as backboone for combiantion of chemo and immunotherapy Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy) cgridelli@libero.it NAB-PACLITAXEL: as backboone for combiantion of chemo and immunotherapy

Experimental approaches to build on active immunotherapies to maximise clinical benefit 1. Drake CG. Ann Oncol. 2012;23(suppl 8):viii41–viii46; 2. Hannani D, et al. Cancer J 2011;17:351–358; 3. Ménard C, et al. Cancer Immunol Immunother 2008;57:1579–1587; 4. Ribas A, et al. Curr Opin Immunol 2013:25:291–296

Mechanisms of immunogenic tumor cell death induced by chemotherapy Emens LA et al, Cancer Immunol Res 2015

Increased antigen loads by chemotherapy Discovery Medicine, 2017

Chemotherapy modulates tumor immunity by mechanisms distinct from immunogenic cell death Emens LA et al, Cancer Immunol Res 2015

PFS & OS Papadmitrakopoulou Va et al. ASCO meeting 2017, abstract N° 9094

CBDCA/nab-paclitaxel + CBDCA/nab-paclitaxel + Phase I-II trials including Nab-paclitaxel and Pembrolizumab in advanced NSCLC NCT01840579 Phase I CBDCA/nab-paclitaxel + Pembrolizumab Stage IV NSCLC NCT02382406 Phase II CBDCA/nab-paclitaxel + Pembrolizumab Stage IV NSCLC Pembrolizumab X4 Nab-PTX X4 NCT02684461 Phase II Nab-PTX X4 Pembrolizumab X4 Stage IV NSCLC No PD after DDP CT R Randomize 1:1:1 Pembrolizumab + Nab-PTX X4

