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Osimertinib plus intermittent selumetinib shows preliminary activity in EGFR-mutated lung cancer
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ATLANTA — Osimertinib plus intermittent selumetinib demonstrated preliminary antitumor activity and acceptable toxicity in patients with EGFR-mutated non-small cell lung cancer whose disease progressed during prior treatment with an EGFR tyrosine kinase inhibitor, according to results of the phase 1b TATTON study presented at American Association for Cancer Research Annual Meeting.
The TATTON trial evaluated osimertinib (Tagrisso, AstraZeneca) in combination with novel treatments, including the potent, highly selective MEK1/MEK2 inhibitor selumetinib (AZD6244/ARRY-142886; AstraZeneca, Array BioPharma, Merck).
As HemOnc Today previously reported, the session — titled, “Can the challenge of NSCLC be MET or will we not MEK it?” — also included two other presentations of results from phase 1b TATTON cohorts.
“The question about EGFR-mutated disease is, is anyone cured? As good as these agents are, is anyone cured?” Roy Herbst, MD, PhD, ensign professor of medicine (medical oncology), professor of pharmacology and chief of medical oncology at Yale Cancer Center, said during the session. “I’m afraid the answer is probably no, due to the resistance that develops.”
Suresh S. Ramalingam, MD, director of the division of medical oncology at Winship Cancer Institute of Emory University, presented data from the dose-finding (part A) and dose expansion (part B) parts of the TATTON study.
“With EGFR-mutated disease, the survival for these patients, thankfully, is now measured in years, not in months,” Ramalingam said. “So we are seeing more and more patients who have received multiple prior regimens.”
Ramalingam and colleagues evaluated 83 adults with advanced EGFR-mutated NSCLC who demonstrated disease progression on a previous EGFR TKI, including third-generation inhibitors, regardless of T790M or KRAS status.
Part A of the study included 36 patients, most of whom were white (n = 18) or Asian (n = 17). Twenty-six of these patients had a baseline exon 19 deletion.
Patients in part A received osimertinib 80 mg once daily plus intermittent or uninterrupted selumetinib. The researchers administered continuous selumetinib 25 mg/50 mg twice daily to Asian patients, whereas other patients received continuous selumetinib 50 mg/75 mg twice daily or intermittent selumetinib 75 mg twice daily on a 4-days-on/3-days-off schedule, or on days 1 and 4 of each week of treatment.
Part B of the study included 47 patients (94% Asian, 64% baseline exon 19 deletion) who received osimertinib plus intermittent selumetinib 75 mg twice daily on a 4-days-on/3-days-off schedule.
Safety, tolerability and preliminary efficacy, assessed by objective response rate, served as the primary outcome. Duration of response and pharmacokinetics served as secondary outcomes.
In part A, the most prevalent treatment-related adverse events included diarrhea (75%), nausea (39%) and fatigue (33%).
Six patients undergoing treatment with continuous selumetinib experienced grade 3 dose-limiting toxicities, including aspartate aminotransferase and alanine aminotransferase increase (50-mg dose); diarrhea, asthenia and dizziness (50-mg dose); diarrhea (n =2; 75-mg dose); diarrhea and nausea (75-mg dose); and pneumonitis (75-mg dose).
Intermittent dosing yielded no dose-limiting toxicities, so the researchers chose the 4/3 schedule for part B.
Among that group, the most common treatment-related adverse events included diarrhea (81%), stomatitis (32%) and paronychia (30%).
Fifteen patients (42%) in part A had confirmed partial responses, 14 (39%) had stable disease at 6 weeks, three (8%) had progressive disease, two (6%) died and two (6%) were not evaluable.
The median duration of response was 16.6 months; 77% had sustained response at 12 months.
In part B, 16 patients (34%) had confirmed partial response, 16 (34%) had stable disease, 11 (23%) had progressive disease, two (4%) died and two (4%) were not evaluable.
The duration of response in part B was 9.1 months, and 31% continued to respond at 12 months. Osimertinib and selumetinib had pharmacokinetic parameters comparable to those previously seen with monotherapy, researchers reported.
“The schedule of osimertinib plus intermittent selumetinib was chosen as the regimen with the most favorable therapeutic index from this experience,” Ramalingam said during the presentation. “We conclude that combining osimertinib with intermittent selumetinib is feasible, with manageable toxicity, and has already demonstrated promising preliminary antitumor activity.”
Ramalingam said studies are ongoing to further investigate this regimen in patients with NSCLC.
“We are conducting analyses to explore the correlation between baseline tyrosine kinase-resistance mechanisms and response to this combination approach,” Ramalingam said. “Finally, there is an ongoing study at Dana-Farber Cancer Institute that looks at this combination in [patients with] newly-diagnosed EGFR-mutated non-small cell lung cancer.”
In his discussion, Herbst reviewed the current standard of care for NSCLC and EGFR-mutated disease in the context of these data from the TATTON expansion cohort studies, and he contemplated the goal of a cure for EGFR-mutated disease. He said although both MEK inhibitors and MET-targeted treatments have shown some antitumor activity, he believes MET currently holds more promise.
“Which of these should we endorse right now, MET or MEK?” he said. “I would say that, given what we’ve seen today, both have some activity, but today, the third day of the baseball season, I would say we’ve MET it.” – by Jennifer Byrne
Reference:
Ramalingam SS, et al. Abstract CT034. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
Disclosures: Ramalingam reports financial relationships with AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Loxo Oncology, Merck, Nektar and Tesaro. Herbst reports financial relationships with AbbVie, AstraZeneca, Biodesix, BristolMyers Squibb, Eli Lilly, EMD Serrano, Genentech/Roche, Heat Biologics, Junshi Pharmaceuticals, Loxo Oncology, Merck, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen and Tesaro; scientific advisory board roles with Infinity Pharmaceuticals, NextCure and Neon Therapeutics; and a board member role with Junshi Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Charu Aggarwal, MD, MPH
Detection of EGFR mutations and other therapeutically targetable mutations has dramatically changed the therapeutic landscape of non-small cell lung cancer. The availability of third-generation EGFR tyrosine kinase inhibitors — primarily osimertinib — has markedly improved outcomes for patients with EGFR-mutant NSCLC, both in the second-line T790M-emergent setting and now in the first-line setting.
Despite this improvement, a subset of patients still does not derive substantial sustained benefit, predominantly by virtue of development of resistance mutations. At this year’s AACR Annual Meeting, we saw data from the TATTON trial, which evaluated osimertinib in combination with a MET or MEK inhibitor.
The study presented by Ramalingam and colleagues evaluated the MEK inhibitor selumetinib in two different dosing schedules in combination with osimertinib. Intermittent dosing schedule of selumetinib — 4 days on and 3 day off — yielded no dose-limiting toxicities and was considered feasible, with minimal additive toxicity.
Although we saw hints of the preliminary antitumor activity for the entire study population, it is important to point out two things. First, even after having received a prior third-generation TKI directed at T790M mutation, the combination was able to generate an overall response rate of 17% in part A of the study and 23% in part B. Even though these are observations from relatively small numbers, this preliminary activity suggests that there may be an incremental advantage of combination therapy, after having already received third-generation TKI. Second, among patients who had not received a prior third-generation TKI, the ORR with this combination was 42% in part A of the study. Parsing these data a little further, the response rate was higher — 57% — among a subset of patients who had a T790M mutation detected, highlighting that osimertinib may be driving the majority of the response rate for this osimertinib-naive population.
Analyses of resistance mechanisms are ongoing and will be extremely valuable in application of these results in a practical clinical setting. Nevertheless, these are intriguing data that should be validated in the larger study, such as the planned phase 2 ORCHARD trial, which will evaluate both targeted and nontargeted combination treatments for patients with advanced EGFR-mutant NSCLC who progressed on frontline osimertinib.
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