Mutation-Targeted Therapy Slows Lung Cancer (NSCLC)
Patients with previously treated advanced non-small cell lung cancer (NSCLC) lived more than twice as long without disease progression when treated with a drug that targets a key resistance mutation versus standard chemotherapy, investigators reported.
Treatment with the oral tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) led to a median progression-free survival (PFS) of 10.1 months as compared with 4.4 months for patients who received standard chemotherapy. A subgroup of patients with brain metastases also lived twice as long without disease progression when treated with the anti-EGFR/T790M agent.
Osimertinib also was better tolerated, associated with a 50% lower incidence of grade ≥3 toxicity than with chemotherapy, Tony Mok, MD, of the Chinese University of Hong Kong, and co-authors reported in the New England Journal of Medicine.
“In this trial, we found that patients with T790M-positive advanced non-small cell lung cancer who received osimertinib had better response rates and a longer duration of progression-free survival than did those receiving platinum therapy plus pemetrexed after first-line EGFR-TKI therapy,” the authors concluded. “The progression-free survival benefit with osimertinib was observed across all predefined subgroups, with hazard ratios of less than 0.50, including in patients with asymptomatic CNS metastases.
“In five prespecified measures of patient-reported symptoms, osimertinib had better results than platinum-pemetrexed.”
The trial began before the emergence of immunotherapy, such as anti-PD1/PD-L1 agents, and more research is needed to evaluate the potential role of immunotherapy in patients with EGFR-positive NSCLC, the authors added.
The published results confirmed findings initially reported in December at the European Lung Cancer Conference. The FDA approved osimertinib for NSCLC in December 2015.
EGFR-TKIs have evolved into standard first-line therapy for advanced NSCLC. Despite initially high response rates, most tumors progress within about a year after starting treatment. About 60% of progressive disease results from development of the T790M point mutation in EGFR. The mutation reduces binding of first- and second-generation EGFR-TKIs to EGFR protein, reducing the drugs’ inhibition of downstream signaling, the authors noted.
Osimertinib targets both EGFR and T790M and has activity in the CNS. In a phase I/II trial, treatment with osimertinib resulted a 61% objective response rate and median PFS of 9.6 months in patients with T790M-positive NSCLC. Two phase II trials involving more than 400 patients yielded similar results, leading to the randomized, phase III AURA3 trial reported by Mok and coauthors.
Investigators at 126 sites enrolled patients who had disease progression after initial EGFR-TKI therapy and presence of the T790M variant, confirmed by the cobas EGFR mutation test (Roche Molecular Diagnostics). All patients provided blood samples at baseline to screening for T790M in circulating tumor DNA.
The patients were randomized 2:1 to daily osimertinib or four cycles of chemotherapy. Patients who remained progression free after completing the planned chemotherapy could continue maintenance treatment with pemetrexed.
The trial had a primary endpoint of investigator-assessed PFS. Data analysis included 419 patients, who had a median follow-up of 8.3 months. The results showed that a 70% reduction in the hazard for progression or death among patients randomized to osimertinib (HR 0.30, 95% CI 0.22-0.41, P<0.001). Objective response rates were 71% with osimertinib and 31% with chemotherapy (P<0.001).
The estimated 6-month PFS was 69% in the osimertinib arm and 37% in the chemotherapy arm. At 12 months, the estimated proportions of patients who were alive and disease free were 44% with osimertinib and 10% with chemotherapy.
About a third of the patients had asymptomatic brain metastasis at enrollment. Median PFS in that subgroup was 8.5 months with osimertinib and 4.2 months with chemotherapy, representing a 68% reduction in the hazard (HR 0.32, 95% CI 0.21-0.49).
The study population included 172 patients who tested positive for the T790M mutation by both tumor and plasma assessment. Median PFS in the subgroup was 8.2 months with osimertinib and 4.2 months with chemotherapy. Response rates were 77% with osimertinib and 39% with chemotherapy.
The incidence of grade ≥3 adverse events was 23% with osimertinib and 47% with chemotherapy. The most commonly reported adverse events with osimertinib (any grade) were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%). Interstitial lung disease-like adverse events occurred in 4% of the osimertinib group (one death) and QT-interval prolongation in 4%.
Third-generation EGFR-TKIs, such as osimertinib, have shown considerable promise for overcoming resistance issues that have limited the efficacy of first- and second-generation agents, the author of a recent review noted. Osimertinib demonstrated 200-fold greater selectivity for the mutation-associated proteins T790M and L858R as compared with wild-type EGFR in studies involving patients with NSCLC that had progressed on first-line EGFR-TKI therapy.
The increased selectivity of osimertinib for T790M also resulted in a more favorable safety profile compared with second-generation EGFR-TKIs, development of which has been held back by dose-limiting toxicity, Haijun Zhang, PhD, of Zhongda Hospital in Nanjing, China, wrote in OncoTargets and Therapy.