In the phase II INSIGHT 2 trial reported in The Lancet Oncology, Yi-Long Wu, MD, and colleagues found that the combination of tepotinib plus osimertinib showed clinically meaningful activity in patients with advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with MET amplification following disease progression on first-line osimertinib.

Yi-Long Wu, MD

Study Details

In the trial, 128 patients enrolled at sites in 17 countries between February 2020 and November 2022 received tepotinib at 500 mg plus osimertinib at 80 mg once daily. Overall, 62% of patients were Asian. MET amplification was identified by central tissue biopsy fluorescence in situ hybridization (FISH) or liquid biopsy next-generation sequencing.

The primary endpoint of the trial was independently assessed objective response in patients with MET amplification by FISH who received tepotinib/osimertinib with at least 9 months of follow-up (primary activity analysis population).

Responses

After a median follow-up of 12.7 months (interquartile range = 9.9–20.3 months), objective responses (all partial) were observed in 49 (50.0%, 95% confidence interval [CI] = 39.7%–60.3%) of 98 patients in the primary activity analysis population. An additional 13 patients (13%) had stable disease lasting ≥ 6 weeks. Median duration of response was 8.5 months (95% CI = 6.1 months to not evaluable); rates at 6 months and 12 months were 66% and 48%, respectively. Median follow-up for progression-free survival was 11.5 months; median progression-free survival was 5.6 months (95% CI = 4.2–8.1 months), with 6- and 9-month rates of 48% and 30%, respectively.

Adverse Events

Among all 128 patients receiving study treatment, the most common treatment-related adverse events of any grade were diarrhea (49%) and peripheral edema (41%). Treatment-related grade ≥ 3 adverse events occurred in 34% of patients, most commonly peripheral edema (5%), decreased appetite (4%), prolonged QT interval (4%), and pneumonitis (3%).

Serious treatment-related adverse events occurred in 13% of patients, most commonly pneumonitis (4%). Treatment-related adverse events led to discontinuation of either agent in 10%. Death considered potentially related to treatment occurred in four patents, due to pneumonitis and dyspnea in one, pneumonitis in one, decreased platelets in one, and respiratory failure in one.

The investigators concluded, “Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.”

Dr. Wu, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital Southern Medical University, Guangzhou, China, and Tae Min Kim, MD, of the Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea, are the corresponding authors for The Lancet Oncology article.

Disclosure: The study was funded by Merck. For full disclosures of the study authors, visit thelancet.com.