Although ROS1-mutated lung cancer accounts for about 1% to 2% of all non–small cell lung cancers (NSCLCs), it is an important druggable oncogene, and new data show that it can be successfully targeted for clinical gain. In a pooled analysis of phase I and II trials in patients with ROS1-positive NSCLC, entrectinib achieved high response rates and durable responses, including in patients with brain metastases.¹ These preliminary results were greeted with enthusiasm at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer.

Robert Doebele, MD, PhD

“The data look very exciting,” said lead author Robert Doebele, MD, PhD, of the University of Colorado, Aurora. “Clinically meaningful, deep, and durable responses were observed, including in patients with baseline brain metastases. The hope is that entrectinib can replace crizotinib (Xalkori) as a first-line therapy against ROS1-positive NSCLC.”

Entrectinib is an oral selective inhibitor of ROS1/NTRK/ALK that is more potent than crizotinib. It was designed to cross the blood-brain barrier and has shown efficacy in the treatment of primary and secondary brain tumors. 

Brain metastasis is common in treatment-naive stage IV NSCLC and is found in more than one-third of patients. Crizotinib or ceritinib (Zykadia) is the current standard of care for ROS1-positive NSCLC, based on PROFILE 1001 data² and a Korean phase II study.³ The central nervous system (CNS) is a common site of first disease progression in patients with ROS1-positive NSCLC treated with crizotinib.

“We believe patients with ROS1-positive NSCLC may benefit from more potent ROS1 inhibitors that are CNS-penetrant, such as entrectinib, in the first-line setting,” he told the audience.

Study Details

At the conference, Dr. Doebele presented the results of an integrated analysis of 53 patients with ROS1-positive NSCLC from 3 different clinical trials of entrectinib across 150 sites in 15 countries. They included phase II STARTRK-2 (37 patients), phase I STARTRK-1 (7 patients), and phase I ALKA-372-001 (9 patients).

At baseline, the median age of patients was 53 years, 64% were female, 35.8% were Asian, and 64.2% were white. More than half (58.5%) were never-smokers, 76% had adenocarcinoma, and the majority received prior systemic therapy. Notably, 43% of patients had brain metastases at study entry.

Dr. Doebele showed a waterfall plot for response. “The vast majority of patients had tumor regression,” he stated. The objective response rate was 77.4% for the 53 patients evaluable for response, and the median duration of response was 24.6 months. Among 23 patients (43.4%) enrolled in the trial with evaluable brain metastases, the intracranial response rate was 55%. The duration of intracranial response was 12.9 months.

At a median follow-up of 15.5 months, the median progression-free survival was 19 months. In 30 patients without brain metastasis at baseline, the median progression-free survival was 26.3 months; in those with brain metastasis at baseline, the median progression-free survival was 13.6 months.

Overall survival is still immature, with a median follow-up of 15.5 months. So far, 9 patients (17%) have died.

Safety Summary

Entrectinib was tolerable. A total of 3.9% of patients discontinued the drug due to adverse events. Treatment-related adverse events led to dose reduction in 27.3% and dose interruption in 25.4%. The rate of serious adverse events was 8.5%. There were no grade 5 adverse events.

In all trials of entrectinib to date in 355 patients, side effects included fatigue, dizziness, weight gain, nausea, constipation, and diarrhea. In this analysis, dysgeusia of all grades was reported in 41.1% of patients.

“Crizotinib is known to have poor blood-brain barrier penetration from studies of ALK-positive NSCLC and the PROFILE 1001 crizotinib trial did not report any data on brain activity, including whether any patients enrolled in the trial had brain metastases. Comparative trials of crizotinib vs entrectinib will probably not be done, due to the rare nature of this oncogene,” Dr. Doebele commented.

“Previous drugs targeting ROS1 such as crizotinib have poor CNS penetration and therefore can allow disease progression in the brain, even before the cancer becomes resistant to the drug. For these patients, we have been using targeted radiation and other strategies to try to control brain metastases while continuing to target ROS1 in the body. We are hopeful that entrectinib will help us control many cases of ROS1-positive cancer in the body and the brain,” Dr. Doebele stated in a news release from the University of Colorado.

Other Drugs Targeting ROS1

Repotrectinib is an investigational ROS1 inhibitor designed to target the G2032R mutation, which is the most common resistance mutation after treatment with crizotinib. This drug is being tested in phase I trials.

Lorlatinib is a third-generation pan tyrosine kinase inhibitor of ALK and ROS1 currently in phase II testing. This drug also penetrates the CNS and has shown responses in the CNS in a small number of patients. ■

DISCLOSURE: Dr. Doebele is a speaker or advisor to Takeda, Ignyta, AstraZeneca, Bayer, Genentech, and F. Hoffmann-La Roche and is a stock shareholder in Rain Therapeutics; has received grant or research support from Ignyta; and has royalty, IP rights, or is a patent holder in Abbott Molecular (patent license), Rain Therapeutics (patent license), and Ignyta (licensing fee for biologic materials). 

REFERENCES

1. Doebele RC, Ahn MJ, Siena S, et al: Efficacy and safety of entrectinib in locally advanced or metastatic ROS1-positive non-small cell lung cancer. 2018 World Conference on Lung Cancer. Abstract 13903. Presented September 24, 2018.

2. Shaw AT, Ou SHI, Bang YJ, et al: Crizotinib in ROS1-rearranged non–small-cell lung cancer. N Engl J Med 371:1963-1971, 2014.

3. Kim SM, Kim HR, Lee JS, et al: Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 35:2613-2618, 2017.