Osimertinib plus Savolitinib Promising for Advanced Non–Small-Cell Lung Cancer and MET-Driven Resistance

Phoebe Starr

June 2019, Vol 10, No 3 - Lung Cancer


Atlanta, GA—The combination of the investigational MET inhibitor savolitinib plus the EGFR inhibitor osimertinib (Tagrisso) achieved encouraging responses in patients with MET-amplified, EGFR-positive non–small-cell lung cancer (NSCLC) and acquired, MET-driven resistance to previous therapies, with an acceptable side-effect profile. These findings represent interim results of 2 expansion cohorts of a phase 1b clinical trial presented at the 2019 American Association for Cancer Research meeting.

“To date, targeted therapy for lung cancer patients with EGFR mutations has consisted solely of monotherapy with various tyrosine kinase inhibitors, although we have known for years that a proportion of resistance to EGFR tyrosine kinase inhibitors results from activation of the MET bypass pathway,” said lead investigator Lecia V. Sequist, MD, MPH, Director, Center for Innovation in Early Cancer Detection, Massachusetts General Hospital Cancer Center, Boston.

“The two-dose expansion arms of the TATTON study show that osimertinib plus savolitinib has an acceptable safety profile. The combination showed encouraging antitumor activity in EGFR-mutant patients with MET amplification as a resistance mechanism after disease progression on first-, second-, or third-generation tyrosine kinase inhibitor,” Dr Sequist said.

MET-Driven Resistance

MET amplification is thought to drive resistance in approximately 5% to 10% of patients whose disease progresses after first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) and in approximately 25% of patients whose disease progresses after third-­generation EGFR TKIs. MET amplification appears to be the most common resistance mechanism to develop after front-line treatment with the third-­generation EGFR TKI osimertinib, which is FDA approved for first-line treatment of patients with NSCLC and EGFR mutation.

The use of an EGFR TKI and a MET inhibitor was studied previously, with disappointing results. Dr Sequist said that previous studies did not select patients for MET amplification, and older drugs were less specific than these 2 drugs, causing more off-target toxicity.

“TATTON studied newer TKIs with increased specificity for EGFR and MET and patients enrolled in the trial had to have documented MET-driven resistance,” Dr Sequist said.

Study Details

TATTON is a phase 1b open-label, multicenter study of osimertinib in combination with novel therapies in patients with advanced NSCLC and EGFR mutation. Patients in the 2 dose-expansion cohorts (cohorts A and B) that Dr Sequist reported on received treatment with osimertinib 80 mg daily combined with savolitinib 600 mg daily. Cohort A (N = 46) received previous treatment with first- and second-generation EGFR TKIs; cohort B (N = 48) received previous treatment with a third-generation EGFR TKI (either osimertinib or investigational third-­generation EGFR TKI).

MET amplification was documented by fluorescence in situ hybridization, next-generation sequencing, or immunohistochemistry.

In cohort A, 89% of the patients had adenocarcinoma; 67% received 1 previous therapy; the other patients received ≥2 previous therapies; and 67% of them had disease progression with first-line EGFR TKI. The combination of osimertinib plus savolitinib was given as a second-line treatment in cohort A.

In cohort B, 94% of the patients had adenocarcinoma; 2% received 1 previous therapy; and the others received ≥2 previous therapies. The combination of osimertinib plus savolitinib was used as third-line therapy in cohort B. The Table lists the responses in each cohort.

Table

In cohort A, the most common adverse events of any grade were nausea (37%), diarrhea (30%), and fatigue, decreased appetite, and pyrexia (28% each). Few events were grade ≥3. Adverse events in cohort B were similar to those in cohort A.

Grade ≥3 adverse events were reported in 43% of cohort A and 23% in cohort B.

“The take-home message is that the combination of osimertinib plus savolitinib is safe and has encouraging activity in patients whose tumors show MET amplification after first-, second-, or third-generation TKI. However, these are preliminary findings and further research is needed to establish the role of this approach,” Dr Sequist said.

Ongoing trials are evaluating treatments for resistance after osimertinib therapy.

“These findings are compelling, and this combination can be considered a ‘win,’ but randomized trials are still needed,” said Roy S. Herbst, MD, PhD, MS, MMS, Chief of Medical Oncology, Yale Cancer Center, New Haven, CT.

MET resistance is a new and important target that is found in about 15% of patients. The data today from TATTON are exciting and represent a high unmet need,” Dr Herbst stated.