Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study

Abstract

Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK-positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK-positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

“…[1][2][3] It has also demonstrated significantly improved progression-free survival (PFS) over single-agent chemotherapy as second-line treatment for patients with ALK-rearranged NSCLC in a randomized phase 3 trial. 4 Crizotinib has been approved in many countries for the treatment of ALK-rearranged NSCLC.…”

New therapeutic perspectives in CCDC6 deficient lung cancer cells

“…Recent advances in genomics have identified a number of genetic alterations in NSCLC that could be therapeutically exploited as predictive biomarkers to guide treatment decisions and customize therapy. 2,3 The use of tyrosine kinase inhibitors to target Epidermal Growth Factor Receptor (EGFR), 4 Anaplstic lymphoma kinase (ALK) 5 and RET protooncogene, rearranged during transfection (RET) 6 is effective, but only in small minority of cases (10)(11)(12)(13)(14)(15)(5)(6)(7) and 2% of NSCLC patients, respectively). A vast majority of NSCLCs do not carry the molecular alterations; thus, disease management is an ongoing challenge.…”

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

“…One lesson from this approach was that the strong signal that eventually led to the rapid approval of crizotinib in ALK+ NSCLC based on its activity in several hundred patients was apparent very early on. Waterfall plots of the first 19 patients and those from over 100 patients had almost identical shapes 65,66 (overall response rate, 53% vs 61%). When the efficacy signals are so strong it is difficult to know how to determine the necessary numbers of patients for a drug approval.…”