Longer-Term Data Help Shape TKI Selection in ROS1+ and ALK+ NSCLC

A wave of selective, central nervous system (CNS)-active TKIs has pushed response rates and progression-free survival (PFS) in oncogene-driven non–small cell lung cancer (NSCLC) to once-unthinkable levels, leaving experts to debate how to approach treatment sequencing in an increasingly crowded field and whether these agents belong in earlier-stage settings.

"There’s no way you can’t not put this in the first-line setting based on these numbers," Edward S. Kim, MD, MBA, of City of Hope, said of frontline taletrectinib (Ibtrozi) during a recent OncLive^® Scientific Interchange and Workshop.¹ Kim is physician-in-chief at City of Hope Orange County, deputy physician-in-chief at City of Hope National Medical Center, professor in the Department of Medical Oncology & Therapeutics Research, physician-in-chief chair, and system director of the Clinical Trials Office in Irvine, California.

Moderated by Joshua K. Sabari, MD, of NYU Langone Health’s Perlmutter Cancer Center in New York, New York, the workshop featured experts dissected key abstracts and data on ROS1- and ALK-directed therapies reported at the 2026 ASCO Annual Meeting and other recent congresses.

How are next-generation TKIs redefining frontline and post-progression care in ROS1+ NSCLC?

ASCO 2026 and the 2026 AACR Annual Meeting featured key updates on data for TKIs in oncogene-driven NSCLC, including those with ROS1-positive disease. For example, in a pooled 3-year analysis of the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials presented at AACR 2026, taletrectinib (n = 157) produced a confirmed overall response rate (ORR) of 89.8% (95% CI, 84.0%-94.1%), a median duration of response (DOR) of 49.7 months (95% CI, 38.6-not reached [NR]), and a median progression-free survival (PFS) of 46.1 months 95% CI, 31.8-NR) among TKI-naive patients.² The median overall survival (OS) was NR (95% CI, NR-NR).

Workshop faculty tied the drug’s tolerability to its TRK-sparing design. In the pooled analysis, updated safety data showed no new signals. Treatment-emergent adverse effects (TEAEs) led to dose interruptions (42.7%), reductions (31.3%), and discontinuation (8.5%), and the most common any-grade TEAEs comprised increased aspartate aminotransferase levels (71.9%), increased alanine aminotransferase levels (68.3%), and diarrhea (64.5%).

Taletrectinib received FDA approval in June 2025 for the treatment of patients with locally advanced or metastatic, ROS1-positive non–small cell lung cancer, based on data from TRUST-II and TRUST-II.³ The FDA is also reviewing a supplemental new drug application (sNDA) that includes updated data for taletrectinib in TKI-naive and TKI-pretreated patients with advanced ROS1-positive NSCLC; the target action date for the sNDA is January 4, 2027.⁴

"I’ve even moved [patients] from repotrectinib [Augtyro] to taletrectinib, who weren’t tolerating [repotrectinib] very well," Joel W. Neal, MD, PhD, of Stanford University School of Medicine, said during the workshop.

For patients with ROS1-positive disease who experienced progression on a TKI, the investigational TRK-sparing inhibitor zidesamtinib (NVL-520) produced ORRs of 41% (95% CI, 27%-57%) after repotrectinib (Augtyro; n = 46) and 47% (95% CI, 24%-71%) after taletrectinib (n = 19), according to updated data from the phase 1/2 ARROS-1 trial (NCT05118789).⁵ These data included ORRs of 67% (n = 12; 95% CI, 35%-90%) and 50% (n = 4; 95% CI, 7%-93%), respectively, in patients harboring ROS1 G2032R mutations.

The FDA is currently reviewing an NDA seeking the approval of zidesamtinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC who received at least 1 prior ROS1 TKI; this application carries a target action date of September 18, 2026.⁶

“They report[ed] the data in the [patients harboring] G2032R [mutations], and they're small numbers, [but] the ORR was about the same…They didn’t report the PFS in that group,” Sarah Goldberg, MD, MPH, of the Yale School of Medicine in New Haven, Connecticut, said. “I guess it's small numbers, but that would be interesting, because the ORRs are not so different. It would be really interesting to see if maybe the PFS is much better in that group [with ROS1 G2032R mutations].”

