ARROS-1 Trial of Zidesamtinib Aims to Address Current TKI Limitations in ROS1+ NSCLC

ROS1 fusion–positive non–small cell lung cancer (NSCLC) is a rare but important lung cancer subtype, constituting 1% to 3% of all reported lung cancer cases. These alterations also occur in other solid tumors such as cholangiocarcinoma, glioblastoma, angiosarcoma, and ovarian cancer. Over 50 ROS1 fusion partners have been identified, each influencing subcellular localization, signaling, metastasis, and drug sensitivity.¹

“ROS1 fusions are rare but important events,” Stephen V. Liu, MD, explained in an interview with OncologyLive. “These types of cancers don’t respond particularly well to immunotherapy. They can respond to chemotherapy, but for years our standard of care has been targeted therapy.”

Despite the array of effective agents targeting ROS1/NTRK within the current armamentarium, these tyrosine kinase inhibitors (TKIs) have limitations that may affect the durability and efficacy of the therapeutic response. These include limited central nervous system (CNS) penetrance, an inability to treat on-target resistance, and TRK-associated neurologic and gastrointestinal toxicities.

Investigators are hoping to address key limitations and toxicity concerns associated with available ROS1/TRK inhibitors for patients with ROS1-positive tumors through the development of the selective ROS1 inhibitor zidesamtinib (NVL-520), which is being evaluated in the phase 1/2 ARROS-1 study (NCT05118789).²

“A selective ROS1 inhibitor is certainly something that we need [in lung cancer],” Liu emphasized in the interview. “It may be more potent, may even be more effective with longer durability, and could have better activity in the brain, but more importantly, it should have a better safety profile. When designing the perfect ROS1 inhibitor, we want one that’s able to overcome resistance mutations, has few toxicities, and has excellent CNS penetration. NVL-520 was designed with this in mind.” Liu is an associate professor of medicine at Georgetown University, as well as the director of thoracic oncology and head of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Current Arsenal of ROS1-Targeted TKIs: Advantages and Limitations

Several TKIs are approved for the treatment of patients with ROS1 fusion–positive NSCLC. Crizotinib (Xalkori) was the first agent to be approved for patients with ROS1 fusion–positive metastatic NSCLC in March 2016.³ This was followed by the March 2019 accelerated FDA approval of entrectinib (Rozlytrek) for the treatment of adult and pediatric patients 12 years or older with solid tumors that harbor an NTRK fusion, as well as adults with TKI-naive, ROS1 fusion–positive metastatic NSCLC.⁴

“Crizotinib proved to be a very effective agent in this setting. It often [produced] periods of disease control measured in years, with [data from] some studies quoting a progression-free survival [PFS] of just over 1 year,” Liu continued. He added, “The ROS1/NTRK inhibitor entrectinib has supplanted crizotinib as my own favored ROS1 inhibitor. Entrectinib shows a similar PFS [to that of crizotinib in this setting] but in a slightly newer, more modern population, and has the advantage of being more effective within the brain. If you [look at] the outcomes with entrectinib and crizotinib in their best-performing studies, the numbers look similar. [However,] we must keep in mind that crizotinib was studied at a time when sequencing and testing for ROS1 was done in a very different way.”

More recently, the FDA approved repotrectinib (Augtyro) in locally advanced or metastatic ROS1 fusion–positive NSCLC on November 15, 2023.⁵ The approval was based on findings from the phase 1/2 TRIDENT-1 trial (NCT03093116), in which patients with ROS1-positive NSCLC in the phase 2 dose-expansion cohorts experienced high response rates regardless of prior exposure to a TKI.

“When you look at entrectinib and repotrectinib, they have a few things in common,” Liu continued. “They’re CNS penetrative and effective in the brain, and they’re very potent—they can work for years. Both [agents] have activity for ROS1 and TRK. It turns out there’s a fair amount of homology between those 2 kinases.”

Other options in this space include lorlatinib (Lorbrena), which the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology lists as a treatment option for TKI-pretreated ROS1 fusion–positive NSCLC.¹ Investigational TKIs such as taletrectinib (AB-106/DS-6051b) are also being studied for ROS1 fusion–positive cancers, with this agent receiving an FDA breakthrough therapy designation for adult patients with advanced or metastatic ROS1-positive NSCLC who are ROS1 inhibitor–naive or had previously received crizotinib.⁶

Notably, entrectinib, lorlatinib, taletrectinib, and repotrectinib are all inhibitors of both ROS1 and TRKA/B/C. Although the use of these ROS1/NTRK–targeted TKIs allows for the use of the same treatment for patients harboring either alteration, Liu cautioned that there can be significant gastrointestinal and neurologic adverse effects (AEs) associated with TRK inhibition that can be dose limiting and negatively affect quality of life. TRKB inhibition in particular has been associated with cognitive impairment, mood/sleep disturbance, dizziness, ataxia, orthostasis, and weight gain.¹

“TRK is responsible for proprioception and plays an important role in gait stability and coordination,” Liu explained. “When we inhibit TRK, it can often lead to dizziness, gait instability, ataxia, and lightheadedness. Although it is [an advantageous] feature if you have an NTRK-driven cancer, it is otherwise quite a flaw. By [giving patients with] ROS1-positive cancer a drug that also inhibits TRK, that’s mediating toxicity but not really helping in terms of cancer control.”

