Crizotinib Established as First-Line Therapy for ALK-Positive NSCLC

Oncology & Biotech News, July 2014, Volume 8, Issue 7

As a first-line treatment, crizotinib (Xalkori) improved progression-free survival (PFS) and objective response rate (ORR) compared with standard chemotherapy in patients with advanced ALK-positive non–small cell lung cancer (NSCLC).

Tony Mok, MD

As a first-line treatment, crizotinib (Xalkori) improved progression-free survival (PFS) and objective response rate (ORR) compared with standard chemotherapy in patients with advanced ALK-positive non—small cell lung cancer (NSCLC).

As such, it represents a standard of care in this patient population, said Tony Mok, MD, at the 2014 ASCO Annual Meeting.

Mok reported the results of a multi-center, randomized, open-label phase III study that compared crizotinib with pemetrexed-platinum chemotherapy in 343 patients with previously untreated advanced nonsquamous ALK-positive NSCLC.

“This is the first first-line comparative study of crizotinib to a doublet,” said Mok, professor of Oncology, The Chinese University of Hong Kong, Shatin, China.

The improvement in median PFS with crizotonib “would establish it as a first-line standard for patients with ALK-positive tumors,” he said. “This definitely will change practice. Right now, crizotinib is approved as first line and second line in the United States, but in Europe, it’s only allowed as second line. With this randomized study, it will also be available as first line in Europe and other countries.”

Crizotinib is an oral receptor tyrosine kinase inhibitor that targets ALK. Previous studies in patients with advanced ALK-positive NSCLC demonstrated its superiority over standard chemotherapy in the second-line setting on the endpoints of PFS and ORR.

Patients in the trial had locally advanced, recurrent, or metastatic non-squamous NSCLC with measurable tumors using RECIST v1.1. ALK rearrangement was determined centrally using a fluorescent in situ hybridization assay. Patients were randomized to crizotinib, 250 mg twice daily, or pemetrexed, 500 mg/m2, plus either cisplatin, 75 mg/m2, or carboplatin, with an area under the curve of 5—6—all administered intravenously every 3 weeks for a maximum of six cycles. Treatment continued until RECIST-defined disease progression, unacceptable toxicity, withdrawal of consent, or death.

Continuation of or crossover to crizotinib after disease progression was allowed for patients randomized to crizotinib or chemotherapy, respectively.

The primary endpoint, PFS, was extended from a median of 7 months in the chemotherapy arm to 10.9 months in the crizotinib arm, for a hazard ratio (HR) of 0.454 in favor of crizotinib (P <.0001). The ORR was also significantly higher with crizotinib (74% vs 45%; P <.0001), with objective responses that were rapid and durable. The median time to response was 6.1 weeks and 12.1 weeks in the crizotonib and chemotherapy arms, respectively. The median duration of response was 49 weeks in patients assigned to crizotinib and 22.9 weeks in those assigned to the chemotherapy doublet.

With 68% of patients still in follow-up, a statistically significant improvement in overall survival (OS) was not reached (HR = 0.82; P =.1804) in either arm. The 1-year survival probability was 84% and 79% for crizotinib and chemotherapy, respectively. At the time of data cutoff, 120 patients on chemotherapy had crossed over to crizotinib. OS analyses were not adjusted for the potentially confounding effects of crossover or other systemic therapies received during survival follow-up, said Mok.

“Adverse events with crizotinib and chemotherapy were consistent with those previously reported in patients with advanced ALK-positive or unselected NSCLC, respectively,” he said. The most common all-causality adverse events with crizotinib were vision disorder (71%), diarrhea (61%), and edema (49%). The most common adverse events in the chemotherapy arm were nausea (61%), fatigue (38%), and decreased appetite (35%).

Grade 3/4 adverse events of any cause that occurred with a frequency of ≥2% and at least a 2-fold difference between treatment arms were elevated transaminases (14% vs 2%), diarrhea (2% vs 1%), decreased appetite (2% vs 1%), and prolongation of the QT interval (2% vs 1%) in the crizotinib arm (vs chemotherapy), and anemia (9% vs 0%), thrombocytopenia (7% vs 0%), leukopenia (5% vs 2%), and vomiting (4% vs 2%) in the chemotherapy arm (vs crizotinib).


Mok T, Kim DW, Wu YL, et al. First-line crizotinib versus pemetrexedcisplatin or pemetrexed-carboplatin in patients with advanced ALK-positive non-squamous non-small cell lung cancer: Results of a phase III study (PROFILE 1014). J Clin Oncol. 2014;32:5s (suppl; abstr 8002).