Published Entrectinib Data Demonstrate Encouraging Responses in ROS1+ NSCLC

Robert C. Doebele, MD, PhD

Robert C. Doebele, MD, PhD

Treatment with entrectinib (Rozlytrek) led to an overall response rate (ORR) of 77% and a median duration of response (DOR) of 24.6 months in patients with ROS1 fusion—positive non–small cell lung cancer (NSCLC), according to updated findings of a pooled analysis published in Lancet Oncology.¹

The pooled analysis includes data from the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials. Previously reported findings demonstrated a 57% ORR in patients with NTRK fusion—positive solid tumors.² Additionally, results showed that entrectinib demonstrated a 78% ORR and a median DOR of 24.6 months in patients with locally advanced or metastatic ROS1-positive NSCLC, with an intracranial ORR of 55.0%.

Based on these earlier findings, as well as data from the phase I/Ib STARTRK-NG study, the FDA granted an accelerated approval to entrectinib in August 2019 for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion, and also approved the agent for the treatment of adults with ROS1-positive, metastatic NSCLC.

The NTRK fusion indication is specific to patients who have a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed on therapy or have no alternative treatments.

“For ROS1-positive lung cancer, entrectinib represents a new and better standard of care due to entrectinib’s effectiveness against ROS1 in the body and especially due to its activity against ROS1-positive brain metastases,” senior study investigator Robert C. Doebele, MD, PhD, director of the University of Colorado Cancer Center Thoracic Oncology Research Initiative, stated in a press release.³ “For NTRK cancers, the picture is a little more complex and I think it depends on an NTRK-positive cancer’s chance of developing brain metastases. Personally, if I were a patient and felt there was any chance of me getting brain [metastases], I would want this brain-penetrating drug.”

The trials enrolled patients across 15 countries and 150 clinical trial sites, and included data of patients ≥18 years old with locally advanced or metastatic solid tumors who harbored ROS1 fusions and were enrolled on either the phase I ALKA-372-001 or STARTRK-1 trial, or the phase II global basket STARTRK-2 study.

Patients in the prespecified integrated efficacy analysis with ROS1-positive fusions (n = 53) had locally advanced or metastatic NSCLC, did not previously receive a ROS1 TKI, had investigator-assessed measurable disease, and an ECOG performance status of 0 to 2. These patients were treated with 600 mg of entrectinib. Fifty-four patients were included in the NTRK efficacy analysis.

In the safety analysis of patients with ROS1—fusion positive NSCLC (n = 134), patients were not all naïve to TKIs; 47 patients had <12 months of follow-up, and 27 patients previously received a ROS1 inhibitor. Additionally, 3 patients had an ECOG performance status ≥2, and 1 patient had ROS1 biomarker ineligibility. However, these 4 patients were permitted in the safety analysis as they had all received ≥1 dose of entrectinib.

All patients had adequate organ function and, in ALKA-372-001 and STARTRK-1, a life expectancy of ≥3 months, and in STARTRK-2, a life expectancy of ≥4 weeks. Those with asymptomatic or previously treated and controlled brain metastases were permitted.

Prior therapy, excluding ROS1 inhibitors, was permitted in ALKA-372-001; prior therapy including crizotinib (Xalkori), ceritinib (Zykadia), and investigational agents were allowed in STARTRK-2.

In all 3 studies, patients were treated with entrectinib once daily at intermittent or continuous dosing schedules. In the dose-escalation ALKA-372-001 study, entrectinib was given at 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg or 1600 mg; in STARTRK-1, the agent was given at 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg. Entrectinib was given only at 600 mg in STARTRK-2. Treatment was given until documented radiographic progression, unacceptable toxicity, or withdrawal of consent. Patients were assessed on imaging at the end of cycle 1 and every 2 cycles thereafter.

The coprimary endpoints were ORR and DOR, both measured by blinded independent central review (BICR). Key secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Additional prespecified secondary endpoints focused on patients with baseline central nervous system (CNS) disease per BICR were intracranial response, intracranial DOR, and intracranial PFS; time to CNS progression in those with measurable CNS disease was a predefined secondary endpoint.

Sixty-four percent of patients were female and more than half (59%) were white, and 51% of patients had an ECOG performance status of 1. Fifty-nine percent patients were never smokers.

