zidesamtinib (NVL-520) / Nuvalent, Royalty - LARVOL DELTA

Pivotal ARROS-1 Efficacy and Safety Data: Zidesamtinib in TKI Pre-treated Patients with Advanced/Metastatic ROS1+ NSCLC (IASLC-WCLC 2025) - P1/2 | "50% of patients received ≥2 (range 1-4) prior ROS1 TKIs, of whom 93% had prior lorlatinib, repotrectinib, and/or taletrectinib. In this pivotal ROS1 TKI pre-treated data set, zidesamtinib demonstrated clinically meaningful activity and durability, including in patients with CNS disease and/or ROS1 G2032R-mutations, and/or in patients who had exhausted available options. Encouraging preliminary activity was also observed in TKI-naïve patients. Zidesamtinib's safety profile was consistent with its highly ROS1-selective, TRK-sparing design."

Clinical • Metastases • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Non Small Cell Lung Cancer • Pulmonary Disease • Solid Tumor • ROS1

As part of this plan, Nuvalent anticipates the following 2026 milestones (PRNewswire) - "Commercial launch in the U.S. of zidesamtinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) who received at least 1 prior ROS1 tyrosine kinase inhibitor (TKI), pending U.S. Food and Drug Administration (FDA) review; Submit data to FDA for potential indication expansion of zidesamtinib in TKI-naïve patients with advanced ROS1-positive NSCLC in the second half of 2026; Submit a New Drug Application (NDA) for neladalkib in TKI pre-treated patients with advanced ALK-positive NSCLC in the first half of 2026; Progress the ongoing ALKAZAR Phase 3 randomized, controlled trial of neladalkib for TKI-naïve patients with ALK-positive NSCLC; Progress the ongoing HEROEX-1 Phase 1a/1b trial of NVL-330 for patients with advanced HER2-altered NSCLC; and; Disclose a new development candidate by year-end 2026."

FDA filing • Launch US • Pipeline update • Trial status • Non Small Cell Lung Cancer

Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors (AACR-NCI-EORTC 2022) - P1/2 | "Rationally designed ROS1 tyrosine kinase inhibitors (TKIs) that surpass the limitations of FDA/EMA-approved (crizotinib/entrectinib) or other investigational agents are a medical need. The novel ROS1 TKI NVL-520 is highly selective and designed to avoid the neurologic toxicities associated with ROS1 TKIs that concurrently inhibit TRK (entrectinib/repotrectinib/taletrectinib)...Patients received a median of 3 (range: 1-9) prior anticancer therapies, including any ROS1 TKI (100%); investigational ROS1 TKI (85%, including lorlatinib in 55%, repotrectinib in 40%); ≥2 ROS1 TKIs (75%); any chemotherapy (80%); ≥2 lines of chemotherapy (50%)... NVL-520 has been well-tolerated up to 100 mg daily with favorable pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (of whom 70% received ≥2 prior ROS1 TKIs plus chemotherapy), including those with brain metastases and the G2032R mutation."

Clinical • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ROS1

Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours (ESMO 2024) - P1/2 | "Pts had a median of 3 (range: 1-11) prior anticancer therapies, including any ROS1 TKI (99%); lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); ≥2 ROS1 TKIs (69%); and chemo (66%). Zidesamtinib demonstrated encouraging efficacy and durability in pts with pretreated ROS1+ NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS mets. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent in pts with TKI-naïve and pretreated ROS1+ NSCLC."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Royalty Pharma Acquires Royalty Interest in Nuvalent’s Neladalkib and Zidesamtinib for Up to $315 Million (The Manila Times) - "The expected royalty duration for both therapies extends through approximately 2041 to 2042....Existing analyst consensus projects neladalkib sales to be approximately $3.5 billion and zidesamtinib sales to be approximately $1.9 billion by 2035."

Commercial • Sales projection • Non Small Cell Lung Cancer

Evolving Therapeutic Landscape of ROS1-Positive Non-Small Cell Lung Cancer: An Updated Review. (PubMed, Curr Oncol) - "Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent Announces FDA Acceptance of New Drug Application for Zidesamtinib for the Treatment of TKI Pre-treated Patients with Advanced ROS1-positive NSCLC (PRNewswire) - "The application has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of September 18, 2026. Nuvalent's NDA submission is based on results for TKI pre-treated patients with advanced ROS1-positive NSCLC enrolled in the global registrational ARROS-1 Phase 1/2 clinical trial."

