Sequential Crizotinib Followed by Alectinib Associated With Survival Benefit in ALK+ NSCLC

Frontline sequential therapy with crizotinib (Xalkori) followed by alectinib (Alecensa) demonstrated survival benefits for patients with ALK-positive non–small cell lung cancer (NSCLC) who develop resistance to, or become intolerant of crizotinib, according to data presented during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.

Regarding the efficacy of crizotinib, the overall response rate (ORR) in patients with at least 1 radiological evaluation (n = 60) was 60% and comprised 1 complete response (CR) and 35 partial responses (PRs; 95% CI, 46.5%-72.4%). The ORR in patients with target lesions (n = 42) was 85.7% and comprised 1 CR and 35 PRs (95% CI, 71.5%-94.6%). Additionally, 2 patients achieved a CR in target lesions, but had a non-CR, non–progressive disease in non-target lesions.

In terms of the intracranial efficacy of crizotinib, the ORR in patients with central nervous system (CNS) metastases (n = 9) was 22.2% and comprised 2 PRs (95% CI, 2.8%-60.0%). The ORR in patients with measurable CNS metastases (n = 5) was 40% and comprised 2 PRs (95% CI, 5.3%-85.3%). Additionally, 1 patient with CNS-related symptoms had no improvement in symptoms after treatment with crizotinib.

Regarding efficacy with alectinib, the ORR in the overall population (n = 61) was 47.5% and comprised 2 CRs and 27 PRs (95% CI, 34.6%-60.7%). The ORR in patients with target lesions (n = 46) was 60.9% and comprised 1 CR and 27 PRs (95% CI, 45.4-74.9%). Additionally, 1 patient achieved a CR in target lesions, but had a non-CR, non–progressive disease in non-target lesions.

In terms of the intracranial activity with alectinib, the ORR in patients with CNS metastases (n = 38) was 47.4% and comprised 7 CRs and 11 PRs (95% CI, 31.0%-64.2%). The ORR in patients with measurable CNS metastases (n = 19) was 68.4% and comprised 2 CRs and 11 PRs (95% CI, 43.4%-87.4%). Moreover, 9 patients with CNS-related symptoms experienced significant improvement in symptoms after alectinib treatment.

“There has been limited data in clinical outcomes, long-term survival, and toleration with sequential therapy of first-line crizotinib followed by alectinib in clinical practice for Chinese patients with advanced ALK-positive NSCLC,” said Zihua Zou, MD, of the Department of Medical Oncology at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College.

The retrospective study obtained medical records of patients with advanced ALK-positive NSCLC who were treated with sequential crizotinib and alectinib at 6 centers in China. Patients could not have received intermittent systemic therapies between crizotinib and alectinib.

Combined treatment to failure was defined as the period from the start of crizotinib to the complete discontinuation of alectinib for reasons including disease progression, death, severe adverse effects (AEs), and patient preference.

Patients (n = 61) were a median age of 49 years (range, 25-81) and 4 patients were 65 years or older. Overall, 29 patients were male and 32 were female. Most patients (n = 50) had an ECOG performance status (PS) of 0 or 1, but 11 patients had an ECOG PS of 2 or greater. Most patients had adenocarcinoma (n = 58), were never smokers (n = 47), and had stage IV or recurrent disease with distant metastases (n = 53).

Ten patients had baseline CNS metastases and 1 patient had CNS-related symptoms.

Reasons for crizotinib discontinuation included disease progression (n = 52), severe AEs (n = 7), and patient preference (n = 2).

Regarding baseline characteristics before the initiation of alectinib, patients (n = 61) were a median age of 49 years (range, 25-81) and 8 patients were aged 65 years or older. Additionally, ECOG PS were between 0 and 1 (n = 40) and 2 or more (n = 21).

Thirty-eight patients had CNS metastases before alectinib. For crizotinib-resistant patients, the number of patients with CNS metastases rose from 7 to 52 patients after crizotinib resistance. Moreover, 11 patients had CNS-related symptoms.

Further results with crizotinib showed that 7 patients had tumor reduction of at least 75%, 16 had tumor reduction between 51% and 75%, 13 had tumor reduction between 26% and 50%, and 6 had tumor reduction of 25% or less. With alectinib, tumor reduction occurred in 3, 13, 12, and 18 patients, respectively.

