Efficacy of pembrolizumab (pembro) monotherapy versus chemotherapy for PD-L1–positive (CPS ≥10) advanced G/GEJ cancer in the phase II KEYNOTE-059 (cohort 1) and phase III KEYNOTE-061 and KEYNOTE-062 studies.

Abstract

427 Background: Pts with advanced gastric/gastroesophageal junction (G/GEJ) cancer received pembro monotherapy (200 mg Q3W) 3L+ in cohort 1 of KEYNOTE-059 (NCT02335411), 2L in KEYNOTE-061 (NCT02370498), or 1L in KEYNOTE-062 (NCT02494583). We present efficacy data for patients with PD-L1 combined positive score (CPS) ≥10 tumors in these trials. Methods: In study 059, 46 pts in cohort 1 with PD-L1 CPS ≥10 received pembro. In study 061, 108 pts with PD-L1 CPS ≥10 received pembro (n=53) or chemotherapy (chemo; n=55). In study 062, 182 pts with CPS ≥10 received pembro (n=92) or placebo + chemo (n=90). Efficacy end points included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). Results: Median follow-up in study 059 was 5.6 mo. Median OS with pembro was 7.9 mo (95% CI, 5.8-11.1), and 12-mo OS was 32.6%. PFS at 6 mo was 17.4%, ORR was 17.4%, and median DOR was 20.9 mo (2.8+ to 34.9+). In study 061, after a median follow-up of 8.8 mo, pembro prolonged OS vs chemo (median 10.4 vs 8.0 mo; HR, 0.64; 95% CI, 0.41-1.02); 12-mo OS was 45.3% for pembro and 23.6% for chemo. Median PFS was 2.7 mo for pembro and 3.4 mo for chemo (HR, 0.86; 95% CI, 0.56-1.33). ORR was 24.5% vs 9.1%, and median DOR was NR (4.1-26.0+) and 6.9 mo (2.6-6.9) for pembro vs chemo. In study 062, median follow-up was 17.4 mo for pembro and 10.8 mo for chemo. Pembro prolonged OS vs chemo (median 17.4 vs 10.8 mo; HR, 0.69; 95% CI, 0.49-0.97); 12-mo OS was 56.5% vs 46.7%. Median PFS was 2.9 mo vs 6.1 mo (HR, 1.09, 95% CI, 0.79-1.49). ORR was 25.0% vs 37.8%, and median DOR was 19.3 mo (1.4+ to 33.6+) vs 6.8 mo (1.5+ to 30.4+) for pembro vs chemo, respectively. Conclusions: Collectively, these data indicate that 1L, 2L, and 3L+ pembro monotherapy showed clinically meaningful efficacy in CPS ≥10, with a more durable response than chemotherapy. Clinical trial information: NCT02335411, NCT02370498, and NCT02494583. [Table: see text]

Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough

“…Although the FDA approval of pembrolizumab in chemorefractory gastric and GEJ adenocarcinoma is contingent on positive PD-L1 testing, there are clearly some patients with PD-L1 negative tumors who derive benefit from this agent. PD-L1 positivity using the CPS of 1 was seen in 57.1% of patients in the KEYNOTE-059 study, and the ORR of these patients was 16% (95% CI, [11][12][13][14][15][16][17][18][19][20][21][22][23]. Of note, patients with PD-L1 negative tumors had a 6% ORR (95% CI, 3-13) [15,16].…”

“…The FDA approval stems from the phase II KEYNOTE-059 study (NCT02335411) of pembrolizumab at a dose of 200 mg i.v. every 3 weeks, which showed an overall response rate (ORR) of 12% (95% confidence interval [CI], [8][9][10][11][12][13][14][15][16][17] in all chemorefractory patients, regardless of PD-L1 status, and 16% (95% CI, [11][12][13][14][15][16][17][18][19][20][21][22][23] in patients with PD-L1-positive tumors (57.1% of patients had PD-L1-positive tumors) [15,16]. These response rates are impressive given the chemotherapy-resistant patient population.…”

Phase I and Biomarker Study of the Wnt Pathway Modulator DKN-01 in Combination with Gemcitabine/Cisplatin in Advanced Biliary Tract Cancer

“…Of note, high DKK1 expression was associated with better response to DKN-01 in a study of DKN-01 combined with pembrolizumab in anti-PD-1/PD-L1-inhibitor-naïve advanced gastroesophageal junction and gastric adenocarcinoma. 35 Despite the limited efficacy of adding DKN-01 to gemcitabine/cisplatin in BTC, the safety, PK, PD, and biomarker analyses from this study provided important insights for the development of DKN-01 in this disease. First, safety analyses in 51 patients with advanced BTC demonstrated that the AE profile were consistent with gemcitabine/cisplatin alone.…”

First-Line Pembrolizumab/Placebo Plus Trastuzumab and Chemotherapy in Her2-Positive Advanced Gastric Cancer: KEYNOTE-811

“…PFS and ORR were similar between the treatment groups, but responses were more durable in patients who received pembrolizumab than those who received paclitaxel (median duration of response [DOR], 18.0 vs 5.2 months, respectively). Post hoc analyses of patients with CPS ≥10 tumors revealed a greater survival benefit for the pembrolizumab group than the paclitaxel group (HR: 0.64; 95% CI: 0.41-1.02) [23]. In the Phase III KEYNOTE-062 study (NCT02494583), first-line pembrolizumab or pembrolizumab + chemotherapy versus chemotherapy was evaluated in patients with CPS ≥1, HER2-negative, advanced gastric cancer [24].…”