Updated clinical data from the PANTHERA study shows promising efficacy for pembrolizumab triple therapy in HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer regardless of a patient’s PD-L1 status.
Worldwide, gastric cancer is the fifth most common cancer and is frequently diagnosed at an advanced stage.1 Advanced gastric cancer, or unresectable local/regional or metastatic cancer, has a poor 5-year prognosis.1 It is treated with systemic combination chemotherapy typically including fluoropyrimidine, a platinum compound, docetaxel, and irinotecan.1 Targeted therapies, such as trastuzumab and ramucirumab, and immune checkpoint inhibitors, such as nivolumab and pembrolizumab, are also used in combination with chemotherapy to treat certain types of gastric cancer.1 HER2 promotes the growth of cancer cells and, in 10% to 20% of cases, is found in gastric cancer.1,2 Testing for HER2 is recommended for all patients with inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma, as HER2-positive gastric cancer can be targeted by trastuzumab.1 The PANTHERA clinical trial, a multicenter phase 1b/2 trial, was performed to study the antitumor activity of triple-combination pembrolizumab, trastuzumab, and chemotherapy as first-line treatment for HER2-positive gastric and gastroesophageal junction (GEJ) cancer. The updated results were presented at the 2021 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
The PANTHERA trial enrolled 43 patients, of which 6 finished 2-year treatment without disease progression. The study protocol was 200 mg pembrolizumab intravenously and 6 mg/kg trastuzumab (8-mg/kg loading dose) on day 1 every 3 weeks; capecitabine 1000 mg/m2 twice daily on days 1 through 14, and 80 mg/m2 cisplatin on day 1 every 3 weeks. The primary study end point was objective response rate (ORR) and secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, safety, and predictive biomarker analysis by targeted next-generation sequencing (NGS). End point analysis revealed an ORR of 76.7%, a median PFS of 8.6 months, and a median OS of 19.3 months. It was also found that 26 patients had a >50% reduction in tumor burden. The PD-L1 status of 38 patients was 55.3% with a combined positive score (CPS) ≥1 and 13.2% with a CPS ≥10. Targeted NGS analysis was run on tumor tissues from 39 patients; all were HER2 immunohistochemistry-positive. Baseline HER2 amplification by NGS was related to survival, and high tumor mutational burden demonstrated a tendency toward better survival. PD-L1, metastatic organ, or baseline tumor burden were not found to be associated with survival. The HER2 mutations L869R and D769H were related to acquired-treatment resistance.
First-line pembrolizumab, trastuzumab, and chemotherapy demonstrated efficacy in HER2-positive advanced gastric or GEJ cancer regardless of patient PD-L1 status.
Source: Rha SY, Lee C-K, Kim HS, et al. A multi-institutional phase 1b/2 trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): molecular profiling and clinical update. J Clin Oncol. 2021;39 (supp_3):218.
- Zhao D, Klempner SJ, Chao J. Progress and challenges in HER2-positive gastroesophageal adenocarcinoma. J Hematol Oncol. 2019;12:50.
- ClinicalTrials.gov. Pembrolizumab, trastuzumab, HER2 positive gastric cancer. Updated April 6, 2021. https://clinicaltrials.gov/ct2/show/NCT02901301. Accessed October 12, 2021.