Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study.

Abstract

4014 Background: In the phase 3 ONO-12 study, 3rd- or later-line nivolumab (N) monotherapy prolonged OS vs placebo in Asian pts with adv G/GEJ cancer (median OS, 5.3 vs 4.1 mo; HR, 0.63; P < 0.0001; ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). The phase 1/2 CheckMate 032 study showed favorable clinical activity of N ± ipilimumab (I) in Western pts with adv CTx-R G/E/GEJ cancer (NCT01928394). We report updated long-term follow-up data of G/E/GEJ pts in CheckMate 032. Methods: Pts received N 3 mg/kg Q2W (N3), N 1 mg/kg + I 3 mg/kg Q3W (N1+I3), or N 3 mg/kg + I 1 mg/kg Q3W (N3+I1). Primary endpoint was ORR. Secondary endpoints included DOR, OS, PFS, and safety. Efficacy in pts by PD-L1 status was assessed. Results: 160 heavily pretreated pts (79% had ≥ 2 prior Tx) were enrolled (N3, n = 59; N1+I3, n = 49; N3+I1, n = 52); 24% had PD-L1+ (≥ 1%) tumors. ORR was 12% in N3, 24% in N1+I3, and 8% in N3+I1. In pts with PD-L1 ≥ 1%, ORR was 19% (3/16) in N3, 40% (4/10) in N1+I3, and 23% (3/13) in N3+I1; in pts with PD-L1 < 1%, ORR was 12% (3/26), 22% (7/32), and 0% (0/30), respectively. Median DOR was 7.1 mo in N3, 7.9 mo in N1+I3, and NA in N3+I1. OS in all pts and in pts with PD-L1 ≥ 1% is in the Table. Grade 3–4 treatment-related AEs reported in ≥ 10% of pts in any treatment arm were diarrhea (N3, 2%; N1+I3, 14%; N3+I1, 2%), ALT increased (N3, 3%; N1+I3, 14%; N3+I1, 4%), and AST increased (N3, 5%; N1+I3, 10%; N3+I1, 2%). Conclusions: N ± I led to durable responses and long-term OS in heavily pretreated Western pts with adv G/E/GEJ cancer, which is consistent with the clinical activity observed in Asian pts in the ONO-12 study. Safety was consistent with prior reports. These data support ongoing investigation of N ± I in pts with adv G/E/GEJ cancer. Clinical trial information: NCT01928394. [Table: see text]

Recent trend in gastric cancer treatment in the USA

“…ORR was higher in PD-1 ligand (PD-L1) positive patients than PD-L1 negative patients (15.5% vs. 5.5%). Checkmate 032 assessed the combination of two checkpoint inhibitors, nivolumab (PD-1 inhibitor) and ipilimumab (cytotoxic T-lymphocyte-associated protein 4 inhibitor), and showed that ORR for combination therapy in PD-L1 positive patients was 40%, which was higher than nivolumab monotherapy [52] . Interestingly, among 7 patients with high microsatellite instability (MSI-H) tumors in Keynote-059, ORR was 57% and the CR rate was 14.3%.…”

Update on targeted therapy and immune therapy for gastric cancer, 2018

“…In a phase II trial, ipilimumab was compared with BSC for patients who had received first-line chemotherapy that was not significantly superior in efficiency as maintenance therapy [43] . Comparing the efficiency of nivolumab as a single agent or in combination with ipilimumab was performed in phase I/II trial (checkmate-032) [44] . The nivolumab + ipilimumab group showed a relatively higher ORR than the nivolumab monotherapy group (14% with nivolumab monotherapy and 26% with nivolumab + ipilimumab).…”

Immune checkpoint blockade therapy for esophageal squamous cell carcinoma

“…Survival result is not published yet. The CheckMate 032 study showed that PD-1 inhibitor in combination with CTLA-4 inhibitor was active in EC, but most population is adenocarcinoma (13). The KEYNOTE-059 study showed that PD-1 inhibitor in addition to 5-FU and cisplatin is manageable safety as the first line therapy for gastric cancer (14).…”

“…PD-L1 expression and microsatellite instability (MSI) are considered as potential biomarker so far (13)(14)(15). MSI-H being a very reliable biomarker but PD-L1 is a poor predictor of response in GI tumors.…”

“…TMB is related to MSI status and TMB as a biomarker is under evolution at the moment (6). PD-L1 positive tumor is sensitive to immune checkpoint blockade therapy in upper gastrointestinal cancer, but unclear in ESCC (13,14). One meta-analysis showed that PD-L1 overexpression was found in 559 patients (41.4%) in 1,350 patients and a poor prognostic factor for ESCC (9).…”