Entrectinib Impresses in Certain Lung Cancers

A majority of patients with advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) obtained durable remissions with the ROS1 inhibitor entrectinib (Rozlytrek), according to an updated integrated analysis of three clinical trials.

Among 161 patients followed for at least 6 months, 67.1% had objective responses, with a median duration of 15.7 months. Median progression-free survival (PFS) also was 15.7 months, and more than 80% of patients were alive at 12 months.

“In this updated analysis, comprising more patients and a longer follow-up than the primary analysis, entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion-positive NSCLC, including those with CNS [central nervous system] metastases,” Fabrice Barlesi, MD, PhD, of Gustave Roussy Cancer Campus in Villejuif, France, and co-authors reported online in the Journal of Clinical Oncology.

ROS1 fusions occur in 1-2% of cases of NSCLC, and about 40% of patients with the disease subtype have brain metastases at diagnosis.

Crizotinib (Xalkori) has approval as first-line therapy for ROS1 fusion-positive metastatic NSCLC but has poor CNS penetration, the authors noted, adding that in about half of patients treated with crizotinib, initial progression occurs only in the CNS.

Entrectinib is designed to cross the blood-brain barrier, and preclinical studies showed that the agent achieves high CNS concentrations, which were associated with strong efficacy in brain-tumor models.

Integrated Analysis

For the analysis, the investigators evaluated entrectinib in three phase I or II clinical trials of patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. A preliminary analysis of a 53-patient efficacy-evaluable population showed a 77% objective response rate (ORR) and a median duration of response (DoR) of 24.6 months.

Among 20 patients with CNS involvement at baseline, 11 (55%) had objective responses, with a median DoR of 12.9 months. The FDA approved the drug on the basis of these findings.

Barlesi and co-authors reported findings from an analysis performed after a median follow-up of 15.8 months. Most (145 of 161) of the efficacy-evaluable patients were from the STARTRK-2 trial, a basket study that enrolled patients with solid tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions.

The trial had co-primary endpoints of ORR and DoR. Secondary endpoints included PFS by independent review, overall survival (OS), and safety.

The data showed that 62.7% of patients had exposure to at least one prior regimen for metastatic disease. About 35% of the patients had CNS lesions, which had been treated with brain radiotherapy in 46% of cases.

The vast majority of patients had some degree of tumor shrinkage and reached the level of objective response in 108 patients. The ORR included 14 complete responses. An additional 14 patients (8.7%) had stable disease.

Median time to response was about a month, and the presence of CNS involvement at baseline did not affect response (62.5% in patients with brain metastases, 69.5% in those without), the researchers reported.

CNS Activity, Safety

The 12-month DoR was 63% and was similar between patients with and without CNS metastasis, the authors reported. In the overall efficacy population, the 12-month PFS rate was 55%. Three of 105 patients without baseline CNS metastases had CNS progression during follow-up.

Survival data remained immature, but the 12-month OS was 81%.

In 24 patients with measurable CNS metastases at baseline, the intracranial ORR was 79%, including three patients (12.5%) who had an intracranial complete response. Among 24 responding patients with or without measurable CNS disease, the 12-month intracranial DoR was 55%, and the median intracranial PFS was 8.3 months.

A safety analysis of 210 patients with ROS1 fusions (regardless of tumor type) showed that most treatment-related adverse events (TRAEs) were grade 1/2. The most common grade 3 TRAEs were weight increase (8.1%), alanine aminotransferase elevation (3.3%), and diarrhea (2.9%).

Grade 4 TRAEs consisted of two cases of hyperuricemia, and one each of hypertriglyceridemia, limbic encephalitis, creatinine phosphokinase increase, anorectal disorder, and myocarditis. Sixteen patients discontinued treatment because of AEs.

In their discussion of the findings, the authors noted that entrectinib is effective against the most common crizotinib resistance mutation.

“Considering the high risk of CNS metastases in NSCLC, entrectinib is well placed as a first-choice TKI [tyrosine kinase inhibitor] rather than after progression on another TKI,” the researchers stated. “Our data provide further confirmation that entrectinib is a CNS-penetrant compound, with intracranial efficacy in patients with ROS1 fusion-positive NSCLC with baseline CNS metastases and limits the risk of CNS progression in those without baseline CNS metastases.”

As compared with other early-generation ROS1 TKIs, “entrectinib arguably has the best characterized intracranial outcomes,” co-author Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York City, told MedPage Today.

“From a safety perspective, the drug is well tolerated with a profile that reflects its inhibition of TRK kinases. It is not a drug that is positioned to be highly active against recalcitrant ROS1 kinase domain mediated resistance to prior ROS1 TKIs,” he said via email.

Another co-author, Anna Farago, MD, of Massachusetts General Hospital Cancer Center in Boston, echoed Drilon’s comments about entrectinib’s CNS efficacy, and also noted differing side-effect profiles among drugs used to treat ROS1 fusion-positive NSCLC.

“With entrectinib, for example, the most frequent side effects include dysgeusia and dizziness, and we can also see additional TRK-mediated side effects (because of potent TRK inhibition), such as weight increase and paresthesia,” she said via email. “With crizotinib, a ROS1/ALK/MET inhibitor, the most frequent side effects include visual disturbance, diarrhea, nausea, and peripheral edema.”