PC02.04 IO Should Be Given with Chemo

Abstract

Lung cancer is the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for almost 85% of all cases. The prognosis of NSCLC patients remains quite unsatisfactory due to the frequent advanced disease stage at diagnosis and the relatively low efficacy of the available systemic treatments. Of note, over the las few years significant progress as inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 have proven to be effective therapies in metastatic NSCLC lacking sensitizing EGFR or ALK mutations, initially in pretreated patients. Subsequently, in metastatic NSCLC patients with PD-L1 expression of at least 50% on tumor cells, upfront pembrolizumab improved median progression-free survival (PFS) and overall survival (OS) compared to standard platinum-based chemotherapy. However, patients with a tumor proportion score (TPS) of 50% or greater represent only some 30% of those with NSCLC, and progression during the first three months is frequent in one third of the cases. To enhance the immune response through PD-1 inhibition, several studies have combined the potential immunogenic effects of cytotoxic chemotherapy with immune checkpoint inhibitors (ICPI), particularly of some chemotherapy regimens such as those pemetrexed-based. The first study that gave some important information regarding the efficacy of combining IO and chemotherapy was Keynote 021, randomized phase II trial of carboplatin plus pemetrexed with and without pembrolizumab. It showed significantly better response rates (RR) and longer PFS with the addition of pembrolizumab to chemotherapy. Over the last two years at least 6 other phase III clinical trials with pembrolizumab (KN 189 and KN 407) have showed the benefits of combined chemotherapy plus IO therapy in terms of PFS and OS (HR 0.49-0.64). Consistent data have been achieved on atezolizumab trials, although the magnitude of the OS benefit (HR 0.78-0.93) have been somehow lower. Randomized studies with nivolumab, durvalumab and avelumab are expected to be reported in the near future. Chemo-immunotherapy combinations are associated with the expected toxicities of chemotherapy and IO on their own. At present, for patients with tumors with TPS >50%, there are no comparative trials of IO monotherapy (e.g. pembrolizumab) as compared to chemotherapy. Across trial comparisons may support the use of IO monotherapy for most of cases. Chemo-IO regimens may be considered for patients requiring rapid responses (e.g. symptomatic patients) or those with aggressive disease. In patients, whose tumors express PD-L1 in 1-49% of cells, chemo-IO combinations are seen as the best treatment options. Of note, in the IMPOWER 150 trial, patients with EGFR/ALK aberrations also benefitted from the addition of atezolizumab to the paclitaxel/carboplatin/bevacizumab regimen. In patients with tumors with negative expression of PD-L1 the benefits on PFS were more debatable but the pembrolizumab-based combos, and to some extend those with atezolizumab, resulted in prolonged survival. The value of certain genomic aberrations (e.g. Keap or LKB1) or low tumor mutational burden (TMB) as a predictive tool in this setting needs further validation. In addition, the results of several ongoing combination studies (CheckMate-9LA, POSEIDON ) investigating two and four drug regimens of PD-(L)1 plus CTLA-4 inhibition with/without chemotherapy are eagerly awaited and will reveal further knowledge of efficacy and tolerability in this setting. References Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. (2015) 373:1627–39. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. (2016) 375:1823–33. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. (2016) 17:1497–508. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. (2018) 378:2078–92. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379: 2040-2051. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018; 378: 2093-2104. Jotte RM, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Abreu DR, Hussein MA, et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. (2018) 36:LBA9000–LBA9000. 10.1200/JCO.2018.36.18_suppl.LBA9000. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al.. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. (2018) 378:2288–301. Socinski MA, Jotte RM, Cappuzzo F, Orlandi FJ, Stroyakovskiy D, Nogami N, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. (2018) 36:9002. Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, et al. IMpower132: PFS and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in stage IV non-squamous NSCLC. In: International Association for the Study of Lung Cancer's (IASLC) 2018 World Conference on Lung Cancer (WCLC); 2018 Sept 23-26. Toronto, ON: (2018). West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 924-937. Borghaei H, Hellmann MD, Paz-Ares LG, Ramalingam SS, Reck M, O'Byrne KJ, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. J Clin Oncol. (2018) 36:9001 10.1200/JCO.2018.36.15_suppl.900. PD-1/PD-L1 and chemotherapy combinations, PD-1/PD-L1 inhibitors, TMB