III Sessione I risultati clinici

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1 10,30-13,15 III Sessione I risultati clinici Moderatori: Michele Maio - Valter Torri

2 10,30-10,45 Melanoma: anti CTLA-4 Vanna Chiarion Sileni

3 Vanna Chiarion Sileni IOV-IRCCS,Padova Melanoma : anti CTLA4

4 Tumor Immunotherapy is an established reality in cancer treatment

7 MS 10 mos vs 6.4 Median FU 21 vs 27.8 vs 6.4 HR= 0.66 p= 0.003

8 Long-Term Survival in a Melanoma Patient with Skin and Lung Disease Screening Week 72 Durable & ongoing response without signs of iraes Week 12 Initial increase in total tumour burden (mwho PD) 9000 CA CA Week 16 Responding SPD / Courtesy of Kaan Harmankaya CT imaging Ipilimumab dosing Dose skipped SPD = Sum of the Product of the perpendicular Diameters (a measure of tumor volume)

9 Time Course of Measurable Clinical Effect with Ipilimumab Ipi Ipi Ipi Ipi Ipi Ipi Ipi Ipilimumab exposure T-cell response beyond Week 12 has not been characterized T-cell activation Total tumor volume * 25% 50% 100% Baseline SD PR CR PD SD PR CR Immune-cell activation and proliferation begins early Measurable clinical effect occurs at variable time points * Tumor volume can include immune-cell infiltrates and tumor cells

11 J Weber et al: Cancer 2013

12 Five-year Survival in Patients with Advanced Melanoma treated with first line Ipilimumab Plus Dacarbazine. A Phase III Trial M. Maio, et al JCO, Ipilimumab + DTIC Censored Placebo + DTIC Censored 0.7 Proportion Alive Months Patients at Risk Ipilimumab + DTIC Placebo + DTIC

13 EAP: Italian experience on 845 pts median follow-up 5.5 ms

14 1-y S 51%, 2-y S =34.6% 1-yS=4.8%, 2-y S 0%

15 Y Koguchi et al Cancer Res. 2015

16 Y Koguchi et al Cancer Res. 2015

17 Subset Ipilimumab OS Analyses by Prior Therapy (N=1861)* Presented By Axel Hauschild at 2014 ASCO Annual Meeting

18 Proportion Recurrence-Free Patients at Risk Ipilimumab Placebo Recurrence-free Survival Ipilimumab 10 mg/kg Placebo Ipilimumab Placebo Events/patients 234/ /476 Median RFS, mo HR (95% CI) 0.75 ( ) Log-rank P= Y RFS rate (%) Y RFS rate (%)* Median: 17.1 mo *Data are not yet mature. Median: 26.1 mo Months Eggermont AM Lancet Oncol 2015

Safety: Immune-related Adverse Events % Patients Ipilimumab (n = 471)* Placebo (n =474) All grades Grade 3-4 All grades Grade 3-4 Any IrAE 90.4 42.0 38.6 2.5 Dermatologic 63.3 4.5 20.9 0 Rash 34.4 1.

19 Safety: Immune-related Adverse Events % Patients Ipilimumab (n = 471)* Placebo (n =474) All grades Grade 3-4 All grades Grade 3-4 Any IrAE Dermatologic Rash Gastrointestinal Diarrhea Colitis** Endocrine Hypophysitis Hypothyroidism Hepatic LFT increase Neurologic Other *5 deaths (1.1%) due to drug-related AEs: 3 colitis, 1 myocarditis, 1 Guillain- Barré syndrome. **GI perforations: ipilimumab, 6 related (1.3%); placebo, 3 unrelated (0.6%).

24 CheckMate 067: Study Design Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Co-primary endpoints: PFS and OS (intent-to-treat population) Secondary and other endpoints: Stratify by: PD-L1 expression* BRAF status AJCC M stage N=314 N=316 N=315 ORR by RECIST v1.1 Predefined tumour PD-L1 expression level as a predictive biomarker of efficacy Safety profile (in patients who received 1 dose of study drug) NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W NIVO 3 mg/kg Q2W + IPI-matched placebo IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo Treat until progression** or unacceptable toxicity 1. Larkin et al. N Engl J Med 2015; 373: Oral presentation by Dr. Jedd Wolchok at the ASCO 2015 Annual Meeting.

25 PFS (Intent-to-Treat) NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) 1.0 Median PFS, months (95% CI) 11.5 ( ) 6.9 ( ) 2.9 ( ) Proportion alive and progression-free NIVO + IPI NIVO HR (99.5% CI) vs. IPI HR (95% CI) vs. NIVO 0.42 ( )* 0.74 ( )** 0.57 ( )* *Stratified log-rank P< vs. IPI **Exploratory endpoint 0.1 IPI 0.0 No. at Risk Months NIVO + IPI NIVO Larkin et al. N Engl J Med 2015; 373: Oral presentation by Dr. Jedd Wolchok at the ASCO 2015 IPI Annual Meeting.

