Entrectinib Data Highlighted as FDA Weighs Approval for ROS1+ NSCLC

Fabrice Barlesi, MD

Patients with ROS1-positive non—small cell lung cancer (NSCLC) showed high response rates and durable responses following treatment with entrectinib, according to findings from a pooled analysis of 3 studies presented at the 2019 European Lung Cancer Congress.

Entrectinib demonstrated systemic efficacy with 77.4% of patients in the overall population showing a response. Strong intracranial activity was also demonstrated in a cohort of patients with CNS disease at baseline who showed an overall response rate (ORR) of 73.9%.

“There are high unmet needs in patients with ROS fusion—positive NSCLC. Brain metastases are common in this population and the CNS is a common site of first progression, therefore use of a CNS-penetrant ROS-1 inhibitor in the first-line setting would be beneficial to these patients,” said Fabrice Barlesi MD, PhD, Marseille University, Assistance Publique-Hopital du Marseille in Marseille, France.

Entrectinib is a potent ROS1 inhibitor that also inhibits TRKA/B/C. Entrectinib was designed to cross the blood-brain barrier and effectively penetrate the CNS to achieve therapeutic levels in the CNS, Barlesi explained.

“In preclinical studies, entrectinib provided more potent ROS1 inhibition than crizotinib, “ he noted.

Barlesi presented results from an integrated efficacy analysis from two phase I entrectinib studies—ALKA-372-001 (EudraCT 2012-000148-88] and STARTRK-1 (NCT02097810)—and the phase II STARTRK-2 (NCT02568267) trial. Based on data from this analysis, the FDA is currently reviewing a new drug application (NDA) for entrectinib as a treatment for patients with metastatic ROS1-positive NSCLC, as well as patients with NTRK fusion—positive locally advanced or metastatic solid tumors. The action date for a decision on the NDA is August 18, 2019.

The 3 trials enrolled patients with NSCLC who had not received prior treatment with a ROS1 inhibitor but harbored a ROS1 fusion, as determined by nucleic acid—based diagnostic platforms. Tumor assessments were done at week 4 and every 8 weeks thereafter by blinded independent central review (BICR; by RECIST v1.1).

The efficacy population comprised 53 patients with a median age of 53 years (range, 27-73). Sixty-four percent of patients were female, 50.9% were ECOG performance status 1, and 58.5% were never-smokers. At baseline, 43.4% of patients had CNS disease.

The safety-evaluable population included 134 patients who received ≥1 dose of entrectinib and had at least 6 months of follow-up. Patient characteristics were similar in this cohort, with the exception that more (50.0%) patients had CNS disease at baseline.

The primary endpoints of all the studies were ORR and duration of response (DOR). Key secondary endpoints included progression-free survival (PFS) and safety. Additional endpoints were intracranial ORR, DOR in patients with intracranial response, and PFS in patients with or without baseline CNS disease.

The ORR of 77.4% in the overall population included 3 (5.7%) patients with a complete response (CR), and the median DOR was 24.6 months (95% CI, 11.4-34.8). The clinical benefit rate was 77.4% (95% CI, 83.8-87.7). In patients with CNS disease, the ORR was 73.9%, with no CRs observed. The median DOR was 12.6 months (95% CI, 6.5-NE).

Median PFS in the overall and CNS-positive cohorts was 19.0 months (95% CI, 12.2-36.6) and 13.6 months (95% CI 4.5-NE), respectively. Overall survival data were not yet mature with a median follow-up of 15.5 months.

The intracranial ORR by BICR assessment was 55% (95% CI, 31.5-76.9), including a CR rate of 20% (n = 4) and a partial response rate of 35% (n = 7). No cases of stable disease were observed. Disease progression occurred in 15% of patients and 30% of patients were nonevaluable. In patients showing an intracranial response, the median DOR was 12.9 months.

“Entrectinib is well tolerated with a manageable safety profile,” Barlesi said. “Most adverse events were grades 1 or 2.”

In the ROS1 safety-evaluable population, at least 1 treatment-related adverse event (TRAE) of any grade was seen in 93% of patients. The most commonly reported TRAEs were dysgeusia (42.5%), dizziness (32.8%), and constipation (32.8%%). TRAEs grade ≥3 included weight gain, which occurred in 7.5% of patients; diarrhea in 2.2%; myalgia and aspartate aminotransferase increase in 1.5% of patients each; and dysgeusia, dizziness, and blood creatinine increase in 0.7% of patients each. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively.

“Entrectinib is highly active in patients with ROS1-positive NSCLC with and without CNS disease; entrectinib demonstrated clinically meaningful deep and durable systemic and intracranial responses,” concluded Barlesi.

Barlesi F, Drilon A, De Braud F, et al. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non—small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 109O.

<<< 2019 European Lung Cancer Congress