[ad_1]
In terms of crizotinib’s intracranial efficacy, the ORR in patients with central nervous system (CNS) metastases (n = 9) was 22.2% and included 2 PR (95% CI, 2.8% at 60,%). The ORR in patients with measurable CNS metastases (n = 5) was 40% and included 2 PR (95% CI: 5.3% -85.3%). In addition, 1 patient with CNS-related symptoms did not experience any improvement in symptoms after treatment with crizotinib.
Regarding efficacy with alectinib, the ORR in the overall population (n = 61) was 47.5% and included 2 CR and 27 PR (95% CI, 34.6% -60.7%). The ORR in patients with target lesions (n = 46) was 60.9% and included 1 CR and 27 PR (95% CI, 45.4-74.9%). In addition, 1 patient achieved CR in the target lesions, but had disease without CR and not progressive in the non-target lesions.
In terms of intracranial activity with alectinib, the ORR in patients with CNS metastases (n = 38) was 47.4% and included 7 CR and 11 PR (95% CI, 31.0% -64.2%). The ORR in patients with measurable CNS metastases (n = 19) was 68.4% and included 2 CR and 11 PR (95% CI: 43.4% -87.4%). In addition, 9 patients with CNS-related symptoms experienced significant improvement in symptoms after treatment with alectinib.
“There are limited data on clinical outcome, long-term survival and safety with sequential treatment of first-line crizotinib followed by alectinib in clinical practice for Chinese patients with advanced stages. ALK– NSCLC positive, ”said Zihua Zou, MD, from 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 the medical records of patients with ALK-NSCLC positive who were treated with sequential crizotinib and alectinib at 6 centers in China. Patients could not have received intermittent systemic therapy between crizotinib and alectinib.
Combination therapy to failure was defined as the time from the start of crizotinib to complete discontinuation of alectinib for reasons such as disease progression, death, serious adverse reactions (AEs) and patient preference.
Patients (n = 61) had a median age of 49 years (range, 25-81) and 4 patients were 65 years or older. A total of 29 patients were men and 32 were women. Most patients (n = 50) had an ECOG Performance Index (PS) of 0 or 1, but 11 patients had an ECOG PS of 2 or greater. Most patients had adenocarcinoma (n = 58), had never smoked (n = 47), and had stage IV or recurrent disease with distant metastasis (n = 53).
Ten patients had CNS metastases at baseline and 1 patient had CNS-related symptoms.
Reasons for discontinuing crizotinib included disease progression (n = 52), severe AEs (n = 7), and patient preference (n = 2).
Regarding baseline characteristics prior to initiation of alectinib, patients (n = 61) had a median age of 49 years (range, 25-81) and 8 patients were 65 years or older. In addition, ECOG PSs were between 0 and 1 (n = 40) and 2 or more (n = 21).
Thirty-eight patients had CNS metastases prior to alectinib. For crizotinib resistant patients, the number of patients with CNS metastases increased from 7 to 52 patients after crizotinib resistance. In addition, 11 patients presented with 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. 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) of crizotinib resistant patients in the crizotinib stage (n = 52) was 15.4 months (95% CI, 11.0-19.5). Additionally, 22 patients experienced intracranial progression, 18 extracranial progression, and 12 intracranial and extracranial progression.
At a median follow-up of 17.1 months, the median PFS during alectinib treatment in patients with crizotinib-resistant disease was 13.5 months (95% CI: 8.5-18.8).
In addition, 16 patients had no rebiopsy, 12 had a rebiopsy with a ALK mutation identified, and 8 patients had a rebiopsy without 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 general population during treatment with crizotinib was 12.7 months (95% CI, 7.6-18.1). In addition, 9 patients continued crizotinib after local or gradual progression.
At a median follow-up of 34.3 months, the median TTF during crizotinib treatment with alectinib was 39.2 months (95% CI, 30.0-49.6). Nine patients continued with alectinib after local or progressive progression; 33 patients discontinued treatment due to disease progression (n = 31) or AEs (n = 2).
Of the 33 patients who discontinued alectinib, 29 received at least 1 subsequent line of treatment and 27 received further TKI ALK.
Patients with secondary ALK mutations that received sensitive ALK TKI had a median PFS of 10.4 months versus 3.1 months in patients without ALK mutation identified (95% CI, 0.016-0.389).
Subsequent TKI ALKs in patients with 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 ILI rate was 66.7%. In the general 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%), visual impairment (29.8%) and rash (10.5%). Grade 3/4 events included diarrhea (5.2%), nausea (1.7%), and increased aminotransferases (8.7%).
Dose interruptions occurred in 24.6% of patients (n = 14) and were most often due to an increase in grade 2 to 4 transaminases (n = 10). Dose reductions occurred in 15.8% of patients (n = 9) and were most often due to an increase in grade 2 to 4 transaminases (n = 7). Additionally, 12.3% of patients (n = 7) discontinued crizotinib permanently due to AEs; An increase in grade 3/4 aminotransferases (n = 5) and recurrent grade 3 diarrhea (n = 2) were serious AEs which led to permanent discontinuation of crizotinib.
Grade 1/2 AEs with alectinib included constipation (39.3%), fatigue (26.8%), edema (28.6%), musculoskeletal pain (33.9%), increased blood pressure creatine kinase (23.3%), increased transaminases (23.2%), increased total bilirubin (33.9%) and rash (12.5%). Grade 3/4 events included an increase in total bilirubin (1.8%).
Dose interruptions occurred in 17.8% of patients (n = 10) and were most often due to an increase in grade 2 to 4 total bilirubin (n = 6). Dose reductions occurred in 8.9% of patients (n = 5) and were most often due to an increase in grade 2 total bilirubin (n = 2) or an increase in grade 2 creatine kinase (n = 2). Additionally, 3.6% of patients (n = 2) discontinued alectinib permanently due to AEs. Grade 4 increase in total bilirubin (n = 1) and grade 5 interstitial pneumonia (n = 1) were serious AEs leading to permanent discontinuation of alectinib.
“ALK the secondary mutation is the main resistance mechanism for alectinib, ”Zou concluded. “Different efficacy in subsequent ALK-TKI between patients with and without ALK the secondary mutation further underscored the importance of rebiopsy in guiding targeted therapy more precisely.
Reference
Zou Z. Clinical results, long-term survival and safety with sequential treatment 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; from September 8 to 14, 2021; virtual. Summary P45.15.
Source link