Zidesamtinib Demonstrates Early-Phase Efficacy and Safety in ROS1 Fusion–Positive NSCLC

Zidesamtinib is a novel, selective ROS1 inhibitor that has activity and improved potency against a variety of ROS1 alterations and resistance mutations, including the ROS1 G2032R solvent-front mutation, and is optimized for CNS penetration. Data from preclinical studies have shown the agent’s ability to selectively inhibit wild-type ROS1 and its resistant variants without inhibiting TRK, thereby reducing the incidence of TRK-related AEs and potentially enhancing response durability.¹

Liu noted that “The ROS1 G2032R resistance mutation is an important feature of this agent. Although, on paper, a drug like repotrectinib or entrectinib might retain some activity in [patients with those] mutations, [it would have to be administered at] high physiologic doses. That would be a weak point. We would [therefore] expect ROS1 G2032R mutations to mediate resistance to the available drugs. [Zidesamtinib], though, should retain activity [in patients with these mutations], and we’ll have to see if that translates in [evidence from] larger studies.”

In October 2022, Nuvalent, Inc, the developer of zidesamtinib, announced preliminary clinical data from the dose-escalation portion of the ARROS-1 trial, which were subsequently reported at the 34th EORTC-NCI-AACR (European Organisation for Research and Treatment of Cancer, National Cancer Institute, American Association for Cancer Research) Symposium, which also took place that month.⁷

In the overall population (n = 35), 77% of patients received 3 or more prior lines of anticancer therapy, 71% received 2 or more ROS1 TKIs and 1 or more lines of chemotherapy, and 80% received a ROS1 TKI other than crizotinib or entrectinib. A total of 57% and 34% of patients were previously exposed to lorlatinib or repotrectinib, respectively.⁷ Liu added, “These data showed that [participants] enrolled in that phase 1 [portion] were heavily pretreated. Patients [had] received anywhere from 1 to 11 prior lines of therapy, but 77% had received 3 or more lines of therapy. Despite that, zidesamtinib was very well tolerated, just as we were hoping for.”

At a data cutoff of September 13, 2022, 48% of patients with response-evaluable NSCLC (n = 21) achieved partial responses, with 76% continuing on the study treatment. Overall response rates (ORRs) with zidesamtinib were also assessed in several subgroups, including patients with ROS1 G2032R mutations (n = 9; ORR, 78%), those with a history of CNS metastases (n = 11; 73%), patients who received 2 or more prior TKIs and at least 1 prior line of chemotherapy (n = 17; 53%), and patients previously treated with lorlatinib or repotrectinib (n = 18; 50%). All patients with ROS1 G2032R mutations experienced tumor shrinkage. Additionally, investigators did not observe CNS progression in any patients in the overall population.⁷

“Importantly, this drug is designed to maintain efficacy in the setting of the G2032R resistance mutation, and in that subset, we saw a response rate of 78%,” Liu emphasized. “[These are] small numbers, but [they are] extremely encouraging.”

Zidesamtinib demonstrated favorable pharmacokinetics, with exposure above all target efficacy thresholds in the periphery and CNS of both ROS1 wild-type and ROS1 G2032R–mutant tumors.

Regarding safety, no dose-limiting toxicities, treatment-related serious AEs, treatment-related dizziness, or AEs leading to treatment reductions or discontinuations were reported in this analysis.⁷

“The most common toxicity seen was fatigue in 11% of patients enrolled in this study. Those were all grade 1 [events]. Nausea occurred in less than 10% [of patients], and liver function test abnormalities [were seen] in only 6% of patients. Again, these were all grade 1,” Liu noted. “Pharmacokinetics were [also] favorable, and we saw a dose-dependent increase in exposure, as one would hope for.”

In February 2024, the FDA granted a breakthrough therapy designation to zidesamtinib for the treatment of patients with ROS1-positive metastatic NSCLC who have previously received 2 or more ROS1 TKIs.⁸

Details of the ARROS-1 Trial

ARROS-1 is a first-in-human, open-label, nonrandomized study designed to establish the optimal dosing, safety, tolerability, and efficacy of zidesamtinib for patients with ROS1 fusion–positive tumors. The study is composed of a phase 1 dose escalation and phase 2 dose expansion. In the phase 1 portion, eligible patients must have histologically or cytologically confirmed locally advanced or metastatic solid tumors displaying ROS1 rearrangements. In the phase 2 dose-expansion study, patients will be assigned to 1 of 5 cohorts based on their specific diagnosis and ROS1 status.² Liu added that patients in the phase 2 portion will also be enrolled based on their number of prior treatment lines.