Do mature ALK+ NSCLC data leave any room to change frontline practice?

Updated 7-year data from the phase 3 CROWN trial (NCT03036488) presented at ASCO 2026 showed that patients with ALK-positive NSCLC treated with lorlatinib (Lorbrena; n = 149) experienced a median PFS that was still not reached (NR; 95% CI, 68.5 months-NR) compared with 9.1 months (95% CI, 7.4-10.9) for patients treated with crizotinib (Xalkori; n = 147; HR, 0.19; 95% CI, 0.13-0.26).⁷ The 7-year PFS rates were 55% vs 3%, respectively.

Given the durability of the long-term CROWN data, workshop participants debated current frontline approaches and the potential for switching patients to lorlatinib.

“Just before the 5-year CROWN data came out, I met a 29-year-old young woman who had metastatic de novo, pretty diffuse, including bone-involved metastatic disease with ALK [positivity],” Bo Wang, MD, of Willamette Valley Cancer Institute in Eugene, Oregon, said. “I already tried to convince her to go on lorlatinib, but when we looked at the toxicity profiles, she really preferred alectinib [Alecensa], so we started [alectinib]. Then the CROWN data came out, and I've spent the last 2 years trying to convince her to switch. And now the 7-year data is out, and I'm going to go back to try to talk to her again. She's 31, right? How do I have that conversation? I'm going to show her the data, but I want to convince her.”

Sabari and D. Ross Camidge, MD, PhD, of the University of Colorado Anschutz in Aurora, countered that switching TKIs to lorlatinib may not be the approach for each patient.

“Maybe you don't need to [switch],” Camidge contended. “Maybe as more time goes by and she hasn't progressed, she's showing that alectinib is the drug for her. And that evidence outweighs anybody else's evidence.”

Regarding alectinib, the 2025 ESMO Congress featured final results from the phase 3 ALEX trial (NCT02075840), which showed that alectinib extended OS to 81.1 months (95% CI, 62.3-not estimable) vs 54.2 months 95% CI, 34.6-75.6) for crizotinib (HR, 0.78; 95% CI, 0.56-1.08; stratified log-rank P = .1320).⁸

In the pretreated setting, the fourth-generation TKI neladalkib (NVL-655) drew interest from panelists, stemming from data from the phase 1/2 ALKOVE-1 trial (NCT05384626), where neladalkib produced an ORR of 31% (95% CI, 26%-37%) in patients who received 1 to 5 prior ALK TKIs with or without chemotherapy (n = 253).⁹ Notably, the ORRs were 46% (95% CI, 335-59%) for those naive to lorlatinib (n = 63) and 26% (95% CI, 20%-33%) for those previously treated with lorlatinib (n = 190).

“If we look specifically at the [ROS1] G1202R mutation, ORR was 68% in the all-comers group [n = 47],” Eric K. Singhi, MD, of The University of Texas MD Anderson Cancer Center in Houston, said. “[The ORR in this subgroup for] lorlatinib-naive [patients] bumped up to 83%.”

Should effective TKIs move into resectable NSCLC? What unmet needs remain in ALK+ and ROS1+ NSCLC?

The move toward early-stage disease proved the session’s most contentious thread. The randomized, double-blind phase 3 TRUST-IV trial (NCT07154706) is testing adjuvant taletrectinib vs placebo in patients with stage IB to IIIA ROS1-positive NSCLC, and several faculty raised concerns regarding the placebo aspect of the study.

"I have no equipoise with this trial. I could not put a patient on it," Goldberg said. “I don't know why we have to keep doing this with tolerable drugs that have really good long activity. We've already shown this [in the metastatic setting]. Lung cancer has a high rate of relapse, and these drugs really work. I know why in practice [we need to do this trial], but I am not happy about it.