FDA filing • PDUFA • Non Small Cell Lung Cancer

Nuvalent…announced the first presentation of patient-reported outcomes data from the Phase 2 portion of the ARROS-1 Phase 1/2 clinical trial of zidesamtinib, an investigational ROS1 inhibitor, as well as encore pivotal efficacy and safety data from the ARROS-1 trial, during two poster presentations at the 2025 IASLC ASCO North America Conference on Lung Cancer… (PRNewswire)

P2 data • Patient reported outcomes • Non Small Cell Lung Cancer

Pivotal ARROS-1 efficacy and safety data: zidesamtinib in TKI pre-treated patients with advanced/metastatic ROS1+ NSCLC (JADPRO 2025) - "BACKGROUND • Zidesamtinib is an investigational ROS1 TKI designed to be highly selective, have activity against diverse ROS1 fusions and ROS1 resistance mutations, be brain-penetrant, and avoid TRK inhibition • ARROS-1 is a global, single-arm, first-in-human Phase 1/2 clinical trial of zidesamtinib in advanced ROS1-positive (ROS1+) NSCLC and other solid tumors • Pivotal data for TKI pre-treated ROS1+ NSCLC and preliminary data for TKI-naïve ROS1+ NSCLC are presented ARROS-1 STUDY DESIGN & POPULATIONS • As of the data cut-off date of March 21, 2023, 514 patients with any ROS1+ solid tumor had been enrolled across Phase 1 and 2 – The safety population included 432 patients with advanced ROS1+ NSCLC who received zidesamtinib 100 mg QD – The efficacy population included 117 ROS1 TKI pre-treated patients with measurable disease by BICR and ≥ 6 months duration of response follow-up – The TKI-naïve cohort included 35 patients with measurable disease by BICR..."

Clinical • Metastases • CNS Disorders • Constipation • Fatigue • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Lung Cancer • Musculoskeletal Pain • Non Small Cell Lung Cancer • Pneumonia • Pulmonary Disease • Respiratory Diseases • Solid Tumor • ROS1

A Study of Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1) (clinicaltrials.gov) - P1/2 | N=359 | Recruiting | Sponsor: Nuvalent Inc. | Trial completion date: Oct 2026 ➔ Dec 2028 | Trial primary completion date: Oct 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent, Inc…announced Monday the completion of its New Drug Application (NDA) submission to the U.S. Food and Drug Administration for zidesamtinib. (Investing.com) - "The application covers use of the drug in tyrosine kinase inhibitor pre-treated patients with advanced ROS1-positive non-small cell lung cancer."

FDA filing • Non Small Cell Lung Cancer

Real-World Insights on Treatment Patterns and Outcomes in ROS1 NSCLC: An Australian Multicenter Study (AURORA) (IASLC-WCLC 2025) - P | "Across all lines, entrectinib (35/93, 38%) and crizotinib (33/93, 35%) were frequently used, followed by lorlatinib (26/93, 28%), NVL-520 (24/93, 26%), repotrectinib (17/93, 18%). First-line ROS1 therapy demonstrated a median survival of 56 months, comparable to PROFILE 1001 (51 months) and exceeding other real-world cohorts (24 months), likely due to reflex molecular testing, targeted therapy access, and trial prioritisation. This real-world data provides valuable insights into the longitudinal patient journey, outcomes with serial therapies, and the potential impact of treatment sequencing."

Clinical • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ROS1

…Data from the phase 1/2 ARROS-1 trial (NCT05118789) presented at the 2025 World Conference on Lung Cancer (Cancer Network) - "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..."

P1/2 data • Non Small Cell Lung Cancer

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 (PRNewswire) - "...addition to preliminary data for TKI-naïve patients, will be presented as part of the Presidential Symposium at the IASLC 2025 World Conference on Lung Cancer (WCLC 2025). The conference is hosted by the International Association for the Study of Lung Cancer and is being held September 6-9, 2025, in Barcelona, Spain."

P1/2 data • Non Small Cell Lung Cancer • ROS1

Nuvalent Highlights Pipeline and Business Achievements, Reiterates Key Anticipated Milestones, and Reports Second Quarter 2025 Financial Results (PRNewswire) - "The company has initiated its rolling NDA submission for zidesamtinib, a novel ROS1-selective inhibitor, in tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC). The FDA agreed to accept the NDA for participation in the Real-Time Oncology Review (RTOR) pilot program, which facilitates earlier submission of topline efficacy and safety results prior to the submission of the complete application, to support an earlier start to the FDA's evaluation of the application. Completion of the NDA submission is targeted for the third quarter of 2025. The NDA submission is based on positive pivotal data for TKI pre-treated patients with advanced ROS1-positive NSCLC enrolled in the global ARROS-1 Phase 1/2 clinical trial."

FDA filing • Non Small Cell Lung Cancer

Nuvalent Presents Pivotal Data from ARROS-1 Clinical Trial of Zidesamtinib for TKI Pre-treated Patients with Advanced ROS1-positive NSCLC at WCLC 2025 (PRNewswire) - "Rolling NDA submission for zidesamtinib in TKI pre-treated advanced ROS1-positive NSCLC initiated under FDA's RTOR program, with completion on track for the third quarter of 2025."

