Preliminary efficacy and intracranial activity observed with zidesamtinib (NVL-520) in the phase 1/2 ARROS-1 trial (NCT05118789) indicates that this selective ROS1 inhibitor could overcome key limitations of available ROS1/TRK inhibitors—including suboptimal central nervous system (CNS) penetrance, a lack of activity against on-target resistance, and TRK-associated neurologic and gastrointestinal toxicities—for patients with 

-positive non–small cell lung cancer (NSCLC), according to Joshua K. Sabari, MD.

Pooled data from the phase 1 and 2 portions of ARROS-1

 showed that, among patients previously treated with at least 1 TKI (n = 117), treatment with zidesamtinib at the recommended phase 2 dose (RP2D) of 100 mg once daily generated an objective response rate (ORR) of 44% (95% CI, 34%-53%).

 Moreover, patients experienced durations of response lasting at least 6, 12, and 18 months at rates of 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%), respectively. In patients who had received only 1 prior ROS1 TKI, including crizotinib (Xalkori) or entrectinib (Rozlytrek) with or without chemotherapy (n = 55), the ORR was 51% (95% CI, 37%-65%). The percentage of patients who remained in response for at least 6, 12, and 18 months was 93% (95% CI, 74%-98%).

“This was a notable phase 1 dose-escalation and -expansion [study] in an all-comer patient population with 

fusion–positive NSCLC,” Sabari said in an interview with 

®. “We saw impressive [clinical activity with zidesamtinib] across all these patient subsets. [As the data mature], we’re only going to see better response rates with a better durability of response, and I hope to see this agent move into the frontline setting.”

-positive metastatic NSCLC with prior exposure to 2 or more ROS1 TKIs.

In the interview, Sabari discussed the limitations of the current arsenal of ROS1-targeted TKIs, the unique design and goal of the ongoing ARROS-1 trial, early-phase efficacy and safety data with zidesamtinib in 

 fusion–positive NSCLC, and the potential role for zidesamtinib in the 

 fusion–positive NSCLC treatment paradigm.

Sabari is the director of High Reliability Organization Initiatives at the Perlmutter Cancer Center and an assistant professor in the Department of Medicine at the NYU Grossman School of Medicine, both in New York, New York.

: Why is there an unmet need for more effective, tolerable targeted agents for patients with 

fusion–positive lung cancer with and without acquired resistance mechanisms?

fusions are quite common. They occur in 1% to 2% of all NSCLC cases, predominantly in patients with adenocarcinoma. It is important to develop novel therapeutic strategies for this patient population. We have multiple agents that are FDA approved, including crizotinib, entrectinib, repotrectinib [Augtyro], and most recently, taletrectinib [Ibtrozi]. That being said, there remains a need for agents that address acquired resistance, particularly those targeting mutations such as G2032R. There is also a need for agents with better CNS penetration. Most importantly, there is a need for agents that are better tolerated—particularly those that spare TRK. It is known that TRK inhibition can cause dizziness, ataxia, and other neurocognitive adverse effects [AEs], so there is an unmet need in this patient population. Despite the availability of multiple approved agents, we still see patients who progress, and we still see patients who need novel therapies in this space.

Could you expand on the design and objectives of the ARROS-1 study?

The phase 1/2 ARROS-1 study evaluated zidesamtinib in [patients with] 

fusion–positive solid tumors. This study was initially a dose-escalation trial, which was then followed by a dose-expansion phase. [The agent was assessed] in all-comers with NSCLC [harboring] 

fusions, [regardless of whether they had exposure to] any ROS1 TKI therapy. This included patients who were naive to ROS1 TKIs, those who had received prior ROS1 TKIs including repotrectinib, and those with known

 resistance mutations such as G2032R prior to repotrectinib. [The study also included] patients who had received [at least] 2 prior lines of ROS1-directed therapy, including lorlatinib [Lorbrena] and repotrectinib. Lastly, we looked at patients who had received only 1 prior ROS1 TKI, such as crizotinib.

What differentiates this trial from prior research with ROS1-targeted agents?

