Immunotherapy in NSCLC

Transcription

1 Immunotherapy in NSCLC Enriqueta Felip Hospital Vall d Hebron University, Barcelona SAMO Interdisciplinary Workshop on Chest Tumors Lucerne, January

2 Immunotherapy in NSCLC: Outline 1 st line as monotherapy 1 st line in combination with anti-ctla4 / CT New combinations Neoadjuvant / adjuvant setting

3 Checkmate 26: Phase III Nivolumab vs Chemotherapy in First-line NSCLC Key Eligibility Criteria Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy 1% PD-L1 a CNS metastases if treated prior to randomization, with return to baseline for at least 2 weeks prior to randomization Stratification factors at randomization: PD-L1 expression (<5% vs 5%) a Histology (squamous vs nonsquamous) R 1:1 Nivolumab 3 mg/kg IV Q2W n=271 PT-DC (Histology dependent) b Maximum of 6 cycles n=27 Primary Endpoint: PFS ( 5% PD-L1+) d Tumor scans Q6W until wk 48 then Q12W Disease Progression Disease progression or unacceptable toxicity Secondary Endpoints: Crossover nivolumab c (optional) PFS ( 1% PD-L1+) d OS ( 1% PD-L1+ and 5% PD-L1+) ORR ( 5% PD-L1+) d Socinski M et al. Oral presentation at ESMO 216

4 Checkmate 26: PFS and OS ( 5% PD-L1+) 1 8 Median PFS, mos (95% CI) Nivolumab n = (3., 5.6) Chemo n = (5.4, 6.9) 1-year PFS rate, % Median OS, mos (95% CI) Nivolumab n = (11.7, 17.4) Chemo n = (1.7, 17.1) 1-year OS rate, % PFS (%) 6 4 HR = 1.15 (95% CI:.91, 1.45), P =.2511 OS (%) 6 4 HR = 1.2 (95% CI:.8, 1.3) Chemotherapy 2 Nivolumab 2 Months Chemotherapy No. of patients at risk: Nivo CT Nivolumab Months No. of patients at risk: Nivo CT All randomized patients ( 1% PD-L1+) HR = 1.17 (95% CI:.95, 1.43) All randomized patients ( 1% PD-L1+) HR = 1.7 (95% CI:.86, 1.33) Socinski M et al. Oral presentation at ESMO 216

5 Checkmate 26: Safety summary Treatment-related AEs, % Any AEs Select AEs AEs leading to discontinuation Nivolumab (n = 267) Any grade Grade Chemotherapy (n = 263) Any grade Grade Treatment-related deaths, n (%) 2 (.7) 3 (1.1) Treatment-related select AEs, % e Any grade Grade 3 4 Any grade Grade 3 4 Skin Gastrointestinal Hepatic Pulmonary Hypersensitivity/infusion reaction Renal Socinski M et al. Oral presentation at ESMO 216

6 KEYNOTE-24: Study design A Phase III, randomized, open-label study of pembrolizumab vs platinum-doublet chemotherapy as firstline therapy in patients with advanced or metastatic NSCLC that expresses PD-L1 in 5% of tumor cells N=35 Key Inclusion Criteria Advanced or metastatic, previously untreated NSCLC PD-L1+ tumor expression 5% No EGFR sensitizing mutation or ALK translocation ECOG PS 1 Primary endpoint: PFS (RECIST v1.1 per blinded, independent central review) Secondary endpoints: ORR, OS, safety, and tolerability Exploratory endpoint: DOR R 1:1 Pembrolizumab 2 mg Q3W (2 years) Optional crossover after disease progression Investigator choice of platinum-based chemotherapy For 4 6 cycles Reck M et al. N Engl J Med. 216

7 KEYNOTE-24: PD-L1 Screening 1934 patients entered screening 1729 submitted samples for PD-L1 assessment 1653 samples evaluable for PD-L1 5 TPS 5% (3%) 1153 TPS <5% Reck M et al. N Engl J Med. 216.

8 KEYNOTE-24: PFS and OS (PD-L1 5%) 1 8 Events, n Median, mo HR (95% CI) Pembro Chemo ( ) P < % 72% 7% 54% PFS, % % 15% 2 62% 5% No. at risk Time (months) OS, % No. at risk Pembr o Events, n 44 Median, mo NR Chemo 64 NR HR (95% CI).6 ( ) Time (months) P.5 Reck M et al. N Engl J Med. 216

9 KEYNOTE-24: Exposure and TRAE Summary Exposure, median (range) Pembrolizumab N = mo (1 d 18.7 mo) Chemotherapy N = mo (1 d 16.8 mo) TRAEs, n (%) 113 (73.4) 135 (9.) Grade (26.6) 8 (53.3) Serious 33 (21.4) 31 (2.7) Led to discontinuation 11 (7.1) 16 (1.7) Led to death 1 (.6) 3 (2.). Reck M et al. N Engl J Med. 216.

