New Approach in Advanced NSCLC: Adding MET Inhibitor Savolitinib

Alexander M. Castellino, PhD

April 01, 2019

ATLANTA — A new approach to the treatment of advanced nonsmall cell lung cancer (NSCLC) has been reported to show clinically meaningful responses.

The investigational drug savolitinib (AstraZeneca), a MET inhibitor, was used in combination with osimertinib (Tagrisso, AstraZeneca) in patients with advanced NSCLC who had developed resistance to prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and had acquired MET amplification.

The finding comes from the company-sponsored TATTON study (NCT02143466) and was presented here at the American Association of Cancer Research (AACR) 2019 Annual Meeting (abstracts CT032, CT033).

"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 and with MET-driven acquired resistance," presenter Lecia V. Sequist, MD, MPH, a thoracic medical oncologist at the Massachusetts General Cancer Center in Boston, said in a statement.   

"The study has shown efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option," she added.

Approached for comment, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston, told Medscape Medical News that osimertinib and savolitinib "is a highly effective and tolerable combination for those patients who have MET amplification as their resistance mechanism to EGFR inhibitors."

"We have been routinely screening for MET amplification for years; the results with the combination of osimertinib and savolitinib are very clinically relevant," she said.

Also approached for comment, Roy S. Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center, Connecticut, told Medscape Medical News that the results with savolitinib and osimertinib were compelling and the combination is "ready for prime time."

However, another arm of the same trial produced negative results.

Adding the MEK inhibitor selumetinib to osimertinib was associated with added toxicity (Abstract CTO34). "Most of the activity was seen in patients given the first- or second-generation EGFR-TKI who have the EGFR T790M mutation and many patients would have done well on osimertinib alone," Herbst told Medscape Medical News.

Rationale for TATTON

TATTON is a Phase 1b, open-label, multicenter study of osimertinib in combination with novel therapeutics conducted in patients with EGFR-mutated advanced NSCLC. The study was designed to allow an investigation of the optimal combination dose and schedule as well as ensuring patient safety by using intensive safety monitoring.

Herbst pointed out that one arm of the TATTON study evaluating the concurrent use of durvalumab (Imfinzi, AstraZeneca), a programmed cell death ligand 1 (PD-L1) inhibitor, and osimertinib was voluntarily suspended after reports of interstitial lung disease (ILD) or ILD-like events.

The other two arms of the study evaluated whether the addition of a MET inhibitor (savolitinib) or MEK inhibitor (selumetinib) could overcome resistance mechanisms that emerged following treatment with first-, second-, or third-generation EGFR-TKIs.

The combination of osimertinib and selumetinib addressed whether the combination could overcome resistance seen due to upregulation of the RAS/RAF/MEK/ERK pathway of acquired resistance to EGFR-TKIs, he added.

Preclinical studies had indicated that following progression on an EGFR-TKI, MET amplification can only be addressed with the combination of an EGFR-TKI and a MET inhibitor. Shaw indicated that the combination maintains target kinase inhibition and also addresses tumor heterogeneity. "Not all tumor cells have the same resistance mechanism," she said.  

Savolitinib MET the Challenge

Patients enrolled to receive the combination of osimertinib and savolitinib were required to have locally advanced or metastatic EGFR-mutated NSCLC that was resistant to other EGFR-TKIs. MET amplification status was determined using next generation sequencing, fluorescent in situ hybridization, or immunohistochemistry.

In cohort 1, patients were enrolled who had progressed on prior first- or second-generation EGFR-TKIs (EGFR T790M-negative cohort). In cohort 2, patients were enrolled who had progressed on prior third-generation EGFR-TKIs (EGFR T790M-positive cohort).

Forty-six patients were enrolled in cohort 1 (median age, 59 years; women, 67%; Asian, 80%). With 67% of patients progressing on the first EGFR-TKI, the combination of osimertinib and savolitinib was used second-line in these patients.

