Pembrolizumab appears safe, effective in advanced gastric cancer

Issue: March 25, 2015

The novel agent pembrolizumab demonstrated promising antitumor activity and manageable toxicity in patients with advanced gastric cancer, according to study results presented at the Gastrointestinal Cancers Symposium.

Perspective from David P. Ryan, MD

Pembrolizumab (Keytruda, Merck) — which is being studied in a variety of several cancer types — is a monoclonal antibody that blocks the PD-1 pathway.

Kei Muro, MD, of the department of clinical oncology at Aichi Cancer Center Hospital in Japan, and colleagues assessed the relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer treated with pembrolizumab.

All patients had recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction. Eligibility was limited to patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining.

Of the 162 patients screened, 65 were identified as PD-L1 positive. From that cohort, 39 patients enrolled in the study. About half of patients (48.7%; n=19) were from Asia-Pacific regions.

Median age of the cohort was 63 years (range, 33-78 years). Most patients in the cohort had undergone prior therapies for their cancers, and 67% had received at least two prior therapies.

Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until they achieved complete response, demonstrated progression or experienced unacceptable toxicity.

Imaging was performed every 8 weeks. Overall response rate served as the primary endpoint. Secondary endpoints included duration of response, PFS and OS.

Median follow-up was 8.8 months (range, 6.2-12.6 months).

At the time of final analysis, 13 patients (33%) remained on therapy.

The overall response rate as determined by central review was 22% (95% CI, 10-39). Overall response rate as determined by investigator review was 33% (95% CI, 19-50).

The median time to response was 8 weeks (range, 7-16 weeks), and the median duration of response was 24 weeks. The 6-month PFS rate was 24%, and the 6-month OS rate was 69%.

Researchers reported one drug-related death due to hypoxia. Four patients experienced a combined five grade 3 to grade 5 drug-related adverse events. They included one case each of peripheral sensory neuropathy, fatigue, hypoxia, pneumonitis and decreased appetite.

“Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer,” the researchers wrote. “These results support the ongoing development of pembrolizumab for gastric cancer.”

For more information:

Muro K. Abstract #3. Presented at: 2015 Gastrointestinal Cancers Symposium; Jan. 15-17, 2015; San Francisco.

Disclosure: The researchers report employment relationships with Merck, as well as stock ownership and other interests in Bayer, Celgene, Johnson & Johnson and Merck.

Perspective

David P. Ryan, MD

In the United States, most cancers of the stomach and esophagus occur within several centimeters of the gastro-esophageal junction. If we combine the statistics for gastric and esophageal cancers, they represent the fifth leading cause of cancer death for men in the United States and the 10th leading cause of cancer death for women in the United States. First-line treatment usually consists of combination chemotherapy (typically FOLFOX or FOLFIRI), and trastuzumab (Herceptin, Genentech) is added for patients with HER-2–amplified disease. Recently, the combination of paclitaxel and ramucirumab (Cyramza, Eli Lilly) — a VEGF-2 receptor antibody — was approved for use in the second-line setting of metastatic gastric cancer based on the results of the RAINBOW study (Wilke H, et al. Abstract LBA7. Presented at: Gastrointestinal Cancers Symposium; Jan. 16-18, 2014; San Francisco). In the RAINBOW study, patients were randomly assigned to paclitaxel or paclitaxel and ramucirumab. There was a statistically significant improvement in OS (9.6 months vs. 7.4 months), PFS (4.4 months vs. 2.9 months) and response rate (28% vs. 16%) among patients who received ramucirumab.
In the setting of recurrent gastric cancer, investigators in the KEYNOTE 012 study evaluated pembrolizumab for those patients with 1% or more PD-L1 expression by immunohistochemistry. Investigators reported a response rate of 22%. Interestingly, the 6-month PFS of 24% suggests there are some patients who are experiencing durable responses, as is seen in both melanoma and lung cancer. Although PD-L1 expression was associated with response rate, the findings were not statistically significant.
This finding raises the question of whether expression of PD-L1 is the appropriate biomarker in patients with gastric cancer. These findings are consistent with what is being reported in patients with melanoma and lung cancer. Although there is some correlation with response to therapy, it certainly isn’t strong enough to make treatment decisions. Furthermore, these findings raise the question of whether we should be evaluating pembrolizumab in all gastric cancer patients, because lack of PD-L1 expression does not preclude response to pembrolizumab. Pembrolizumab represents an exciting possibility for patients with gastric cancer, and hopefully it and other PD-1 pathway inhibitors can be evaluated quickly in registration studies.

David P. Ryan, MD

Massachusetts General Hospital Cancer Center

Disclosures: Ryan reports no relevant financial disclosures.