NVL-520 for ROS1-Positive Solid Tumors

Recruiting at 79 trial locations

Overseen By Nuvalent

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nuvalent Inc.

Disqualifiers: Other oncogenic drivers, Allergy, Major surgery, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

359 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called NVL-520 (also known as Zidesamtinib) for individuals with advanced solid tumors that have a specific genetic change known as ROS1-positive. The main goal is to assess the safety and effectiveness of NVL-520 in treating these cancers, particularly a type of lung cancer called NSCLC. The trial includes different groups based on previous treatments, making it potentially suitable for those with ROS1-positive cancer who have undergone specific past treatments like certain chemotherapy or targeted therapies. The study aims to determine the right dose and evaluate how well the treatment shrinks tumors. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does mention that ongoing anticancer therapy is an exclusion criterion, which might imply that you need to stop such treatments before joining.

Is there any evidence suggesting that NVL-520 is likely to be safe for humans?

Research shows that zidesamtinib (NVL-520) is safe for people with ROS1-positive solid tumors. In studies, most patients tolerated zidesamtinib well, with few serious side effects, and any issues were mostly manageable.

Researchers have administered this experimental treatment to 514 patients at different doses to find the safest and most effective dose. As this study is in its early stages, it helps researchers understand how the body processes the drug. Safety information from these studies will guide further research to ensure the treatment is safe for more people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

NVL-520 is unique because it targets ROS1-positive tumors with a new mechanism of action, potentially offering more precise treatment compared to existing options. Unlike standard treatments like crizotinib or entrectinib, NVL-520 is specifically designed to overcome resistance that often develops with current therapies. Researchers are excited because NVL-520 may provide a more effective option for patients who have exhausted other treatments, and its oral daily dosing could offer more convenience and flexibility in managing the condition.

What evidence suggests that NVL-520 might be an effective treatment for ROS1-positive solid tumors?

Research has shown that zidesamtinib (NVL-520), the investigational treatment in this trial, may help treat ROS1-positive solid tumors, including non-small cell lung cancer (NSCLC). Studies have found that it can lead to long-lasting improvements in patients who have already tried other treatments. Early results indicate that patients experienced significant tumor shrinkage and sustained benefits. In one large study, patients with advanced ROS1-positive solid tumors showed positive results with zidesamtinib, even after previous treatments. This trial will evaluate zidesamtinib across various cohorts, including those who have received different prior therapies, to further assess its potential as a treatment option for ROS1-positive tumors. ^{1 5 6 7 8}

Who Is on the Research Team?

Vivek Upadhyay, MD, MBI

Principal Investigator

Nuvalent Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors, especially non-small cell lung cancer (NSCLC), that have a specific genetic change called ROS1 rearrangement. Patients should have tried other cancer treatments unless they're in one special group. They need to be healthy enough overall and not currently on another clinical study or recent major surgery.

Inclusion Criteria

I am 12 years or older and weigh more than 40 kg.

My advanced cancer has a confirmed ROS1 rearrangement.

My organs and bone marrow are functioning well.

Exclusion Criteria

My cancer is driven by a specific genetic change, not ROS1.

I am allergic to ingredients in NVL-520.

Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Determine the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of NVL-520 in patients with advanced ROS1-positive solid tumors

Approximately 4-8 weeks

Phase 2 Expansion

Evaluate the objective response rate (ORR) and other secondary outcomes such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS) in patients with advanced ROS1-positive NSCLC and other solid tumors

2-3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• NVL-520

Trial Overview NVL-520 is being tested to see how safe it is and what dose works best against these cancers. The first phase figures out the right dose; the second checks how well it shrinks tumors using independent reviews, also looking at survival times and other health benefits.

How Is the Trial Designed?

Group I: Phase 1 dose escalation Experimental Treatment 1 Intervention

Zidesamtinib (NVL-520) oral daily dosing

Group II: Cohort 2e Experimental Treatment 1 Intervention

ROS1+ solid tumor and progressed on any prior therapy

Group III: Cohort 2d Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with ≥2 prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy

Group IV: Cohort 2c Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy

Group V: Cohort 2b Experimental Treatment 1 Intervention

ROS1+ NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy

Group VI: Cohort 2a Experimental Treatment 1 Intervention

ROS1+ NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy

Who Is Running the Clinical Trial?

Nuvalent Inc.

Lead Sponsor

Trials

6

Recruited

1,400+

Published Research Related to This Trial

In a study of 208 never-smoking patients with lung adenocarcinoma, 3.4% had ROS1 rearrangements, which were associated with a significantly higher objective response rate (60.0%) and longer progression-free survival when treated with pemetrexed compared to those without ROS1/ALK rearrangements.

The findings suggest that ROS1 rearrangements are more common in selected patients than previously thought, indicating that testing for ROS1 can help identify patients who may benefit from targeted therapies, especially in East-Asian populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. Kim, HR., Lim, SM., Kim, HJ., et al.[2020]

A patient with ROS1-rearranged non-small cell lung cancer (NSCLC) showed a good response to lorlatinib after failing immune-chemotherapy, suggesting that lorlatinib may be a more effective second-line treatment for similar patients.

Monitoring immune factors during treatment revealed that increased PD-L1 expression in tumor tissue could predict limited benefits from immune-chemotherapy, highlighting the importance of assessing the tumor immune microenvironment for better treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with ROS1-rearranged lung adenocarcinoma. Yue, D., Qian, J., Chen, Z., et al.[2022]

ROS1 fusion events occur in 1%-2% of non-small-cell lung cancer (NSCLC) patients and are associated with specific patient demographics, including younger individuals, women, and non-smokers, indicating a distinct molecular subtype of NSCLC.