The 48 patients in cohort 2 were a median age of 59 years, 56% were men, and 77% were Asian. Of these patients, 27% had received three or more prior therapies and only one patient had progressed on first-line EGFR-TKI. In this cohort the combination of osimertinib and savolitinib was evaluated in the third-line setting.

Most common adverse events (AEs) with the combination (cohort 1/cohort 2) were nausea (37%/52%), vomiting (22%/38%), diarrhea (30%/27%), fatigue (28%/25%), decreased appetite (28%/23%), and pyrexia (26%/21%).

In cohorts 1 and 2, grade ≥ 3 AEs occurred in 43% and 23% of patients,and serious AEs were reported in 37% and 29% of patients, respectively. In cohort 2, osimertinib was discontinued in 21% of patients, and 10% of patients discontinued savolitinib.

The 46 patients in cohort 1 showed an objective response rate (ORR) of 52% and all had partial responses. Median duration of response was 7.1 months.

In cohort 2, the ORR was 25% and, again, all responses were partial responses. Median duration of response was 9.7 months.

"These data are impressive," Herbst said, adding: "This combination is useful for refractory disease."

However, he pointed out the need for randomized trials to confirm these results and to better define selection criteria.

The combination of osimertinib and savolitinib is now being evaluated in the Phase 2 SAVANNAH (NCT03778229) study in patients with EGFR-mutant, MET amplified NSCLC who have progressed on osimertinib. 

Selumetinib Did Not MEK It

The arm of TATTON that evaluated the combination of osimertinib and selumetinib enrolled patients with advanced EGFR-mutated NSCLC with disease progression on prior EGFR-TKIs, which included third-generation agents. Patients were allowed to enroll regardless of T790M or KRAS status.

Part A was a dose-finding study that evaluated several continuous and intermittent dosing regimens of selumetinib with osimertinib given once daily. Because of toxicities seen with the continuous-dosing regimen, patients enrolled into the dose expansion Part B cohort received selumetinib 75 mg given orally twice daily on the intermittent dosing schedule 4/3 (4 days on therapy and 3 days off therapy).

Although ORR was 34% (all partial responses), "there were very few responses in patients who were negative for the EGFR T790M mutation," Herbst noted, adding that this is an interesting option to evaluate in the front-line setting.

"Continuous dosing of selumetinib is definitely toxic. The combo was better tolerated when selumetinib is dosed intermittently. There may be a subset of patients for whom this combination may be effective, but the data are too early right now," Shaw said.

Osimertinib and selumetinib will continue to be evaluated in a Phase 2 study in treatment-naive patients with advanced NSCLC with EGFR mutations (NCT03392246).

The TATTON trial was funded by AstraZeneca. Sequist has reported consulting agreements with Genentech, Merrimack Pharmaceuticals, AstraZeneca, and Blueprint Medicines; and receiving honorarium from AstraZeneca. Her institution receives research funding on her behalf from AstraZeneca, Novartis, Boehringer Ingelheim, Merrimack Pharmaceuticals, Blueprint Medicines, and LOXO Oncology. Herbst has reported consulting for AbbVie, ARMO Biosciences, AstraZeneca, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serrano, Genentech/Roche, Genmab, Heat Biologics, LOXO Oncology, Merck, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, and Tocagen. Shaw has reported receiving honoraria from Pfizer, Roche, Genentech, Novartis, Guardant, and Foundation Medicine; serving in a consulting or advisory role for Pfizer, Roche, Genentech, Chugai, Novartis, Ariad/Takeda, Ignyta, Daiichi Sankyo, Taiho Pharmaceutical, EMD Serono, LOXO Oncology, Blueprint Medicines, KSQ Therapeutics, Natera, TP Therapeutics, and Bayer; and receiving research funding from Pfizer, Roche, Genentech, Novartis, Ignyta, Ariad, and TP Therapeutics.

AACR 2019. Abstract CT032, CT033, CT034.

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