Most of the prior trials that we’ve had [in 

 fusion–positive NSCLC) have evaluated [patients with disease] progression on crizotinib, and that’s how we developed repotrectinib and taletrectinib. The ARROS-1 trial includes a patient population that has been previously treated with repotrectinib. This is a heavily pretreated patient population ranging from 1 to 4 prior lines of therapy. It is exciting to see that even in patients who are pretreated with repotrectinib, particularly those who have G2032R resistance mutations, we saw very high and durable response rates.

How do you see the broader inclusion criteria in ARROS-1 helping in the transition of zidesamtinib from bench to bedside?

Resistance mechanisms develop in all patients receiving targeted therapies. In clinical practice, we identify these mutations and then we can recapitulate them in the laboratory using patient-derived xenograft models. Bringing that back from the lab to the clinic, we’re then able to test these agents in patients who have these specific acquired resistance mutations [after treatment with] crizotinib or entrectinib. [In preclinical studies], we saw robust activity [with zidesamtinib] in repotrectinib-naive patients with the G2032R resistance mutation. It is exciting to see that the data generated in animal models and cell lines in the laboratory can be brought back into the clinic; to see those results [reproduced] in humans is quite impressive.

How would you characterize both the systemic and intracranial activity of zidesamtinibin the TKI-pretreated and -naive cohorts of ARROS-1 based on data presented at the 2024 ESMO Congress?

In the all-comer [patient population], a 44% ORR [was observed], including 2 complete responses. Notably, among patients who had received prior repotrectinib, a 38% response rate was reported, with 3 of 8 patients responding. [Notably, these patients] predominantly had the 

 G2032R resistance mutation. Interestingly, in patients who also harbored the G2032R mutation, but were also naive to repotrectinib, the ORR was 72%. In patients with 2 or more prior ROS1 TKIs in all-comers, the ORR was 41%. In those who were naive to repotrectinib, the ORR was 47%; in those who had received only 1 prior ROS1 TKI, the ORR was 73%.

Durable responses were observed across the entire cohort, with the median duration of response not reached. Given the importance of CNS activity, intracranial ORRs were reported in 50% of patients. Historically, agents such as crizotinib and entrectinib have shown limited CNS penetration; however, agents like taletrectinib, repotrectinib, and now zidesamtinib demonstrate significant intracranial activity.

What should be known about the tolerability of this agent relative to other ROS1-directed TKIs in NSCLC?

Safety remains an important issue in the treatment of patients with 

 fusion–positive NSCLC. A lot of our agents such as repotrectinib, inhibit TRK A, B, and C, leading to neurologic AEs like dizziness in up to 30% of patients. Taletrectinib, a newer FDA-approved agent, spares TRK B but continues to inhibit TRK A and C, offering a reduced—but still present—risk of neurologic toxicity. In contrast, zidesamtinib was specifically designed to avoid TRK inhibition altogether, so we don’t see neurologic toxicities in this population.

We did see grade 1 peripheral edema in 14% [of patients, although] 5% had grade 2 peripheral edema. We also saw grade 1 aspartate aminotransferase and alanine aminotransferase level elevations [in 11% of patients, respectively], and weight increase in 11% of all-comers. There were no treatment-related AEs that led to treatment discontinuation, and the dose reduction rate was 8%. This was significantly lower than what we’ve experienced in the past with repotrectinib or therapies like entrectinib.

How does zidesamtinib’s mechanism of action contribute to that low rate of dose reduction in this trial?

Because zidesamtinib spares TRK, we don’t see the CNS toxicity with this agent [that we see] with other agents like repotrectinib or potentially even taletrectinib. The very nature of this agent, the way that it was developed, truly removes this potential toxicity from the clinic.

Pending further positive data from the TKI-naive cohort, where could you see this agent being positioned in the 

Zidesamtinib is a best-in-class, ROS1-selective, TRK-sparing therapy. We are now enrolling newly diagnosed, untreated patients in the frontline. This is potentially practice-changing for the 

 fusion–positive NSCLC patient population.

