A potent, a next-generation ALK inhibitor has demonstrated promising efficacy in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer (NSCLC), according to data presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium.1
Preplanned interim analysis of the phase III eXalt3 study showed a median progression-free survival of 25.8 months with ensartinib in the intent-to-treat population of patients with locally determined ALK-positive NSCLC vs 12.7 months with crizotinib (hazard ratio [HR] = 0.51; P = .0001). Moreover, in patients with centrally confirmed ALK-positive disease, median progression-free survival has not been reached with ensartinib (HR = 0.45; P < .0001).
With longer follow-up, ensartinib is also trending toward further improved median progression-free survival in patients without brain metastases at baseline, authors of the study reported.
Leora Horn, MD, MSc, FRCPC
“Ensartinib showed superior efficacy in the brain over crizotinib in patients with known brain metastases at baseline, with a favorable safety profile,” said lead study author Leora Horn, MD, MSc, FRCPC, Ingram Associate Professor of Cancer Research at Vanderbilt Ingram Cancer Center and Associate Professor of Medicine in the Division of Hematology/Oncology at the Vanderbilt University Medical Center, Nashville. “Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC.”
As Dr. Horn explained, oncogenic rearrangements of the ALK gene occur in approximately 5% to 7% of patients with NSCLC.2 Ensartinib, a once-daily oral ALK inhibitor, has demonstrated 10 times greater potency than crizotinib in enzymatic assays, she explained, and showed antitumor activity in phase I/II trials of patients with crizotinib-refractory, advanced ALK-positive NSCLC, including those with brain metastases.3-5
For the phase III eXalt3 study, Dr. Horn and colleagues enrolled patients with stage IIIB/IV NSCLC who had ALK-positive disease, as determined by local U.S. Food and Drug Administration–approved assays or central confirmation by fluorescent in situ hybridization. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no prior ALK inhibitor therapy, and up to one prior chemotherapy regimen. Investigators stratified patients by prior chemotherapy, ECOG performance status, region of the world, and presence of brain metastases at baseline.
Patients were randomly assigned to either ensartinib (225 mg daily) or crizotinib (250 mg twice daily). No crossover was allowed, said Dr. Horn, who reported the trial was fully accrued as of November 2018.
The primary endpoint of the study was blinded independent review committee–assessed median progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 in the intent-to-treat population. Key secondary endpoints included overall survival, response rate, duration of response, and time to treatment failure in the brain.
An interim analysis was planned at approximately 75% of median progression-free survival events by blinded independent review committee in the intent-to-treat population (143/190 events).
Durable Responses, Superior Efficacy Against Brain Metastases
As of July 1, 2020, data cutoff, treatment was ongoing in 64 patients receiving ensartinib (45%) and 25 patients receiving crizotinib (17%), noted Dr. Horn. She added that 139 blinded independent review committee–assessed median progression-free survival events (73%) had occurred in the intent-to-treat population. In the modified intent-to-treat population of patients with centrally confirmed ALK-positive disease, 119 blinded independent review committee–assessed events (63%) had occurred.
In the intent-to-treat population, patients randomly assigned to ensartinib had a median progression-free survival of 25.8 months vs 12.7 months with crizotinib (HR = 0.51; P = .0001). In the modified intent-to-treat population, however, median progression-free survival has not been reached with ensartinib vs 12.7 months with crizotinib (HR = 0.51; P = .0001).
The objective response rate for patients treated with ensartinib was 75% compared with 67% for patients treated with crizotinib. Complete response rates were 14% and 6%, respectively.
“Ensartinib showed superior efficacy in the brain over crizotinib in patients with known brain metastases at baseline, with a favorable safety profile.”— Leora Horn, MD, MSc, FRCPC
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The median duration of response has not been reached for patients given ensartinib vs 27.3 months for patients given crizotinib. Furthermore, although 58.7% of patients remained on ensartinib at 36 months, said Dr. Horn, just 26.7% of patients randomly assigned to crizotinib were still on treatment at that time.
In patients with measurable brain metastases at baseline, the objective response rate with ensartinib was also superior to that with crizotinib (64% vs 21%). In patients without measurable brain metastases at baseline, the 12-month relapse rate was 4.2% for patients given ensartinib compared with 23% for patients given crizotinib (HR = 0.32; P = .0001). Median overall survival has not been reached in either treatment group.
Finally, ensartinib demonstrated a favorable safety profile, said Dr. Horn. She noted that low-grade rash and transaminitis were the most frequent treatment-related adverse events.
DISCLOSURE: Dr. Horn has served as a consultant for Amgen, AstraZeneca, Bayer, EMD Serono, Incyte, Merck, Roche/Genentech, Pfizer, and Xcovery and received research funding from Xcovery and Bristol Myers Squibb.
1. Horn L, Wang Z, Wu G, et al: Phase 3 randomized study of ensartinib vs crizotinib in anaplastic lymphoma kinase (ALK)-positive NSCLC patients: eXalt3. 2020 World Conference on Lung Cancer. Presidential Symposium. Abstract 2.
2. Tsao AS, Scagliotti GV, Bunn PA Jr, et al: Scientific advances in lung cancer 2015. J Thorac Oncol 11:613-638, 2016.
3. Lovly CM, Heuckmann JM, de Stanchina E, et al: Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res 71:4920-4931, 2011.
4. Horn L, Infante JR, Reckamp KL, et al: Ensartinib (X-396) in ALK-positive non-small cell lung cancer: Results from a first-in-human phase I/II, multicenter study. Clin Cancer Res 24:2771-2779, 2018.
5. Yang Y, Zhou J, Zhou J, et al: Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: A multicentre, phase 2 trial. Lancet Respir Med 8:45-53, 2020.
Invited discussant of the eXalt3 trial, Christine M. Lovly, MD, PhD, Associate Professor of Oncology and Hematology, and Ingram Professor of Cancer Research, and Co-Leader of the Translational Research and Interventional Oncology Program at Vanderbilt University Medical Center and Vanderbilt Ingram ...