Zidesamtinib Exhibits Durable Activity in Pretreated ROS1+ Advanced NSCLC

Responses also occurred in patients who had received at least 2 prior ROS TKIs, with an ORR of 38%, and patients who were previously exposed to repotrectinib experienced an ORR of 47%.

Zidesamtinib elicited an objective response rate (ORR) of 44% (95% CI, 34%-53%) and a complete response (CR) rate of 1% in patients with advanced ROS1-positive non–small cell lung cancer (NSCLC) who had received between 1 and 4 prior lines of ROS1 TKI therapy with or without chemotherapy, according to data from the phase 1/2 ARROS-1 trial (NCT05118789) presented at the 2025 World Conference on Lung Cancer¹

The data showed that among those who had previously received either crizotinib (Xalkori) or entrectinib (Rozlytrek) with or without chemotherapy, the ORR was 51% (95% CI, 37%-65%), with a CR rate of 2%. The ORR in patients who had received only crizotinib with or without chemotherapy was 68%; the ORR in patients who had received only entrectinib with or without chemotherapy was 33%.

Responses also occurred in patients who had received at least 2 prior ROS TKIs, with an ORR of 38% (95% CI, 26%-52%). Patients who were previously exposed to repotrectinib (Augtyro) experienced an ORR of 47%, with duration of response (DOR) ranging from 3.5 months to 17.2 months. Patients who had received prior taletrectinib (Ibtrozi) had an ORR of 43%, with a DOR ranging from 5.2 months to 7.0+ months.

“In the pivotal dataset for TKI pretreated patients with advanced ROS1-positive NSCLC, zidesamtinib demonstrated a clinical profile consistent with its preclinical design goals,” Alexander E. Drilon, MD, lead study author and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “[We saw] durable activity, including in heavily pretreated patients who have exhausted available options, including prior repotrectinib and taletrectinib, and patients with the ROS1 G2032R resistance mutation.”

What Was the Design of the ARROS-1 Trial?

ARROS-1 is a global, first-in-human trial evaluating the safety and efficacy of zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors. Phase 1 evaluated the agent at doses ranging from 25 mg to 150 mg once daily in ROS1 TKI–pretreated patients with ROS1-positive solid tumors. In phase 2, patients with either ROS1 TKI–pretreated or naive disease received the recommended phase 2 dose (RP2D) of 100 mg once daily.

The primary objectives of phase 2 were to evaluate the ORR per blinded independent central review (BICR). Secondary objectives included additional assessments for DOR, time to response, clinical benefit rate, progression-free survival (PFS), overall survival, intracranial activity, overall safety and tolerability, confirmation of pharmacokinetic profile, and patient-reported outcomes.

A total of 514 patients had been enrolled in the pooled phase 1 and 2 populations. The pivotal safety population included 432 patients with advanced ROS1-positive NSCLC who had received the RP2D of the agent. The pivotal efficacy population included 117 patients with ROS1 TKI–pretreated NSCLC with measurable disease by BICR who had been treated by May 31, 2024, and had at least 6 months of DOR follow-up. Preliminary findings for the ROS1 TKI–naive cohort were also shared for the 35 patients who had been treated by August 31, 2024.

Baseline characteristics of the pivotal efficacy population revealed that the median age was 57 years (range, 31-83). Most patients were female (56%), never smokers (68%), and resided in North America (42%) or Europe (32%). Most patients had an ECOG performance status of 1 (62%) vs 0 (38%), and 49% had active central nervous system (CNS) disease. A secondary ROS1 mutation was present in 36% of cases (G2032R, 22%).

The median number of prior anticancer therapies was 2 (range, 1-11), and 53% of patients had received prior chemotherapy. A total of 47% (n = 55) of patients had received prior crizotinib (n = 28; 51%) or entrectinib (n = 27; 49%). Only 4 patients (3%) received either repotrectinib or taletrectinib. Among patients who had received at least 2 prior lines of therapy (n = 58; 50%), 93% (n = 54) had received lorlatinib ([Lorbrena] n = 43; 74%), repotrectinib (n = 15; 26%), or taletrectinib (n = 5; 9%).

What DOR and PFS Data Were Shared During IASLC 2025 World Conference on Lung Cancer?

At a median follow-up of 11.1 months (range, 0.2-25.6), the median PFS was 9.7 months (95% CI, 5.5-not evaluable [NE]) in patients who had received any prior ROS1 TKI. The median DOR was 22 months (95% CI, 17-NE). The percentages of patients who remained in response for at least 6, 12, and 18 months were 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%), respectively. The 6-, 12-, and 18-month PFS rates were 57% (95% CI, 47%-66%), 48% (95% CI, 38%-57%), and 40% (95% CI, 24%-55%), respectively.

At a median follow-up of 11.8 months (range, 1.2-25.6), the median PFS was 23.8 months (95% CI, 23.8-NE) in patients who had received 1 prior ROS1 TKI. The median DOR was 22 months (95% CI, 22-NE). The percentages of patients who remained in response for at least 6, 12, and 18 months were all 93% (95% CI, 74%-98%). The 6-, 12-, and 18-month PFS rates were 70% (95% CI, 56%-81%), 68% (95% CI, 53%-79%), and 68% (95% CI, 53%-79%), respectively.