Nuvalent announces positive pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News release. Nuvalent. June 24, 2025. Accessed July 21, 2025. https://investors.nuvalent.com/2025-06-24-Nuvalent-Announces-Positive-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC

Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-520. News release. Nuvalent. February 27, 2024. Accessed July 21, 2025. https://investors.nuvalent.com/2024-02-27-Nuvalent-Receives-U-S-FDA-Breakthrough-Therapy-Designation-for-NVL-520

Articles

Zidesamtinib (NVL-520) shows promise in overcoming limitations of current ROS1/TRK inhibitors for ROS1-positive NSCLC, with notable efficacy and CNS activity. The ARROS-1 trial demonstrated a 44% objective response rate in patients previously treated with TKIs, with durable responses and significant intracranial activity. Zidesamtinib's TRK-sparing design minimizes neurologic toxicities, offering a favorable safety profile compared to existing therapies. The FDA granted breakthrough therapy designation for zidesamtinib, highlighting its potential to become a frontline treatment for ROS1 fusion–positive NSCLC, pending further positive data.

Joshua K. Sabari, MD, discusses the design of the phase 1/2 ARROS-1 study, as well as key efficacy data with zidesamtinib in ROS1 fusion–positive NSCLC.

Zidesamtinib Is Set to Overcome the Limitations of Current ROS1 TKIs in ROS1+ NSCLC

Dr Sabari on Efficacy of Zidesamtinib in TKI-Pretreated, Advanced, ROS1+ NSCLC

“In all-comers, we saw a 44% ORR, 31 out of 71 patients with a response, including 2 complete responses. What was most interesting is that in those patients who had [received] prior repotrectinib, [we saw an ORR of] 38%.”

Joshua K. Sabari, MD, an assistant professor in the Department of Medicine at the NYU Grossman School of Medicine; as well as the director of High Reliability Organization Initiatives at the NYU Perlmutter Cancer Center, discussed key efficacy data from the phase 1/2 ARROS-1 trial (NCT05118789), which is investigating the selective ROS1 inhibitor zidesamtinib (NVL-520) in patients with advanced 

-positive non–small cell lung cancer (NSCLC).

 showed that in all-comers in the TKI-pretreated population (n = 71), the overall response rate (ORR) was 44%, including 2 complete responses. Among patients who had received prior repotrectinib (Augtyro) and had a 

 G2032R mutation (n = 8), the ORR was 38%. Among patients who had not received prior repotrectinib and had a 

 G2032R mutation (n = 18), the ORR was 72%.

In the population of all-comers who had received at least 2 prior ROS1 TKIs (n = 51), the ORR was 41%. This rate was 47% in repotrectinib-naive patients who had received 2 or more prior ROS1 TKIs (n = 36). Additionally, among patients who had received 1 prior ROS1 TKI (n = 11)—crizotinib (Xalkori), the ORR was 73%.

These responses were also durable, Sabari explained. In the all-comer population, the median duration of response was not reached (NR; 95% CI, 10.3 months-NR).

Regarding the central nervous system (CNS) activity of zidesamtinib, the intracranial ORR was 50% among evaluable all-comers (n = 8). Historically, other ROS1 TKIs like crizotinib and entrectinib (Rozlytrek) have not demonstrated effective CNS penetration in patients with NSCLC, according to Sabari. However, next-generation ROS1 TKIs—including taletrectinib (Ibtrozi), repotrectinib, and now zidesamtinib—have shown effective levels of intracranial activity, Sabari concluded.

Videos

Joshua K. Sabari, MD, discusses response rates observed with zidesamtinib in patients with advanced ROS1-positive non–small cell lung cancer.

The novel, brain-penetrant, selective ROS1 inhibitor zidesamtinib (NVL-520) was well tolerated and yielded durable responses in patients with advanced 

-positive non–small cell lung cancer (NSCLC) previously treated with at least 1 TKI, according to data from the phase 1/2 ARROS-1 trial (NCT05118789).

