Entrectinib Impresses for ROS1-Positive NSCLC

Myung-Ju Ahn, MD

Treatment with entrectinib induced an objective response rate (ORR) of 68.8% by blinded independent central review (BICR), which included 2 complete responses (6.3%), for patients with ROS1 fusion-positive advanced non—small cell lung cancer (NSCLC), according to findings presented at the 2017 World Conference on Lung Cancer (WCLC).¹

Entrectinib, a potent and selective inhibitor of ROS1 and TRK, also demonstrated activity in the central nervous system (CNS), with an intracranial ORR by BICR of 83.3% for those with measurable CNS lesions at baseline (95% CI, 35.9%-99.6%). Furthermore, the agent was well tolerated, with most treatment-related adverse events (AEs) being grade 1 or 2 in severity.

"Entrectinib demonstrated clinically meaningful and durable benefit in ROS1-positive NSCLC," said investigator Myung-Ju Ahn, MD, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center. "In addition, entrectinib demonstrated strong CNS activity, the response rate was 83% in patients with measurable CNS disease at baseline."

The efficacy findings presented at WCLC were for 32 patients with ROS1-positive NSCLC treated with entrectinib in the phase II STARTRK-2 trial, phase I STARTRK-1 study, and the phase I ALKA-372-001 trial. Safety findings were from 203 patients with various histologies and genetic alterations treated with entrectinib across the 3 basket studies. The data cutoff for the analysis was September 13, 2017.

For the 32 ROS1 fusion-positive patients, the median age was 52 years, 72% were female, and 38% were Asian. ECOG performance status (PS) was primarily 0 or 1 (91%), with 9% of patients having an ECOG PS of 2. Most patients were never smokers (72%) and 50% had received ≥3 prior therapies, primarily chemotherapy (84%). Thirty-four percent of patients (n = 11) had CNS metastases at baseline, 4 of which had not yet received prior treatment for CNS metastases.

By investigator assessment, the ORR was 78.1% with entrectinib (95% CI, 60.0%-90.7%), with an ORR of 72.7% in those specifically with CNS disease at baseline (8 of 11). Variation between investigator response and BICR were due to a lack of post-baseline scans for 3 patients and 2 patients having non-measurable disease by BICR.

"The duration of treatment is quite durable," said Ahn. "There are patients who have been on entrectinib treatment for more than 3 years, and many of them are ongoing for 1 to 2 years."

Across the 3 studies, entrectinib showed mild toxicity, with no treatment-related grade 4 or 5 AEs reported. Treatment-related AEs led to a dose interruption for 32% of patients and dose reductions were required for 19% of patients; however, treatment-related AEs led to treatment discontinuation for just 3% of patients, Ahn noted.

The most common AEs of any grade were dysgeusia (38%), fatigue (29%), constipation (23%), dizziness (23%), weight increase (19%), diarrhea (17%), nausea (16%), and paresthesia (16%). The most frequent treatment-related grade 3 AEs were weight increase (5%), anemia (4%), and fatigue (3%). Overall, serious treatment-related AEs were experienced by 9% of patients.

"Weight gain was through increased appetite or calorie intake, which is most likely due to the mechanism of action of entrectinib. This is good for patients, since most patients are satisfied with their increase in appetite," Ahn said.

The only currently FDA-approved agent for the treatment of ROS1-mutant NSCLC is crizotinib (Xalkori); although a head-to-head comparison is unlikely, in preclinical work, entrectinib was 30 times more potent against ROS1 than crizotinib, Ahn noted. Moreover, entrectinib was designed to cross the blood-brain barrier, a trait that crizotinib lacks.

In addition to findings for ROS1, entrectinib has also demonstrated promising results for patients with NTRK-positive NSCLC. In findings for this population presented at the 2016 AACR annual meeting,² the ORR in those with NTRK rearrangements (n = 5) was 100%. Based on these findings, the FDA granted the agent a breakthrough therapy designation in May 2017.

Several studies continue to enroll patients to investigate entrectinib, including the global phase II STARTRK-2 trial, which includes patients with NTRK 1/2/3, ROS1, or ALK gene rearrangements, regardless of cancer type (NCT02568267). Based on communications with the FDA, Ignyta, the company developing entrectinib, anticipates submission of a new drug application for the treatment in 2018.

References

1. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564.
2. Drilon A, De Braud FG, Siena S, et al. Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT007.

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Overall, 53% of patients remained on the study and continued to receive treatment with entrectinib. By BICR, after a median follow-up of 12.9 months, the median duration of response was 28.6 months (95% CI, 6.8-34.8). After a median follow-up of 8.5 months, the median progression-free survival was 29.6 months with entrectinib (95% CI, 7.7-36.6).