Cohorts 2a, 2b, 2c, and 2d will include adult patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC harboring a ROS1 rearrangement. Cohort 2e, which is the exploratory cohort, will comprise patients aged at least 12 years with a body weight exceeding 40 kg with confirmed locally advanced or metastatic ROS1-positive solid tumors other than NSCLC. Excluding those in cohort 2a, all enrolled patients must have received prior anticancer treatment. Patients must also have measurable disease according to RECIST 1.1 criteria and demonstrate adequate baseline organ function and bone marrow reserve. Key exclusion criteria for the study include expression of a known oncogenic driver alteration other than ROS1, major surgery within 4 weeks of the first dose of the study drug, and ongoing treatment with an anticancer therapy.²

“Importantly, [patients] must have “washed out” from prior therapy, so a ertain amount of time has to elapse between [the conclusion of their] last therapy and [the initiation of the] new therapy. However, understanding how quickly targeted agents are eliminated by the body, that washout period is fairly small,” Liu explained.

In phase 1, patients received once-daily doses of oral zidesamtinib at either 25 mg, 50 mg, 75 mg, 100 mg, or 125 mg.7 At the data cutoff of May 17, 2023, investigators established the recommended phase 2 dose (RP2D) at 100 mg of zidesamtinib once daily, which will be administered to all cohorts in the dose-expansion portion.⁹

The primary objectives of the phase 1 component were to establish the maximum tolerated dose of zidesamtinib as well as the RP2D for further investigation. The primary end point in the phase 2 portion is ORR as assessed by blinded independent central review. Key secondary end points include duration of response, time to response, PFS, overall survival, and clinical benefit rate.²

“[In the phase 2 study], we’ll really be looking at [response] durability. We’ll want to understand for whom this drug works best, and what mediates resistance if this drug were to stop working,” Liu expanded.

The study is being conducted globally across 44 locations in North America, Europe, Asia, and Australia, and enrollment in the single-arm, open-label phase 2 portion is ongoing. Investigators plan to enroll approximately 225 patients into the study.⁹

“Our hope is that, as the study progresses, we’ll see increasing activity [with zidesamtinib] in earlier lines of therapy. Hopefully those response rates will go even higher,” Liu concluded. “[Another] important question is whether [zidesamtinib] should be our new standard of care, even in the frontline setting. Zidesamtinib has an elegant, rational design, and certainly has the potential to be best in class. We eagerly await an update on the ARROS-1 data set.”

References

1. Drilon A, Horan JC, Tangpeerachaikul A, et al. NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations. Cancer Discov. 2023;13(3):598-615. doi:10.1158/2159-8290.CD-22-0968
2. A study of NVL-520 in patients with advanced NSCLC and other solid tumors harboring ROS1 rearrangement (ARROS-1). ClinicalTrials.gov. Updated March 8, 2024. Accessed May 7, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05118789
3. FDA approves crizotinib capsules. FDA. March 11, 2016. Accessed May 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-capsules
4. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Updated August 16, 2019. Accessed May 8, 2024. https://www.fda.gov/drugs/resources-information-approved-
   drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc
5. FDA approves repotrectinib for ROS1-positive non–small cell lung cancer. FDA. Updated November 16, 2023. Accessed May 8, 2024. https://www.fda.gov/drugs/resources-information-
   approved-drugs/fda-approves-repotrectinib-ros1-positive-non-small-cell-lung-cancer
6. AnHeart Therapeutics receives FDA breakthrough therapy designation for taletrectinib in ROS1-positive non–small cell lung cancer. News release. AnHeart Therapeutics. August 3, 2022. Accessed May 8, 2024. https://www.anhearttherapeutics.com/news/press-releases/080322/
7. Nuvalent reports preliminary phase 1 clinical data from ARROS-1 trial that support best-in-class potential of NVL-520 for patients with ROS1-positive NSCLC. News release. Nuvalent, Inc. October 28, 2022. Accessed May 8, 2024. https://investors.nuvalent.com/2022-10-28-Nuvalent-Reports-Preliminary-Phase-1-Clinical-Data-from-ARROS-1-Trial-that-Support-Best-In-Class-Potential-of-NVL-520-for-Patients-withROS1-Positive-NSCLC
8. Nuvalent receives US FDA breakthrough therapy designation for NVL-520. News release. Nuvalent, Inc. February 27, 2024. Accessed May 8, 2024. https://investors.nuvalent.com/2024-02-27-Nuvalent-Receives-U-S-FDA-Breakthrough-Therapy-Designation-for-NVL-520
9. Nuvalent initiates the phase 2 portion of ARROS-1 clinical trial for patients with ROS1-positive NSCLC and other solid tumors. News release. Nuvalent, Inc. September 5, 2023.Accessed May 8, 2024. https://investors.nuvalent.com/2023-09-05-Nuvalent-Initiates-the-Phase-2-Portion-of-ARROS-1-Clinical-Trial-for-Patients-with-ROS1-Positive-NSCLC-and-other-Solid-Tumors