FDA filing • P1/2 data • Non Small Cell Lung Cancer

Assessment of two new ROS1+ NSCLC patient-derived cell lines as in vitro models for TKI resistance studies (EACR 2025) - "The IC50 values of unmutated ROS1+ Ba/F3 cells for crizotinib, entrectinib, lorlatinib, repotrectinib and zidesamtinib were 31.4; 44.6; 14.3; 14.9 and 29.9 nM, respectively...Interestingly, these cells were resistant to lorlatinib, while the patient is – after being treated with lorlatinib+cis-platinum+pemetrexed, now currently successfully treated with lorlatinib mono-therapy... In this study we showed that PC1 cells generated from a crizotinib-resistant patient were resistant to all ROS1 inhibitors tested. The G2032R mutated PC2 cells generated from a crizotinib and lorlatinib resistant patient were sensitive to repotrectinib, but not to zidesamtinib. This PC2 cell line can be used to assess off-target resistance mechanism to zidesamtinib."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • ARID1A • CD74 • PIK3CA • PIK3CG • ROS1

Nuvalent Announces Timing of Pivotal Data for TKI Pre-treated Patients with Advanced ROS1-positive NSCLC from ARROS-1 Clinical Trial of Zidesamtinib (PRNewswire) - "Nuvalent...announced that the company will host a webcast and conference call on Tuesday, June 24, 2025 at 8:00 a.m. ET, to discuss pivotal data for zidesamtinib, a novel ROS1-selective inhibitor, in TKI pre-treated patients with advanced ROS1-positive non-small cell lung cancer from the global ARROS-1 Phase 1/2 clinical trial."

P1/2 data • Non Small Cell Lung Cancer

Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations. (PubMed, Mol Cancer Ther) - "At clinically relevant concentrations, zidesamtinib robustly inhibited >1,500 pooled ROS1 mutants with virtually no resistance emerging (≤1%), outperforming comparators crizotinib, entrectinib, and repotrectinib. Zidesamtinib also induced more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model. A 2.2 Å co-crystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with TRK, consistent with its selective ROS1-targeting design and supported by computational modeling. Taken together, these data support zidesamtinib's potential as a novel best-in-class ROS1 inhibitor."

Journal • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent Announces Publication in Molecular Cancer Therapeutics Reinforcing Rational Molecular Design of Zidesamtinib as a Novel ROS1-Selective Inhibitor (PRNewswire) - "The manuscript explores the activity of zidesamtinib and other approved or investigational ROS1 TKIs at clinically relevant concentrations against ROS1 resistance mutations, including the most commonly occurring resistance mutation, ROS1 G2032R, in preclinical mutagenesis screens and an intracranial ROS1 G2032R xenograft model. Findings presented in the manuscript show that, at clinically relevant concentrations, zidesamtinib suppressed on-target resistance in ENU mutagenesis screens simulating first-line and later-line treatment and inhibited ROS1 G2032R brain tumors more effectively than the other ROS1 TKIs evaluated....The company expects to report pivotal clinical data for TKI pre-treated patients with advanced ROS1-positive NSCLC from the ARROS-1 Phase 1/2 trial in the first half of 2025 in support of an anticipated New Drug Application submission by mid-year 2025, with an initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC."

FDA filing • P1/2 data • Preclinical • Brain Cancer • CNS Tumor • Non Small Cell Lung Cancer

Crystal structure of drug-resistant ROS1 G2032R in complex with zidesamtinib, a clinical-stage ROS1 inhibitor with best-in-class potential (AACR 2025) - "Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib are FDA-approved for treatment of ROS1-positive NSCLC. Analysis of our ROS1 G2032R crystal structure and FEP modeling provide a structural explanation for how ROS1 G2032R impairs the binding of many ROS1 TKIs while maintaining high sensitivity to zidesamtinib. The data presented here, together with previously disclosed preclinical and clinical data, support our design of zidesamtinib as a differentiated ROS1 TKI with best-in-class potential for the treatment of ROS1-positive NSCLC."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK2 • ROS1

ANS03, a novel, orally bioavailable small-molecule type II ROS1/NTRK inhibitor, effectively overcomes clinically relevant ROS1/NTRK resistance mutations and exhibits potent antitumor activity in preclinical tumor models (AACR 2025) - "ANS03 also had better activity against the ROS1 L2086F mutation when compared to both Repotrectinib and NVL-520. Non-clinical studies of ANS03 showed it is a potent, orally bioavailable Type II ROS1/NTRK inhibitor with remarkable activity against various pathogenetic ROS1/NTRK alterations and with favorable absorption, distribution, pharmacokinetics, efficacy, and tolerability profiles in vivo. The compound will enter Phase 1 clinical development in the US and China soon."

Preclinical • Oncology • NTRK • NTRK1

Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. (PubMed, Cancer) - "First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%...Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges...Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability...In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent to Present New Preclinical Data on ALK-Selective Inhibitor, Neladalkib, and ROS1-Selective Inhibitor, Zidesamtinib, at AACR Annual Meeting 2025 (PRNewswire) - "Nuvalent...announced upcoming poster presentations further characterizing the preclinical profiles of its novel ALK-selective inhibitor, neladalkib, and novel ROS1-selective inhibitor, zidesamtinib, at the American Association for Cancer Research (AACR) Annual Meeting 2025 from April 25-30, 2025, in Chicago."

Preclinical • Oncology

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting. (PubMed, Lung Cancer) - "For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1