10 Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS 5%: Data from KEYNOTE-24 Pembrolizumab was associated with a significantly greater improvement from baseline to Week 15 in HRQoL vs. platinum-doublet (difference in LS mean 7.8 [95%CI 2.8, 12.8], p=.2) Pembrolizumab showed slower deterioration in HRQoL due to symptoms (p=.29) Time to deterioration (EORTC QLQ-LC13 composite endpoint of cough, chest pain and dyspnea) Time to deterioration (survival analysis) Events, n (%) HR (95%CI) Pembro (n=51) 46 (3.5).66 (.44,.97) Chemo (n=148) 58 (39.2) p= Time, months Brahmer et al. J Thorac Oncol 216; 11(suppl): abstr PL4a.1

11 CheckMate % PD-L1 expression level mos (mos) Nivo 17.7 Doc % PD-L1 expression level mos (mos) Nivo 19.4 Doc % PD-L1 expression level mos (mos) Nivo 19.9 Doc OS (%) Nivo Doc HR (95% CI) =.58 (.43,.79) Time (mos) 3 1 HR (95% CI) =.43 (.3,.62) Time (mos) 3 1 HR (95% CI) =.4 (.27,.58) Time (mos) <1% PD-L1 expression level mos (mos) Nivo 1.5 Doc <5% PD-L1 expression level mos (mos) Nivo 9.8 Doc <1% PD-L1 expression level mos (mos) Nivo 9.9 Doc OS (%) Nivo Doc Time (mos) Based on a July 2, 215 DBL. Symbols represent censored observations HR (95% CI) =.87 (.63, 1.19) HR (95% CI) =.96 (.73, 1.27) HR (95% CI) =.96 (.74, 1.25) Time (mos) Time (mos) 3

12 OAK, OS, PD-L1 Expression on 5% TC or 1% IC TC3 or IC3; 16% of patients Overall Survival, % Atezolizumab Docetaxel Median 8.9 mo (95% CI, 5.6, 11.6) HR,.41 a (95% CI,.27,.64) P<.1 b Minimum follow-up = 19 months Median 2.5 mo (95% CI, 17.5, NE) Months a Unstratified HR. b P values for descriptive purpose only. Barlesi F, et al. Ann Oncol. 216;27(suppl 6): Abstract LBA44.

13 495 locally or metastatic NSCLC pts biopsy Pembrolizumab 2 or 1 mg/ Kg q 3 w or 1 mg/k q 2 w

14 PFS and OS Subgroup Analyses CheckMate 26: Nivolumab vs Chemotherapy in First-Line NSCLC Patients, n Unstratified HR Unstratified HR (95% CI) Subgroup Nivolumab Chemotherapy PFS OS PFS OS Overall years <65 years Male Female ECOG PS = ECOG PS Squamous Non-squamous Never smoker Former smoker Current smoker % PD-L Nivolumab Chemotherapy Nivolumab Chemotherapy Socinski MA, et al. Ann Oncol. 216;27(suppl 6): Abstract LBA7.

15 NEW STANDARD IN FRONT LINE THERAPY FOR ADVANCED NSCLC EGFR 12-15% ALK 3-5% ROS1 1% PD-L1 ~15% For PD-L1 >5%, pembrolizumab

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17 Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1 Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study Study objective To evaluate atezolizumab monotherapy in PD-L1-selected advanced NSCLC patients results from Cohort 1 of the phase 2 BIRCH trial Key patient inclusion criteria Locally advanced or metastatic NSCLC Tumour PD-L1 expression by IHC (TC2/3 and/or IC2/3 No brain metastases ECOG PS or 1 (n=667) Primary endpoint ORR (RECIST v1.1) R Cohort 1 (1L) No prior chemo Atezolizumab 12 mg IV q3w (n=138) Cohort 2 (21L) 1 prior platinum chemo Atezolizumab 12 mg IV q3w (n=271) Cohort 3 (3L+) 2 prior chemo (incl. 1 platinum) Atezolizumab 12 mg IV q3w (n=254) Secondary endpoints PFS, DoR, OS, safety PD Loss of clinical benefit Loss of clinical benefit Garassino et al. J Thorac Oncol 216; 11(suppl): abstr OA3.2