Drilon also reported that there were no progression events in patients who received only crizotinib (DOR range, 7.3+ months to 23.2+ months). The 6-, 12-, and 18-month PFS rates were all 89% (95% CI, 70%-96%), and the median was not reached in this population.

A total of 71% (95% CI, 46%-86%) and 56% (95% CI, 29%-76%) of patients who received at least 2 prior ROS1 TKIs remained in response for 6 and 12 months, respectively.

Did Zidesamtinib Show Activity in the CNS and in ROS1 G2032R–Resistant Populations?

Among patients who had received any prior ROS1 TKI and had an acquired ROS1 G2032R mutation, the ORR, 6-month DOR, and 12-month DOR rates were 54% (95% CI, 33%-73%), 79% (95% CI, 47%-93%), and 60% (95% CI, 28%-81%), respectively.

Among patients who had previously received crizotinib or entrectinib and had an acquired ROS1 G2032R mutation, the ORR, 6-month DOR, and 12-month DOR rates were 83% (95% CI, 36%-100%), 80% (95% CI, 20%-97%), and 80% (95% CI, 20%-97%), respectively.

Drilon also noted that responses occurred in patients with the ROS1 G2032R mutation after treatment with 2 or more prior ROS1 TKIs, including lorlatinib or repotrectinib, as well as in other mutational subtypes, including G1957A, L1982V, S1986F, F2004C/V, G2032K, and D2033N.

Within the population of patients who had measurable CNS lesions at baseline and had received any prior ROS1 TKI, the intracranial ORR (IC-ORR), 6-month IC-DOR, and 12-month IC-DOR rates were 48% (95% CI, 35%-62%), 79% (95% CI, 56%-91%), and 71% (95% CI, 46%-87%), respectively.

Within the population of patients who had measurable CNS lesions at baseline and had received crizotinib only, the IC-ORR, 6-month IC-DOR, and 12-month IC-DOR rates were 85% (95% CI, 55%-98%), 91% (95% CI, 51%-99%), and 91% (95% CI, 51%-99%), respectively. The IC-CR rates were 20% and 54% in patients who had received any prior ROS1 TKI or crizotinib as their only prior TKI, respectively.

Drilon explained that CNS responses were observed also in patients who had received at least 1 prior brain-penetrant TKI, including entrectinib, lorlatinib, repotrectinib, or taletrectinib. In this population, the IC-ORR was 37% (95% CI, 23%-53%), including 4 IC-CRs. No CNS progression occurred in patients who entered the study without brain metastases at baseline.

What Was the Safety Profile of Zidesamtinib in the ARROS-1 Trial?

All patients had received at least 1 dose of the study drug. The median duration of exposure was 5 months (range, 0-32). Treatment-emergent adverse effects (TEAEs) that occurred in at least 15% of patients who received the RP2D of zidesamtinib included peripheral edema (all grade, 36%; grade ≥3, 0.7%), constipation (17%; 0%), elevated blood creatine phosphokinase ([CPK]; 16%; 3.5%), fatigue (16%; 0.7%), and dyspnea (15%; 3.0%).

Ten percent of patients required dose reduction because of a TEAE, the most common being peripheral edema (n = 8), increased blood CPK (n = 4), peripheral sensory neuropathy (n = 4), arthralgia (n = 3), and paresthesia (n = 3). Two percent of patients discontinued treatment because of a TEAE, and the most common reason was pneumonia (n = 3).

“[The agent was] generally well tolerated, with low rates of dose reduction and treatment discontinuation, and a safety profile consistent with its ROS1-selective, TRK-sparing design,” Drilon reported.

The only treatment-related adverse effect that occurred in more than 15% of patients was peripheral edema (29%).

What Were the Preliminary Data in the ROS TKI–Naive Cohort?

The ORR in this cohort was 89%, and 96% of patients remained in response for at least 12 months. The IC-ORR was 83% and there were no cases of CNS progression among confirmed CNS responders.

“Encouraging preliminary data in a TKI-naïve population support ongoing investigation in the frontline setting,” Drilon concluded.

Pivotal data from the trial will serve as the basis for the developer’s ongoing rolling new drug application submission for the agent to the FDA in the TKI-pretreated population^.2 According to the developer, the company is expected to complete the application in the third quarter of 2025.

Disclosures: No disclosures were listed for Drilon.

References

1. Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and safety data: zidesamtinib in TKI-pretreated patients with advanced/metastatic ROS1+ NSCLC. Presented at: 2025 International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4540.
2. Nuvalent presents pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC at WCLC 2025. News release. Nuvalent. September 7, 2025. Accessed September 7, 2025. https://www.prnewswire.com/news-releases/nuvalent-presents-pivotal-data-from-arros-1-clinical-trial-of-zidesamtinib-for-tki-pre-treated-patients-with-advanced-ros1-positive-nsclc-at-wclc-2025-302548220.html