ABI-007-ST-001 Phase I Study of Nivolumab + nab®-Paclitaxel Regimens in Solid Tumors: Results From the Pancreatic Cancer and Non-Small Cell Lung Cancer Cohorts George B, Kelly K, Ko A, Soliman HH, Trunova N, Wainberg ZA, Waterhouse DM, O’Dwyer PJ, Hochster HS nab® is a registered trademark of Celgene Corporation. George B, et al. Poster at ESMO 2016 [abstract 2027].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Background and Objectives1 Chemotherapy leads to tumor lysis and release of tumor antigens, which may prime the immune system for checkpoint inhibitors2 Combining chemotherapeutic agents, including nab-paclitaxel (nab-P), with an immune checkpoint inhibitor has demonstrated antitumor activity in patients with mTNBC3 and NSCLC4 Here we present interim results from 2 of the 3 cohorts (PC and NSCLC) of a phase I safety trial of nivo + nab-P in advanced PC (± Gem), advanced NSCLC (+ Carbo), and MBC Safety, including DLTs, and preliminary efficacy for patients from the PC (Arms A and B) and NSCLC (Arm C) cohorts in Part 1 were assessed in this analysis 1. George B, et al. Poster at ESMO 2016 [abstract 2027]. 2. Chen DS, Mellman I. Immunity. 2013;39:1-10. 3. Adams S, et al. J Clin Oncol. 2016;34(suppl) [abstract 1009]. 4. Camidge DR, et al. J Thorac Oncol. 2015;10(9 suppl 2):S176 [Oral presentation 02.07].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Study Designa This interim analysis examines only Part 1 of Arms A, B, and C. Part 1 Part 2 Patients with LAPC or MPC with 1 prior CT regimen Arm Ab nab-P 125 mg/m2 d1, 8, 15 of 28-day cycle + nivo 3 mg/kg d1 and 15 of 28-day cycle (n ≈ 6) Arm A Safety expansion with RP2D (n ≈ 20) If Arm A deemed safe If dose level safe CT-naive patients with LAPC or MPC R Arm Bb nab-P 125 mg/m2 d1, 8, 15 of 28-day cycle + Gem 1000 mg/m2 d1, 8, 15 of 28-day cycle + nivo 3 mg/kg d1 and 15 of 28-day cycle (n ≈ 6) If dose level safe Arm B Safety expansion with RP2D (n ≈ 14) Arm Cb,d nab-P 100 mg/m2 d1, 8, 15 of 21-day cycle × 4 cycles + Carbo AUC 6 d1 of 21-day cycle × 4 cycles + nivo 5 mg/kg d15 of 21-day cyclee (n ≈ 6) Stage IIIB/IV NSCLC No prior therapyc If Arm C deemed safe If dose level safe Arm C Safety expansion with RP2D (n ≈ 14) Stage IIIB/IV NSCLC No prior therapyc R If dose level safe Arm Dd,f nab-P 100 mg/m2 d1, 8, 15 of 21-day cycle × 4 cycles + Carbo AUC 6 d1 of 21-day cycle × 4 cycles + nivo 5 mg/kg d15 of 21-day cycleg (n ≈ 6) Arm D Safety expansion with RP2D (n ≈ 14) Footnotes George B, et al. Poster at ESMO 2016 [abstract 2027].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Methods Endpoints Primary To identify DLTs (Part 1) To determine percentage of patients with grade 3/4 TEAEs or treatment discontinuation due to a TEAE (Parts 1 and 2) Secondary TEAEs leading to dose reduction, dose delay, or treatment discontinuation PFS (investigator assessed)a; OS; DCRa; ORRa; and DORa DLT Evaluationb Criteria Received ≥ 2 cycles of nivo + standard nab-P therapy and remained on study for 14 additional calendar days after the last dose of nivo in the second cycle Received ≥ 1 nivo dose and discontinued treatment due to DLT prior to completing 2 cycles of nivo Statistical Analysis Endpoints and 95% CIs were calculated using descriptive statistics Safety data are summarized for all treated patients and nivo-treated patients separately a Based on RECIST v1.1. b Up to 6 DLT-evaluable patients will be enrolled initially in each treatment arm at the given dose level for DLT assessment. George B, et al. Poster at ESMO 2016 [abstract 2027].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Selected Patient Characteristics NSCLC (Arm C) Arm A (n = 11) Arm B (n = 6) All Treated (n = 21) Nivo Treated (n = 18)a Age, median (range), y < 65, n (%) ≥ 65, n (%) 62.0 (57 - 77) 6 (54.5) 5 (45.5) 71.0 (64 - 78) 1 (16.7) 5 (83.3) 65.0 (43 - 77) 9 (42.9) 12 (57.1) 66.5 (43 - 77) 7 (38.9) 11 (61.1) Sex, female, n (%) 4 (66.7) 15 (71.4) 13 (72.2) Histology, n (%) Adenocarcinoma Squamous 11 (100) NA 6 (100) 7 (33.3) 6 (33.3) Data cutoff dates: 25 May 2016 (NSCLC), and 28 June 2016 (PC) a Two patients, who did not receive nivo, discontinued treatment due to AEs; data for 1 patient who did not receive nivo are pending. George B, et al. Poster at ESMO 2016 [abstract 2027].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Safety Most Common Grade 3/4 Adverse Eventsa, n (%) PC Arm A (n = 11) Arm B (n = 6) Anemia 2 (18.2) 2 (33.3) Neutropenia Pulmonary embolism NR NSCLC (Arm C) All Patients (n = 21) Nivo-Treated Patients (n = 18) 6 (28.6) 6 (33.3) 4 (19.0) 4 (22.2) Hypokalemia 3 (14.3) 3 (16.7) No DLTs observed among the 7 DLT-evaluable patients in Arm A 1 DLT observed among the 6 DLT-evaluable patients in Arm B No DLTs observed among the 5 DLT-evaluable patients in Arm C No grade 3/4 pneumonitis was reported Grade 2 pneumonitis occurred in 1 patient (Arm C), but it resolved after 7 days a All patients will be followed for AEs for up to 100 days or until patient withdraws consent from the entire study. George B, et al. Poster at ESMO 2016 [abstract 2027].

Median nivo treatment durations for patients were as follows: Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Treatment Discontinuation and Duration PC: 9 patients in Arm A discontinued treatment (8 due to PD, 1 patient withdrew); 1 patient in Arm B discontinued treatment (due to “other” reasons) NSCLC: In Arm C, 7 patients discontinued treatment: 4 due to PD, 2 due to AEs, and 1 due to “other” reasons 4 of the 5 nivo-treated patients who discontinued treatment did so due to PD Median nivo treatment durations for patients were as follows: Arm A: 12.6 weeks (range, 3 - 40) Arm B: 15.5 weeks (range, 10 - 21) Arm C: 21.1 weeks (range, 3 - 47) George B, et al. Poster at ESMO 2016 [abstract 2027].