18 Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1 Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study Frequency, % Key results 49% 42% 34% 34% 25% 18% CR/PR TC3 or IC3 TC2/3 or IC2/3 TC2 and IC2 SD In patients with advanced NSCLC, atezolizumab showed promising efficacy and had a similar safety profile to previous atezolizumab studies TC3 or IC3 = TC 5% or IC 1% PD-L1 expressing cells; TC2 and IC2 = 5% but IC <1% and TC <5% PD-L1 expressing cells; TC2/3 or IC2/3 = TC or IC 5% PD-L1 expressing cells, respectively. Safety summary, n (%) n=138 Total patients with 1 AE 126 (91) Grade 5 2 (1) AEs led to dose interruption 39 (28) TRAEs 83 (6) Grade 5 TRAEs led to withdrawal 5 (4) SAEs 45 (33) TC3 or IC3 (n = 65) TC2/3 or IC2/3 (n = 138) TC2 and IC2 (n = 73) mos, months (95%CI) 26.9 (12., NE) 23.5 (18.1, NE) 23.5 (18.1, NE) 1-year OS rate, % (95%CI) 61.5 (49., 74.) 66.4 (58.1, 74.6) 7.7 (59.8, 81.6) Garassino et al. J Thorac Oncol 216; 11(suppl): abstr OA3.2

19 JAVELIN Solid Tumor: Safety and Clinical Activity of Avelumab (Anti- PD-L1) as First-Line Treatment in Patients with Advanced NSCLC Study objective To evaluate the safety and clinical activity of avelumab as first-line therapy in a cohort of patients with NSCLC (dose expansion phase, 1b) Methods Patients with stage IV or recurrent NSCLC with no prior treatment received avelumab 1 mg/kg IV (1 h) q2w Key results 16 (1.3%) patients had a potentially immune-related TRAE; grade 3 adrenal insufficiency in 1 (.6%) patient only. No grade 3 4 pneumonitis; grade 1 2 pneumonitis in 4 (2.6%) patients and 11 (7.1%) patients discontinued treatment following a TRAE mpfs 17.6 weeks (95%CI 11.6, 23.6) with 24-week PFS rate of 37.2% ORR 22.4% (95%CI 16.2, 29.8) and DCR 65.4%. ORR was higher in those aged 65 years, females and ECOG PS Conclusion Early results indicate that avelumab has a durable anti-tumour activity and is well tolerated Verschraegen et al. J Thorac Oncol 216; 11(suppl): abstr OA3.3

20 IMpower 11 and JAVeLIN lung 1: Study designs Phase III, open-label trials of anti PD-L1 vs Pt-based doublet chemotherapy for first-line treatment of stage IV, PD-L1 positive NSCLC IMPOWER 11 1,2 N=57 Key Inclusion Criteria Stage IV NSCLC Treatment-naïve PD-L1 positive TC and IC ECOG PS 1 Primary Endpoints: PFS Study Sponsor: Roche R 1:1 Atezolizumab NSQ Pemetrexed + cisplatin/carboplatin SQ Gemcitabine + cisplatin/carboplatin Until disease progression, unacceptable toxicity, or death JAVELIN LUNG 1 3 N=42 Key Inclusion Criteria Stage IV or recurrent NSCLC Treatment-naïve PD-L1 positive tumor ECOG PS 1 Primary Endpoints: PFS, OS Study Sponsor: Pfizer R Avelumab NSQ Pemetrexed + cisplatin/carboplatin SQ Paclitaxel + carboplatin, or gemcitabine + cisplatin/carboplatin Until disease progression, unacceptable toxicity, or death. Clinicaltrials.gov. NCT Accessed September 8, Herbst RS et al. Poster presented at ESMO Asia TiP. 3. Clinicaltrials.gov. NCT Accessed September 8,

21 Checkmate 12 (Nivo ± IPI arms): study design Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS or 1 Nivolumab 3 mg/kg IV Q2W a Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q12W b Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W b Until disease progression c or unacceptable toxicity Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks Exploratory endpoints: OS, efficacy by PD-L1 expression

22 Checkmate 12: 1L Nivolumab ± Ipilimumab: Efficacy by Tumor PD-L1 Expression 1 8 Nivo 3 Q2W + Ipi 1 Q6/12W 92 ORR (%) n Overall <1% 1% 5% PD-L1 expression 5 CRs (1%) were achieved in the nivolumab monotherapy cohort (1 in a patient with tumor PD-L1 expression <1%) 6 CRs (8%) were achieved in the nivolumab + ipilimumab cohorts a (3 in patients with tumor PD- L1 expression <1%)

23 Checkmate 12: 1L Nivolumab ± Ipilimumab: PFS by tumor PD-L1 expression Nivo 3 Q2W + Ipi 1 Q6/12W PFS (%) All treated patients (n = 77) 1% PD-L1 (n = 46) 5% PD-L1 (n = 13) 1 Median 8. mo (95% CI 4.1, 13.2) Median 12.7 mo (95% CI 7.8, 23.) Median NR (95% CI 7.8, NR) Months Months Months All treated patients (n = 52) 1% PD-L1 (n = 32) 5% PD-L1 (n = 12) Nivo 3 Q2W PFS (%) Median 3.6 mo (95% CI 2.3, 6.6) Median 3.5 mo (95% CI 2.2, 6.6) Median 8.3 mo (95% CI 2.2, NR) Months Months Months 23