In the neoadjuvant setting, the phase 2 LORIN trial (NCT05740943) being conducted in China is evaluating lorlatinib in patients wtih stage III ALK-positive disease.¹⁰ Findings shared at ASCO 2026 showed evaluable patients (n = 32) achieved a pathologic complete response rate of 47% and a major pathologic response rate of 81%. Among patients who had unresectable disease at enrollment (n = 24), 75% were able to undergo surgery.

“[Patients in LORIN] received 3 cycles of neoadjuvant lorlatinib, with many of them being converted to resectable [disease], which I thought was quite interesting,” Sabari said. “What was really fascinating is looking at these pCR rates. I was sort of blown out of the water here. We know that for EGFR TKI, we don't see this high rate of pCR. We need chemotherapy with osimertinib [Tagrisso].”

References

1. Early Career Data Review: Key Advances in Oncogene-Driven NSCLC With a Focus on ROS1 and ALK Targeted Therapies. An OncLive Scientific Interchange and Workshop. OncLive. May 31, 2026. Accessed July 20, 2026.
2. Bazhenova L, Nieva J, Nagasaka M, et al. Taletrectinib in tyrosine kinase inhibitor (TKI)-naïve patients with ROS1+ non-small cell lung cancer (NSCLC): updated data from TRUST-I and TRUST-II. Cancer Res. 2026;86(suppl 8):CT300. doi:10.1158/1538-7445.AM2026-CT300
3. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. FDA. June 11, 2025. Accessed July 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-taletrectinib-ros1-positive-non-small-cell-lung-cancer
4. Nuvation Bio announces FDA acceptance of supplemental new drug application for Ibtrozi (taletrectinib) with updated duration of response in advanced ROS1-positive non-small cell lung cancer. News release. Nuvation Bio. May 6, 2026. Accessed July 20, 2026. https://investors.nuvationbio.com/news/news-details/2026/Nuvation-Bio-Announces-FDA-Acceptance-of-Supplemental-New-Drug-Application-for-IBTROZI-taletrectinib-with-Updated-Duration-of-Response-in-Advanced-ROS1-Positive-Non-Small-Cell-Lung-Cancer/default.aspx
5. Liu G, Drilon AE, Besse B, et al. Zidesamtinib in patients with ROS1-positive NSCLC previously treated with repotrectinib or taletrectinib. Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT248.
6. Nuvalent announces FDA acceptance of new drug application for zidesamtinib for the treatment of TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. November 19, 2025. Accessed July 20, 2026. https://investors.nuvalent.com/2025-11-19-Nuvalent-Announces-FDA-Acceptance-of-New-Drug-Application-for-Zidesamtinib-for-the-Treatment-of-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC
7. Mok TS, Solomon BJ, Felip E, et al. Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ non-small cell lung cancer: 7-year update from the phase 3 CROWN study. J Clin Oncol. 2026;44(suppl 16):8502. doi:10.1200/JCO.2026.44.16_suppl.8502
8. Mok TSJ, Camidge DR, Dziadziuszko R, et al. Final overall survival (OS) and safety analysis of the Phase 3 ALEX study of alectinib vs crizotinib in patients with previously untreated, advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Ann Oncol. 2025;36(suppl 2):S1614-1615. doi:10.1016/j.annonc.2025.09.018
9. Lin JJ, Felip E, Cho BC, et al. ALKOVE-1: neladalkib (NVL-655) efficacy and safety in advanced ALK-positive NSCLC. J Clin Oncol. 2026;44(suppl 16):8503. doi:10.1200/JCO.2026.44.16_suppl.8503
10. Zhang C, Hu Y, Jiang B-Y, et al. Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: A phase 2 multicenter study (LORIN). J Clin Oncol. 2026;44(suppl 16):8002. doi:10.1200/JCO.2026.44.16_suppl.8002