CheckMate 12: Safety and Efficacy of First Line Nivolumab and Ipilimumab in Advanced Non-Small Cell Lung Cancer Abstract 31 Hellmann MD, Gettinger SN, Goldman J, Brahmer J, Borghaei H, Chow LQ, Ready NE, Gerber DE, Juergens R, Shepherd FA, Laurie SA, Young T, Geese WJ, Agrawal S, Li X, Antonia SJ
Rationale for Combined Immune Checkpoint Blockade With Nivolumab and Ipilimumab in Non-Small Cell Lung Cancer Nivolumab and ipilimumab enhance T-cell antitumor activity through distinct and complementary mechanisms 1 The combination of nivolumab and ipilimumab is approved in the US and EU for metastatic melanoma and has demonstrated encouraging clinical benefit across a number of tumor types 2- PFS With Nivo or Nivo + Ipi vs Ipi Alone in Previously Untreated Advanced Melanoma Proportion Alive and Progression-Free 1..9.8.7.6..4.3.2.1. Nivo + Ipi Nivo Ipi 3 6 9 12 1 18 21 Months Nivolumab monotherapy is approved in the US and EU for adults with locally advanced/metastatic NSCLC with progression either during or after platinum-doublet chemotherapy 1. Callahan MK, et al. Front Oncol. 21;4:38. 2. Wolchok JD, et al. N Engl J Med. 213;369(2):122-133. 3. Hammers HJ, et al. J Clin Oncol. 21;33(suppl):416. 4. Larkin J, et al. N Engl J Med. 21;373(1):23-34.. Rizvi NA, et al. Presented at: The 16 th World Conference on Lung Cancer, September 6-9, 21; Denver, CO, United States: ORAL2.. Ipi, ipilimumab; Nivo, nivolumab; NSCLC, non-small cell lung cancer; PFS, progression-free survival
Phase I CheckMate 12 Study Design: Nivolumab Plus Ipilimumab in First-Line NSCLC Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS or 1 Previous cohorts: Nivo 1 + Ipi 3 q 3 w x 4 Nivo 3 + Ipi 1 q 3 w x 4 Nivo 1 + Ipi 1 q 3 w x 4 Nivo 1 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w + Ipi 1 q 12 w Nivo 3 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w until disease progression a or unacceptable toxicity Until disease progression a 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 The safety and tolerability of the nivo ipi combination was improved with less frequent ipilimumab dosing Schedules with nivolumab 3 mg/kg also showed increased clinical efficacy in a previous analysis Here, we report longer follow-up on nivolumab 3 mg/kg plus ipilimumab schedules b ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate; OS, overall survival, PD-L1, programmed cell-death ligand 1; RECIST, response evaluation criteria in solid tumors. Rizvi NA, et al. Presented at: The 16 th World Conference on Lung Cancer, September 6-9, 21; Denver, CO, United States: ORAL2.. a Patients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit; b February 216 database lock; Ipilimumab and nivolumab dosing are shown in mg/kg IV (eg, nivo 1 = nivolumab 1 mg/kg IV)
Phase I CheckMate 12 Study Design: Nivolumab Plus Ipilimumab in First-Line NSCLC Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS or 1 Previous cohorts: Nivo 1 + Ipi 3 q 3 w x 4 Nivo 3 + Ipi 1 q 3 w x 4 Nivo 1 + Ipi 1 q 3 w x 4 Nivo 1 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w + Ipi 1 q 12 w Nivo 3 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w until disease progression a or unacceptable toxicity Until disease progression a 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 The safety and tolerability of the nivolumab ipilimumab combination was improved with less frequent ipilimumab dosing Schedules with nivolumab 3 mg/kg also showed increased clinical efficacy in a previous analysis Here, we report longer follow-up on nivolumab 3 mg/kg plus ipilimumab schedules b. Rizvi NA, et al. Presented at: The 16 th World Conference on Lung Cancer, September 6-9, 21; Denver, CO, United States: ORAL2.. a Patients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit; b February 216 database lock; Ipilimumab and nivolumab dosing are shown in mg/kg IV (eg, nivo 1 = nivolumab 1 mg/kg IV)