24 Checkmate 12: 1L Nivolumab ± Ipilimumab safety summary Nivo 3 Q2W (n = 52) Any grade Grade 3 4 Nivo 3 Q2W + Ipi 1 Q12W (n = 38) Any grade Grade 3 4 Nivo 3 Q2W + Ipi 1 Q6W (n = 39) Any grade Grade 3 4 Treatment-related AEs, % Treatment-related AEs leading to discontinuation, % There were no treatment-related deaths After an additional 6 months of follow-up in the Q12W and Q6W combination cohorts, rates of treatment-related AEs with nivolumab + ipilimumab remained similar to those previously reported Hellmann MD, et al. Lancet Oncol 216 Dec 5. [Epub ahead of print].

25 Checkmate 227: Study Design Key Inclusion Criteria: Stage IV or recurrent NSCLC No prior systemic therapy for advanced disease No EGFR/ALK mutations sensitive to available targeted inhibitor therapy R 1:1:1 PD-L1+ ( 1%) Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W Nivolumab monotherapy 24 mg Q2W Chemotherapy Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W Tumor scans Q6W until week 48 then Q12W Disease progression or unacceptabl e toxicity CNS metastases permitted if adequately treated 2 weeks prior to randomization PD-L1- (<1%) Nivolumab 36 mg Q3W + Chemotherapy Chemotherapy Stratification Factor Randomization: Histology (squamous vs non-squamous) Clinicaltrials.gov. NCT (CheckMate 227)

26 Durvalumab + tremelimumab: Phase Ib study design N=12 Key Inclusion Criteria Immunotherapy-naïve 1 line of prior therapy Locally advanced or metastatic NSCLC ECOG PS 1 Primary objectives: Safety, DLT/MTD Secondary objectives: ORR, PK, disease control at 24 weeks, immunogenicity Dose escalation for 12 months T1 Cohort Durvalumab 3 2 mg/kg Q4/2W* Tremelimumab 1 mg/kg Q4W x6 then Q12W x3 T3 Cohort Durvalumab 1 2 mg/kg Q4/2W* Tremelimumab 3 mg/kg Q4W x6 then Q12W x3 T1 Cohort Durvalumab 15 mg/kg Q4W Tremelimumab 1 mg/kg Q4W x6 then Q12W x3 ORR PD-L1 status All patients PD-L1 expression D1 2 Q4/2W (T1) D1 2 Q4/2W (T3) D15 Q4W (T1) D1 Q2W monotherapy n/n (%) n/n (%) n/n (%) n/n (%) 6/26 (23) 5/25 (2) /9 () 32/2 (16) 25% 2/9 (22) 2/5 (4) /4 () 23/84 (27) <25% 4/14 (29) 2/17 (12) /4 () 5/92 (5) % 4/1 (4) 1/1 (1) /3 () 1/33 (3) Phase III dose identified: durvalumab 2 mg/kg plus tremelimumab 1 mg/kg Q4W Antonia S et al. Lancet Oncol. 216;17(3):299-38

27 MYSTIC: Study Design Phase III, open-label, first-line therapy study of durvalumab ± tremelimumab vs SOC in NSCLC N=192 Key Inclusion Criteria Treatment-naïve Evidence of Stage IV NSCLC No activating EGFR or ALK rearrangement ECOG PS 1 No mixed SCLC or NSCLC NOS No prior immunomodulatory therapy No brain metastases/spinal cord compression unless asymptomatic, treated, and stable No active or prior documented inflammatory bowel disease R 1:1:1 Durvalumab 2 mg/kg Q4W + tremelimumab 1 mg/kg Q4W Durvalumab 2 mg/kg Q4W Platinum-doublet chemotherapy Paclitaxel + carboplatin Pemetrexed + cisplatin or carboplatin Gemcitabine + cisplatin or carboplatin Primary Endpoints: OS, PFS (combination vs SOC). Clinicaltrials.gov. NCT

28 NEPTUNE: Study Design Phase III, open-label, global study of durvalumab in combination with tremelimumab vs Pt-based chemotherapy in first-line treatment of advanced or metastatic NSCLC N=8 Key Inclusion Criteria Treatment-naïve Evidence of Stage IV NSCLC No activating EGFR or ALK rearrangement PD-L1 positive* or negative ECOG PS or 1 No mixed SCLC or NSCLC NOS No brain metastases/spinal cord compression unless asymptomatic, treated, and stable No active or prior documented inflammatory bowel disease Primary Endpoint: OS R Durvalumab 2 mg/kg Q4W + tremelimumab 1 mg/kg Q4W n=4 SOC Pt-based doublet chemotherapy Carboplatin + paclitaxel NSQ: Carboplatin/cisplatin + pemetrexed SQ: Carboplatin/cisplatin + gemcitabine n=4 Clinicaltrials.gov. NCT

