No abstract

Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progressionfree survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P ¼0.01; 9 weeks: 71.1% vs 40%, P ¼0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01). Conclusion: Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.

TPS192 Background: Pts with adv G/GEJ cancer have an OS of ≈ 1 y, indicating an unmet medical need for new first-line treatments. Expression of PD-L1 is observed in up to 40% of pts with G/GEJ cancer and is associated with poor prognosis. In the randomized phase 3 ATTRACTION-2 study, NIVO demonstrated superior overall survival vs placebo with a 38% reduction of the risk of death (median OS, 5.3 vs 4.1 mo; HR, 0.62 P< 0.0001) and increased the OS rate at 12 mo (27% vs 12%; Boku N et al ESMO 2017) in pts with adv CTX-R (≥ 2 lines) G/GEJ cancer. In the phase 1/2 CheckMate-032 study in pts with CTX-R G/GEJ/esophageal cancer (79% ≥ 2 prior Tx lines), NIVO 1 mg/kg + IPI 3 mg/kg had a manageable safety profile and resulted in 24% ORR (40% ORR in pts with PD-L1+ tumors), a median OS of 6.9 mo, and a 35% OS rate at 12 mo (Janjigian Y et al ASCO 2017). In the phase 1 CheckMate-012 trial, NIVO + CTX had clinical activity and manageable safety in pts with NSCLC (Rizvi NA et al J Clin Oncol 2016). These positive results support investigation of NIVO, NIVO + IPI, and NIVO + CTX in earlier lines of treatment for G/GEJ cancer. The open-label, phase 3 CheckMate 649 trial will evaluate NIVO + IPI and NIVO + CTX vs CTX alone as first-line treatment for pts with adv G/GEJ cancer (NCT02872116). Methods: 1266 pts aged ≥ 18 y with untreated, inoperable adv/metastatic G/GEJ cancer (histologically confirmed adenocarcinoma) regardless of PD-L1 status will be randomized to receive either NIVO + IPI, NIVO + CTX (capecitabine/oxaliplatin [XELOX] or fluorouracil/leucovorin/oxaliplatin [FOLFOX]), or investigator choice of XELOX or FOLFOX. Tumor tissue for determination of PD-L1 status (Dako assay) must be provided from ≤ 6 mo before study treatment. No prior systemic treatment, including HER2 inhibitors, are allowed. Pts with known HER2+ status, suspected autoimmune disease, grade > 1 peripheral neuropathy, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ (≥ 1%) tumors. Other endpoints include OS in all pts; PFS and time to symptom deterioration in all pts and in pts with PD-L1+ tumors; and safety. Clinical trial information: NCT02872116.

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.