MET/EGFR Combo Effective for Advanced NSCLC

Myung-Ju Ahn, MD

The combination of osimertinib (Tagrisso) and the MET inhibitor savolitinib showed signs of efficacy for pretreated patients with MET-positive, EGFR-mutant non—small cell lung cancer (NSCLC), regardless of prior treatment with a T790M-directed therapy, according to findings from part B of the TATTON trial presented at the 2017 World Conference on Lung Cancer (WCLC).¹

Across patients in the phase Ib study (N = 64), the objective response rate (ORR) was 47% with the combination of osimertinib and savolitinib. In those pretreated with a T790M-directed therapy (n = 30), the ORR was 33% and in those with T790M-negative disease (n = 23) the ORR was 61%. In patients with T790M-positive disease (n = 11), the ORR was 55% for the combination.

"This combination showed encouraging antitumor activity in 3 groups of MET-positive patients, regardless of T790M status or prior T790M treatment," said investigator Myung-Ju Ahn, MD, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center. "Further investigation of this combination is required, and this combination may provide a new treatment option in the patient treatment pathway."

MET amplification or a MET-based mechanism of resistance is seen in approximately 22% of patients with NSCLC who progress on first-line EGFR TKIs. Moreover, using tissue biopsy samples, MET amplification is commonly found after acquired resistance to osimertinib, Ahn noted. "More than 600 patients were screened, with 270 actually delivering tissue. Among them, 67 were positive for MET, which is around 25%," she noted.

Part B of the phase Ib TATTON study enrolled 66 patients with MET-positive, EGFR-mutated advanced NSCLC across 3 cohorts. The first group (n = 30) contained those who received prior treatment with a T790M-directed TKI; the second group contained patients with T790M alterations who had not received a prior T790M-directed therapy (n = 12). The final arm (n = 24) included patients with T790M-negative tumors who had not received a T790M-directed therapy.

In part A of the trial, patients with EGFR-mutant NSCLC received the combination in a dose escalation cohort. The final response rate in this group was 18%. The established dose for part B was osimertinib at 80 mg plus savolitinib at 600 mg.

In part B of the trial, the median age was 59.5 years, the majority were Asian (86%), and 58% were female. The primary ECOG performance status was 1 (65%). Eight percent of patients had locally advanced disease, and the remainder had metastatic NSCLC. All patients had progressed on ≥1 prior EGFR TKI.

In the centrally confirmed group, ORRs, which consisted entirely of partial responses, were 28%, 57%, and 53% in the T790M pretreated, T790M-positive, and T790M-negative groups, respectively. The DCR across each group was 80%, 100%, and 93%, respectively.

"The response is quite encouraging, given the T790M-negative and given the third-generation treated patients; however, we don't have any published duration of response data yet," said Ahn. "In terms of response, I think it is quite encouraging, and I think it is important to continue to screen these patients for MET."

The most common all-grade adverse events (AEs) regardless of cause were nausea (44%), vomiting (35%), decreased appetite (30%), fatigue (30%), and rash (23%). Grade ≥3 AEs were experienced by 50% of patients, with the most common all-cause events being vomiting (8%), AST/ALT increase (6%), and rash (6%). The most common serious AEs, occurring in 4% of patients each, were pneumonia, dyspnea, acute kidney injury, and pyrexia.

Osimertinib was discontinued for 50% of patients, primarily due to progressive disease (35%) and AEs (11%). Savolitinib was discontinued for 59% of patients due to AEs (30%) and progressive disease (24%). At the data cutoff, 41% of patients were still receiving the combination, and 9% continue to receive osimertinib alone.

The study continues to enroll patients across South Korea, Taiwan, and the United States (NCT02143466). Additionally, savolitinib was also explored in combination with gefitinib in Chinese patients with EGFR-mutant, MET-positive NSCLC following prior treatment with an EGFR TKI.² In this study, the ORR was 31%, all partial responses. These responses occurred primarily in the T790M-negative patients (52%).

“Secondary resistance mechanisms often emerge during treatment with mutation-targeted medicines, leading to disease progression," Ahn noted. "The data presented at WCLC demonstrate the potential of utilizing savolitinib in MET-driven lung cancers to address resistance challenges.”

References:

1. Ahn M-J, Han J-Y, Sequist LV, et al. TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8985.
2. Yang J-J, Fang J, Shu Y, et al. A phase Ib trial of savolitinib plus gefitinib for Chinese patients with EGFR-mutant MET-amplified advanced NSCLC. Presented at: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 2017; Yokohama, Japan. Abstract 8995.

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In those with centrally confirmed MET-positive disease by FISH (N = 47), the ORR was 40%, and 47% of patients had stable disease (SD) for ≥6 weeks. The disease control rate (DCR; ORR plus SD) was 87%. The median duration of response was not yet reached at the August 31, 2017, data cutoff (range, 1.6-9.7).