29 CheckMate 12 (Nivo + chemo arms): study design An open-label, randomized, multi-arm, phase I trial of nivolumab in combination with chemotherapy or targeted agents, or as monotherapy in patients with Stage IIIb/IV NSCLC N=412 Key Inclusion Criteria Newly diagnosed and confirmed Stage IIIb/IV NSCLC ECOG PS 1 Chemotherapy naïve Prior EGFR TKI acceptable R Nivolumab 1 mg/kg Q3W Gemcitabine 125 mg/m 2 + cisplatin 75 mg/m 2 x4 Nivolumab 1 mg/kg Q3W Pemetrexed 5 mg/m 2 + cisplatin 75 mg/m 2 x4 Nivolumab 1 mg/kg Q3W Paclitaxel 2 mg/m 2 + carboplatin AUC 6 x4 Nivo Q3W Until progressive disease or discontinua tion due to toxicity Primary Outcome Measures: Safety and tolerability Secondary Outcome Measures: ORR PFS rate at 24 weeks Nivolumab 5 mg/kg Q3W Paclitaxel 2 mg/m 2 + carboplatin AUC 6 x4 Rizvi NA et al. J Clin Oncol216;34(25):

30 Checkmate 12: PFS and OS, nivo + chemo Group Median OS, months (range) 1-Year OS, % 2-Year OS, % Nivo 1 mg/kg + Gem-Cis 11.6 ( ) 5 25 Nivo 1 mg/kg + Pem-Cis 19.2 ( ) Nivo 1 mg/kg + Pac-Carb 14.9 ( ) 6 27 Nivo 5 mg/kg + Pac-Carb NR ( ) Group Median PFS, months (range) 24-Week PFS, % Nivo 1 mg/kg + Gem-Cis 5.7 ( ) 51 Nivo 1 mg/kg + Pem-Cis 6.8 ( ) 71 Nivo 1 mg/kg + Pac-Carb 4.8 ( ) 38 Nivo 5 mg/kg + Pac-Carb 7.1 ( ) 51 OS (%) Nivo 1 mg/kg + Gem-Cis Nivo 1 mg/kg + Pem-Cis Nivo 1 mg/kg + Pac-Carb Nivo 5 mg/kg + Pac-Carb PFS (%) Nivo 1 mg/kg + Gem-Cis Nivo 1 mg/kg + Pem-Cis Nivo 1 mg/kg + Pac-Carb Nivo 5 mg/kg + Pac-Carb Time Since First Dose (months) Time Since First Dose (months) Rizvi NA et al. J Clin Oncol. 216;24(25):

31 KEYNOTE-21: Study Design Key Eligibility Criteria Untreated stage IIIB or IV nonsquamous NSCLC No activating EGFR mutation or ALK translocation Provision of a sample for PD-L1 assessment a ECOG PS -1 No untreated brain metastases No ILD or pneumonitis requiring systemic steroids R (1:1) a N=1 23 Pembrolizumab 2 mg Q3W for 2 years + Carboplatin AUC 5 mg/ml/min + Pemetrexed 5 mg/m 2 Q3W for 4 cycles b Carboplatin AUC 5 mg/ml/min + Pemetrexed 5 mg/m 2 Q3W for 4 cycles b PD Pembrolizuma b 2 mg Q3W for 2 years Primary endpoint: ORR (RECIST v1.1 per blinded, independent central review) Secondary endpoints: PFS, OS, safety Exploratory endpoint: Relationship between antitumor activity and PD-L1 TPS Langer CJ et al. Oral presentation at ESMO 216. LBA46.

32 ORR, % (95% CI) % KEYNOTE-21: Response Δ26% P=.16 29% ORR, % (95% CI) % 54% ORR by PD-L1 expression level 8% 26% 13% 39% 35% 38% Pembrolizumab + Chemotherapy Chemotherapy Alone <1% n=21 1% n=39 1%-49% 5% n=19 n=2 <1% 1% 1%-49% n=23n=4 n=23 5% n=17 Pembrolizumab + Chemotherapy Chemotherapy Alone Langer CJ et al. Oral presentation at ESMO 216. LBA46.

33 KEYNOTE-21: PFS AND OS PFS, % Pembro + chemo Events, n Chemo alone 33 77% 63% HR (95% CI) (.31.91) 13. mo 8.9 mo P=.12 OS, % Pembro + chemo Events, n Chemo alone % 92 % HR (95% CI) 13.9 ( ) 75% 72% No. at risk Time, months No. at risk Time, months Langer CJ et al. Oral presentation at ESMO 216. LBA46.