Pooled findings from the phase 1 and 2 portions showed that all patients previously treated with at least 1 TKI (n = 117) who received zidesamtinib at the recommended phase 2 dose (RP2D) of 100 mg once daily achieved an objective response rate (ORR) of 44% (95% CI, 34%-53%); the 6-, 12-, and 18-month duration of response (DOR) rates were 84% (95% CI, 71%-92%), 78% (95% CI, 62%-88%), and 62% (95% CI, 28%-84%), respectively.

Furthermore, patients who had received only 1 prior ROS1 TKI—crizotinib (Xalkori) or entrectinib (Rozlytrek) with or without chemotherapy (n = 55)—experienced an ORR of 51% (95% CI, 37%-65%). The DOR rates at 6, 12, and 18 months were all 93% (95% CI, 74%-98%), and DOR data continue to mature.

Regarding safety, zidesamtinib was well tolerated in patients with advanced 

-positive NSCLC (n = 432) treated at the RP2D as of the data cutoff of March 21, 2025. The median duration of exposure was 5 months (range, 0-32). Notably, the most frequent treatment-emergent adverse effects (TEAEs) observed in at least 15% of patients included peripheral edema (36%), constipation (17%), increased blood CPK (16%), fatigue (16%), and dyspnea (15%).

TEAEs led to dose reductions in 10% of patients, and 2% of patients discontinued treatment due to TEAEs.

“Continued innovation for patients with 

-positive NSCLC is needed. Limitations of currently available ROS1 TKIs can lead to trade-offs between efficacy and tolerability in the frontline, and there is no clear targeted therapy care standard for TKI-pretreated patients," Alexander Drilon, MD, ARROS-1 trial investigator and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, stated in a news release. "These data demonstrate the potential for zidesamtinib to deliver meaningful clinical outcomes for [patients who previously received] TKIs, including those progressing with brain metastases or treatment-emergent resistance mutations, and to offer a favorable tolerability profile consistent with its goal of avoiding off-target [AEs] through ROS1-selectivity.”

Of note, Nuvalent, the developer of zidesamtinib, completed a pre–new drug application (NDA) meeting with the FDA, in which the NDA submission will seek an indication for the novel inhibitor for the treatment of TKI-pretreated patients with locally advanced or metastatic

-positive NSCLC. The developer plans on initiating a rolling NDA submission in July 2025, with completion aimed for the third quarter of 2025.

The dose-escalation and -expansion study evaluated the safety and tolerability of zidesamtinib to determine the RP2D, along with antitumor activity in patients with advanced 

-positive NSCLC or solid tumors at least 18 years of age.

Phase 1 of the trial included patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors with documented 

 rearrangements. Phase 2 of the study comprised cohorts 2a, 2b, 2c, and 2d, which included patients with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with 

 rearrangements. Cohort 2e in phase 2 included patients 12 years of age or older weighing 40 kg or greater with histologically or cytologically confirmed, locally advanced or metastatic solid tumors with 

Patients on the study were also required to have received prior anticancer treatment, except those in cohort 2a. In phase 1, patients needed evaluable target or nontarget disease per RECIST 1.1 criteria; those in phase 2 needed measurable disease according to RECIST 1.1 criteria. All patients, regardless of cohort, were required to have adequate baseline organ function and bone marrow reserve.

-positive solid tumors were treated with zidesamtinib at any starting dose across both phases of the trial.

 Specifically, 432 patients with advanced 

-positive NCSLC received zidesamtinib at the RP2D.

The primary end point of phase 2 was ORR per RECIST 1.1 criteria by blinded independent central review (BICR).

 Key secondary end points include DOR, intracranial ORR (IC-ORR), and safety.

In the primary analysis, the population included TKI pretreated patients (n = 117) with advanced 

-positive NSCLC measurable disease were treated with zidesamtinib at the RP2D before May 31, 2024. The DOR follow-up was at least 6 months for most responders. Notably, patients had received a median of 2 prior lines of treatment (range, 1-11), and 53% received prior chemotherapy.

