Pembrolizumab Plus Chemo Emerges as New Option for Advanced, HER2–Negative Gastric/GEJ Cancer

A read out from the phase 3 KEYNOTE-859 at the February ESMO Virtual Plenary hints pembrolizumab/chemotherapy is a new treatment choice for locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma.

The addition of pembrolizumab (Keytruda) to fluoropyrimidine- and platinum-containing chemotherapy has shown statistically significant and clinically meaningful improvements in outcomes compared with chemotherapy alone in patients with locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.1

The marked improvements with pembrolizumab plus chemotherapy were in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). These results come the phase 3 KEYNOTE-859 study and were presented on day 1 of the February European Society of Medical Oncology (ESMO) Virtual Plenary by Sun Young Rha, PhD, a medical oncologist in the Department of Internal Medicine at Yonsei University College of Medicine, in Seoul, Korea.

“Gastric cancer still has large morbidity and mortality worldwide. Despite available treatments, the 5-year survival rate for advanced gastric cancer is less than 10%. Chemotherapy is the main component to the first-line treatment of advanced gastric cancer,” explained Rha, during the presentation. “Regardless of tumor histology or HER2 status, the preferred chemotherapy is a 5-fluorourcil [5-FU] platinum doublet.”

Around the world, guidelines for frontline advanced gastric cancer treatment differ, Rha shared. This is especially true for regimens that contain PD-1 inhibitors.

“Although regulatory approvals and guideline recommendations are different globally, immunotherapy is becoming the standard-of-care [SOC] for the first-line treatment of metastatic gastric cancer,” said Rha.

The randomized, double-blind, phase 3 KEYNOTE-859 study (NCT03675737) was designed to evaluate the use of the PD-L1 inhibitor, pembrolizumab, in addition to SOC chemotherapy. The study registered 2409 patients who had histologically or cytologically confirmed disease that was locally advanced unresectable, or metastatic. All patients had no prior treatment, had known PD-L1 status, were HER2 negative, and had an ECOG performance status of 0 or 1.

A total of 1579 patients were randomized to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy. In the experimental arm, patients received 200 mg via intravenous (IV) infusion every 3 weeks for at least 35 cycles in combination with IV 5-FU 800 mg/m2 per day on days 1 to 5 with IV cisplatin 80 mg/m2, every 3 weeks (FP). In addition, patients received the capecitabine 1000 mg/m2 orally twice daily on days 1-14 with oxaliplatin 130 mg/m2 every 3 weeks (CAPOX regimen). In the control arm, patients received matching doses of placebo plus chemotherapy with the same dose schedule.

Patients were stratified by geographic location, level PD-L1 expression (<1 v ≥1), and choice of chemotherapy (FP v CAPOX). These stratification factors were considered when assessed the primary end point of OS, and the secondary end points of PFS, ORR, duration of response (DOR), and safety.

Baseline characteristics showed that the intent-to-treat (ITT) population was largely made up of males over the age of 65 years. In terms of geographic region, 33.3% of the pembrolizumab arm and 33.2% of the placebo arm were Asian. Europeans, Israelis, North Americans, and Australians made up 25.4% of the pembrolizumab arm and 25.6% of the placebo arm. The remaining 41.3% in the pembrolizumab arm and 41.2% on the placebo arm were from other places in the world. The ECOG performance status was 1 for more than 60% of patients in both treatment arms, a PD-L1 ≥ 1 was observed in more than 75% of patients both arms, and a PD-L1 score of≥ 10 was observed in more than 30% of patients in each arm.

At a median follow-up of 31.0 months (range, 15.3-46.3 months), the median OS in the ITT population was 12.9 months (95% CI, 11.9-14.0 months) in the pembrolizumab arm compared with 11.5 months (95% CI, 10.6-12.1 months) in the placebo arm (HR, 0.78; 95% CI, 0.70-0.87; P < .0001). At 12 months, the OS rate with pembrolizumab and chemotherapy was 52.7% vs 46.7% with placebo and chemotherapy. The 24-month OS rate was 28.2% in the pembrolizumab arm compared with 18.9% with placebo. The OS benefit was carried across all subgroups assessed.

The median PFS observed in the pembrolizumab arm was 6.9 months (95% CI, 6.3-7.2 months) vs 5.6 months (95% CI, 5.5-5.7 months) with placebo (HR, 0.76; 95% CI, 0.67-0.85; P < .0001). PFS benefit was shown in all subgroups.

The ORR shown with pembrolizumab, and chemotherapy was 51.3% (95% CI, 47.7%-54.8%), which included a 9.5% complete response (CR) rate and a 41.8% partial response (PR) rate. In comparison, the ORR in observed in patients treated with placebo and chemotherapy was 42.0% (95% CI, 38.5%-45.5%). The CR rate in the control arm was 6.2%, and the PR rate was 35.7%. The median DOR was 8.0 months (1.2+ to 41.5+ months) with the experimental combination vs 5.7 months (1.3+ to 34.7+ months) with the control.

Treatment-related adverse events (TRAEs) of any grade were seen in 95.7% of the pembrolizumab arm vs 93.5% of the placebo 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. There were treatment discontinuations in 26.4% of the pembrolizumab arm compared with 20.1% of the placebo arm.

The most common TRAEs occurred in at least 15% of patients of the pembrolizumab and placebo groups combined. The 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%).

Any-grade immune-mediated AEs occurred in 27.1% of the pembrolizumab arm vs 9.3% of the placebo arm. These events were grade 3-5 in 7.9% of patients treated with pembrolizumab vs 1.7% of those who received placebo. 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 vs placebo arm, respectively.

According to Rha, data from KEYNOTE-859 support the use of pembrolizumab in combination with chemotherapy to treat locally advanced or metastatic, HER2-negative gastric or GEJ adenocarcinoma.


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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