ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.
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Dr. Suresh S. Ramalingam
In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.
“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.
The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.
Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.
In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.
Therapeutic rationale
Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.
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Dr. Roy S. Herbst
In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.
As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.
In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.
In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.
An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.
In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.
The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.
The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.