The most commonly received TKI was crizotinib or entrectinib (with or without chemotherapy) in 47% of patients. In this subgroup, 51% of patients were previously treated with crizotinib, and 49% of patients were previously treated with entrectinib; 47% of these patients previously received chemotherapy. Moreover, 50% of patients had received 2 or more prior ROS1 TKIs with or without chemotherapy, with 93% having received prior lorlatinib (Lorbrena), repotrectinib (Augtyro), or taletrectinib (Ibtrozi). Secondary 

 resistant mutations were observed in 36% of patients, and 49% had active central nervous system (CNS) disease by BICR.

 G2032R resistance mutations in the primary analysis population (n = 26), the ORR was 54% (95% CI, 33%-73%), and the 6- and 12-month DOR rates were 79% (95% CI, 47%-93%) and 60% (95% CI, 28%-81%), respectively. Those with a 

 G2032R mutation who had received 1 prior ROS1 TKI with or without chemotherapy (n = 6) achieved an ORR of 83% (95% CI, 36%-100%). The DOR rate at 6 and 12 months was 80% (95% CI, 20%-97%).

Preliminary data among TKI-naive patients (n = 35) showed that the ORR was 89%, and the DOR ranged from 1.9+ months to 13.9+ months. The 6- and 12-month DOR rates were both 96% (95% CI, 76%-99%). In patients with measurable intracranial lesions (n = 6), the IC-ORR was 83% and the intracranial CR rate was 67%. Of note, the IC-DOR ranged from 4.6 months to 11.1 months without CNS progression in responders.

Among patients with measurable CNS lesions per BICR at baseline (n = 56), the IC-ORR was 48%, including an intracranial complete response (CR) rate of 20% and 2 unconfirmed partial responses. The 12-month IC-DOR rate was 71% (95% CI, 46%-87%). Additionally, the IC-ORR was 85% in patients who only received prior crizotinib (n = 13), including 54% of patients who experienced intracranial CRs. Only 1 CNS progression event occurred in CNS responders in this group.

"Bringing a drug from ideation to pivotal data in just a few short years is a rare opportunity, and I would like to express my sincere gratitude for the tireless dedication of the Nuvalent team and for the patients, caregivers, and investigators that have helped us achieve this milestone for zidesamtinib," James Porter, PhD, chief executive officer at Nuvalent, added in the news release.

 "[This] announcement brings us a critical step closer to achieving our goal of becoming a fully integrated, commercial-stage biopharmaceutical company able to deliver a new, potential best-in-class treatment option to all patients with advanced 

Nuvalent announces positive pivotal data from ARROS-1 clinical trial of ziesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC. News Release. Nuvalent. June 24, 2025. Accessed June 27, 2025. https://investors.nuvalent.com/2025-06-24-Nuvalent-Announces-Positive-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC

A study of NVL-520 in patients with advanced NSCLC and other solid tumors harboring ROS1 rearrangement (ARROS-1). ClinicalTrials.gov. Updated March 7, 2025. Accessed June 27, 2025. https://clinicaltrials.gov/study/NCT05118789

Zidesamtinib, a novel ROS1 inhibitor, demonstrated promising efficacy and tolerability in patients with advanced ROS1-positive NSCLC previously treated with TKIs, according to the ARROS-1 trial. The trial reported an ORR of 44% in TKI-pretreated patients, with durable responses observed. Safety data indicated that zidesamtinib was well tolerated, with manageable adverse effects. The drug's potential to address limitations of existing ROS1 TKIs and its favorable safety profile highlight its promise as a treatment option. Nuvalent plans to submit an NDA for zidesamtinib in 2025.

Zidesamtinib, a selective ROS1 inhibitor, was well tolerated and showed antitumor activity in pretreated, advanced ROS1-positive NSCLC.

Reviewing Recent Developments in ROS1-Positive NSCLC | Supplements and Featured Publications

Zidesamtinib Is Set to Overcome the Limitations of Current ROS1 TKIs in ROS1+ NSCLC

Dr Sabari on Efficacy of Zidesamtinib in TKI-Pretreated, Advanced, ROS1+ NSCLC

Zidesamtinib Produces Durable Responses in TKI-Pretreated, ROS1+ NSCLC