The addition of the immune checkpoint inhibitor, pembrolizumab, to standard first-line therapy with trastuzumab plus chemotherapy is safe and active enough in first-line HER-2 positive metastatic esophagogastric cancer to justify a larger randomized trial in the same setting, an open-label, single-arm, phase II trial suggests.
At a median follow-up of 13 months (interquartile range (IQR), 11.7-23.5 months), median progression-free survival (PFS) was 13 months (95% CI, 8.6 months to not reached) while median overall survival (OS) was 27.3 months (95% CI, 18.8 months to not reached) following treatment with pembrolizumab plus trastuzumab and chemotherapy, Yelena Janjigian, MD, Memorial-Sloan Kettering Cancer Center, New York, and colleagues reported in Lancet Oncology.
The most common grade 3 or 4 adverse events (AEs) were lymphocytopenia in 19% of patients, decreased electrolytes in 16% of patients, and anemia in 11% of patients.
Only two patients discontinued treatment because of grade 3 AEs, investigators added.
“To our knowledge, this is the first study to evaluate the synergistic potential of pembrolizumab, trastuzumab, and chemotherapy for previously untreated metastatic oesophagogastric cancer,” researchers observed.
“The efficacy of this combination is [now] being evaluated in the randomized, double-blind phase 3 KEYNOTE 811 trial,” they added.
Study Design
A total of 37 patients were enrolled in the study. Patients had previously untreated gastric, esophageal, or gastroesophageal junction cancer and a left ventricular ejection fraction of at least 53%.
“At the discretion of the treating investigators, patients initially received an induction cycle of 200 mg flat dose of intravenous pembrolizumab…and an 8 mg/kg loading dose of intravenous trastuzumab,” Janjigian and colleagues explained.
On the second cycle — or the first cycle for those who did not receive the induction cycle with the anti-PD-1 antibody/anti-HER21 combination — patients received either 130 mg/m2 of intravenous (IV) oxaliplatin or 80 mg/m2 of IV cisplatin on day 1; 850 mg/m2 of oral capecitabine twice a day for 2 weeks followed by 1 week off or IV 5-fluorouracil, 800 mg/m2 per day on days 1 to 5 and a 200 mg dose of pembrolizumab plus 6 mg/kg of trastuzumab, both given IV within 7 days of the first day of each 3-week cycle of chemotherapy.
Treatment continued until unacceptable toxicity or disease progression.
“Pretreatment tumor and blood samples were collected and analyzed using MSK-IMPACT, a next-generation sequencing platform that detects mutations, copy-number alterations and select rearrangements in 100s of cancer-associated genes”, investigators explained.
“The primary endpoint of this phase 2 study was 6-month progression-free survival, defined as the proportion of patients alive and free of progression at 6 months,” study authors observed.
The median duration of treatment was 10 months (IQR, 5.7-13.7 months). The median number of oxaliplatin cycles received was 6 (IQR, 5-8 cycles) while the median number of cycles patients received of the combination of pembrolizumab, trastuzumab and fluoropyrimidine given was 10 (IQR, 7-17 cycles).
At 6 months, 26 (70%; 95% CI, 54-83%) of the 37 patients who received treatment were free of disease progression.
Median PFS and 12-month OS did not differ significantly between those who received the initial induction cycle of pembrolizumab and trastuzumab followed by pembrolizumab, trastuzumab, and chemotherapy beginning with cycle 2 and those who received pembrolizumab, trastuzumab and chemotherapy as initial treatment.
Three patients or 8% of the group died of their disease before the 6-month end point while 8 patients or 22% had disease progression at the same point in time.
At 12 months, the overall survival rate was 80% (95% CI, 68-95%), the authors noted.
All 35 patients with measurable disease at baseline had evidence of tumor regression ranging in magnitude from a reduction of 20% to a reduction of 100%, they added.
Importantly, 91% of those with measurable disease achieved an objective response (95% CI, 78-97%) while 17% of patients with measurable disease achieved a complete response—high for this tumor type, as the authors observed.
Another 74% of patients achieved a partial response while disease stabilized in 9% of patients overall.
Anti-HER2/Anti-PD-1 Induction
As the authors pointed out, 25 out of the 37 patients received the induction anti-HER2/anti-PD-1 combination, the remaining 12 patients receiving pembrolizumab, trastuzumab and chemotherapy as initial treatment.
However, “median progression-free survival and 12-month overall survival did not significantly differ between these groups,” Janjigian and colleagues reported.
Almost all patients developed treatment-related AEs, the most common being neuropathy, hyperglycemia, fatigue, nausea, anemia, diarrhea, vomiting and transaminitis.
“All patients with treatment-related adverse events required at least one dose reduction, primary for nausea, fatigue or neuropathy,” investigators acknowledged.
Notably, patients were enrolled regardless of whether they expressed PD-L1 but PD-L1 expression did not correlate with clinical benefit.
Findings based on DNA sequencing of pretreatment tissue and plasma samples indicated that patients with HER2 amplification had more durable responses to the trastuzumab-based combination than HER2-postive patients who did not have HER2 amplification.
Failure to confirm HER2 positively in patients has previously been shown to lead to less benefit from trastuzumab and chemotherapy, with one study showing overall survival for patients with confirmed HER2 positivity of 30.7 months versus 7.9 months in patients for whom secondary HER2 testing was negative.
“It is therefore possible that the absence of confirmation of HER2 status before treatment initiation in our study could have led to an underestimation of the activity of the pembrolizumab, trastuzumab, chemotherapy combination,” the authors speculated.
The authors also speculated that the activity of the anti-PD-1/anti-HER2 combination might be attributed to the ability of trastuzumab to induce antibody-dependent cell-mediated cytotoxicity, an action that could prime antitumor immune responses by enhancing presentation of tumor antigens.
Limitations of the study include its single-arm design, modest sample size, and the fact that it was carried out in a single center, thus possibility limiting the generalizability of the findings.
Commenting on the study, editorialist Yukiya Narita MD, Aichi Cancer Center Hospital, Nagoya, Japan and colleagues pointed out that the combination of pembrolizumab and chemotherapy did not improve survival in HER2-negative, PD-L1 positive metastatic gastric or gastroesophageal cancer when given as first-line treatment.
They also pointed out that the clinical activity of anti-HER2 therapies in gastroesophageal cancer has not been seen beyond fist-line trastuzumab plus chemotherapy.
Thus, “results [from this study] are quite encouraging and will inform the next randomized clinical trial,” they observed. “[And] given the promising anti-tumor activity reported in this study, the combination of pembrolizumab with trastuzumab and chemotherapy might act synergistically through an immune-mediated mechanism,” they added.
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First-line pembrolizumab plus trastuzumab and chemotherapy was found to be safe and active in HER2-positve esophageal, gastric, or gastroesophageal junction cancer.
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The efficacy of the same anti-PD-1/anti-HER2 combination plus chemotherapy is now being evaluated in a randomized, phase III trial.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by Merck.
Janjigian has received research funding provided to her institution from Rgenix, Boehringer Ingelheim, Bayer, Genentech/Roche, Bristol-MyersSquibb, Eli Lilly, and Merck, and served on advisory boards for Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck, Daiichi-Sankyo, and AstraZeneca.
Narita reported receiving grants and personal fees from Ono Pharma and Bristol-Myers Squibb and personal fees from Eli Lilly, Yakult Honsha, Daiichi-Sankyo, and Taiho.
Cat ID: 120
Topic ID: 78,120,730,16,188,120,23,935,192