34 KEYNOTE-21: SAFETY SUMMARY Exposure, median (range) Pembro + Chemo n=59 8. mo (1 d-16.1 mo) Chemo Alone n= mo (1 d-15.3 mo) Treatment-related AEs, n (%) 55 (93) 56 (9) Grade (39) 16 (26) Led to discontinuation 6 (1) 8 (13) Led to death 1 (2) 2 (3) Langer CJ et al. Oral presentation at ESMO 216. LBA46.

35 Immunotherapy, 1st line in wt patients NSCLC PD-L1 strong (> 5%) Pembrolizumab Ongoing studies CT vs CT+anti-PD1/PD-L1 CT vs CT+anti-PD1/PD-L1+bevacizumab CT vs anti-pd1 vs anti-pd1+anti-ctla4

36 Immunotherapy in stage IV A role in 1 st line treatment Anti-PD1/anti-PDL1 as monotherapy for selected populations (PDL1+); low percentage of patients Combination of anti-ctla4 + anti-pd1/anti-pdl1 for selected patients; toxicity may be an issue Combination of CT + anti-pd1/anti-pdl1; less relevance of predictive markers More predictive markers beyond PDL1 expected

37 Melero et al, Nature Reviews Cancer 15

38 JVDF (NCT ) Phase Ia/b Study Design Phase Ia: DLT Assessment (n = 6 to 12) Phase Ib: Cohort Expansion (n = 155) a Primary: Safety and tolerability Secondary: PK Primary: Safety and tolerability Secondary: PK and preliminary efficacy Exploratory: Biomarkers and immunogenicity Schedule 1: Gastric/GEJ, BTC design (n = 3 to 6) Ram 8 mg/kg, day 1 and 8 Pembro 2 mg fixed, day 1 Both IV every 3 weeks Schedule 2: Gastric/GEJ, NSCLC, UC design (n = 3 to 6) Ram 1 mg/kg, day 1 and 8 Pembro 2 mg fixed, day 1 Both IV every 3 weeks Interim Analysis Cohort A: 15 Gastric/GEJ (2 nd -3 rd Line) Cohort A1: 25 BTC (2 nd -3 rd Line) b Cohort A2: 25 Gastric/GEJ (1 st Line) b Cohort B: 15 Gastric/GEJ (2 nd -3 rd Line) Cohort C: 25 NSCLC (2 nd -4 th Line) Cohort D: 25 UC (2 nd -4 th Line) Cohort E: 25 NSCLC (1 st Line) b Final Analysis a Patients may continue treatment for up to 35 cycles, until confirmed progressive disease or discontinuation for any other reason. b Protocol was recently amended to add cohorts A1, A2, and E; cohorts are currently enrolling. DLT dose-limiting toxicity; PK, pharmacokinetics; Ram, ramucirumab; Pembro, pembrolizumab Herbst RS, et al. Ann Oncol. 216;27(suppl 6): Abstract LBA38.

39 Decreased Tumor Burden in NSCLC Patients (RECIST 1.1) Herbst RS, et al. Ann Oncol. 216;27(suppl 6): Abstract LBA38.

40 Progression-Free Survival by PD-L1 Status Herbst RS, et al. Ann Oncol. 216;27(suppl 6): Abstract LBA38.

41 Efficacy and Safety of Necitumumab and Pembrolizumab Combination Therapy in Stage IV Nonsquamous NSCLC Study objective To assess the safety and efficacy of necitumumab combined with pembrolizumab in patients with stage IV NSCLC Key patient inclusion criteria Stage IV NSCLC Progression after 1 platinumbased chemotherapy ECOG PS 1 (n=34) Necitumumab 6 mg or 8 mg IV D1, 8 q3w + pembrolizumab 2 mg IV D1 q3w PD/ toxicity/ death Primary endpoints Tolerability, ORR by RECIST 1.1 Secondary endpoints PFS Besse et al. J Thorac Oncol 216; 11(suppl): abstr MA9.11

42 Efficacy and Safety of Necitumumab and Pembrolizumab Combination Therapy in Stage IV Nonsquamous NSCLC Key results ORR for necitumumab + pembrolizumab was 29.4% and was effective in patients with differing PD-L1 expression Median PFS was 6.9 months (95%CI 2.7, NR) Toxicity for the combined regimen was no different to that for individual profiles Patients N/n ORR, % Patients n ORR, % Total Prior systemic therapy EGFR TKI in first line No EGFR TKI in first line Smoking history Current/former Never PD-L1 expression Negative Weak positive Strong positive Conclusion In a pre-treated nonsquamous NSCLC population with differing PD-L1 expression levels, these initial data suggest activity combining necitumumab and pembrolizumab Besse et al. J Thorac Oncol 216; 11(suppl): abstr MA

43 Immunotherapy in stage IV Studies will analyze role of immunotherapy combinations after PD to immunotherapy However, many studies, many compounds, many combinations may challenge defining guidelines

