KEYNOTE-811 Trial of Pembrolizumab Combo Improves PFS in HER2+ Gastric/GEJ Cancer

Yelena Y. Janjigian, MD

Updated findings from the phase 3 KEYNOTE-811 trial (NCT03615326) showed that adding pembrolizumab (Keytruda) to the combination of trastuzumab (Herceptin) and chemotherapy improved progression-free survival (PFS) compared with placebo plus trastuzumab and chemotherapy for the first-line treatment of patients with metastatic HER2-positive gastric or gastroesophageal junction (GEJ) cancer, specifically patients whose tumors had a PD-L1 combined positive score (CPS) of 1 or more.^1,2

Findings presented at the 2023 ESMO Congress and simultaneously published in The Lancet showed at the second interim analysis conducted at a median follow-up of 28.3 months (interquartile range [IQR], 19.4-34.3) for the pembrolizumab arm and 28.5 months (IQR, 20.1-34.3) for the placebo arm, patients treated with the pembrolizumab regimen (n = 350) experienced a median PFS of 10.0 months (95% CI, 8.6-11.7) vs 8.1 months (95% CI, 7.0-8.5) for those given the placebo regimen (n = 348; HR, 0.72; 95% CI, 0.60-0.87; P = .0002). In patients with a PD-L1 CPS of 1 or more, the median PFS was 10.8 months (95% CI, 8.5-12.5) for the pembrolizumab arm (n = 298) and 7.2 months (95% CI, 6.8-8.4) for the placebo arm (n = 296; HR, 0.70; 95% CI, 0.58-0.85).

Furthermore, findings from the third interim analysis at a median follow-up 38.4 months (IQR, 29.5-44.4) in the pembrolizumab group and 38.6 months (IQR, 30.2-44.4) in the placebo group, the median PFS was 10.0 months (95% CI, 8.6-12.2) vs 8.1 months (95% CI, 7.1-8.6) for the overall populations in the pembrolizumab and placebo arms, respectively (HR, 0.73; 95% CI, 0.61-0.87). In patients with a PD-L1 CPS of at least 1, the median PFS was 10.9 months (95% CI, 8.5-12.5) for the pembrolizumab arm vs 7.3 months (95% CI, 6.8-8.5) for the placebo arm (HR, 0.71; 95% CI, 0.59-0.86).

Additional data from the third interim analysis showed that the pembrolizumab regimen elicited a median overall survival (OS) of 20.0 months (95% CI, 17.8-22.1) vs 16.8 months (95% CI, 15.0-18.7) for the placebo regimen in the overall population (HR, 0.84; 95% CI, 0.70-1.01). The median OS in patients with a PD-L1 CPS of 1 or more was 20.0 months (95% CI, 17.9-22.7) vs 15.7 months (95% CI, 13.5-18.5) for the pembrolizumab and placebo arms, respectively (HR, 0.81; 95% CI, 0.67-0.98).

“The addition of pembrolizumab to first-line trastuzumab and chemotherapy led to meaningful improvement in PFS and overall response rate [ORR], particularly in patients with dual overexpression of HER2 and PD-L1 in their tumor,” lead study author Yelena Y. Janjigian, MD, chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York, said in a presentation of the data.

In May 2021, the FDA granted accelerated approval to pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced, unresectable, or metastatic HER2-positive gastric or GEJ adenocarcinoma, based on ORR data from the first interim analysis of KEYNOTE-811.³

Anatomy of human body with digestive system: © Rasi - stock.adobe.com

At the 2023 ESMO Congress, investigators presented findings from additional interim analyses.^1,2

The randomized, placebo-controlled study enrolled patients 18 years of age or older with a confirmed diagnosis of previously untreated, unresectable or metastatic gastric or GEJ adenocarcinoma with HER2 status of immunohistochemistry (IHC) 3+ or 2+/in situ hybridization–positive. Patients also needed to have measurable disease, an ECOG performance status of 0 or 1, a life expectancy of more than 6 months, and satisfactory organ function.

Patients were randomly assigned 1:1 to receive either 200 mg of intravenous (IV) pembrolizumab or placebo once every 3 weeks in combination with IV trastuzumab at 6 mg/kg once every 3 weeks (following a loading dose of 8 mg/kg) and chemotherapy consisting of either 800 mg/m² of IV fluorouracil on days 1 to 5 of each 3-week cycle and 80 mg/m² of IV cisplatin once every 3 weeks, or 1000 mg/m² of oral capecitabine twice daily on days 1 to 14 of each 3-week cycle and 130 mg/m2 of IV oxaliplatin once every 3 weeks.

