ROS1-Directed Therapies Lead the Way in NSCLC

Since the development of crizotinib (Xalkori), oncologists can now choose from an array of later-generation drugs in the realm of ROS1-positive non–small cell lung cancer (NSCLC) that have displayed improved efficacy and reduced toxicity, allowing therapy to be personalized to a patient’s treatment goals, according to Jorge J. Nieva, MD.¹

“The great news is that we have a world of choices,” Nieva, associate professor of clinical medicine at the Keck School of Medicine of USC in Los Angeles, California, said during a presentation at the 26th Annual International Lung Cancer Congress. “For the vast majority of us in the US, we’re going to have more drugs than we have patients with ROS1-positive disease. Every successive generation [of agents] seems to get better than the last one.”

Nieva noted that ROS1-positive NSCLC is too rare to perform comparison studies. He said that 5 other targeted agents beyond crizotinib can be used in this disease setting: entrectinib (Rozlytrek), repotrectinib (Augtyro), taletrectinib (Ibtrozi), lorlatinib (Lorbrena), and zidesamtinib. “Zidesamtinib is not yet FDA approved, and lorlatinib is not approved in [patients with] ROS1-positive disease, but it does have significant ROS1 activity,” Nieva noted.

Making Comparisons

Noting the differences between the agents, Nieva referenced a study published in the Journal of Comparative Effectiveness Research, comparing entrectinib with crizotinib for the treatment of patients with ROS1 fusion– positive NSCLC.² Data revealed that although entrectinib yielded significantly better response rates compared with crizotinib across treatment scenarios (OR, 2.43-2.74), progression-free survival (PFS) data were similar between the 2 agents.

Another study that compared repotrectinib with crizotinib in patients with ROS1-positive NSCLC showed that patients who received repotrectinib experienced a significant PFS benefit vs those given crizotinib following population adjustment (HR, 0.44; 95% CI, 0.29–0.67).³

“The PFS data are similar [between entrectinib and crizotinib],” Nieva commented. “[However], looking at repotrectinib vs crizotinib, the HR [for PFS] is much better [in favor of] repotrectinib in that matching-adjusted indirect comparison [MAIC].” Data from a third MAIC indicated that taletrectinib led to significant overall survival (OS) and PFS benefits compared with crizotinib for treating patients with ROS1-positive NSCLC.⁴

After population adjustment, patients in the taletrectinib group experienced a 52% reduction in the risk of disease progression or death vs crizotinib (HR, 0.48; 95% CI, 0.27–0.88).

Moreover, taletrectinib reduced patients’ risk of death by 66% compared with crizotinib (HR, 0.34; 95% CI, 0.15–0.77).

Findings from another MAIC revealed that taletrectinib also led to an OS benefit vs entrectinib in patients with ROS1-positive disease who did not receive a prior tyrosine kinase inhibitor (TKI; adjusted HR, 0.48; 95% CI, 0.27–0.88).⁵ Taletrectinib was also superior compared with entrectinib in terms of PFS (adjusted HR, 0.42; 95% CI, 0.27–0.65) and duration of response (DOR; adjusted HR, 0.35; 95% CI, 0.21–0.60).

In terms of taletrectinib vs repotrectinib, f indings from another MAIC showed that the overall response rate (ORR) among TKI-naive patients with ROS1-positive NSCLC who received taletrectinib (n = 152) was 88.8% (95% CI, 82.7%–93.3%) compared with 78.9% (95% CI, 67.6%-87.7%) in the repotrectinib group (n = 71).⁶ Treatment with taletrectinib led to a DOR benefit vs repotrectinib (HR, 0.76; 95% CI, 0.404-1.438). However, the HR for PFS was 0.93 (95% CI, 0.656–1.311).

Nieva concluded his presentation by explaining that the choice between agents for patients with ROS1-positive NSCLC often comes down to toxicity. He noted that crizotinib can lead to central nervous system (CNS) toxicities, as well as nausea, vomiting, diarrhea, and fatigue, but these are usually manageable. Entrectinib and repotrectinib can both lead to weight gain, constipation, and diarrhea, he added.

Nieva explained that taletrectinib does not lead to as many instances of CNS toxicity; however, it does more often cause gastrointestinal toxicities such as liver function test abnormalities, diarrhea, and nausea.

“I’d like to see more trials [that are similar to] the [phase 3] FLAURA2 trial [NCT04035486] that look at these agents in combination with chemotherapy so that we can [get treatment] intensification and longer-term disease control for these patients,” Nieva concluded.

REFERENCES:

1. Nieva JJ. ROS1. Presented at: 26th Annual International Lung Cancer Congress; July 25-27, 2025; Huntington Beach, CA.

2. Chu P, Antoniou M, Bhutani MK, et al. Matching-adjusted indirect comparison: entrectinib versus crizotinib in ROS1 fusion-positive non-small cell lung cancer. J Comp Eff Res. 2020;9(12):861-876. doi:10.2217/cer-2020-0063

3. Wolf J, Goring S, Lee A, et al. Population-adjusted indirect treatment comparisons of repotrectinib among patients with ROS1+ NSCLC. Cancers (Basel). 2025;17(5):748. doi:10.3390/cancers17050748

4. Nagasaka N, Liu G, Pennell N, et al.LBA2: Taletrectinib vs crizotinib in ROS1-positive (ROS1+) non-small cell lung cancer (NSCLC): a matching-adjusted indirect comparison (MAIC). J Thorac Oncol. 2025;20(3):S1-S1. doi:10.1016/S1556-0864(25)00195-9

5. Nagasaka M, Liu G, Pennell NA, et al. Taletrectinib vs entrectinib in ROS1-positive NSCLC: a matching-adjusted indirect comparison. Presented at: International Society for Pharmacoeconomics and Outcomes Research Congress; May 13-16, 2025; Montreal, Canada. Abstract CO151.

6. Nagasaka M, Liu G, Pennell NA, et al. Taletrectinib vs repotrectinib in ROS1-positive (ROS1+) non–small cell lung cancer (NSCLC): A matching-adjusted indirect comparison (MAIC). Ann Oncol. 2024;35(suppl 4):S1640-S1641. doi:10.1016/j.annonc.2024.10.670