44 Multimodality approach in non-metastatic tumors Ongoing adjuvant studies with anti-pd1/anti-pdl1 strategies Neoadjuvant trials with immunotherapy planned (promising results in small studies) Major pathologic response in 7/18 (39%) patients treated with 2 doses of nivolumab (Forde ESMO 16) Ongoing studies with consolidation immunotherapy in stage III (PACIFIC, NCT trials) Ongoing studies of integration of CT/RT/immunotherapy (Nicolas-ETOP)

45 Thanks!!!

46 Clinical case

47 Q1. Anti PD-1 or anti PD-L1 drugs given as monotherapy are associated with different iraes; in what percentage of patients do these AEs occur? 1. ~7% 2. ~5% 3. ~25% 4. 5% 15% 5. <5%

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49 CheckMate 57 iraes Nivolumab (n = 287) Docetaxel (n = 268) Any Grade Grade 3 4 a Any Grade Grade 3 4 a Endocrine, % Hypothyroidism 7 Gastrointestinal, % Diarrhea Hepatic, % ALT increased AST increased Includes events reported in 2.5% of patients. a No grade 5 events were reported at DBL;1 grade 5 event for nivolumab was reported post-dbl. Borghaei H, et al. N Engl J Med. 215;373(17): Pulmonary, % Pneumonitis 3 1 <1 <1 Skin, % Rash Pruritus Erythema Hypersensitivity/Infusion reaction, % Infusion-related reaction <1 < <1 3 3 <1

50 KEYNOTE-1 iraes Herbst RS, et al. Lancet. 216;387(127):

51 Clinical Case, Diagnosis, and Medical History 63 year-old man, smoker (7 pack/year) July 214, diagnosed of lung ADC stage T2N2M1 (bilateral lung metastases, bone metastases, 2 brain mets) NGS-wt SABRT for the brain mets achieving PR Cis/pem 4 cycles with SD, then maintenance pem February 215, PD in lung lesion, bone and brain mets remained in PR

52 Baseline CT (March 16, 215) Nodule in right lower lobe, 42 mm Nonmeasurable lesions, brain mets, bone mets, lung mets, supraclavicular and mediastinal lymph node involvement

53 Clinical Case, Immunotherapy Treatment March 2, 215: Started pembrolizumab C4D1: First evaluation PR C5D1: Maculopapular rash in upper part of both lower extremities (appeared in last week of treatment)

54 54

55 Q2. What skin toxicity is most common with anti PD-1/anti PD-L1 agents? 1. Purpura 2. Maculopapular rash 3. G3 erythema 4. G3 pruritus 5. Stevens-Johnson syndrome

56 Skin Toxicity Incidence Manifestations Note Rash (14%) Pruritus (1%) Low or moderate grade Rash typically focal with a maculopapular appearance occurring on the trunk, back, or extremities Cases of Stevens-Johnson syndrome and toxic epidermal necrosis have been only sporadically reported Some skin reactions occurred in the context of infusion - related reaction Lacouture ME, et al. J Am Acad Dermatol. 214;71(1):

57 How Do We Grade Immune-Related Skin Disorders? Involved body surface area can be evaluated using the rule of nines AE Grade 1 Grade 2 Grade 3 Grade 4 Erythema multiforme Pruritus Purpura Rash maculopap ular Target lesions covering <1% BSA and not associated with skin tenderness Mild or localized Topical intervention indicated Combined area of lesions covering <1% BSA Target lesions covering 1% 3% BSA and associated with skin tenderness Intense or widespread Intermittent Skin changes from scratching (eg, edema, papulation, excoriations, lichenification, oozing/crusts) Oral intervention indicated Limiting instrumental ADL* Combined area of lesions covering 1% 3% BSA Bleeding with trauma Target lesions covering >3% BSA and associated with oral or genital erosions Intense or widespread Constant Limiting self-care ADL* or sleep Oral corticosteroid or immunosuppressive therapy indicated Combined area of lesions covering >3% BSA Target lesions covering >3% BSA Associated with fluid or electrolyte abnormalities ICU care or burn unit indicated *Instrumental ADL refer to preparing meals, shopping for groceries or Spontaneous clothes, using the bleeding telephone, managing money, etc. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Please refer to NCI-CTCAE Macules/papules version 4.3 for definition covering of severity/grade Macules/papules of other skin rashes. National Cancer Institute Common 1% 3% Terminology BSA with Criteria or for Adverse Events (CTCAE) v4.3. covering >3% BSA without symptoms (eg, p and Accessed February 216. Macules/papules covering <1% BSA with or without symptoms (eg, pruritus, burning, tightness) pruritus, burning, tightness) Limiting instrumental ADL* with or without associated symptoms Limiting self-care ADL* - - -