26 PFS in Patient Subgroups Total population BRAF Wild-type Mutant M Stage M1c Baseline LDH ULN >ULN >2x ULN Age (yr) 65 and <75 75 PD-L1 Expression Level <5% 5% Events/patients NIVO + IPI NIVO Hazard Ratio (95% CI) 151/ ( ) 174/ ( ) 103/ ( ) 117/ ( ) 48/ ( ) 57/ ( ) 100/ ( ) 111/ ( ) 82/ ( ) 100/ ( ) 69/ ( ) 73/ ( ) 28/ ( ) 30/ ( ) 48/ ( ) 37/ ( ) 15/ ( ) 24/ ( ) 103/ ( ) 122/ ( ) 28/ ( ) 33/ ( ) NIVO or NIVO + IPI better IPI better

27 Slide 16 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

28 Patients Reporting Event, % Safety Summary by Key Subgroups Any Grade NIVO + IPI (N=313) Grade 3 4 Any Grade NIVO (N=313) Treatment-related AE Age 65 and <75 years Age 75 and <85 years M1c disease PD-L1 expression 5% Patients with BOR of CR Treatment-related AE leading to discontinuation Grade Treatment-related death* 0 <1 BOR = best overall response; CR = complete response *One death in the NIVO group was reported as neutropaenia. Treatment-related AEs reported with IPI were consistent with prior experience

29 Keynote-006 OS at the Second Interim Analysis Presented By Lynn Schuchter at 2015 ASCO Annual Meeting

30 CheckMate 064: Study Design Randomized, open-label, phase 2 study evaluating the safety and efficacy of two immune checkpoint inhibitors given sequentially with planned switch Induction Period 1 Induction Period 2 Continuation Period Randomiz e Cohort A N= ~70 Cohort B N= ~70 NIVO 3 mg/kg Q2W x 6 IPI 3 mg/kg Q3W x 4 IPI 3 mg/kg Q3W x 4 NIVO 3 mg/kg Q2W x 6 Week # W 3W NIVO 3 mg/kg Q2W Until PD, unacceptable toxicity, or withdrawal of consent TA TA TA Database lock; May 22, 2015 TA = Tumor Assessment; = Biopsy Timepoint; PD = Progressive Disease 29

31 Baseline Patient Characteristics A: NIVOàIPI (N=68) B: IPIàNIVO (N=70) Mean age (yrs) Gender Male (%) ECOG performance status of 0 (%) M stage M1c (%) LDH >ULN (%) LDH >2x ULN (%) BRAF V600 mutant (%) Prior systemic therapy for metastatic disease (%) PD-L1 expression 5% (%) Brain metastases (%)

32 Efficacy Summary Week 13 Week 25 A: NIVOàIPI (N=68) B: IPIàNIVO (N=70) A: NIVOàIPI (N=68) B: IPIàNIVO (N=70) Confirmed ORR, % (95% CI) ( ) 20.0 ( ) Complete response, % Unconfirmed ORR, % (95% CI)* ( )** 22.6 ( ) Progression rate, % (95% CI) 38.2 ( ) 61.4 ( ) 38.2 ( ) 60.0 ( ) *Statistical design required that Week 25 response be confirmed with a Week 33 scan; a confirmatory scan was not required for Week 13 assessment. **Includes 1 unconfirmed complete and 2 unconfirmed partial responses (total of 31 objective responses [47.7%]). 31

33 Tumor Burden Change From Baseline at Week A: NIVOàIPI B: IPIàNIVO 75 Reduction from Baseline in Target Lesion (%) at Week Median change: -50% (from -27% at week 13) Median change: -17% (from +10% at week 13) Patients Confirmed responder 30% reduction in tumor burden by RECIST v1.1 32

34 Patient Disposition A: NIVOàIPI (N=68) B: IPIàNIVO (N=70) Patients continuing on treatment 31% 24% Reasons for discontinuation Disease progression 27% 56% Study drug toxicity 31% 14% Death 0 0 Other * 12% 6% Patients continued with 1 dose in Induction Period 2 85% 76% Patients continued with 1 NIVO dose in Continuation Period 47% 46% * Includes: AEs unrelated to study drug, patient request to discontinue study treatment, withdrawal of consent 33

35 Treatment-related Grade 3-4 AEs 60% 50% 50% 43% Primary Endpoint 52% A: NIVOàIPI (N=68) 40% B: IPIàNIVO 38% (N=70) 30% 24% 28% 22% 20% 10% 7% 0% Induction Induction Induction NIVO Continuation There were no study drug-related deaths in either cohort Treatment-related grade 3-4 AEs leading to discontinuation Cohort A: 24%, Cohort B: 27% * 95% CI: 37.6% 62.4% ** 95% CI: 31.1% 55.3% ⱡ AEs are counted only once for both induction periods 34

36 Summary PD1i > ipilimumab in ORR, PFS, OS; < AE PD1i + ipi > ipi in ORR, PFS,OS; >> AE PD1i ipi > di ipi; = PD1i IPI PD1i > di ipi; < PD1i, > AE PD1i

37 Major Treatment Advances For Metastatic Melanoma Presented By Michael Atkins at 2015 ASCO Annual Meeting

40 NIVO +IPI in metastatic renal cancer phase I N1/3 Discontinuation due to tox 10% 26%

41 Mobilizing the Immune System to Treat Cancer: Immune Checkpoint Strategies James Patrick Allison ASCO 2012

Immunotherapy for Melanoma. Michael Postow, MD Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center

Immunotherapy for Melanoma. Michael Postow, MD Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center Immunotherapy for Melanoma Michael Postow, MD Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center Conflicts of Interest Bristol-Myers Squibb: -Research support -Participated