Entrectinib Delivers Durable Responses in ROS1+, NTRK+ Lung Cancer

Filippo De Braud, MD

Patients with ROS1-positive and NTRK-positive non—small cell lung cancer (NSCLC) had frequent and durable responses, which appeared to deepen over time in some cases, with the multikinase inhibitor entrectinib (Rozlytrek), an integrated analysis of three clinical trials suggested.¹

The analysis showed objective response rates of 79.2% for patients with ROS1-positive NSCLC and 70% for those with NTRK-positive NSCLC. During an additional 5 months of follow-up since prior analyses, 2 more patients with ROS1-positive disease achieved complete responses.

Median duration of response exceeded 2 years in the ROS1-positive group, Filippo De Braud, MD, of the Istituto Nazionale dei Tumori in Milan, reported at 2019 ESMO Congress.

“In line with the primary data, in patients with ROS1-positive and NTRK-positive non—small cell lung cancer after an additional 5 months of follow-up, entrectinib was well tolerated and showed clinically meaningful and durable system and intracranial responses,” De Braud and colleagues concluded in a poster presentation.

Invited discussant Ross Soo, MB BS, PhD, of National University Hospital in Singapore, reviewed data for multiple next-generation ROS1 inhibitors, including entrectinib. The data showed high response rates, ranging from 62% to 82%, and evidence that the responses are durable, though duration of response has yet to be reported for some of the agents.

The drugs varied in their intracranial activity, though most of the studies involved few patients. The integrated analysis of entrectinib studies comprised the largest patient cohort (n = 53) of any of the agents reviewed and the largest group of patients with brain metastases (n = 20).

A key challenge that lies ahead for all of the agents is elucidation of mechanisms of acquired resistance, said Soo. In the case of entrectinib, the challenge encompasses ROS1-positive and NTRK-positive NSCLC.

NSCLC associated with ROS1 and NTRK gene fusions account for 1% to 2% and <1%, respectively, of all cases of the disease. Entrectinib inhibits ROS1, TRKA/B/C, and ALK and has both systemic and central nervous system (CNS) activity.

Three phase I/II trials assessed the safety and efficacy of entrectinib in a total of 53 patients with previously untreated ROS1+ and NTRK+ NSCLC. In an initial integrated analysis of data from the three trials, entrectinib had promising activity (objective response rate of 77% by blinded independent central review) in ROS1+ disease, including patients with CNS involvement at baseline.²

The same integrated analysis showed a median duration of response of 24.6 months; median PFS of 13.6 and 26.3 months, respectively, in patients with CNS disease and those without; and an objective response rate of 55% in 20 patients with CNS disease and a median response duration of 13 months.

Another integrated analysis of the three trials showed that entrectinib has systemic and intracranial activity in patients with NTRK+ NSCLC.³

De Braud and colleagues reported findings of the three trials after an additional 5 months of follow-up. The analysis included 53 patients with advanced/metastatic ROS1-positive NSCLC (20 with baseline CNS involvement) and 10 patients with locally advanced/metastatic NTRK-positive NSCLC. All of the patients had previously untreated disease. A safety analysis included 355 patients who had received at least one dose of entrectinib, including 134 with ROS1-positive NSCLC and 68 patients with NTRK-positive solid tumors.

The primary endpoints were objective response rate and duration of response by independent review in patients with and within CNS disease at baseline. With an additional 5 months of follow-up, the objective response rate in the ROS1-positive patients continued to increase, from 77% to 79.2%. The response rate remained stable at 70% in the 10 patients with NTRK-positive NSCLC.

In the prior analyses, 3 patients with ROS1+ NSCLC attained complete response. The new analysis showed 2 additional complete responses, for a rate of 9.4%. One patient with NTRK-positive NSCLC had a complete response.

The median duration of response for the ROS1-positive subgroup remained at 24.6 months, and the median PFS was 19.0 months. Overall survival could not be estimated, said De Braud.

An analysis of outcomes by CNS status showed that patients with ROS1-positive disease and CNS involvement at baseline had a response rate of 73.9% versus 83.3% for patients without CNS disease. Median duration of response was not estimable for the patients with CNS disease, and median PFS was 13.6 months for patients with CNS disease and 21.1 months for those without.

Intracranial response to entrectinib remained at 55% (11 of 20). The median response duration was 12.9 months, and median PFS was 7.7 months.

The safety analysis showed no new safety signals and that entrectinib was generally well tolerated, as most adverse events were grade 1/2 severity.

References

1. De Braud FG, Siena S, Barlesi F, et al. Entrectinib in locally advanced/metastatic ROS1 and NTRK fusion-positive non-small cell lung cancer (NSCLC): Updated integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at 2019 ESMO Congress; September 27-October 2, 2019; Barcelona, Spain. Abstract 1488PD.
2. 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. Ann Oncol. 2019;30(Suppl2):abst 109O.
3. Doebele R,&#8239;Paz-Ares L,&#8239;Farago AF, et al. Entrectinib in&#8239;NTRK-fusion positive (NTRK-FP) non-small cell lung cancer (NSCLC): Integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT131:

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