MAPS-2 (IFCT-1501): Nivolumab  Ipilimumab in Recurrent Malignant Pleural Mesothelioma CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

MAPS-2 (IFCT-1501): Background Malignant pleural mesothelioma: rare, aggressive cancer with limited tx options[1,2] In newly diagnosed pts, bevacizumab addition to pemetrexed/cisplatin significantly prolonged mOS (18.8 vs 16.1 mos with pemetrexed/cisplatin alone; HR: 0.77)[3] In relapsing pts, pemetrexed ± carboplatin associated with ORR ~ 20% and mOS < 10 mos[4] Inflammatory T-cell infiltration observed in MPM, with ~ 20% to 60% of tumors PD-L1 positive[5,6] Pts with high CD4+/CD8+ T-cell ratios had improved survival vs pts with low ratios (HR: 0.67)[5] PD-L1 expression associated with poor prognosis (mOS: PD-L1 positive, 4.79 mos; PD-L – negative, 16.3 mos)[7] Preliminary results suggested clinical activity with pembrolizumab[8] and nivolumab[9] monotherapy in previously treated pts with MPM Current report evaluates efficacy and safety of nivolumab ± ipilimumab in MPM pts who progressed after 1-2 lines of chemotherapy[10] mOS, median OS; MPM, malignant pleural mesothelioma; tx, treatment. References: Levin PA, et al. Onco Targets Ther. 2017;10:2057-2066. Nowak AK, et al. J Thorac Oncol. 2012;7:1449-1456. Zalcman G, et al. Lancet. 2016;387:1405-1414. Scherpereel A, et al. Eur Respir J. 2010;35:479-495. Thapa B, et al. J Thorac Oncol. 2017;12:850-859. Khanna S, et al. J Thorac Oncol. 2016;11:1993-2005. Cedrés S, et al. PLoS One. 2015;10:e0121071. Alley EW, et al. Lancet Oncol. 2017;18:623-630. Quispel-Janssen J, et al. IASLC 2016. Abstract OA13.01. Scherpereel A, et al. ASCO 2017. Abstract LBA8507. Slide credit: clinicaloptions.com References in slidenotes.

MAPS-2 (IFCT-1501): Study Design Randomized, multicenter, noncomparative phase II trial with 1-step Fleming design (each arm independent)[1] Stratified by histologic subtype (epithelioid vs sarcomatoid + biphasic), treatment line (second vs third), cis/pem chemosensitivity (PD ≥ 3 mos vs < 3 mos) Until disease progression, unacceptable toxicity, or up to 2 yrs Nivolumab 3 mg/kg IV Q2W (n = 63) Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W (n = 62) Pts with MPM, validated histological diagnosis, unresectable cancer that progressed after 1-2 CT lines (including a pem-plat doublet), ECOG PS 0/1, weight loss < 10%, tumor tissue available (N = 125) BICR, blinded independent central review; cis, cisplatin; CT, chemotherapy; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; MPM, malignant pleural mesothelioma; PD, progressive disease; pem, pemetrexed; plat, platinum; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors. Primary endpoint: 12-wk DCR per BICR with modified RECIST criteria for MPM[2] Secondary endpoints: safety, PFS, OS, QoL, predictive utility of tumor PD-L1 score, prognostic utility of biomarkers 1. Scherpereel A, et al. ASCO 2017. Abstract LBA8507. 2. Byrne MJ, et al. Ann Oncol. 2004;15:257-260. Slide credit: clinicaloptions.com

MAPS-2 (IFCT-1501): Baseline Characteristics Nivo (n = 63) Nivo + Ipi (n = 62) Median age, yr (range) 72.3 (32.5-87.2) 71.2 (48.1-88.1) Male sex, n (%) 47 (75) 53 (85) Histologic subtype, n (%) Epithelioid Sarcomatoid/mixed (biphasic) 51 (81) 12 (19) 9 (15) ECOG PS, n (%) 1 2 19 (31) 42 (69) 25 (40) 36 (58) 1 (2) Smoking status, n (%) Smoker Never smoker 33 (53) 29 (47) 35 (56) 27 (44) Characteristic Nivo (n = 63) Nivo + Ipi (n = 62) No. earlier CT lines, n (%) 1 2 > 2 44 (70) 16 (25) 3 (5) 43 (69) 18 (29) 1 (2) TNM (1995) stages III-IV, n (%) 56 (89.0) 51 (83.4) Median weight, kg (range) 75 (42.0-108.0) 73 (43.0-126.0) Leukocytes < 8.3 x 109/L, n (%) 43 (68) 41 (66) Hemoglobin > 12 g/L, n (%) 33 (52) 37 (60) Platelets < 350 x 109/L, n (%) 46 (73) CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; Ipi, ipilimumab; Nivo, nivolumab; PS, performance status. Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