Crizotinib is the only approved treatment for ROS1-rearranged NSCLC, showing significant benefits in progression-free survival and quality of life, and is recommended as the standard first-line therapy for patients with this genetic alteration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizotinib inhibition of ROS1-positive tumours in advanced non-small-cell lung cancer: a Canadian perspective. Bebb, DG., Agulnik, J., Albadine, R., et al.[2023]

In a phase 2 study involving 59 patients with ROS1-positive non-small cell lung cancer (NSCLC), ensartinib demonstrated a modest objective response rate of 27% and a median progression-free survival of 4.6 months, indicating its potential efficacy in this patient population.

The treatment was generally well-tolerated, with most adverse events being mild to moderate (grades 1-2), and only 25.4% of patients experiencing severe (grade 3 or higher) treatment-related adverse events, suggesting an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study. Ai, X., Wang, Q., Cheng, Y., et al.[2021]

In a study of 21 patients with ROS1-rearranged non-small cell lung cancer (NSCLC) treated with crizotinib from 2014 to 2020, crizotinib demonstrated good tolerability and effectiveness, although outcomes were lower than those seen in clinical trials.

The study highlighted the importance of timely initiation of crizotinib therapy, as delays in treatment, especially in patients with brain metastases, were associated with poorer clinical responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Management and Outcomes of Crizotinib-Treated ROS1-Rearranged NSCLC: A Retrospective Canadian Cohort. Gibson, AJW., Box, A., Cheung, WY., et al.[2022]

ROS1 translocations occur in 1-2% of all non-small cell lung cancer (NSCLC) cases and 3-6% of pulmonary adenocarcinoma cases, and can be detected using in situ hybridization techniques.

Treatment with the ROS1 inhibitor crizotinib shows a high response rate of 70-80% and a median progression-free survival of about 19 months, indicating that targeted therapy is effective and generally well tolerated for patients with ROS1-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[ROS1-Translocations in Non-Small Cell Lung Cancer]. Warth, A., Weichert, W., Reck, M., et al.[2016]

DS-6051b is a new selective inhibitor that shows significant effectiveness against ROS1- or NTRK-rearranged cancers, including those resistant to crizotinib due to mutations like ROS1-G2032R.

In preclinical models, DS-6051b demonstrated strong growth inhibition in both wild type and G2032R mutant ROS1-rearranged cancers, suggesting it could be a promising treatment option for patients with crizotinib-resistant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Katayama, R., Gong, B., Togashi, N., et al.[2021]

In a study of 80 patients with advanced ROS1+ non-small-cell lung cancer (NSCLC), lorlatinib demonstrated a median progression-free survival of 7.1 months and an overall survival of 19.6 months, indicating its efficacy as a treatment option.

The treatment showed a high central nervous system response rate of 72% and an overall response rate of 45%, with a manageable safety profile, as 13% of patients discontinued due to toxicity, consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study. Girard, N., Galland-Girodet, S., Avrillon, V., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05118789

NCT05118789 | A Study of Zidesamtinib (NVL-520) in ... A Study of Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1). ClinicalTrials.gov ID ...

2. onclive.com onclive.com/view/pivotal-arros-1-efficacy-and-safety-data-zidesamtinib-in-tki-pretreated-patients-with-advanced-metastatic-ros1-nsclc

Pivotal ARROS-1 Efficacy and Safety Data: Zidesamtinib in ... Ross Camidge, MD, PhD, discusses a pivotal phase 2/3 clinical trial (ARROS-1) evaluating the efficacy and safety of zidesamtinib in patients ...

3. investors.nuvalent.com 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 Announces Positive Pivotal Data from ARROS-1 ... As of the data cut-off date of March 21, 2025, 514 patients with ROS1-positive solid tumors had received zidesamtinib at any starting dose ...

4. cancernetwork.com cancernetwork.com/view/zidesamtinib-may-yield-meaningful-outcomes-in-advanced-ros1-nsclc

Zidesamtinib May Yield Meaningful Outcomes in ... With a data cutoff of March 21, 2025, 514 patients with ROS1-positive solid tumors received zidesamtinib at any starting dose across the phase 1 ...

5. oncologynewscentral.com oncologynewscentral.com/nsclc/zidesamtinib-shows-early-signs-of-efficacy-durability-in-pretreated-ros1-nsclc

Zidesamtinib Shows Early Signs of Efficacy, Durability in ... Zidesamtinib Shows Early Signs of Efficacy, Durability in Pretreated ROS1-Positive NSCLC · Durable Responses Demonstrated · Efficacy Against ...

6. onclive.com onclive.com/view/zidesamtinib-data-align-with-clinical-expectations-in-pretreated-ros1-advanced-nsclc

Zidesamtinib Data Align With Clinical Expectations in ... Zidesamtinib achieved a 44% ORR and 1% CR rate in advanced ROS1-positive NSCLC patients with prior ROS1 TKI therapy. The ARROS-1 trial showed ...

7. investors.nuvalent.com investors.nuvalent.com/2025-08-13-Nuvalent-to-Present-Pivotal-Data-from-ARROS-1-Clinical-Trial-of-Zidesamtinib-for-TKI-Pre-treated-Patients-with-Advanced-ROS1-positive-NSCLC-at-WCLC-2025-Presidential-Symposium

Nuvalent to Present Pivotal Data from ARROS-1 Clinical ... The completed Phase 1 portion enrolled ROS1-positive NSCLC patients who previously received at least one ROS1 TKI, or patients with other ROS1- ...

8. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)02832-1/fulltext

1256MO Phase I/II ARROS-1 study of zidesamtinib (NVL- ... Zidesamtinib demonstrated encouraging efficacy and durability in pts with pretreated ROS1+ NSCLC, including those who had exhausted available therapies, with ...