Treatment with the anti-PD-1 therapy Keytruda (pembrolizumab) plus Lenvima (lenvatinib), an orally available TKI, in combination with chemotherapy missed the primary end point of the phase 3 LEAP-015 trial for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma, according to a press release from Merck.
Although the combination regimen demonstrated a statistically significant improvement in progression-free survival (PFS)—one of the study’s dual primary end points—and objective response rate (ORR), a key secondary endpoint, compared with standard of care chemotherapy, during the final analysis, investigators found that treatment did not meet its other primary end point of overall survival (OS).
Regarding safety, the Keytruda and Lenvima-based combination regimen had a consistent safety profile of that observed in previously reported studies evaluating the combination. The company shared that these results will be shared at an upcoming medical meeting, and that a full evaluation of the data from this study is ongoing.
“Locally advanced unresectable or metastatic gastroesophageal adenocarcinoma remains a challenging disease to treat and a leading cause of cancer death worldwide,” Dr. Gregory Lubiniecki, Vice President of Global Clinical Development at Merck Research Laboratories, stated in the press release. “These study results add to our understanding of this combination and will inform our future research as we strive to improve outcomes for more patients with cancer.”
Background Information on the Combination Regimen and the LEAP-015 Trial
Gastric, or stomach, cancer develops slowly and often goes undetected until an advanced stage, with over 70% of cases diagnosed late. Adenocarcinomas, arising from the stomach’s mucosal lining, account for 90% to 95% of these cases. In 2022, approximately 969,000 global cases and 660,000 deaths were reported, making it the fifth most diagnosed cancer and cause of cancer-related death. In the U.S., an estimated 26,890 new cases and 10,880 deaths are expected in 2024, with a five-year survival rate of 7% for distant-stage disease.
Esophageal cancer ranks as the 11th most common cancer and seventh leading cause of cancer death worldwide, with 511,000 new cases and 445,000 deaths in 2022. In the U.S., an estimated 22,370 new cases and 16,130 deaths are expected in 2024, with a five-year survival rate of 6% for advanced disease. Adenocarcinoma, the most common esophageal cancer type in the U.S., often occurs in the lower esophagus and is rising in incidence globally.
To combat this unmet need in patients, Merck currently has more than 1,600 trials studying Keytruda across a wide variety of cancers. Keytruda is an anti–PD-1 therapy which increases the ability of the body’s immune system to help detect and fight tumor cells. Also a humanized monoclonal antibody, the agent blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which then activates T lymphocytes, affecting both tumor and healthy cells.
The randomized, open-label LEAP-015 trial is evaluating Keytruda in addition to Lenvima with chemotherapy versus chemotherapy alone for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma. part 1 of the study is a safety run-in and part 2 is the main study. In part 2 of the study, OS and PFS assessed by blinded independent central review (BICR) serve as co-primary end points in patients whose tumors express PD-L1 and in all patients. ORR and duration of response as assessed by BICR in patients whose tumors express PD-L1 and in all patients, as well as safety, serve as secondary end points of the trial.
In Part 2 of the study, 880 patients were randomly assigned in a 1:1 fashion to receive Keytruda plus Lenvima and chemotherapy. The induction phase lasted approximately 12 weeks, during which patients received 400 milligrams (mg) of intravenous (IV) Keytruda every six weeks for two cycles, oral Lenvima at 8 mg daily, and chemotherapy. In the consolidation phase, patients received either 400 mg of IV Keytruda every six weeks for two cycles for up to 16 doses plus oral Lenvima at 20 mg daily or continued chemotherapy with maximum cycles.
Other Indications
Keytruda plus Lenvima has been approved in the U.S. by the FDA, as well as in the European Union, Japan and other countries, for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Notably, the company shared that they are evaluating the combination in hepatocellular carcinoma and esophageal cancer across multiple clinical trials.
In gastric cancer, Keytruda is approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. It is also approved in combination with Herceptin (trastuzumab), fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of locally advanced, unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma with PD-L1 expression.
In esophageal cancer, the agent is also approved by regulatory agencies in combination with platinum- and fluoropyrimidine-based chemotherapy in locally advanced or metastatic esophageal or GEJ carcinoma, specifically in those who are not candidates for surgical resection or definitive chemoradiation.
The company emphasized that, "Results from the LEAP-015 trial do not affect the current approved indications for Keytruda plus Lenvima or other ongoing trials from the LEAP clinical program," in the press release.
“Gastric and gastroesophageal cancers continue to present challenges due to their heterogeneity and generally poor prognoses,” Dr. Corina Dutcus, Senior Vice President and Oncology Global Clinical Development Lead at Eisai Inc., concluded in the release. “While the LEAP-015 trial did not show a statistically significant increase in overall survival, we were pleased to observe an improvement in progression-free survival and objective response rate for patients treated with Keytruda plus Lenvima in combination with chemotherapy. These results contribute to the scientific community’s collective understanding of these complex diseases and add to the body of knowledge in oncology research. We are deeply grateful to the patients, caregivers and investigators who participated in this study.”
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