THE ADDITION of the MET inhibitor savolitinib to the EGFR inhibitor osimertinib led to activity in patients with MET-amplified, EGFR-mutated non–small lung cancer (NSCLC) with acquired resistance to previous therapies, according to interim results from two expansion cohorts of a phase Ib clinical trial.1,2 Results for both cohorts were presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR).
Lecia V. Sequist, MD
“To date, targeted therapy for patients with lung cancer who have 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 Lecia V. Sequist, MD, who presented these results at a press conference. Dr. Sequist is a thoracic medical oncologist and Director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center, Boston.
“The two dose-expansion arms of the TATTON study demonstrated 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 a first-, second-, or third-generation tyrosine kinase inhibitor,” she noted.
Study Rationale
MET AMPLIFICATION has been identified as a resistance mechanism in approximately 5% to 10% of patients who experience disease progression after first- or second-generation EGFR tyrosine kinase inhibitors and in about 25% of those with disease progression after third-generation EGFR tyrosine kinase inhibitors. Recent data suggest that MET amplification is the most common resistance mechanism to develop after front-line treatment with osimertinib.3
Older trials of the combination of an EGFR tyrosine kinase inhibitor plus a MET inhibitor were not successful. However, this may have been due to inappropriate patient selection as well as use of less-selective drugs. “In TATTON, newer tyrosine kinase inhibitors with increased specificity for EGFR and MET were used. Patients enrolled in the trial had to have documented MET-driven resistance,” she explained.
“The take-home message is that the combination of osimertinib plus savolitinib is safe and has encouraging activity in patients whose tumors show <em>MET</em> amplification after first-, second-, or third-generation tyrosine kinase inhibitors.”— Lecia V. Sequist, MD
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TATTON is a phase Ib open-label, multicenter study of osimertinib in combination with novel therapies conducted in patients with EGFR-mutated advanced NSCLC. Another arm that evaluated osimertinib plus the MEK inhibitor selumetinib had negative results, including increased toxicity; a separate arm that looked at the combination of osimertinib plus the anti–programmed cell death ligand 1 inhibitor durvalumab was closed early due to toxicity.
Dose-Expansion Cohorts
THE DOSE used in the expansion cohorts was osimertinib at 80 mg daily combined with savolitinib at 600 mg daily. Patients enrolled in cohort A (n = 46) had received prior treatment with first-and second-generation EGFR tyrosine kinase inhibitors; those in cohort B (n = 48) received prior treatment with a third-generation EGFR tyrosine kinase inhibitor (either osimertinib or an investigational third-generation EGFR tyrosine kinase inhibitor). Patients were required to have documented MET amplification using either fluorescence in situ hybridization, next-generation sequencing, or immunohistochemistry.
In cohort A, the median age was 56 years; 67% were female; 80% were Asian; and 89% had adenocarcinoma. A total of 67% had 1 prior therapy, 13% had 2 prior therapies, 13% had 3 prior therapies, and 7% had more than 3 prior therapies. Nearly two-thirds of patients experienced disease progression on a first-line EGFR tyrosine kinase inhibitor, and osimertinib plus savolitinib was given in the second line to patients in cohort A.
Key Findings
THE PRELIMINARY response rate was 52% (all partial responses). The median duration of response was 7 months, and the median time to response was 43 days. The most common adverse events of any grade were nausea (37%), diarrhea (30%), fatigue, decreased appetite, and pyrexia (28% each).
In cohort B, the median age was 59; 44% were female; 77% were Asian; and 94% had adenocarcinoma. A total of 2% had 1 prior therapy, 44% had 2 prior therapies, 27% had 3 prior therapies, and 27% had more than 3 prior therapies. In this cohort, the combination of osimertinib plus savolitinib was evaluated as third-line therapy.
MET AMPLIFICATION TARGETED IN TATTON TRIAL
- Patients with EGFR-mutated, MET-amplified non–small cell lung cancer that progressed on previous EGFR tyrosine kinase inhibitor therapy had encouraging responses to combination therapy with osimertinib (EGFR inhibitor) and savolitinib (MET inhibitor) with acceptable safety.
- The combination approach targeting EGFR and MET will be studied further.
The preliminary response rate in cohort B was 25% (all partial responses). The median duration of response was 9 months, and the median time to response was 46 days. Toxicities of any grade were similar to those seen in cohort A. Grade 3 or higher adverse events occurred in 43% of cohort A and 23% of 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 tyrosine kinase inhibitors. However, these findings are preliminary, and further research is needed to establish the role of this approach,” Dr. Sequist said.
Osimertinib is now approved by the U.S. Food and Drug Administration as front-line therapy for patients with EGFR mutations. Only a small number of patients enrolled in the TATTON trial had been previously treated with osimertinib.
Two trials are planned to evaluate patients who develop resistance after osimertinib. The ongoing phase II SAVANNAH trial is focusing on the combination of osimertinib plus savolitinib in patients with EGFR-mutant, MET-amplified NSCLC. The phase II ORCHARD trial will study both targeted and nontargeted treatments in patients with advanced EGFR-mutant NSCLC. ■
DISCLOSURE: Dr. Sequist is an advisory board member for AstraZeneca, Blueprint, Genentech, and Merrimack; has received research funding from AstraZeneca, Blueprint, Boehringer-Ingelheim, Merrimack, and Novartis; and has received honoraria from AstraZeneca.
REFERENCES
1. Yu H, Ahn MJ, Kim SW, et al: TATTON phase 1b expansion cohort: Osimertinib plus savolitinib for patients with EGFR-mutant, MET-amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor tyrosine kinase inhibitor. 2019 AACR Annual Meeting. Abstract CT032. Presented March 31, 2019.
2. Sequist LA, Lee JS, Han JY, et al: TATTON phase 1b expansion cohort: Osimertinib plus savolitinib for patients with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor tyrosine kinase inhibitor. 2019 AACR Annual Meeting. Abstract CT033. Presented March 31, 2019.
3. Ramalingam SS, Cheng Y, Zhou C, et al: Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study. ESMO 2018 Congress. Abstract LBA50. Presented October 19, 2018.