58 How Do We Grade Immune-Related Skin Disorders? Involved body surface area can be evaluated using the rule of nines AE Grade 1 Grade 2 Grade 3 Grade 4 Skin hypopigment ation Stevens- Johnson syndrome Urticaria Hypopigmentation or depigmentation covering <1% BSA No psychosocial impact - - Urticarial lesions covering <1% BSA Topical intervention indicated Hypopigmentation or depigmentation covering >1% BSA Associated psychosocial impact Urticarial lesions covering 1% 3% BSA Oral intervention indicated - - Skin sloughing covering <1% BSA with associated signs (eg, erythema, purpura, epidermal detachment, and mucous membrane detachment) Urticarial lesions covering >3% BSA IV intervention indicated Skin sloughing covering 1% 3% BSA with associated signs (eg, erythema, purpura, epidermal detachment, and mucous membrane detachment) - *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Please refer to NCI-CTCAE version 4.3 for definition of severity/grade of other skin rashes. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v p and Accessed February 216.

59 Time to Onset of First Treatment-Related Select AEs in Nivolumab-Treated Patients in Pooled CheckMate 17/57 a Patients with 1 event from first dose until 3 days post-treatment in a given category were counted only once in the time interval corresponding to the first event, patients with multiple events from categories within the same time interval were counted once in each category. Barlesi F, et al. Ann Oncol. 216;27(suppl 6):abstract 1215PD.

60 Management of Skin Toxicities Grade 1 rash Management strategies Drug therapy/workup Consult Follow-up Study physician Specialist Consider symptomatic treatment including oral antipruritics (eg, diphenhydramine or hydroxyzine) and topical therapy (eg, urea cream) N/A N/A N/A Dose modifications (study drug/study regimen) No dose modifications 1. AZ dosing modification and toxicity management guidelines. 19 August 216 Version. Accessed August 216; 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines. Prevention and treatment of cancerrelated infections. Version Accessed March 216.

61 Management of Skin Toxicities Grade 2 rash Management strategies Drug therapy/workup Consul t Followup Study physician Specialist General If symptoms improve If symptoms worsen or persist Consider symptomatic treatment including oral antipruritics (eg, diphenhydramine or hydroxyzine) and topical therapy (eg, urea cream) Consider moderate-strength topical steroid If no improvement of rash/skin lesions occurs within 3 5 days or is worsening despite symptomatic treatment and/or use of moderate-strength topical steroid, discuss with study physician Obtain dermatology consult N/A N/A If no improvement of rash/skin lesions occurs within 3 5 days or is worsening despite symptomatic treatment and/or use of moderatestrength topical steroid, promptly start systemic steroids such as prednisone 1 2 mg/kg/day PO or IV equivalent Consider skin biopsy if the event is persistent for >1 2 weeks or recurs Dose modifications (study drug/study regimen) For persistent (>1 2 weeks) Grade 2 events, hold scheduled study drug/study regimen until resolution to Grade 1 or baseline If toxicity worsens then treat as Grade 3 If toxicity improves to Grade 1 or baseline, then resume study drug/study regimen after completion of steroid taper

62 Management of Skin Toxicities Grade 3 and 4 rash Management strategies Drug therapy/workup Consul t Followup Study physician Specialist General If symptoms improve Promptly initiate empiric IV methylprednisolone 1 4 mg/kg/day or equivalent Consider hospitalization Monitor extent of rash (Rule of Nines) Consider skin biopsy (preferably more than 1) as clinically feasible Discuss with study physician If symptoms worsen or N/A persist Dose modifications (study drug/study regimen) Grade 3 Grade 4 Consult dermatology N/A Once the patient is improving, gradually taper steroids over 28 days and consider prophylactic antibiotics, antifungals, and anti-pcp treatment (refer to current NCCN guidelines for treatment of cancer-related infections [Category 2B recommendation] 2 ) Hold study drug/study regimen until resolution to Grade 1 or baseline If temporarily holding the study drug/study regimen does not provide improvement of the Grade 3 skin rash to Grade 1 or baseline within 3 days, then permanently discontinue study drug/study regimen Permanently discontinue study drug/study regimen

63 Clinical Case, irae Grade, Management, and Evolution Diagnosis of G2 maculopapular rash After consultation with dermatologist, the patient started oral diphenhydramine and topical therapy (eg, urea cream) It was decided not to administer the anti PD-1/anti PD-L1 therapy and control in 1 week After 1 week, maculopapular rash improved to G1, anti PD- 1/anti PD-L1 treatment was resumed Oct 27, 216: C29D1, pruritus G1

64 Latest CT (January 12, 217) Nodule in right lower lobe, 1 mm Nonmeasurable lesions, lung metastases, supraclavicular and mediastinal lymph nodes, improved; bone and brain mets without changes