Yelena Y. Janjigian, MD from Memorial Sloan Kettering Cancer Center speaks about ASCO 2021 Abstract FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Combined With Trastuzumab and Chemotherapy as First-line Treatment in Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma.

Link to Article:
https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-combined-with-trastuzumab-and-chemotherapy-as-first-line-treatment-in-locally-advanced-unresectable-or-metastatic-her2-positive-gastric-or-g/

Merck's anti-PD-1 therapy, KEYTRUDA, has been approved by the United States Food and Drug Administration (FDA) 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) cancer. This indication received accelerated approval based on tumor response rate and response durability; continued approval for this indication could be dependent on clarification and explanation of clinical advantage in confirmatory trials. This approval is based on findings from the ongoing Phase 3 KEYNOTE-811 trial, which found that KEYTRUDA in combination with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin resulted in a statistically significant objective response rate (ORR) of 74 percent (95 percent CI, 66-82) for patients who received the KEYTRUDA-containing regimen versus 52 percent The full response rate was 11% and the partial response rate was 63 percent in patients who administered the KEYTRUDA regimen. The full response rate was 3.1 percent and the partial response rate was 49 percent in patients who received trastuzumab and chemotherapy alone.

Immune-mediated adverse reactions, which can be serious or lethal, can affect any organ system or tissue, and they can affect several body systems at the same time. Pneumonitis, colitis, leukemia, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and risks with allogeneic hematopoietic stem cell transplantation are all immune-mediated adverse reactions that may arise before or after treatment with KEYTRUDA. The list of important immune-mediated adverse reactions does not contain both serious and fatal immune-mediated adverse reactions. To ensure that KEYTRUDA is used safely, it is important to identify and control immune-mediated adverse reactions as soon as possible. KEYTRUDA should be delayed or permanently discontinued, and corticosteroids should be prescribed if appropriate, depending on the nature of the adverse reaction. Infusion-related responses to KEYTRUDA may be serious or life-threatening. When given to a pregnant woman, KEYTRUDA has the potential to damage the fetus due to its mechanism of action. See "Selected Important Safety Facts" below for more information.

The FDA's Real-Time Oncology Evaluation (RTOR) pilot software was used to review this request.

Information in Support of the Approval

KEYNOTE-811 (ClinicalTrials.gov, NCT03615326) was a multicenter, randomized, double-blind, placebo-controlled study that included 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously undergone systemic treatment for metastatic disease. The chemotherapy protocol (5-fluorouracil [5-FU] plus cisplatin [FP regimen] or capecitabine plus oxaliplatin [CAPOX regimen]) and regional area (Europe/Israel/North America/Australia, Asia, or Rest of the World) were used to stratify the randomization. Patients were randomly assigned to one of the following treatment arms (1:1):


KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator's options 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 for up to six cycles and capecitabine 1,000 mg/m2 bid for 14 days (CAPOX). On Day 1 of each series, KEYTRUDA was given before trastuzumab and chemotherapy; or

Placebo, trastuzumab, and the investigator's option of chemotherapy regimen: FP or CAPOX, dosed as before.

Except for oral capecitabine, all research drugs were given as an intravenous infusion every three weeks. Treatment with KEYTRUDA was extended for a period of 24 months or before RECIST v1.1 identified worsening of disease as assessed by blinded independent central examination (BICR) or intolerable toxicity. ORR and length of reaction (DOR) by BICR using RECIST v1.1, updated to adopt a maximum of 10 target lesions and a maximum of five target lesions per organ, were major outcome measures measured in an interim efficacy study.


ORR and DOR were tested among the first 264 patients randomized at the time of the interim study. The 264 patients had a median age of 62 years (range, 19 to 84), with 41% being 65 or older; 82 percent were male; 63 percent were white, 31 percent Asian, and 0.8 percent were black; 47 percent had an Eastern Cooperative Oncology Group (ECOG) PS of 0, and 53 percent had an ECOG PS of 1. Ninety-seven percent of patients had stage IV metastatic illness, and three percent had locally progressed unresectable disease. Eighty-seven percent of tumors had PDL1 with a CPS 1 expression. Ninety-one percent (n=240) of the tumors were not microsatellite instability-high (MSIH), two percent (n=2) were MSIH, and eight percent (n=22) had no identified status. CAPOX was given to 87 percent of the patients.


Patients who received KEYTRUDA in combination with trastuzumab and chemotherapy had a statistically important better ORR than those who received placebo in combination with trastuzumab and chemotherapy.