% Change From Baseline in Total Length Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions Arm A: Pancreatic Cancerb Active on study Discontinued treatment Never received nivo Best Overall Response CR PR SD PD Treatment Discontinuation Progression AE Other reason 160 120 80 % Change From Baseline in Total Length 40 −40 −80 1 2 3 4 5 6 7 8 Months on Treatment 2 patients had a PR and 4 had SD a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients. George B, et al. Poster at ESMO 2016 [abstract 2027].

% Change From Baseline in Total Length Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions Arm B: Pancreatic Cancerb Active on study Discontinued treatment Never received nivo Best Overall Response CR PR SD PD Treatment Discontinuation Progression AE Other reason 160 120 80 % Change From Baseline in Total Length 40 −40 −80 1 2 3 4 5 Months on Treatment 3 patients had a PR and 3 had SD a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients. George B, et al. Poster at ESMO 2016 [abstract 2027].

% Change From Baseline in Total Length Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Efficacy: Change from Baseline in Total Lengtha of Target Lesions Arm C: Non-Small Cell Lung Cancerb Active on study Discontinued treatment Never received nivo Best Overall Response CR PR SD PD Treatment Discontinuation Progression AE Other reason 50 % Change From Baseline in Total Length −50 −100 1 2 3 4 5 6 7 8 9 10 Months on Treatment 9/21 patients had a PR and 10 had SD; data pending for 2 patients 9/18 nivo-treated patients in Arm C had a PR, 8 had SD; 1 patient data pending a Total length = sum of the longest diameters of the non-nodal target lesions and the shortest axis of lymph nodes. All tumor response evaluations were unconfirmed. b All treated patients. George B, et al. Poster at ESMO 2016 [abstract 2027].

Phase I Study of Nivolumab + nab-Paclitaxel: NSCLC and PC Authors’ Conclusions These interim results indicate that the addition of nivo to standard nab-P regimens may be feasible in patients with PC and advanced NSCLC Addition of nivo to nab-P or nab-P/Carbo was tolerable, with no DLTs or unexpected AEs in Arm A or Arm C, and 1 DLT in Arm B Grade 3/4 pneumonitis, an AE occasionally seen in studies of other checkpoint inhibitors, was not observed Based on the promising safety findings and the antitumor activity in Part 1 of Arms A and C: Patients with advanced PC are currently enrolling in Arm B for first-line treatment with nivo + nab-P + Gem Patients with advanced NSCLC are currently enrolling in Part 2 of Arm C for first-line treatment with nivo + nab-P + Carbo George B, et al. Poster at ESMO 2016 [abstract 2027].

Liu et al, ASCO 2017

Liu et al, ASCO 2017

CBDCA/nab-paclitaxel + CBDCA+nab-paclitaxel Atezolizumab in 1-line: phase III trials combined to chemo in Non squamous NSCLC CLOSED Impower 130 CBDCA/nab-paclitaxel + Atezolizumab 1200 mg q21 Stage IV Non squamous NSCLC ECOG PS 0–1 R Randomize 1:2 CBDCA+nab-paclitaxel Primary endpoint N. pts Stratified by PD-L1 status PFS 550 TC3-any IC vs TC0/1/2-IC2/3 vs TC0/1/2-IC01

CBDCA/nab-paclitaxel + CBDCA+nab-paclitaxel Atezolizumab in 1-line: phase III trials combined to chemo in Squamous NSCLC CLOSED IMpower 131 CBDCA/paclitaxel + Atezolizumab 1200 mg q21 Stage IV Squamous NSCLC ECOG PS 0–1 R Randomize 1:1:1 CBDCA/nab-paclitaxel + Atezolizumab 1200 mg q21 CBDCA+nab-paclitaxel Primary endpoint N. pts Stratified by PD-L1 status PFS 1200 TC3-any IC vs TC0/1/2-IC2/3 vs TC0/1/2-IC01