Responses additionally occurred in sufferers who had obtained no less than two prior ROS TKIs, with an ORR of 38%.
Amongst sufferers with superior ROS1-positive non-small cell lung most cancers (NSCLC) who had beforehand obtained one to 4 strains of prior ROS1 tyrosine kinase inhibitor remedy with or with out chemotherapy, remedy with zidesamtinib resulted in an goal response fee (ORR) of 44% and an entire response (CR) fee of 1%, medical trial outcomes have proven.1,2
Knowledge from the section 1/2 ARROS-1 trial have been introduced on the Worldwide Affiliation for the Examine of Lung Most cancers (IASLC) 2025 World Convention on Lung Most cancers and confirmed that amongst those that had beforehand obtained both Xalkori (crizotinib) or Rozlytrek (entrectinib) with or with out chemotherapy, the ORR was 51% with a CR fee of two%. The ORR in sufferers who had obtained solely Xalkori with or with out chemotherapy was 68%; the ORR in sufferers who had obtained solely Rozlytrek with or with out chemotherapy was 33%.
Responses additionally occurred in sufferers who had obtained no less than two prior ROS TKIs, with an ORR of 38%. Sufferers who have been beforehand uncovered to Augtyro (repotrectinib) skilled an ORR of 47%, with length of response (DOR) starting from 3.5 months to 17.2 months. Sufferers who had obtained prior Ibtrozi (taletrectinib) had an ORR of 43%, with a DOR starting from 5.2 months to seven-plus months.
Glossary
Goal response fee: sufferers who responded partially or utterly to remedy.
Full response: the disappearance of most cancers.
Development-free survival: the time a affected person lives with out their illness spreading or worsening.
“Within the pivotal dataset for TKI pretreated sufferers with superior ROS1-positive NSCLC, zidesamtinib demonstrated a medical profile in step with its preclinical design objectives,” Dr. Alexander E. Drilon, lead examine writer and chief of the Early Drug Improvement Service at Memorial Sloan Kettering Most cancers Middle in New York, stated in the course of the presentation. “[We saw] sturdy exercise, together with in closely pretreated sufferers who’ve exhausted out there choices, together with prior [Augtyro] and [Ibtrozi], and sufferers with the ROS1 G2032R resistance mutation.”
What Was the Design of the ARROS-1 Trial?
ARROS-1 is a worldwide, first-in-human trial evaluating the protection and efficacy of zidesamtinib in sufferers with superior ROS1-positive NSCLC and different stable tumors. Section 1 evaluated the agent at doses starting from 25 mg to 150 mg as soon as day by day in ROS1 TKI–pretreated sufferers with ROS1-positive stable tumors. In section 2, sufferers with both ROS1 TKI–pretreated or naive illness obtained the really helpful section 2 dose (RP2D) of 100 mg as soon as day by day.
A complete of 514 sufferers had been enrolled within the pooled section 1 and a pair of populations. The pivotal security inhabitants included 432 sufferers with superior ROS1-positive NSCLC who had obtained the RP2D of the agent. The pivotal efficacy inhabitants included 117 sufferers with ROS1 TKI–pretreated NSCLC with measurable illness by BICR who had been handled by Might 31, 2024, and had no less than six months of DOR follow-up. Preliminary findings for the ROS1 TKI–naive cohort have been additionally shared for the 35 sufferers who had been handled by August 31, 2024.
Baseline traits of the pivotal efficacy inhabitants revealed that the median age was 57 years. Most sufferers have been feminine (56%), by no means people who smoke (68%) and resided in North America (42%) or Europe (32%). Most sufferers had an ECOG efficiency standing of 1 (62%) versus 0 (38%), and 49% had energetic central nervous system (CNS) illness. A secondary ROS1 mutation was current in 36% of circumstances (G2032R, 22%).
The median variety of prior anticancer therapies was two, and 53% of sufferers had obtained prior chemotherapy. A complete of 47% of sufferers had obtained prior Xalkori (51%) or Rozlytrek (49%). Solely 4 sufferers (3%) obtained both Augtyro or Ibtrozi. Amongst sufferers who had obtained no less than two prior strains of remedy (50%), 93% had obtained Lorbrena (lorlatinib), Augytro or Ibtrozi.
What DOR and PFS Knowledge Have been Shared Throughout IASLC 2025 World Convention on Lung Most cancers?
At a median follow-up of 11.1 months, the median PFS was 9.7 months in sufferers who had obtained any prior ROS1 TKI. The median DOR was 22 months. The chances of sufferers who remained in response for no less than six, 12 and 18 months have been 84%, 78% and 62%, respectively. The six-, 12-, and 18-month PFS charges have been 57%, 48% and 40%, respectively.