MAPS-2 (IFCT-1501): Response at 12 Wks DCR evaluated by BICR in first 108 eligible pts (primary endpoint per statistical plan) 12-Wk Response, n (%) Nivo (n = 54) Nivo + Ipi Objective response 10 (18.5) 14 (25.9) SD 13 (24.1) DCR 24 (44.4) 27 (50.0) PD 28 (51.9) 23 (42.6) NE/not done/missing 2 (3.7) 4 (7.4) BICR, blinded independent central review; DCR, disease control rate; Ipi, ipilimumab; ITT, intent to treat; NE, not evaluable; Nivo, nivolumab; PD, progressive disease; SD, stable disease; wk, week. Similar pattern of response in ITT population of 125 pts DCR in ITT: nivo, 25/63 (39.7%); nivo + ipi, 32/62 (51.6%) Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

MAPS-2 (IFCT-1501): Preliminary PFS, OS in ITT Population Median follow-up: 10.4 mos Endpoint in ITT Nivo (n = 63) Nivo + Ipi (n = 62) Median PFS, mos (95% CI) 4.0 (2.8-5.7) 5.65 (3.25-10.4) Median OS, mos (95% CI) 10.4 (6.7-NR) NR Ipi, ipilimumab; ITT, intent to treat; Nivo, nivolumab; NR, not reached. Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

MAPS-2 (IFCT-1501): Drug-Related AEs During First 6 Infusions Drug-Related AE, n (%) Nivo (n = 63) Nivo + Ipi (n = 61) All grades 49 (77.8) 53 (86.9) Gr 3/4 6 (9.5) 11 (18.0) Gr 5 0 (0) 2 (3.3)* Drug-Related AEs, n (%) Nivo (n = 63) Nivo + Ipi (n = 61) Any Gr 3/4 Gr 3-4 Nonhematologic AEs in > 10% of pts Asthenia/fatigue 25 (39.7) 26 (42.6) 2 (3.3) Diarrhea* 4 (6.3) 12 (19.7) Decreased appetite 12 (19.0) 8 (13.1) Nausea/ vomiting 8 (12.7) 1 (1.6) Pruritus† 7 (11.5) Hematologic AEs‡ All hematologic 11 (7.5) Thrombopenia Anemia 10 (15.9) *Both grade 5 cases also categorized as tx-related deaths. 0 tx-related deaths with nivo vs 3 with nivo + ipi 1 each: fulminant hepatitis, encephalitis, acute kidney failure after 12 wks PD, toxicity most common causes of d/c PD: nivo, 84.0%; nivo + ipi, 58.1% Toxicity: nivo, 6.0%; nivo + ipi, 27.9% AE, adverse event; d/c, discontinuation; Gr, grade; Ipi, ipilimumab; Nivo, nivolumab; PD, progressive disease; tx, treatment. *P = .035. †P = .04. ‡No cases of neutropenia or febrile neutropenia observed in either arm. Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

MAPS-2 (IFCT-1501): Drug-Related AEs of Special Interest With Checkpoint Inhibitors Data collected during first 6 infusions Drug-Related AEs, n (%) Nivo (n = 63) Nivo + Ipi (n = 61) Any Gr 3/4 Hyperthyroidism 2 (3.2) 4 (6.6) Hypothyroidism 1 (1.6) Arthritis Stomatitis 5 (7.9) Eye disorders AST increased 3 (4.9) ALT increased Rash 3 (4.8) Drug-Related AEs, n (%) Nivo (n = 63) Nivo + Ipi (n = 61) Any Gr 3/4 Cardiac disorders 3 (4.9) 1 (1.6) Colitis 2 (3.3) Dermatitis bullous Polyneuropathy Lipase increased 2 (3.2) Hyperglycemia Psoriasis AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Gr, grade; Ipi, ipilimumab; Nivo, nivolumab. Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

MAPS-2 (IFCT-1501): Conclusions In pts with MPM that progressed after 1-2 chemotherapy regimens, both nivolumab and nivolumab + ipilimumab met the primary endpoint of improved 12-wk DCR 12-wk DCR in first 108 eligible pts: nivo, 44.4%; nivo + ipi, 50.0% Median OS notably prolonged with both nivolumab and nivolumab + ipilimumab (10.4 mos vs NR, respectively) Investigators reported manageable toxicity despite 3 treatment-related deaths with nivolumab + ipilimumab Drug-related grade 3/4 AEs: nivo, 9.5%; nivo + ipi, 18.0% Investigators concluded that nivolumab ± ipilimumab potentially a new option as second-/third-line treatment for relapsing MPM AE, adverse event; DCR, disease control rate; Ipi, ipilimumab; MPM, malignant pleural mesothelioma; Nivo, nivolumab; NR, not reached. Slide credit: clinicaloptions.com Scherpereel A, et al. ASCO 2017. Abstract LBA8507.

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