The median progression-free survival (PFS) for crizotinib-resistant patients during the stage of crizotinib (n = 52) was 15.4 months (95% CI, 11.0-19.5). Moreover, 22 patients experienced intracranial progression, 18 experienced extracranial progression, and 12 experienced intracranial plus extracranial progression.

At a median follow-up of 17.1 months, the median PFS during alectinib treatment for patients with crizotinib-resistant disease was 13.5 months (95% CI, 8.5-18.8).

Additionally, 16 patients had no rebiopsy, 12 had rebiopsy with a secondary ALK mutation identified, and 8 patients had rebiopsy without a secondary ALK mutation identified. ALK mutations identified included G1202R (n = 4), I1171N (n = 4), L1196Q (n = 1), I1171T (n = 1), L1196M plus G1202R (n = 1), and F1174L plus G1269A plus E1210K (n = 1).

The median time to treatment failure (TTF) in the overall population during crizotinib treatment was 12.7 months (95% CI, 7.6-18.1). Additionally, 9 patients continued crizotinib after local or gradual progression.

At a median follow-up of 34.3 months, the median TTF during treatment from crizotinib to alectinib was 39.2 months (95% CI, 30.0-49.6). Nine patients continued alectinib after local or gradual progression; 33 patients discontinued treatment because of disease progression (n = 31) or AEs (n = 2).

Of the 33 patients who discontinued alectinib, 29 received at least 1 line of subsequent therapy, and 27 received other ALK TKIs.

Patients with secondary ALK mutations who received sensitive ALK TKI had a median PFS of 10.4 months vs 3.1 months in patients without a secondary ALK mutation identified (95% CI, 0.016-0.389).

Subsequent ALK TKIs in patients with secondary ALK mutations included lorlatinib (n = 6), ceritinib (n = 4), brigatinib (n = 1), and ensartinib (n = 1). In patients without secondary ALK mutations, subsequent ALK TKIs included brigatinib (n = 2), lorlatinib (n = 2), ensartinib (n = 1) and ceritinib (n = 1).

Finally, the estimated 3-year overall survival (OS) rate was 84.5% in crizotinib-resistant patients. The estimated 5-year OS rate was 66.7%. In the overall population, the estimated rates were 87.1% and 68.6%, respectively.

Regarding safety, grade 1/2 AEs with crizotinib in evaluable patients (n = 57) included constipation (14%), diarrhea (42.2%), nausea (47.3%), vomiting (21%), edema (43.8%), increased aminotransferase (40.3%), vision impairment (29.8%), and rash (10.5%). Grade 3/4 events included diarrhea (5.2%), nausea (1.7%), and increased aminotransferase (8.7%).

Dose interruptions occurred in 24.6% of patients (n = 14) and were most commonly because of grade 2 to 4 increased aminotransferase (n = 10). Dose reductions occurred in 15.8% of patients (n = 9) and were most commonly because of grade 2 to 4 increased aminotransferase (n = 7). Additionally, 12.3% of patients (n = 7) permanently discontinued crizotinib because of AEs; grade 3/4 increased aminotransferase (n = 5) and repeated grade 3 diarrhea (n = 2) were severe AEs that led to permanent crizotinib discontinuation.

Grade 1/2 AEs with alectinib included constipation (39.3%), fatigue (26.8%), edema (28.6%), musculoskeletal pain (33.9%), increased creatine kinase (23.3%), increased aminotransferase (23.2%), increased total bilirubin (33.9%), and rash (12.5%). Grade 3/4 events included increased total bilirubin (1.8%).

Dose interruptions occurred in 17.8% of patients (n = 10) and were most commonly because of grade 2 to 4 increased total bilirubin (n = 6). Dose reductions occurred in 8.9% of patients (n = 5) and were most commonly because of grade 2 increased total bilirubin (n = 2) or grade 2 increased creatine kinase (n = 2). Additionally, 3.6% of patients (n = 2) permanently discontinued alectinib because of AEs. Grade 4 increased total bilirubin (n = 1) and grade 5 interstitial pneumonia (n = 1) were severe AEs that led to permanent alectinib discontinuation.

“ALK secondary mutation is the main resistance mechanism of alectinib,” Zou concluded. “Different efficacy in subsequent ALK-TKI between patients with and without ALK secondary mutation further emphasized the importance of rebiopsy to guide targeted therapy more precisely.”

Reference

1. Zou Z. Clinical outcomes, long-term survival and toleration with sequential therapy of first-line crizotinib followed by alectinib in advanced ALK+NSCLC. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Abstract P45.15.