Treatment landscape changes but challenges persist for ROS1 or NTRK fusion–positive lung cancer

MDedge News

Patients with non–small cell lung cancer harboring ROS1 or NTRK fusions may face a particularly challenging journey. These cancers, while relatively rare, can be less responsive to conventional treatment, experts say, and may exhibit more aggressive behavior than cancers that are not gene fusion positive.

The situation has improved somewhat with the recent approvals of the tyrosine kinase inhibitors (TKIs) entrectinib and larotrectinib, which according to investigators are associated with high rates of response that tend to be durable in patients with ROS1 or NTRK fusion–positive cancers.

However, making sense of the emerging data for these TKIs has proven to be challenging, as there are no head-to-head studies for the inhibitors, and the patient populations studied vary widely, complicating any potential comparisons between therapies.

Data not easy to compare

Case in point are the latest reports on entrectinib (Rozlytrek), a potent, multitargeted TKI that has activity against ROS1, NTRK, and ALK. In integrated analyses of three phase 1 or 2 trials, recently published in Lancet Oncology, objective responses to entrectinib were seen in 77% of ROS1 TKI-naive patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC), but in just 57% of those with NTRK fusion–positive solid tumors.

By comparison, a pivotal integrated analysis of three larotrectinib phase 1 or 2 trials, objective responses were seen in 75% of patients, a figure that investigators in the entrectinib study acknowledged as higher than what they had observed.

However, weighing the differences between these two TKIs is challenging, because of the differences in study design and patient population, the investigators said.

Notably,CNS metastases, which portend a poor prognosis, were present in 22% of the entrectinib-treated patients at baseline, versus just 2% in the larotrectinib cohort, said Ulrik Lassen, MD, PhD, in an editorial accompanying the entrectinib analyses.

“These data emphasize that different patient populations with gene fusion–positive cancers are not easy to compare,” wrote Dr. Lassen of the department of oncology at Rigshospitalet, Copenhagen.

The recent entrectinib analyses included a combined total of 107 patients from the ongoing, single-arm studies ALKA-372-001, STARTRK-1, and STARTRK-2.

“The collection of additional data after the approval of entrectinib will be important to gain real-world experience and improve strategies for identifying patients with rare gene fusions who might benefit from such targeted therapies,” Dr. Lassen said.

Durable disease control in ROS1 fusion–positive NSCLC

In one integrated analysis, Alexander Drilon, MD, and colleagues reported on TKI-naive patients from the ongoing phase 1 or 2 studies who had ROS1 fusion–positive NSCLC and received entrectinib orally at doses of 600 mg or higher once daily.

ROS1 fusions are “enriched” in NSCLCs and seen in about 1%-2% of cases, Dr. Drilon, research director of early drug development at Memorial Sloan Kettering Cancer Center, N.Y., and coauthors wrote in their report in Lancet Oncology. As many as 36% of these patients had brain metastases at the time of a diagnosis of advanced disease, they added.

“Targeted therapy for patients with ROS1 fusion–positive NSCLC requires effective coverage of the CNS,” said Dr. Drilon and coauthors in the report, which also pointed to the “suboptimal CNS penetration” of an earlier-generation multitargeted TKI, crizotinib (Xalkori).

Objective responses were noted in 41 of 53 patients (77%) evaluable for efficacy, while the median duration of response was 24.6 months. Beyond those primary endpoints, investigators also reported a median progression-free survival of 19.0 months.

“These outcomes exceed the activity of first-line chemotherapy and immunotherapy in NSCLC, supporting the current standard of care for ROS1 fusion–positive NSCLC,” said Dr. Drilon and coauthors in a discussion of the results.

The efficacy results of this analysis were “comparable” to those previously achieved for crizotinib and ceritinib, despite a poorer-prognosis entrectinib-treated cohort that included a high proportion (greater than 40%) of patients with intracranial metastases at baseline, investigators said.

Likewise, the results were comparable to what was seen in a small series of ROS1 TKI-naive patients treated with lorlatinib (Lorbrena).

While investigators acknowledged limitations of cross-trial comparisons, they added that conducting a randomized trial of entrectinib versus crizotinib would be “challenging” because of the low incidence of ROS1 gene fusions in NSCLC.

Entrectinib was well tolerated, with “uncommon” serious side effects that were typically manageable with dose interruptions or reductions, according to investigators.

In the larger cohort of patients evaluable for safety, which included patients who were or were not TKI-naive, grade 1-2 adverse events were seen in 79 of 134 patients (59%), while 15 patients (11%) had serious treatment-related adverse events, primarily including nervous system or cardiac disorders.

Dr. Alexander Drilon of Memorial Sloan Kettering Cancer Center, New York

credit: Will Pass/MDedge News

Clinically meaningful responses in NTRK fusion–positive cancers

In a similar integrated analysis, Robert C. Doebele, MD, and coinvestigators reported on 54 patients from the three phase 1 or 2 trials who had advanced or metastatic NTRK fusion–positive solid tumors, including 10 (or 19%) who had NSCLC. Of note, this analysis excluded any patient with a ROS1 or ALK gene rearrangement.

The frequency of NTRK gene fusions varies by tumor type, occurring in about 0.3% of solid tumors overall, Dr. Doebele of the University of Colorado at Denver, Aurora, and coauthors wrote in their analysis in Lancet Oncology, which included patients with 10 different tumor types.

As noted earlier in this article, objective responses were seen in 31 of 54 patients, or 57%, though the report also highlighted a 70% response rate in the NSCLC subgroup (7 of 10 patients).

The larger proportion of patients with CNS metastases at baseline versus the larotrectinib study (22% versus 2%, respectively) was just one factor that could account for the lower response rate with entrectinib, investigators said. For example, in the larotrectinib analysis, less-responsive cancers such as thyroid and colorectal cancer were “much less represented” than in the entrectinib analysis, they said.

Disease control was durable in the overall cohort of patients with NTRK fusion–positive cancers, according to the investigators, who reported a median duration of response of 10 months and median progression-free survival of 11 months.

A high proportion of entrectinib-treated patients had a response and durable antitumor activity, according to the investigators; however, they said findings of the integrated analysis were limited by the single-arm study design and the relatively small number of patients.

“The ongoing STARTRK-2 and STARTRK-NG trials will hopefully provide additional data to support the use of entrectinib as a targeted treatment for patients with NTRK fusion-positive tumors who have, or are at risk of developing, CNS metastases.” Dr. Doebele and coauthors concluded in their report.

The studies were funded by Ignyta and Hoffmann-La Roche. Study authors declared interests related to Ignyta, Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, and Rain Therapeutics, among others. Dr. Lassen declared personal fees from Bayer.

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