G2032R Resistance Data Is Reshaping Second-Line Sequencing in ROS1+ NSCLC

This article is part 2 of a 2-part series from a Case-Based Roundtable event. Read part 1.

After progression on a frontline ROS1 tyrosine kinase inhibitor (TKI), the ROS1 G2032R solvent-front mutation is the most common acquired resistance mechanism, and it sterically blocks binding of earlier-generation inhibitors such as crizotinib (Xalkori) and entrectinib (Rozlytrek). Repotrectinib (Augtyro) and taletrectinib (Ibtrozi) were both engineered around that resistance pattern, but with no trial comparing them head to head after progression, oncologists are largely sequencing therapy on mutation-specific coverage and central nervous system (CNS) activity rather than on a clear efficacy leader.

In a virtual Case-Based Roundtable event for oncologists across the Rocky Mountain and Southwest regions, Eric K. Singhi, MD, a thoracic medical oncologist at UT MD Anderson Cancer Center, reviewed second-line efficacy and safety data across the ROS1 TKIs alongside a case of a patient who progressed on frontline entrectinib. Singhi noted that repotrectinib and taletrectinib were purpose-built to fit around the altered binding pocket created by G2032R, which is why both remain active where earlier agents fail.

CASE SUMMARY

• A patient with advanced ROS1 fusion–positive NSCLC was initiated on entrectinib in the first-line setting, achieving a partial response.
• The patient maintained response for 18 months before developing worsening symptoms consistent with progressive disease.

Workup at Progression

• CT chest reveals an increase in size of the primary tumor with new contralateral pulmonary nodules, confirming systemic progression.
• Brain MRI demonstrates 3 new small lesions, indicating new intracranial involvement.
• Repeat NGS identifies a ROS1 G2032R mutation

EVENT RECAP

For this patient, 69.2% of participants said they would offer taletrectinib next, 23.1% chose repotrectinib, and 1 participant favored a clinical trial; no one selected lorlatinib (Lorbrena).

Robert Yoo, DO, of Ironwood Cancer & Research in Scottsdale, Arizona, explained the structural logic behind that split. "The binding site of glycine is very small, and it was changed to arginine, so anything that's big cannot fit. The molecule that's small enough is really taletrectinib or repotrectinib," he said.

Sanjay Oommen, MD, of Texas Oncology in Coppell, Texas, weighed the same 2 agents differently: "I picked repotrectinib because the CNS activity is more, and because I think the G2032R coverage is more robust with repotrectinib compared to taletrectinib, though I don't know what the second-line [progression-free survival (PFS)] is for either."

The panel then reviewed the National Comprehensive Cancer Network (NCCN) second-line algorithm, which lists repotrectinib and taletrectinib specifically as options for resistance mutations such as G2032R, alongside entrectinib, crizotinib, or lorlatinib depending on prior therapy.¹ Participants agreed that CNS-only or oligoprogressive disease often warrants local therapy, typically stereotactic radiosurgery, before or alongside a systemic switch, with several noting they would loop in radiation oncology and consider serial circulating tumor DNA to guide the decision. The guideline also recommends repeat plasma or tissue profiling at progression to identify acquired resistance mutations, which is how this case's G2032R mutation was found.

For an entrectinib-pretreated patient (this case's exact scenario), a subgroup analysis from TRUST-II (NCT04919811) reported a confirmed objective response rate (cORR) of 80.0% (95% CI, 44.4%-97.5%) with taletrectinib, including 1 complete response and 7 partial responses.² Across broader TKI-pretreated cohorts, the phase 2 TRIDENT-1 trial (NCT03093116) of repotrectinib reported a cORR of 41% and, specifically in patients with G2032R, an objective response rate (ORR) of 58%;³ pooled TRUST-I (NCT04395677) and TRUST-II data for taletrectinib reported a cORR of 61.7% and a G2032R-specific ORR of 61.5%.²

Antonious Hazim, MD, of Mayo Clinic in Phoenix, Arizona, said taletrectinib has become his default. "My preferred agent is taletrectinib, both for frontline and for patients who progress on an earlier-generation ROS1 TKI," he said, describing generally good tolerability aside from occasional dizziness.

Singhi acknowledged that once patients progress beyond a second ROS1 TKI, options thin quickly. Yoo described losing a patient within weeks of an otherwise reassuring scan. "Even 2 weeks ago I celebrated, [the patient’s] MRI looks amazing, and then 3 weeks later they have new leptomeningeal disease," he said, calling the postprogression biology unusually unpredictable. Singhi pointed participants toward antibody-drug conjugate and PRMT5-inhibitor trials, and toward testing for MTAP loss, as areas of active investigation for patients who exhaust available ROS1 TKIs.

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DISCLOSURES: Dr Singhi reports receiving research support from Rexanna’s Foundation for Fighting Lung Cancer; and receiving advisory board fees from AstraZeneca, Novocure, Amgen, Janssen, Regeneron, Bristol Myers Squibb, Bayer, Boehringer Ingelheim, Eli Lilly, CARIS, and Nuvation Bio.

REFERENCES

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 5.2026. Accessed August 12, 2026. https://tinyurl.com/5xcz9jxu

2. Bazhenova L, et al. TRUST I/II: updated pooled efficacy outcomes of taletrectinib in TKI-naive ROS1+ non-small cell lung cancer. Presented at: American Association for Cancer Research (AACR) Annual Meeting; 2026. Abstract CT300.

3. Cho BC, et al. TRIDENT-1: updated efficacy of repotrectinib in TKI-pretreated ROS1+ non-small cell lung cancer. Presented at: World Conference on Lung Cancer (WCLC) 2025. Abstract MA02.03.