Phase I CheckMate 12 Study Design: Nivolumab Plus Ipilimumab in First-Line NSCLC Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS or 1 Previous cohorts: Nivo 1 + Ipi 3 q 3 w x 4 Nivo 3 + Ipi 1 q 3 w x 4 Nivo 1 + Ipi 1 q 3 w x 4 Nivo 1 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w + Ipi 1 q 12 w Nivo 3 q 2 w + Ipi 1 q 6 w Nivo 3 q 2 w until disease progression a or unacceptable toxicity Until disease progression a 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 The safety and tolerability of the nivolumab ipilimumab combination was improved with less frequent ipilimumab dosing Schedules with nivolumab 3 mg/kg also showed increased clinical efficacy in a previous analysis Here, we report longer follow-up on nivolumab 3 mg/kg plus ipilimumab schedules b. Rizvi NA, et al. Presented at: The 16 th World Conference on Lung Cancer, September 6-9, 21; Denver, CO, United States: ORAL2.. a Patients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit; b February 216 database lock; Ipilimumab and nivolumab dosing are shown in mg/kg IV (eg, nivo 1 = nivolumab 1 mg/kg IV)
Baseline Patient Characteristics Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Median age, years (range) 68 (-91) 62 (47-87) Male, % 4 62 Nonsquamous histology, % 82 8 Disease stage, % Stage IIIB Stage IV ECOG PS, % 1 Smoking status, % Never Former/current EGFR mutation status, % Mutant Wildtype Unknown PD-L1 quantifiable, N (%) 1%, n/n (%) %, n/n (%) 1%, n/n (%) 2%, n/n (%) %, n/n (%) 11 89 32 68 9 11 74 16 31 (82) 21/31 (68) 16/31 (2) 13/31 (42) 1/31 (32) 6/31 (19) 3 97 41 4 23 74 1 67 23 3 (77) 23/3 (77) 19/3 (63) 1/3 () 8/3 (27) 7/3 (23)
Baseline Patient Characteristics Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Median age, years (range) 68 (-91) 62 (47-87) Male, % 4 62 Nonsquamous histology, % 82 8 Disease stage, % Stage IIIB Stage IV ECOG PS, % 1 Smoking status, % Never Former/current EGFR mutation status, % Mutant Wildtype Unknown PD-L1 quantifiable, N (%) 1%, n/n (%) %, n/n (%) 1%, n/n (%) 2%, n/n (%) %, n/n (%) 11 89 32 68 9 11 74 16 31 (82) 21/31 (68) 16/31 (2) 13/31 (42) 1/31 (32) 6/31 (19) 3 97 41 4 23 74 1 67 23 3 (77) 23/3 (77) 19/3 (63) 1/3 () 8/3 (27) 7/3 (23)
Baseline Patient Characteristics Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Median age, years (range) 68 (-91) 62 (47-87) Male, % 4 62 Nonsquamous histology, % 82 8 Disease stage, % Stage IIIB Stage IV ECOG PS, % 1 Smoking status, % Never Former/current EGFR mutation status, % Mutant Wildtype Unknown PD-L1 quantifiable, N (%) 1%, n/n (%) %, n/n (%) 1%, n/n (%) 2%, n/n (%) %, n/n (%) 11 89 32 68 9 11 74 16 31 (82) 21/31 (68) 16/31 (2) 13/31 (42) 1/31 (32) 6/31 (19) 3 97 41 4 23 74 1 67 23 3 (77) 23/3 (77) 19/3 (63) 1/3 () 8/3 (27) 7/3 (23)
Safety Summary Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related AEs, % 82 37 72 33 Treatment-related AEs leading to discontinuation, % 11 13 8 There were no treatment-related deaths Treatment-related grade 3-4 AEs led to discontinuation at a third of the rate seen with older combination arms using higher or more frequent doses of ipilimumab 6 Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock AE, adverse event 6. Antonia SJ, et al. Presented at: The Chicago Multidisciplinary Symposium in Thoracic Oncology 214 Annual Meeting; October 3-November 1, 214; Chicago, IL, United States: Poster 168.