The treatment regimen continued for a maximum of 35 cycles (2 years) or until disease progression, intolerable toxicity, a decision by the investigator to halt treatment, or withdrawal of consent by the patient. Imaging assessments occurred at week 6 and then every 6 weeks thereafter.

Patients were stratified by geographic region, PD-L1 CPS, and chemotherapy choice.

The primary end points of the trial consisted of PFS per RECIST v1.1 criteria and OS in the intent-to-treat population. ORR and duration of response (DOR) were secondary end points. Notably, exploratory end points included health-related quality of life, identification of molecular, genetic, and genomic correlates of treatment, and PFS and ORR per iRECIST criteria.

The median age of patients were 62 years (range, 19-85) and 63 years (range, 32-85) in the pembrolizumab and placebo groups, respectively; a majority of patients across both treatment groups were male (81% and 80% for pembrolizumab and placebo, respectively) and had an ECOG performance state of 1 (58% and 58%). Across both groups, 32% of patients were from Australia, Europe, Israel, and North America, 34% were from Asia, and 34% were from the rest of the world.

Regarding histology , patients in the pembrolizumab cohort had diffuse (19%), intestinal (57%), or unknown (24%) subtypes. Patients in the placebo group had diffuse (15%), intestinal (54%), or unknown (31%) subtypes. Furthermore, 69% and 65% of patients in the pembrolizumab and placebo groups had a primary tumor location of the stomach, respectively. Notably, 85% of patients in both groups had a PD-L1 CPS of 1 or more. Two percent of patients in the pembrolizumab group vs 1% in the placebo group had microsatellite instability–high disease.

The chemotherapy of choice was capecitabine/oxaliplatin in 85% and 85% of patients in the pembrolizumab and placebo groups, respectively, and fluoropyrimidine/cisplatin was used in in 15% and 14% of patients, respectively.

Additional data showed that the ORR was 73% (95% CI, 68%-77%) in patients treated with pembrolizumab, including a complete response (CR) rate of 17%, a partial response (PR) rate of 56%, and stable disease (SD) rate of 19%. The disease control rate (DCR) was 92% (95% CI, 88%-94%) and the median DOR was 11.3 months (range, 1.1+ to 49.7+).

The ORR in patients treated with placebo was 60% (95% CI, 55%-65%), including a CR rate of 11%, a PR rate of 49%, a SD rate of 27%, a DCR of 87% (95% CI, 83%-91%), and a median DOR of 9.5 months (1.4+ to 48.7+).

Patients who were randomly assigned to the study who received at least 1 dose of the treatment were evaluated for safety. In the pembrolizumab group (n = 350) and placebo group (n = 346), 99% and 100% of patients experienced any-grade treatment-related adverse effects (TRAEs), respectively. The rates of grade 3/4 TRAEs were 58% and 50%, respectively. The rates of serious TRAEs were 26% and 23%, respectively. Four patients (1%) in the pembrolizumab arm and 3 patients (1%) in the placebo arm experienced grade 5 TRAEs. Discontinuation of any drug due to TRAEs occurred in 36% and 33% of patients treated with pembrolizumab vs placebo, respectively.

The most frequent TRAEs of any grade included diarrhea at 47% in the pembrolizumab group and 42% in the placebo group, nausea at 44% in the pembrolizumab group and 44% in the placebo group, and anemia at 31% in the pembrolizumab group and 33% in the placebo group.

Janjigian concluded by saying that although the data PFS suggest consideration of this regimen as a first-line treatment option for patients with metastatic HER2-positive gastric/GEJ cancer, the OS benefits of this regimen are yet to be determined.

“Based on these results, now this combination of pembrolizumab, trastuzumab, and chemotherapy in the first-line setting for HER2-positive and PD-L1–positive tumors is approved in Europe. The [OS] analysis is ongoing, though the study is complete,” Janjigian said.

References

1. Janjigian YY, Kawazoe A, Bai Y, et al. embrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424

2. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: survival results from the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Lancet Oncol. Published online October 20, 2023. doi: 10.1016/S0140-6736(23)02033-0

3. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. News release. FDA. May 5, 2021. Accessed October 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer