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Rociletinib, AZD9291 active in EGFR inhibitor-resistant NSCLC
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The EGFR inhibitors rociletinib and AZD9291 demonstrated encouraging activity in patients with non–small cell lung cancer that progressed during treatment with other EGFR tyrosine kinase inhibitors, according to study results published in The New England Journal of Medicine.
Patients with EGFR T790M mutations derived the greatest benefit from these novel agents, results showed.
First- and second-generation EGFR tyrosine kinase inhibitors typically demonstrate strong activity in patients with EGFR mutations, inducing response rates between 50% and 70%. However, resistance develops and often is mediated by the EGFR T790M gene mutation, present in more than half of resistant cases. This resistance develops at a median 9 to 13 months, according to study background.
With no approved therapies to specifically target the EGFR T790M gene mutation, clinicians often rely on cytotoxic chemotherapy, but median survival after EGFR T790M mutations emerge is typically less than 2 years.
In separate studies, researchers evaluated rociletinib (CO-1686, Clovis Oncology) and AZD9291 (AstraZeneca) to assess its activity in patients with EGFR-mutated NSCLC, including those with T790M resistance mutations.
Lecia V. Sequist, MD, MPH, medical oncologist at Massachusetts General Hospital Cancer Center and assistant professor of medicine at Harvard Medical School, and colleagues conducted a phase 1/phase 2 study to assess rociletinib in 130 patients.
Lecia V. Sequist
All patients had EGFR-mutated NSCLC that progressed during prior treatment with an EGFR inhibitor, and patients had undergone a median four prior treatments.
The initial group of 57 patients received the free-base form of rociletinib at doses ranging from 150 mg daily to 900 mg twice daily. The remaining 73 patients received the hydrogen bromide salt version of rociletinib at doses ranging from 500 mg twice daily to 1,000 mg twice daily. Treatment was administered in continuous 21-day cycles.
Safety, side-effect profile, pharmacokinetics and preliminary antitumor activity served as the primary study objectives.
An efficacy analysis included 63 patients with confirmed T790M status (positive, n = 46; negative, n = 17) who either received a free-base dose of 900 mg twice daily or the hydrogen bromide salt form at any dose.
Researchers reported an objective response rate of 59% (95% CI, 45-73) among patients with T790M-positive disease and 29% (95% CI, 8-51) among patients with T790M-negative disease.
The disease control rate — defined as the proportion of patients who achieved complete or partial response plus those who achieved stable disease — was 93% among patients with T790M-positive disease vs. 59% among patients with T790M-negative disease. Median PFS also was longer in the T790M-positive group (13.1 months; 95% CI, 5.4-13.1) than the T790M-negative group (5.6 months; 95% CI, 1.3-not reached).
Overall, researchers reported infrequent and mild treatment-related adverse events. The most common grade 3 adverse event was hyperglycemia, which developed in 22% of patients who received therapeutic doses.
The researchers acknowledged their study was limited due to the relatively small number of patients who have been treated with rociletinib to date.
“The response rate of 59% and prolonged disease control among some T790M-positive patients are encouraging — particularly because there are no approved therapies that specifically target T790M, although several other molecules are in development,” Sequist and colleagues wrote.
In a separate study, Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology, scientific director of the Belfer Institute for Applied Cancer Science and senior physician at Dana-Farber Cancer Institute, as well as professor of medicine at Harvard Medical School, and colleagues evaluated AZD9291 in 253 patients with advanced NSCLC.
The trial included 31 patients in dose-escalation cohorts and 222 patients in dose-expansion cohorts. All patients had radiological documentation of disease progression after previous treatment with EGFR inhibitors.
Safety, pharmacokinetics and efficacy served as the primary objectives. Doses ranged from 20 mg to 240 mg once daily.
Researchers reported no dose-limiting toxicities among the 31 patients in the dose-escalation cohorts. The most common adverse events in the dose-expansion cohorts were diarrhea (47%), rash (40%), nausea (22%) and decreased appetite (21%).
Overall, Jänne and colleagues reported an objective response rate of 51% (95% CI, 45-58). Objective response rates were 61% (95% CI, 52-70) among the 127 evaluable patients with confirmed T790M mutations and 21% (95% CI, 12-34) among the 61 patients without centrally detectable T790M mutations.
Researchers reported longer median PFS among T790M-positive patients (9.6 months; 95% CI, 8.3-not reached) than the T790M-negative patients (2.8 months; 95% CI, 2.1-4.3).
A higher percentage of T790M-positive patients demonstrated response duration of 6 months or longer (88% vs. 69%).
“This [study] suggests that a structurally distinct EGFR inhibitor, one that is selective for the mutated form of EGFR, can be clinically effective and has a side-effect profile that is not dose limiting in the majority of patients in whom T790M-mediated drug resistance has developed,” Jänne and colleagues wrote.
In an editorial that accompanied both studies, Ramaswamy Govindan, MD — professor of medicine in the division of medical oncology at Washington University School of Medicine in St. Louis — expressed cautious optimism about the future of lung cancer treatment based on the data from these and other investigations.
“These studies underscore the importance of repeating biopsies with molecular analysis at the time of disease progression in patients with EGFR-mutated NSCLC,” Govindan wrote. “A variety of mechanisms contribute to disease progression after initial therapy with the first-generation EGFR tyrosine kinase inhibitors. Apart from the emergence of the T790M mutation, cancer cells can activate other oncogenes … undergo a phenotypic change to small cell lung cancer or activate survival pathways that lead eventually to treatment resistance. Finding EGFR T790M in tumor specimens after initial therapy with first-generation EGFR tyrosine kinase inhibitors now has practical relevance.” – by Anthony SanFilippo
References:
Govindan, R. N Engl J. Med. 2015:doi10.1056/NEJMoa1500181.
Jänne PA, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1411817.
Sequist LV, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1413654.
Disclosure: Researchers involved with the rociletinib study report research funding and honoraria from; employment with; consultant or advisory board roles with; and stock ownership in Clovis Oncology. Researchers involved with the AZD9291 study report research funding or honorarium from; employment with; consultant, advisory board or speaker’s bureau roles with; and stock ownership in AstraZeneca. Govindan reports consultant fees from Clovis Oncology. See the studies for full lists of all authors’ relevant financial disclosures.