Array of Agents Allow for Treatment Individualization in ROS1+ NSCLC

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Following the development of crizotinib (Xalkori), later generations of drugs in the realm of ROS1-positive non–small cell lung cancer (NSCLC) have displayed improved efficacy and reduced toxicity, allowing therapy to be personalized to a given 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 University of Southern California Keck School of Medicine in Los Angeles, 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. “The newer drugs, repotrectinib and taletrectinib, have [shown] remarkable progression-free survival [PFS] data, and many of these drugs have excellent intracranial activity.”

Unpacking the Differences Between Agents for ROS1-Positive Disease

To discuss the differences between the agents, Nieva referenced a series of matching-adjusted indirect comparisons (MAICs). In a MAIC published in the Journal of Comparative Effectiveness Research, investigators compared entrectinib with crizotinib for the treatment of patients with ROS1-positive NSCLC.2 Data revealed that although entrectinib yielded significantly better response rates compared with crizotinib across treatment scenarios (OR, 2.43-2.74), PFS data were similar between the 2 agents.

Nieva then transitioned to discussing another MAIC that compared repotrectinib with crizotinib in patients with ROS1-positive NSCLC.3 Findings 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).

“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 MAIC.”

Data from a third MAIC indicated that taletrectinib led to significant OS and PFS benefits compared with crizotinib for the treatment of 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 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, findings from a 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).

In patients who previously received a TKI, the ORRs in the taletrectinib (n = 104) and repotrectinib (n = 56) arms were 55.8% (95% CI, 45.7%-65.5%) and 37.5% (95% CI, 24.9%-51.5%), respectively. Treatment with taletrectinib also conferred a DOR benefit vs repotrectinib in this subgroup (HR, 0.86; 95% CI, 0.419-1.776). The PFS HR was 0.97 (95% CI, 0.578-1.612).

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 has a different toxicity profile compared with the other agents. Treatment with the drug 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

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