Osimertinib combinations promising for NSCLC patients with acquired resistance to EGFR–TKIs
medwireNews: Data from the phase Ib TATTON trial suggest that patients with EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on prior EGFR–tyrosine kinase inhibitor (TKI) therapy could benefit from the addition of either the MET inhibitor savolitinib or the MEK inhibitor selumetinib to osimertinib.
Findings from the multicohort study were reported at the AACR Annual Meeting 2019, held in Atlanta, Georgia, USA.
Lecia Sequist (Massachusetts General Hospital Cancer Center, Boston, USA), who presented the savolitinib data, explained that MET-driven resistance develops in up to 10% of patients who progress on first- or second-generation EGFR–TKIs and in up to 25% of those who progress during treatment with the third-generation EGFR–TKI osimertinib.
Therefore, the TATTON researchers investigated the combination of osimertinib 80 mg/day and savolitinib 600 mg/day in individuals with MET-positive disease based on fluorescence in situ hybridization, next-generation sequencing, or immunohistochemistry. One group of participants had previously been treated with first- or second-generation EGFR inhibitors and did not carry the T790M mutation, while the other had received a third-generation agent.
Just over half (52%) of the 46 patients who had progressed after a first- or second-generation EGFR–TKI achieved a partial response that lasted for a median of 7.1 months. There were no complete responses and 35% of participants had stable disease for 6 weeks or more.
Among the 48 patients with disease progression following treatment with a third-generation EGFR–TKI, the objective response rate (ORR) was 25%; all responses were partial and the median duration of response was 9.7 months. Forty-four percent of the participants in this group had stable disease.
Sequist described the risk–benefit profile of the combination as “acceptable.” She noted that aspartate aminotransferase elevations (8%), neutropenia (8%), fatigue (7%), and pain (7%) were the most frequent side effects of grade 3 or worse in the group that had received first- or second-generation EGFR inhibitors, while decreased appetite (6%), fatigue (4%), and vomiting (4%) were most common in the other group.
“Our data suggest that the combination of osimertinib and savolitinib could overcome MET-driven resistance mechanisms, but further research is needed to determine the final effectiveness of this therapy,” concluded Sequist.
The trial also evaluated three different schedules of osimertinib and selumetinib in 36 patients. In the two continuous regimens osimertinib was given at a dose of 80 mg/day, while selumetinib was given at 25 mg twice daily to Asian patients and at 50 mg twice daily to patients from other countries, with escalation to 50 mg and 75 mg, respectively. The third regimen was an intermittent one in which osimertinib 80 mg/day was administered alongside selumetinib 75 mg twice a day on the first and fourth day of each week; in this case escalation involved transitioning to a 4 days on, 3 days off schedule.
As reported by Suresh Ramalingam (Emory University School of Medicine, Atlanta), the combination appeared to have antitumor activity in this setting, although the response rate varied by prior treatment and T790M status. Specifically, the ORR was 17% for those who had received prior treatment with a third-generation EGFR–TKI, and was 57% for osimertinib-naïve T790M-positive patients and 14% for osimertinib-naïve T790M-negative patients.
The findings were similar in the dose-expansion phase, which used the escalated intermittent regimen and included 47 participants. The ORRs were a respective 23% and 67% for patients who had and had not received a third-generation EGFR inhibitor.
And adverse events of at least grade 3 that were possibly related to study treatment occurred in a corresponding 33% and 17% of patients. Diarrhea was the most frequently occurring side effect of this grade in the overall dose-expansion cohort.
Ramalingam concluded: “Combining osimertinib with intermittent selumetinib was feasible with manageable toxicity, and demonstrated preliminary anti-tumor activity.”
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