Safety Summary Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Nivo 3 Q 2 W (n = 2) Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 Treatment-related AEs, % 82 37 72 33 71 19 Treatment-related AEs leading to discontinuation, % 11 13 8 1 1 There were no treatment-related deaths Treatment-related grade 3-4 AEs led to discontinuation at a third of the rate seen with older combination arms using higher or more frequent doses of ipilimumab 6 Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock 6. Antonia SJ, et al. Presented at: The Chicago Multidisciplinary Symposium in Thoracic Oncology 214 Annual Meeting; October 3-November 1, 214; Chicago, IL, United States: Poster 168.
Treatment-Related Select AEs Nivo 33 Q Q2W 2 W + Ipi 1 Q Q12W W Nivo 3 Q Q2W 2 W + Ipi 1 Q6WQ 6 W Nivo 3 Q Q2W2 W 6 (n = 38) (n = 39) (n = 2) Total Patients With an Event, % 4 3 2 1 3 8 18 3 3 3 37 1 18 3 3 8 31 14 2 1 2 2 4 4 21 Grade 1 2 Grade 3 4 All treatment-related pulmonary events were pneumonitis Grade 1-2 hypersensitivity/infusion reaction occurred in % and 6% of patients in the nivo 3 q 2 w + ipi 1 q 12 w and monotherapy groups, respectively Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock; Select AEs are those with potential immunologic etiology that require frequent monitoring/intervention
Summary of Efficacy Nivo 3 Q 2 W + Ipi 1 Q 12 W (n = 38) Nivo 3 Q 2 W + Ipi 1 Q 6 W (n = 39) Nivo 3 Q 2 W (n = 2) Confirmed ORR, % (9% CI) 47 (31, 64) 39 (23, ) 23 (13, 37) Median duration of response, months (9% CI) NR (11.3, NR) NR (8.4, NR) NR (.7, NR) Median length of follow-up, months (range) 12.9 (.9-18.) 11.8 (1.1-18.2) 14.3 (.2-3.1) Best overall response, % Complete response Partial response Stable disease Progressive disease Unable to determine Median PFS, months (9% CI) 8.1 (.6, 13.6) 3.9 (2.6, 13.2) 3.6 (2.3, 6.6) 1-year OS rate, % (9% CI) NC 69 (2, 81) 73 (9, 83) Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock except for OS data, which are based on an August 21 database lock 47 32 13 8 39 18 28 1 8 1 27 38 12 NC, not calculated (when >2% of patients are censored); NR, not reached 8
Kinetics of Response Change in Target Lesion Size From Baseline, % 6 4 2 Nivo 3 Q 2 W + Ipi 1 Q 6 W Time, Months 12/1 responders (8%) in the q 6 w arm and 14/18 responders (78%) in the q 12 w arm had a response by time of first scan (week 11) 12/1 responders (8%) in the q 6 w arm and 12/18 responders (67%) in the q 12 w arm had an ongoing response at time of database lock PD, progressive disease; SD, stable disease 2 4 6 8 1 2 4 6 8 1 12 14 16 18 No response (PD + SD) Response First response Includes all patients with baseline target lesion and 1 post-baseline assessment of target lesion (n = 33)
