Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan, shares results from the phase 3 KEYNOTE-585 study, evaluating neoadjuvant and adjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab among patients with locally advanced, resectable gastric or gastroesophageal junction (G/GEJ) cancer.

The results showed a statistically significant improvement of pathological complete response with pembrolizumab, but not of event-free survival. Dr Shitara stated, “These results suggest we need additional research to apply the checkpoint inhibitor in the perioperative setting for gastric cancers.”

These results were first presented at the 2023 European Society for Medical Oncology Annual Congress in Madrid, Spain.

Transcript:

Hello, my name is Kohei Shitara. I'm a GI medical oncologist working at the National Cancer Center Hospital West, Japan.  At this ESMO meeting, I presented the data from KEYNOTE-585 study. This is a global, randomized, double-blinded placebo-controlled trial to evaluate pembrolizumab about the perioperative setting in combination with chemotherapy for patients with gastric and GEJ adenocarcinoma at locally advanced disease.

In background, surgical resection remains the gold standard for patients with locally advanced gastric and GEJ cancer. However, high recurrence rate following surgery requires a multi-modal treatment strategy including perioperative chemotherapy. As everyone knows, PD-1 inhibitors improve the survival of a metastatic gastric cancer patient, but its efficacy in perioperative setting remains unknown.

In this study, we have 2 cohorts. The first is the main cohort, which enrolls patients with a clinical T3 or higher primary lesion with or without lymphadenal metastasis and without distant metastasis. And these patients were randomized to receive pembrolizumab or a placebo, which was given in combination with the chemotherapy composed of capecitabine or 5-FU plus cisplatin. The combination of therapy was given every 3 weeks for 3 cycles, followed by surgical resection. And after surgery, an additional 3 cycles of chemotherapy, as well as an additional 11 cycles of pembrolizumab or placebo, was continued. The primary end point of this main cohort was pathological complete response (pathCR) rate, event-free survival, and overall survival. We also have a different cohort to investigate FLOT plus pembrolizumab, since this KEYNOTE-585 trial was planned before the pivotal FLOT4 trial, and the safety of FLOT plus a PD-1 inhibitor was not reported. Similar patients were randomized to receive FLOT plus pembrolizumab or FLOT plus placebo, and the primary end point of this cohort was safety.

Patient characteristics were well balanced between 2 arms. Around half of patients were enrolled from Asia in the main cohort, and the majority of patients had clinical T3 or higher and gastric primary lesion. Over 9% of patients had MSI-high status, which was relatively higher than that of metastatic population as expected. And most of the patients enrolled into the FLOT cohort was non-Asian population. Perioperative chemotherapy, especially neoadjuvant chemotherapy, was completed in more than 90% of patients, and surgery with curative intent was performed in around 85% of patients. R0 resection was achieved in 80% patients with pembrolizumab and 75% with placebo in the main cohort.

As a primary end point, pathCR rate was significantly improved with the use of pembrolizumab plus chemotherapy compared with chemotherapy plus placebo. Actual pathCR rate was 12.9% with pembrolizumab and 2% with placebo. So there was 10.9% improvement with a statistically significant difference. And the results were consistent in most of the subgroups, of note the MSI-high population showed a very high pathCR rate as expected. 

The most important primary end point was event-free survival. This showed a separation of survival curve after 10 months, and the median was 44 months with pembrolizumab and 25 months with placebo. There was around 20 months difference. And the 3-year EFS rate also showed a 10% difference. The hazard ratio of 0.81, with a p-value of 0.0189, which was unfortunately higher than that of predefined significant threshold. So technically, this study didn't show a significant improvement of EFS by adding pembrolizumab. Overall survival is still under follow-up, with a hazard ratio of 0.90 after this interim analysis. The safety profile was very similar to that of metastatic population.

In summary, this KEYNOTE-585 study showed a statistically significant improvement of the pathological complete response rate with pembrolizumab plus chemotherapy. But the difference in event-free survival was not statistically significant. OS follow-up is still ongoing. And the safety results were very similar to that of metastatic population. These results suggest we need additional research to apply the checkpoint inhibitor in the perioperative setting for gastric cancers. Thank you.

Source:

Shitara K, Rha SY, Wyrwicz LS, et al. Pembrolizumab plus chemotherapy vs chemotherapy as neoadjuvant and adjuvant therapy in locally-advanced gastric and gastroesophageal junction cancer: The phase III KEYNOTE-585 study. Presented at ESMO Annual Congress; October 20-24, 2023; Madrid, Spain. LBA74