As reported in The Lancet Oncology, Lecia V. Sequist, MD, and colleagues have found activity and an acceptable risk-benefit profile with the combination of the third-generation EGFR tyrosine kinase inhibitor osimertinib and the MET tyrosine kinase inhibitor savolitinib in patients with EGFR mutation–positive, MET-amplified non–small cell lung cancer (NSCLC) who had disease progression after treatment with EGFR tyrosine kinase inhibitors.

Lecia V. Sequist, MD

Study Details

The current report from the international study is an interim analysis from two expansion cohorts. An initial cohort consisted of 144 patients who had been previously treated with a third-generation EGFR tyrosine kinase inhibitor or who had not been previously treated with a third-generation EGFR tyrosine kinase inhibitor and were either Thr790Met-negative or Thr790Met-positive. These patients received osimertinib at 80 mg and savolitinib at 600 mg daily (300 mg in patients weighing ≤ 55 kg after a protocol amendment; n = 8).

A subsequent cohort consisted of 42 patients who had not previously received a third-generation EGFR tyrosine kinase inhibitor and were Thr790Met-negative. These patients received osimertinib at 80 mg plus savolitinib at 300 mg daily.

Safety Profile

Adverse events of grade ≥ 3 occurred in 57% of patients in the initial cohort, with the most common being increased aspartate aminotransferase (7%) and decreased neutrophils (7%), and in 38% of those in the subsequent cohort, with the most common being pneumonia (12%) and drug hypersensitivity (7%). Serious adverse events were reported in 45% of patients in the initial cohort, with the most common being anaphylactic reaction (4%) and pneumothorax (4%), and in 26% of patients in the subsequent cohort, with the most common being pneumonia. Two deaths in the initial cohort—due to acute renal failure and an unknown cause—were considered possibly related to treatment.

Responses

Among 138 evaluable patients in the initial cohort, an objective response (all partial responses) was  observed in 48% of patients, including 30% of 69 patients with previous third-generation EGFR tyrosine kinase inhibitor treatment, 65% of 51 who were Thr790Met-negative with no prior third-generation EGFR tyrosine kinase inhibitor treatment, and 67.5% of 18 who were Thr790Met-positive with no prior third-generation EGFR tyrosine kinase inhibitor treatment. At the time of analysis, the median duration of response among all patients in the cohort was 9.5 months, with 67% remaining in response at 6 months.

Among 36 evaluable patients in the subsequent cohort, an objective response (all partial responses) was observed in 64% of patients. At the time of analysis, the median duration of response was 8.0 months, with 71% of patients maintaining response at 6 months.

The investigators concluded, “The combination of osimertinib and savolitinib has an acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation–positive, advanced NSCLC, who had disease progression on a previous EGFR tyrosine kinase inhibitor. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR tyrosine kinase inhibitors.”

Geoffrey Oxnard, MD, of the Department of Thoracic Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.

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