Efficacy by Tumor PD-L1 Expression ORR, % (n/n) <1% PD-L1 1% PD-L1 % PD-L1 Median PFS (9% CI), months <1% PD-L1 1% PD-L1 % PD-L1 1-year OS rate (9% CI), % <1% PD-L1 1% PD-L1 % PD-L1 Nivo 3 Q 2 W + Ipi 1 Q 12 W 3 (3/1) 7 (12/21) 1 (6/6) 4.7 (.9, NR) 8.1 (.6, NR) 13.6 (6.4, NR) NC 9 (66, 97) NC Nivo 3 Q 2 W + Ipi 1 Q 6 W Nivo 3 Q 2 W (/7) 7 (13/23) 86 (6/7) 2.4 (1.7, 2.9) 1.6 (3.6, NR) NR (7.8, NR) NC 83 (6, 93) 1 (1, 1) 14 (2/14) 28 (9/32) (6/12) 6.6 (2., 11.2) 3. (2.2, 6.6) 8.4 (2.2, NR) 79 (47, 93) 69 (, 82) 83 (48, 96) Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock except for OS data, which are based on an August 21 database lock
Efficacy Across all Tumor PD-L1 Expression Levels 1 Nivo 3 Q 2 W + Ipi 1 Q 6 / 12 W (pooled) Nivo 3 Q 2 W 92 8 78 64 ORR, % 6 4 2 43 23 18 14 7 28 4 31 4 44 n = 77 2 17 14 44 32 3 26 28 2 18 18 13 12 All <1% 1% % 1% 2% % Overall <1% 1% % 1% PD-L1 Expression 2% % Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock
Efficacy By Smoking and EGFR Mutation Status 1 Smoking Status 1 EGFR Mutation Status 8 Nivo 3 Q2W + Ipi 1 Q6/12W (pooled) a 8 Nivo 3 Q2W + Ipi 1 Q6/12W (pooled) ORR, % 6 4 27 Nivo 3 Q2W 46 27 ORR, % 6 4 c Nivo 3 Q2W b 41 3 2 2 14 9 n 11 11 6 41 Never smoked Current/former smoker n 8 Mutant 7 4 Wild-type 3 Never Smoker Current/Former Smoker EGFR Mutant EGFR Wild-Type Combination data based on a February 216 database lock; monotherapy data based on a March 21 database lock a Excludes 1 patient with unknown smoking status (nivo 3 q 2 w + ipi 1 q 6 w) b In patients with non-squamous histology only c Must be interpreted with caution: of these 4 responders, 1 did not have a classical exon 19 deletion or L88R EGFR activating mutations, 3 were former/current smokers, and 3 had high PD-L1 expression levels
Case of Pathological Complete Response in One Patient Treated With Nivo 3 Q 2 W + Ipi 1 Q 6 W 4-year-old male (former smoker, 2 packyear) with metastatic large-cell lung cancer (PD-L1 <1% a ) 3% total tumor size reduction by RECIST Radiographic residual lesions in the lung and mediastinal lymph nodes, without distant disease Change From Baseline, % 6 4 2 2 4 6 8 1 Partial Response Treatment Initiated Treatment Discontinuation (due to rash and grade 2 pneumonitis) Date Resection Before Nivo + Ipi Therapy Following Nivo + Ipi Therapy No Viable Tumor in Resected Residual Lesion Right upper lobe wedge resection (nodule #1) Mar-216 a Patient was included as having partial response and PD-L1 expression unknown in analysis at time of database lock Courtesy of Dr. William Travis, MSKCC
Nivolumab Plus Ipilimumab in First-Line NSCLC: Conclusions Nivolumab 3 mg/kg q 2 w plus ipilimumab 1 mg/kg (q 6 w or q 12 w) is well tolerated Frequency of treatment-related AEs leading to discontinuation was similar to nivolumab monotherapy (11% 13%) There were no treatment-related deaths Nivolumab plus ipilimumab has promising efficacy 39% 47% ORR; median duration of response not reached Efficacy with nivolumab plus ipilimumab is enhanced with increasing PD-L1 expression 1% tumor PD-L1 expression: 7% ORR; 83% 9% 1-year OS rates % tumor PD-L1 expression: 92% (12/13) ORR Nivolumab 3 mg/kg q 2 w plus ipilimumab 1 mg/kg q 6 w schedule is being evaluated in further studies, including the phase 3 CheckMate 227 trial (NCT2477826)