Crizotinib Demonstrates Durable Activity in ROS1+ NSCLC

Yi Long Wu, MD

Crizotinib (Xalkori) induced a nearly 72% overall response rate and a median progression-free survival of almost 16 months in a single-arm phase II trial of 127 patients with ROS1-positive advanced non—small cell lung cancer (NSCLC).

Treatment with the tyrosine kinase inhibitor led to objective responses in 91 of the 127 patients (71.7%; 95% CI, 63.0-79.3), including 17 (13.4%) complete responses and 74 (58.3%) partial responses. The median progression-free survival was 15.9 months (95% CI, 12.9-24.0) and the median duration of response was 19.7 months (95% CI, 14.1—not reached). Forty-five patients (35.4%) were still in follow-up for PFS at data cutoff.

“Crizotinib provided meaningful clinical benefit in East Asian patients with ROS1-positive advanced NSCLC, with durable clinical responses and improvements in QOL and symptom burden,” first author Yi-Long Wu, MD, Guangdong Lung Cancer Institute, Guangzhou, China, and coinvestigators wrote.

“Results from this study, to our knowledge the largest phase II trial in ROS1-positive advanced NSCLC to date, provide additional compelling clinical evidence to support the use of crizotinib in this molecular subgroup of patients with NSCLC.”

The phase II, open-label, trial enrolled patients at 37 sites in China, Japan, South Korea, and Taiwan. The study began in September 2013 with a July 2016 data cutoff. Patients had ROS-1 positive advanced NSCLC and had received 3 or fewer lines of prior systemic therapies.

Patients received oral crizotinib at a starting dose of 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. At the investigator’s discretion, patients could continue treatment beyond progression if they had ongoing clinical benefit.

Tumor assessments were performed at baseline, every 8 weeks until cycle 8, and every 12 weeks thereafter until disease progression or discontinuation. Brain and bone scans were to be performed at baseline and, if lesions were present, repeat brain scans were taken every 8 weeks and repeat bone scans were taken every 12 weeks.

Median patient age was 51.5 years (range, 22.8-79.7) and 83.5% of the cohort was aged <65 years. Most patients (71.7%) were nonsmokers and 57.5% of patients were female. Nearly all (97.6%) patients had adenocarcinoma and 95.3% had metastatic disease. Twenty-three patients (18.1%) had brain metastases at baseline.

Fifty-three patients (41.7%) had received 1 prior therapy, 31 (24.4%) had received 2, and 19 (15.0%) had undergone 3 previous treatments. Twenty-four (18.9%) patients were treatment-naïve.

Median PFS was 10.2 months (95% CI, 5.6-13.1) in patients with baseline brain metastases (n = 23) and 18.8 months (95% CI, 13.1—not reached) in those without (n = 104). Wu et al warned against over-interpreting this finding because of the small sample size of patients with baseline brain metastases.

Median duration of follow-up for overall survival (OS) was 21.4 months (95% CI, 20.1-23.0). Median OS was 32.5 months (95% CI, 32.5—not reached), but investigators considered OS data to be immature because 59.8% of patients remained on treatment. Probabilities of survival were 92.0% (95% CI, 85.7-95.6) at 6 months and 83.1% (95% CI, 75.2-88.6) at 12 months.

Median time to first tumor response was 1.9 months (range, 1.6-15.8), which coincided with the first on-treatment tumor assessment. The disease control rate was 88.2% (95% CI, 81.3-93.2) at week 8 and 80.3% (95% CI, 72.3-86.8) at week 16. Of the 63 patients who experienced disease progression while on-treatment, 43 (68.3%) continued treatment with crizotinib for ≥3 weeks postprogression for a median duration of 20.7 weeks (range, 3.3-92.7).

The investigators reported that patients derived clinical benefit irrespective of presence of brain metastases at baseline, number of prior lines of chemotherapy, enrollment country, age, sex, smoking status, or ECOG performance score.

At the data cutoff, the median duration of crizotinib treatment was 18.4 months (range, 0.1-34.1) and 63 patients (49.6%) were still receiving crizotinib. Dose reductions and dosing interruptions associated with treatment-related adverse events (TRAEs) were reported in 15.7% and 22.8% of patients, respectively.

Overall, 32 patients experienced grade 3/4 TRAEs, most often neutropenia (10.2%) and elevated transaminases (5.5%). One patient permanently discontinued crizotinib in association with grade 1 treatment-related diarrhea.

Thirty-nine patients (30.7%) died by the data cutoff, most often due to disease progression (n = 35). Two patients died of pneumonia, 1 died of respiratory failure, and the cause of death was unknown in 1 patient. There were no cases of treatment-related pneumonitis reported.

Overall, 10 patients (7.9%) experienced a grade 5 AE, though none were related to crizotinib.

Wu YL, Yang JCH, Kim DW, et al. Phase II study of crizotinib in East Asian patients with ROS1-positive advanced non—small-cell lung cancer [published online March 29, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.75.5587.