FDA Considers Pembrolizumab/Chemotherapy for Approval in Advanced Gastric/GEJ Cancer

KEYNOTE-859 findings are under review by the FDA as the regulatory body considers an approval application for pembrolizumab plus chemotherapy for the treatment of locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

The FDA has accepted a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.1

The sBLA is supported by findings from the phase 3 KEYNOTE-859 clinical trial (NCT03675737), in which pembrolizumab plus chemotherapy showed a statistically significant improvement in overall survival (OS) compared with chemotherapy alone in a HER2-negative patient population. The OS result was irrespective of PD-L1 expression status. To review the sBLA, the FDA has set a target action date of December 16, 2023.

“The 5-year survival rate for patients diagnosed with metastatic gastric cancer is estimated to be only six percent, and eighty percent of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma have HER2-negative disease,” said Scot Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories. “We are committed to working closely with the FDA to bring [pembrolizumab] to more patients with gastric and gastroesophageal junction cancer who are in need of additional treatment options that may help them live longer.”

[Early stage gastric cancer tumor on the stomach wall angle view 3d illustration] | Image Credit © [LASZLO] - [stock.adobe.com]

Image Credit: © LASZLO [stock.adobe.com]

In the phase 3, randomized, double-blind KEYNOTE-859 study, 1578 patients with HER2-negative, locally advanced or metastatic gastric/GEJ cancer were evaluated. Patients were randomized 1:1 to receive either pembrolizumab 200 mg plus fluoropyrimidine- and platinum-containing chemotherapy based no investigator’s choice or placebo. Investigator’s choice of chemotherapy could have contained either 5-fluorouracil (5-FU) plus cisplatin or capecitabine plus oxaliplatin. The primary end point assessed in the study was OS, and the secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response per RECIST v1.1, and safety.2

Results from the study were presented during the February European Society of Medical Oncology (ESMO) Virtual Plenary. Efficacy findings were from the intent-to-treat population and safety findings were from the as-treated population.

At a median follow-up of 31.0 months (range, 15.3-46.3 months), the median OS was 12.9 months (95% CI, 11.9-14.0 months) with pembrolizumab plus chemotherapy vs 11.5 (95% CI, 10.6-12.1 months) with placebo plus chemotherapy (HR 0.78, 95% CI 0.70-0.87; P < .0001). The median PFS was 6.9 months (95% CI, 6.3-7.2 months) vs 5.6 months (95% CI, 5.5-5.7 months), respectively (HR 0.76, 95% CI, 0.67-0.85; P < .0001). The survival results were consistent in the subgroup populations.

Pembrolizumab plus chemotherapy led to an ORR of 51.3% (95% CI, 47,7%-54.8%) compared with 42.0% (95% CI, 38.5%-45.5%) in the placebo plus chemotherapy arm (P = .00009). The median DOR observed with pembrolizumab plus chemotherapy was 8.0 months (range, 1.2+ to 41.5+) compared with 5.7 months (1.3+ to 34.7+).

For safety, treatment-related adverse events (TRAEs) of any grade were seen in 95.7% of the pembrolizumab plus chemotherapy arm vs 93.5% of the placebo plus chemotherapy arm. TRAEs were grade 3-5 among 59.4% of the pembrolizumab arm vs 51.1% of the placebo arm, and TRAEs led to death in 1.0% vs 2.0%, respectively. Serious TRAEs occurred in 23.4% of pembrolizumab arm vs 18.6% of the placebo arm. Treatment discontinuations occurred in 26.4% of the pembrolizumab plus chemotherapy arm compared with 20.1% of the placebo plus chemotherapy arm. The most common TRAEs occurred in at least 15% of patients of the pembrolizumab/chemotherapy and placebo/chemotherapy groups combined. The most commonly occurring TRAEs included nausea (41.4% v 41.4%), diarrhea (32.1% v 27.2%, anemia (31.0% v 26.9%), vomiting (27.4% v 22.2%), and platelet count decrease (25.0% v 22.5%).

Immune-mediated AEs of any-grade were observed in 27.1% of the pembrolizumab/chemotherapy arm vs 9.3% of the placebo/chemotherapy arm. Immune-mediated AEs were grade 3-5 in 7.9% of patients treated with pembrolizumab/chemotherapy vs 1.7% of those who received placebo/chemotherapy. Immune-mediated AEs led to death in fewer than 1% of patient in each arm. Hypothyroidism and hyperthyroidism were the 2 most common immune-mediated AEs having occurred in 15.3 vs 4.3% and 5.6% vs 1.7% of patients in the pembrolizumab plus chemotherapy vs placebo plus chemotherapy arm, respectively.


1. FDA accepts application for Merck’s Keytruda® (pembrolizumab) plus chemotherapy as first-line treatment for locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. News release. Merck. April 13, 2023. Accessed April 13, 2023. https://bit.ly/3GHLV5A

2. Rha SY, Wyricz LS, Weber PEY, et al. Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. Ann Oncol. 2023;34(3):313-320. doi:10.1016/j.annonc.2023.01.006

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