ROS1-Positive Lung Cancer: Key Takeaways from the Roundtable Discussions

Edgardo Santos Castillero, MD, recently moderated 2 Case-Based Roundtable events focused on the treatment of ROS1-positive non–small cell lung cancer (NSCLC). The discussions brought together medical oncologists from across the United States to review the evolving treatment landscape for this rare but clinically important molecular subtype, including recent efficacy and safety data on newer-generation ROS1 inhibitors, ongoing challenges in generating high-quality trial data for uncommon genomic alterations, and where the field may be headed next.

In an interview with Targeted Oncology^TM, Santos Castillero, physician lead at The Oncology Institute, Lung Cancer Center of Excellence; clinical associate professor, Charles E. Schmidt College of Medicine, Florida Atlantic University; and president, Florida Society of Clinical Oncology, shared the key takeaways from these conversations.

Targeted Oncology: What do you see as most significant about the trials discussed at your roundtable events?

Edgardo Santos Castillero, MD: The most important thing we discussed in our roundtable was reviewing the amount of data that has been developed in recent years in this pathway in NSCLC. We've gone from the first generation of ROS1 TKIs—crizotinib [Xalkori], roughly 15 years ago—to drugs that are more potent with better toxicity profiles. At this point, it seems we have a very active compound for patients with locally advanced or metastatic ROS1-altered disease.

What were the key takeaways about the therapies discussed in the presentation?

I'd say the key takeaway from the 2 roundtables I led is that our medical oncologists from different regions in the United States are very aware of the data developed in this pathway, which is encouraging. They're tracking developments in terms of both efficacy and toxicity. Following a recent update on TRUST-I [NCT04395677] and TRUST-II [NCT04919811] at the AACR [American Association for Cancer Research] Congress this past April, the inhibitor taletrectinib [Ibtrozi] showed a median duration of response and median progression-free survival of [45.6 months in tyrosine kinase inhibitor (TKI)–naive patients]—unheard of in this space compared with prior compounds.¹ These are major steps forward: the response rate this inhibitor induces, combined with the duration of response is clinically significant. A median duration of response of [44.9 months in TKI-naive patients and 17 months in TKI-pretreated patients], in my opinion and that of my colleagues, combined with a favorable toxicity profile, may make this drug very attractive for use in the first line.

Were there any comments or concerns from other participants that stood out to you during your discussions?

First, and this isn't unique to ROS1—it applies to other targetable pathways in NSCLC as well—it's very difficult to conduct well-designed phase 3 trials because the incidence of these mutations or genomic alterations is often quite rare. It's hard to identify these patients and enroll them in clinical trials, so we lack phase 3 data not just in ROS1 but also in ALK, RET, and others. Instead, we develop new agents and compare them to prior ones to see whether efficacy and toxicity have improved. That was a shared concern among all participants.

Second, and related, because these alterations are so rare, there's a lack of clinical experience with any single agent. Some colleagues have experience with the newest inhibitor but not the ones that came before it, and vice versa—some have experience with repotrectinib [Augtyro] or entrectinib [Rozlytrek] but not the newest agents. That's because the incidence of ROS1 alterations in lung cancer is only about 1% to 2%.² It's difficult for clinicians to gain firsthand experience across multiple agents to compare them, and that was another point that stood out during our 2 roundtables.

Were there any other interesting topics of discussion during your roundtables?

ROS1 inhibitors have traditionally had issues with [central nervous system (CNS) adverse] effects, in part because some of them have activity against a pathway called TRKB [tropomyosin receptor kinase B]; the more activity an inhibitor has against TRKB, the more CNS effects a patient tends to experience. Taletrectinib, the newest inhibitor, is more selective and has less TRKB activity than others, but issues like dizziness can still occur. It's worth remembering that while many [patients with] lung cancer are elderly, ROS1-positive patients tend to be younger—often with families, careers, and responsibilities. For these patients, dizziness and other symptoms like peripheral neuropathy or dysgeusia can be especially burdensome. In my opinion, and that of my colleagues at these roundtables, the improved toxicity profile of taletrectinib represents a major step forward.

The other common issue across ROS1 inhibitors is [gastrointestinal (GI)] toxicity—nausea, vomiting, constipation. In TRUST-I and TRUST-II, the majority of patients resolved GI symptoms within a median of 1 day, and 90% did not require any clinical management to alleviate them. We also discussed where the field is heading: agents such as foritinib and zidesamtinib [are] currently in phase 1 and phase 2/2b development, and we're looking forward to learning more about these as they potentially move into clinical practice.

Is there any other emerging research in this area that you're looking forward to?

As I mentioned, working with rare genomic alterations is challenging, but the prevalence and incidence of lung cancer in the United States remain high and continue to rise. Even at 1% to 2% of adenocarcinoma cases, we're talking about thousands of patients—a meaningful number that warrants continued research investment.

Beyond the agents I've already mentioned, drugs used in other settings—such as brigatinib [Alunbrig], a potent ALK inhibitor, and lorlatinib [Lorbrena]—also have some ROS1 activity, and there's research exploring that further. We'll need to see how promising newer compounds perform, including their ability to rescue patients who progress on taletrectinib or repotrectinib.

It's also worth noting that when a ROS1 inhibitor isn't potent enough, tumor cells can escape treatment. One common resistance mechanism is the G2032R mutation. Both repotrectinib and taletrectinib retain good activity against this mutation, so we can rescue patients who develop it. The open question now is: as we use these more potent, selective inhibitors, what resistance mechanisms will emerge next? There's a lot of ongoing research into that, both to address the current problem and to develop novel agents that can rescue patients progressing on taletrectinib or repotrectinib.

One thing I'd like to see more of in the future, beyond research into resistance mechanisms and newer agents, is the development of real-world data. Because the incidence of ROS1 alterations is so low, it's very difficult to design large, traditional clinical trials that would identify the single best compound. Real-world data can give clinicians important insight into the best therapeutic option for a given patient based on how they present, who they are, and what comorbid conditions they may have. I think that kind of real-world observation is really important for us to continue developing.

REFERENCES

1. Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1+ non–small cell lung cancer: TRUST. J Clin Oncol. 2025;43:1920-1929. doi:10.1200/JCO-25-00275

2. Desilets A, Repetto M, Yang SR, Drilon A. Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. Cancer. 2025 Mar 15;131 Suppl 1(Suppl 1):e35784. doi: 10.1002/cncr.35784. PMID: 40171848; PMCID: PMC12551656.