Results showed that 41 patients achieved a response (ORR 77%; 95% CI, 64-88) at the time of the data cutoff, which included 3 (6%) complete responses (CRs), 38 (72%) partial responses (PRs), and 1 (2%) patient with stable disease. The median PFS was 19.0 months (95% CI, 12.2-36.6).

Additionally, responses did not differ by upstream gene partner type; of patients with CD74-ROS1 fusions (n = 21), the ORR was 86%, and of those with non—CD74-ROS1 fusions (n = 20), the ORR was 65%. Ten (83%) of twelve patients with unknown fusions also responded to entrectinib. The median DOR was 14.6 months, 14.2 months, and 21.5 months for CD74-ROS1, non—CD74-ROS1, and unknown fusions, respectively.

In patients with baseline CNS disease (n = 23), the ORR was 74%, which included a 74% PR rate and a 17% progressive disease rate. Nine percent of responses were missing or unevaluable. The median DOR was 12.6 months (95% CI, 6.5—not estimable [NE]). The median PFS was 13.6 months (4.5–NE). The intracranial ORR was 55% (95% CI, 32-77); regarding best intracranial response, the CR rate was 20%, PR rate was 35%, the progressive disease (PD) rate was 15%, the non–CR/or non–PD rate was 20%, and 10% of responses were missing or unevaluable.

Those without CNS baseline disease (n = 30) showed an ORR of 80%, which comprised a 10% CR rate, 70% PR rate, 3% stable disease rate, 10% non-CR/PD rate, and 7% of responses that were missing or unevaluable. The median DOR was 24.6 months (95% CI, 11.4-34.8) and the median PFS was 26.3 months (95% CI, 15.7-36.6).

At the time of data cutoff, 18 (34%) of 53 patients had a CNS progression event, and the median time to CNS progression was not estimable (95% CI, 15.1—NE) at a median follow-up 15.5 months.

In the safety-evaluable population of patients with ROS1 fusion—positive NSCLC (n = 134), the median duration of treatment was 8.3 months. All patients reported ≥1 all-grade treatment-emergent adverse event; most events were grade 1/2 in severity. Three patients had a dose reduction for adverse events (AEs), which included confusion, depression, and mental status change; 20 (15%) patients needed dose reductions for nervous system disorders, the most common being dizziness (6%) and paresthesia (2%).

Fifty-nine percent of treatment-related adverse events (TRAEs) were grade 1/2, and grade 3 TRAEs occurred in 41 (31%) patients and grade 4 in five (4%). The most common grade 3/4 AEs were weight increase (8%) and neutropenia (4%); no AE-related deaths occurred.

There were 21 serious TRAEs reported in 11% of patients, the most frequently reported of which were nervous system disorders (3%) and cardiac disorders (2%). Other TRAEs that occurred in <3 patients included pyrexia, hypotension, anorectal disorder, blood creatinine increased, dehydration, and mental status changes.

TRAEs that led to dose reductions occurred in 34% of patients and discontinuation in 5%. AEs that led to discontinuation, all in <1% of patients, were cardiac tamponade, cardiogenic shock, myocarditis, pericardial effusion, dyspnea, pneumonitis, pulmonary embolism, edema peripheral, pneumonia, anorectal disorder, diarrhea, large intestine perforation, vomiting, limbic encephalitis, and myoclonus.

At the time of data cutoff, there were 9 (7%) deaths in this population, all of which were unrelated to treatment.

In addition to entrectinib’s FDA approval, the agent was approved by the Japan’s Ministry of Health, Labour and Welfare in June 2018 for the treatment of adult and pediatric patients with NTRK fusion—positive, advanced recurrent solid tumors.

“The genes ROS1 and NTRK are on a growing list of known genetic drivers of non—small cell lung cancer. In addition to showing the benefit of entrectinib against cancers caused by these fusion genes, these results highlight the importance of genetic testing in NSCLC, especially when patients are diagnosed with the condition in the absence of other risk factors,” Doebele concluded in the press release. “Only by testing for genes like ROS1 and NTRK can we match these genetic drivers of cancer with drugs like entrectinib.”

References

1. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1—2 trials [published online ahead of print December 11, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30690-4.
2. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17.
3. Lancet Oncology: Entrectinib effective, well-tolerated against ROS1 and NTRK lung cancers, especially with brain metastases [news release]. University of Colorado Cancer Center. Published December 13, 2019. https://bit.ly/35xVsrq. Accessed December 13, 2019.