Ensartinib prolongs PFS vs. crizotinib in ALK-positive non-small cell lung cancer
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Ensartinib significantly increased PFS compared with crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer, according to an interim analysis of the phase 3, open-label eXalt3 study.
Leora Horn, MD, MSc, Ingram associate professor of cancer research in the division of hematology/oncology and clinical director of the thoracic oncology program at Vanderbilt-Ingram Cancer Center, presented the results during the International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium.
“Oncogenic arrangements of the ALK gene occur in approximately 5% to 7% of patients with NSCLC,” Horn said during the presentation. “Ensartinib [X-396, Xcovery] is a potent, next-generation, once-daily oral anaplastic lymphoma kinase [ALK] inhibitor with broad preclinical activity against ALK resistance mutations. Its potency is more than 10 times greater than that of crizotinib [Xalkori; Pfizer, EMD Serono] in enzyme assays.”
Ensartinib demonstrated safety and antitumor activity in a phase 1/phase 2 trial that included patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK-targeted tyrosine kinase inhibitor or progressed on crizotinib or second-generation ALK inhibitors.
The current phase 3 trial included 290 patients (intention-to-treat-population) with locally tested, ALK-positive NSCLC, an ECOG performance status of 0 to 2 and no prior ALK inhibitor treatment. Researchers randomly assigned patients to 225 mg once-daily ensartinib (n = 143) or 250 mg twice-daily crizotinib (n = 147). Treatment crossover was not permitted.
Patients in the ensartinib and crizotinib groups had similar baseline characteristics, including median age (54 years vs. 53 years), prior chemotherapy (24% vs. 29%) and baseline brain metastases (33% vs. 39%).
A modified intention-to-treat-population included 247 patients with centrally confirmed ALK-positive disease, including 121 patients in the ensartinib group and 126 patients in the crizotinib group.
PFS served as the primary endpoint. Secondary endpoints included OS, overall response rate and time to treatment failure in the brain. An interim analysis was planned after 75% of PFS events among the intention-to-treat-population.
At data cutoff on July 1, 45% of patients in the ensartinib group and 17% of patients in the crizotinib group continued to receive treatment. Researchers observed 139 PFS events (73% of events) in the intention-to-treat-population and 119 events (63% of events) in the modified intention-to-treat-population.
Median PFS was 25.8 months with ensartinib vs. 12.7 months with crizotinib in the intention-to-treat population (HR = 0.51; 95% CI, 0.35-0.72), and was not reached with ensartinib vs. 12.7 months with crizotinib in the modified intention-to-treat population (HR = 0.45; 95% CI, 0.3-0.66).
The ensartinib group in the modified intention-to-treat population demonstrated higher rates of confirmed systemic ORR (75% vs. 67%), complete response (14% vs. 6%) and intracranial ORR among patients with measurable brain metastases (64% vs. 21%), as well as a lower time to treatment failure rate in the brain among patients with no baseline brain metastases (4.2% vs. 23.9% at 1 year; HR = 0.32; 95% CI, 0.15-0.64).
Median duration of response in the modified intention-to-treat population was not reached with ensartinib vs. 27.3 months with crizotinib, and median OS was not reached in either treatment group (HR = 0.88; 95% CI, 0.52-1.5). However, both groups had 2-year OS rates of 78%.
Grade 3 or grade 4 treatment-related adverse events occurred among 8% of patients in the ensartinib group, of whom 9% discontinued treatment, and 6% of patients in the crizotinib group, of whom 7% discontinued treatment.
“With longer follow-up, ensartinib is trending toward further improved median PFS overall and in those without brain metastases at baseline,” Horn said. “Ensartinib showed superior efficacy in the brain over crizotinib and represents a new first-line treatment option for patients with ALK-positive NSCLC.”
Perspective
Back to TopChristine M. Lovly, MD, PhD
Ensartinib showed promising efficacy in the first-line treatment setting for patients with advanced ALK-positive NSCLC. There are now multiple options for first-line ALK TKI therapy, but how do we continue to move the needle?
The questions we need to address in the field in 2020 include how to select among the available options for first-line ALK TKI.The biological factors to consider when making this selection include duration of benefit, extent of CNS activity and toxicity profile, among others. Second, what are the molecular mechanisms of primary and acquired resistance to ALK TKI therapy? Third, how do we best sequence ALK TKI therapy, and fourth, what are the best combination therapies to advance?
Perspective
Back to Top
Miguel Villalona-Calero, MD
This study shows that yet another multitargeted TKI has superior clinical activity compared with crizotinib among patients with TKI-naive lung cancer who harbor ALK rearrangements in their tumors. Researchers observed longer PFS, as well as better CNS metastatic control.
Four other TKIs have demonstrated similar advantages compared with crizotinib. Toxicity profile and resistance mutations known to be targeted by the TKI appeared to be the most quantifiable differences among these next-generations agents.
It is certainly good news to have choices for first-line treatment, but perhaps more important is having choices following initial therapy, given individual variations in tolerability and the stated differences in post-exposure resistance profiles. Genomic analyses for toxicity risk stratifications and for early detection of drivers of resistance are now, more than ever, of paramount importance in the management of these patients.
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Horn L, et al. Abstract LBA 2. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer Virtual Presidential Symposium; Aug. 8, 2020.
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