At a median follow-up of 11.8 months, the median PFS was 23.8 months in sufferers who had obtained one prior ROS1 TKI. The median DOR was 22 months. The chances of sufferers who remained in response for no less than six, 12 and 18 months have been all 93%. The six-, 12- and 18-month PFS charges have been 70%, 68% and 68%, respectively.
Drilon additionally reported that there have been no development occasions in sufferers who obtained solely Xalkori. The 6-, 12-, and 18-month PFS charges have been all 89% and the median was not reached on this inhabitants.
A complete of 71% and 56% of sufferers who obtained no less than two prior ROS1 TKIs remained in response for six and 12 months, respectively.
Did Zidesamtinib Present Exercise within the CNS and in ROS1 G2032R–Resistant Populations?
Amongst sufferers who had obtained any prior ROS1 TKI and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR, and 12-month DOR charges have been 54%, 79% and 60%, respectively.
Amongst sufferers who had beforehand obtained Xalkori or Rozlytrek and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR and 12-month DOR charges have been 83%, 80% and 80%, respectively.
Drilon additionally famous that responses occurred in sufferers with the ROS1 G2032R mutation after remedy with two or extra prior ROS1 TKIs, together with Lobrena or Augtyro, in addition to in different mutational subtypes, together with G1957A, L1982V, S1986F, F2004C/V, G2032K, and D2033N.
Throughout the inhabitants of sufferers who had measurable CNS lesions at baseline and had obtained any prior ROS1 TKI, the intracranial ORR (IC-ORR), six-month IC-DOR and 12-month IC-DOR charges have been 48%, 79% and 71%, respectively.
Throughout the inhabitants of sufferers who had measurable CNS lesions at baseline and had obtained Xalkori solely, the IC-ORR, six-month IC-DOR and 12-month IC-DOR charges have been 85%, 91% (95% CI, 51%-99%), and 91% (95% CI, 51%-99%), respectively. The IC-CR charges have been 20% and 54% in sufferers who had obtained any prior ROS1 TKI or crizotinib as their solely prior TKI, respectively.
Drilon defined that CNS responses have been noticed additionally in sufferers who had obtained no less than 1 prior brain-penetrant TKI, together with entrectinib, lorlatinib, repotrectinib, or taletrectinib. On this inhabitants, the IC-ORR was 37% (95% CI, 23%-53%), together with 4 IC-CRs. No CNS development occurred in sufferers who entered the examine with out mind metastases at baseline.
What Was the Security Profile of Zidesamtinib within the ARROS-1 Trial?
All sufferers had obtained no less than one dose of the examine drug. The median length of publicity was 5 months. Remedy-emergent unwanted side effects that occurred in no less than 15% of sufferers who obtained the RP2D of zidesamtinib included peripheral edema (all grade, 36%; grade 3 or increased, 0.7%), constipation (17%; 0%), elevated blood creatine phosphokinase ([CPK]; 16%; 3.5%), fatigue (16%; 0.7%) and dyspnea (15%; 3.0%).
Ten p.c of sufferers required dose discount due to a treatment-emergent facet impact, the most typical being peripheral edema (eight sufferers), elevated blood CPK (4 sufferers), peripheral sensory neuropathy (4 sufferers), arthralgia (three sufferers), and paresthesia (three sufferers). Two p.c of sufferers discontinued remedy due to a treatment-emergent facet impact, and the most typical motive was pneumonia (three sufferers).
“[The agent was] usually properly tolerated, with low charges of dose discount and remedy discontinuation, and a security profile in step with its ROS1-selective, TRK-sparing design,” Drilon reported.
The one treatment-related hostile impact that occurred in additional than 15% of sufferers was peripheral edema (29%).
What Have been the Preliminary Knowledge within the ROS TKI–Naive Cohort?
The ORR on this cohort was 89%, and 96% of sufferers remained in response for no less than 12 months. The IC-ORR was 83% and there have been no circumstances of CNS development amongst confirmed CNS responders.
“Encouraging preliminary information in a TKI-naïve inhabitants help ongoing investigation within the frontline setting,” Drilon concluded.
Pivotal information from the trial will function the premise for the developer’s ongoing rolling new drug software submission for the agent to the Meals and Drug Administration within the TKI-pretreated inhabitants. In keeping with the developer, the corporate is anticipated to finish the applying within the third quarter of 2025.
References
- Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and security information: zidesamtinib in TKI-pretreated sufferers with superior/metastatic ROS1+ NSCLC. Introduced at: 2025 Worldwide Affiliation for the Examine of Lung Most cancers 2025 World Convention on Lung Most cancers; September 6-9, 2025; Barcelona, Spain. Summary 4540.
- Nuvalent presents pivotal information from ARROS-1 medical trial of zidesamtinib for TKI pre-treated sufferers with superior ROS1-positive NSCLC at WCLC 2025. Information launch. 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
