1L HER2+ G/GEJC：KEYNOTE-811 Approved

KEYTRUDA Is the First Anti-PD-1 Therapy Approved in Combination With Trastuzumab and Chemotherapy for the First-line Treatment of These Patients

本次加速批准基于ORR和DoR的优效性，后续亟待临床获益的完整证明，好一出声东击西

KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response; continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. This approval is based on data from the ongoing Phase 3 KEYNOTE-811 trial, in which KEYTRUDA in combination with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin demonstrated a statistically significant objective response rate (ORR) of 74% (95% CI, 66-82) for patients who received the regimen with KEYTRUDA versus 52% (95% CI, 43-61) for those who received trastuzumab and chemotherapy alone (p<0.0001). For patients who received the regimen with KEYTRUDA, the complete response rate was 11% and the partial response rate was 63%. For patients who received trastuzumab and chemotherapy alone, the complete response rate was 3.1% and the partial response rate was 49%.

早前37人的Ph2 single arm的结果：ORR 87%，12mo OS 76%

后续启动Ph3 KEYNOTE-811，主要终点PFS和OS

https://clinicaltrials.gov/ct2/show/NCT03615326

Data Supporting the Approval

The approval was based on data from KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Randomization was stratified by PD‑L1 expression (Combined Positive Score [CPS] ≥1 or CPS <1), chemotherapy regimen (5-fluorouracil [5-FU] plus cisplatin [FP regimen] or capecitabine plus oxaliplatin [CAPOX regimen]), and geographic region (Europe/Israel/North America/Australia, Asia or Rest of the World). Patients were randomized (1:1) to receive one of the following treatment arms:

  • KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to six cycles and 5-FU 800 mg/m2/day for five days (FP) or oxaliplatin 130 mg/m2 up to six to eight cycles and capecitabine 1,000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle; or

  • Placebo, trastuzumab, followed by investigator’s choice of chemotherapy regimen: FP regimen or CAPOX regimen, dosed as above

At the time of the interim analysis, ORR and DOR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range, 19 to 84), 41% age 65 or older; 82% male; 63% white, 31% Asian and 0.8% Black; 47% Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (stage IV), and 3% had locally advanced unresectable disease. Eighty-seven percent had tumors that expressed PD‑L1 with a CPS ≥1. Ninety-one percent (n=240) had tumors that were not microsatellite instability-high (MSI‑H), 1% (n=2) had tumors that were MSI‑H, and in 8% (n=22), the status was not known. Eighty-seven percent of patients received CAPOX.

A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results showed:

安全性还是要注意

The safety analysis of the study included 217 patients with HER2-positive gastric cancer who received KEYTRUDA 200 mg, trastuzumab, and CAPOX (n=189) or FP (n=28) every three weeks, compared to 216 patients who received placebo, trastuzumab, and CAPOX (n=187) or FP (n=29) every three weeks. The median duration of exposure to KEYTRUDA was 5.8 months (range, 1 day to 17.7 months). KEYTRUDA and placebo were discontinued due to adverse reactions in 6% of patients in each arm. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased aspartate aminotransferase (AST) (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased alanine aminotransferase (ALT) (2.3%) and vomiting (2.3%).

In the KEYTRUDA arm versus placebo, there was a difference of ≥5% in the incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs. 44%) and nausea (49% vs. 44%). There were no clinically meaningful differences in the incidence of Grade 3-4 toxicity between the two arms.

There was a difference of ≥5% in the incidence between patients treated with KEYTRUDA versus standard of care for increased ALT (34% vs. 29%) and increased creatinine (20% vs. 10%). There were no clinically meaningful differences in the incidence of Grade 3-4 toxicity between the two arms.

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