Yelena Y. Janjigian, MD

As reported in Nature by Yelena Y. Janjigian, MD, and colleagues, the first interim analysis of the phase III KEYNOTE-811 trial has shown a significantly higher objective response rate with the addition of pembrolizumab to trastuzumab and chemotherapy in patients with previously untreated advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.

The analysis from the trial supported the May 2021 accelerated approval of pembrolizumab in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy in this setting on the basis of response rate and duration of response.

Study Details

In the double-blind trial, 434 patients from sites in 20 countries were randomly assigned between October 2018 and June 2020 (intention-to-treat population) to receive pembrolizumab at 200 mg (n = 217) or placebo (n = 217) every 3 weeks plus trastuzumab and investigator’s choice of fluorouracil/cisplatin (n = 189 vs 187) or capecitabine/oxaliplatin (n = 28 vs 30). Trastuzumab was given at 6 mg/kg once every 3 weeks after a loading dose of 8 mg/kg. Chemotherapy consisted of: fluorouracil at 800 mg/m² on days 1 to 5 and cisplatin at 80 mg/m² once every 3 weeks; or capecitabine at 1,000 mg/m² twice daily on days 1 to 14 and oxaliplatin at 130 mg/m² once every 3 weeks. Treatment continued for up to 35 cycles or until disease progression or unacceptable toxicity. Overall, 81% of patients had a PD-L1 combined positive score of at least 1.

The current interim analysis evaluated objective response rate on blinded independent central review using Response Evaluation Criteria in Solid Tumors v1.1 among the first 264 patients enrolled (efficacy population) and safety in 433 patients who received at least one dose of study treatment. The efficacy population consisted of 133 patients in the pembrolizumab group and 131 in the control group. In the efficacy population, the selected chemotherapy regimen was fluorouracil/cisplatin in 115 vs 115 patients and capecitabine/oxaliplatin in 18 vs 16 patients.

Responses

Median follow-up was 9.9 months (range = 0.1–19.4 months) in the intention-to-treat population and 12.0 months (range = 8.5–19.4 months) in the efficacy population. Objective response was observed in 99 (74.4%, 95% confidence interval [CI] = 66.2%–81.6%) of 133 patients in the pembrolizumab group vs 68 (51.9%, 95% CI = 43.0%–60.7%) of 131 in the control group, yielding a 22.7% improvement for the pembrolizumab group (95% CI = 11.2%–33.7%, P = .00006). Complete response was observed in 15 patients (11.3%) vs 4 patients (3.1%). Stable disease was observed in an additional 29 patients (21.8%) vs 49 patients (37.4%). Disease control rates were 96.2% (95% CI = 91.4%–98.8%) vs 89.3% (95% CI = 82.7%–94.0%).

Median response duration was 10.6 months (range = > 1.1 to > 16.5 months) in the pembrolizumab group vs 9.5 months (range = > 1.4 to > 15.4 months) in the control group, with 50.5% vs 44.1% of responses ongoing as of data cutoff (June 2020). An estimated 70.3% vs 61.4% of responses lasted at least 6 months, and 58.4% vs 51.1% lasted at least 9 months.

Adverse Events

Among 217 vs 216 patients in the safety population, grade ≥ 3 adverse events occurred in 57.1% of the pembrolizumab group vs 57.4% of the control group. The most common in both groups were anemia (8.5% vs 9.3%), decreased platelets (7.8% vs 6.9%), diarrhea (7.4% vs 8.3%), and decreased neutrophils (7.4% vs 7.4%). Serious adverse events occurred in 31.3% vs 38.4% of patients. Adverse events led to discontinuation of any component of study treatment in 24.4% vs 25.9%, including discontinuation of pembrolizumab vs placebo in 5.5% vs 6.9%. Potential immune-related adverse events or infusion reactions occurred in 33.6% and 20.8%, including infusion reactions in 18.0% vs 13.0%. The most common immune-related events in the pembrolizumab group were pneumonitis (5.1%), colitis (4.6%), and hypothyroidism (4.6%). Adverse events led to death in 7 patients (3.2%) vs 10 patients (4.6%) patients, with death considered related to treatment in 2 patients (0.9%) in each group.

The investigators concluded: “These promising initial findings of KEYNOTE-811 suggest that the combination of pembrolizumab, trastuzumab, and chemotherapy may be a transformative treatment option for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma and support exploring the combination in patients with earlier stages of disease.”

Dr. Janjigian, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Nature article.

Disclosure: The study was funded by Merck Sharp & Dohme Corp. For full disclosures of the study authors, visit www.nature.com.