Savolitinib plus osimertinib combination therapy triumphs in treatment of mutated lung cancer
Combination therapy with the MET inhibitor savolitinib and the EGFR inhibitor osimertinib showed robust and durable clinical responses among patients with EGFR-mutated and MET-amplified non-small-cell lung cancer (NSCLC), according to results of the phase Ib TATTON study presented at AACR 2019.
The TATTON results were presented in two cohorts, each with more than 40 patients with EGFR-mutant, MET-amplified NSCLC treated with osimertinib 80 mg once daily plus savolitinib 600 mg once daily. The first cohort analyzed treatment response after progression on prior first-/second-generation EGFR tyrosine kinase inhibitor (TKI) therapy. The second cohort analyzed response to the combination therapy after progression on prior third-generation EGFR TKI therapy. [Yu H, et al, AACR 2019, abstract CT032; Sequist LV, et al, AACR 2019, abstract CT033]
Results from the first cohort (n=46; median age, 59 years; 67 percent female) showed an objective response rate (ORR) of 52 percent with the combination therapy. The median duration of response was 7.1 months. The second cohort (n=48; median age, 59 years; 56 percent male) demonstrated an ORR of 28 percent, with a median duration of response of 9.7 months.
“Data from the TATTON trial demonstrate, for the first time, the benefit of adding a MET inhibitor to an EGFR inhibitor in patients with EGFR-mutant NSCLC with MET-driven acquired resistance. The study has shown efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option,” said study investigator Dr Lecia Sequist from the Massachusetts General Hospital, Boston, Massachusetts, US.
The most common adverse events (AEs) experienced by patients in the first cohort were nausea (37 percent), diarrhoea (30 percent), fatigue (28 percent), decreased appetite (28 percent), pyrexia (26 percent), and vomiting (22 percent). Around one-third of the patients had an AE leading to discontinuation of treatment.
The most common all-causality AEs experienced by patients in the second cohort were nausea (52 percent), vomiting (38 percent), diarrhoea (27 percent), fatigue (25 percent), decreased appetite (23 percent), and pyrexia (21 percent). Serious AEs were reported in 29 percent of the patients.
“Overall, the regimen was tolerable, although there was added toxicity with the combination of osimertinib and savolitinib compared with osimertinib given alone. Our understanding of the AE profile of this combination therapy and how to manage these AEs is improving,” Sequist commented.
“Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance, but certainly further research is needed to determine the final effectiveness of this therapy,” she added.
The ongoing phase II SAVANNAH study (NCT03778229) will further evaluate the combination of osimertinib and savolitinib in these patients with EGFR-mutant, MET-positive NSCLC whose disease has progressed on prior osimertinib.
Studies have reported that high MET expression is associated with a worse prognosis in patients with NSCLC. The rate of MET amplification in NSCLC has been reported to range from 1 percent to 39 percent. [J Cancer 2018;9:1836-1845]