumab; SUN, sunitinib. Escudier B, et al. LBA5. Presented at ESMO 2017, Madrid, Spain, 8–12 September, 2017.

36. Atezolizumab + Bevacizumab vs Sunitinib for Untreated Advanced RCC (IMmotion151) Randomized, open-label phase III study Primary endpoints: PFS (investigator assessed) in PD-L1+ pts, OS in ITT pts PD-L1+ defined as ≥ 1% staining on tumor-infiltrating immune cells by IHC Secondary endpoints: PFS in ITT pts, OS in PD-L1+ pts, ORR, DoR , PFS and ORR (IRC assessed), pt-reported outcomes, safety Motzer RJ, et al. ASCO GU 2018. Abstract 578. Treatment-naive pts with advanced or metastatic RCC of clear cell and/or sarcomatoid histology, KPS ≥ 70, and tissue available for PD-L1 staining (N = 915) Atezolizumab 1200 mg IV Q3W + Bevacizumab 15 mg/kg IV Q3W (n = 454) Sunitinib 50 mg/day PO 4 wks on, 2 wks off (n = 461) Stratified by MSKCC risk score, liver metastases, PD-L1 (< 1% vs ≥ 1%)

37. IMmotion 151: Survival PFS benefit with atezolizumab + bevacizumab may increase as PD-L1 expression increases Motzer RJ, et al. ASCO GU 2018. Abstract 578. Outcome, Mos Atezo + Bev Sunitinib HR (95% CI) P Value Median PFS by investigator PD-L1+ * † ITT 11.2 11.2 7.7 8.4 0.74 (0.57-0.96) 0.83 (0.70-0.97) .02 -- Median PFS by IRC PD-L1+ † ITT 8.9 9.6 7.2 8.3 0.93 (0.72-1.21) 0.88 (0.74-1.04) -- -- Median OS ‡ PD-L1+ † ITT* NR NR 23.3 NR 0.68 (0.46-1.00) 0.81 (0.63-1.03) -- .09 *Coprimary endpoint. † Investigators and IRC blinded to PD-L1 status. ‡ OS data are immature.

38. Sum m ary 41 IO has an established role in the treatment of mRCC ( Nivolumab) New standard established with recent IO data in first line mRCC ( int/ poor risk) A number of ongoing studies in the first line setting with IO combination studies show promise Cost and access present a major challenge which needs to be overcome

39. Outli n e 42 Immunotherapy in Bladder Cancer Immunotherapy in Kidney Cancer Immunotherapy in Prostate cancer

40. Role of immune system in Prostate Cancer Martincorena I, Campbell PJ. Science. 2015;349:1483-9 High mutational load may correlate with immunogenicity, and provides valuable prognostic information 43

41. PD-1 Inhibition in MMR-Deficient Cancers Le DT, et al. ASCO 2016. Abstract 103. Le DT, et al. N Engl J Med. 2015;372:2509-2520. Radiographic Response With Pembrolizumab -100 MMR-P CRC MMR-D CRC MMR-D non-CRC Change From BL in the Sum of Longest Diameters (%) 20% increase (PD) 100 50 -50 30% decrease (PR) Biochemical Response With Pembrolizumab MMR-P CRC MMR-D CRC MMR-D non-CRC Change in Tumor Marker Level (%) Days 0% (no change) 200 -100 100 200 400 300 100 Pt PFS (%) PFS with Pembrolizumab Mos MMR-D (mPFS: NR) 100 50 3 6 12 15 18 21 24 27 30 MMR-P (mPFS: 2.3 mos) 9 OS (%) Mos MMR-D (mOS: NR) OS with Pembrolizumab 100 50 3 6 12 15 18 21 24 27 30 MMR-P (mOS: 5.98 mos) 9

42. KEYNOTE-016: Responses to Pembrolizumab in MMR-Deficient Tumors Radiographic responses across 12 tumor types at 20 wks (N = 86) Le DT, et al. Science. 2017;357:409-413. Ampulla of Vater Cholangiocarcinoma Colorectal Endometrial cancer Gastroesophageal Neuroendocrine Osteosarcoma Pancreas Prostate Small Intestine Thyroid Unknown primary 100 50 -50 -100 Change From Baseline SLD (%) Prostate Prostate (n = 1)

43. MMR Mutations in mCRPC 3/150 (2%) had MMR mutations 4/150 (2.7%) were MSI-high Patient Cases With DNA Repair Defects Reprinted from Robinson D, et al . Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. Copyright © 2015 with permission from Elsevier Inc.

44. Conclusion

45. Thank You Dr Alok Gupta MD, DM, Consultant Medical Oncologist Max Super Speciality Hospital, Saket Phone No. 9167164364 Email: [email protected]