Core Insights - Nuvalent, Inc. is a clinical-stage biopharmaceutical company focused on developing precisely targeted therapies for cancer, specifically targeting clinically proven kinase targets [3]. Company Participation - The CEO James Porter, Ph.D., and CFO Alexandra Balcom will participate in a fireside chat during the UBS 2025 Virtual Oncology Day on October 1, 2025, at 3:30 p.m. ET [1]. Webcast Information - A live webcast of the event will be available on the company's website and archived for 30 days post-presentation [2]. Company Overview - Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, along with multiple discovery-stage research programs [3]. - The company leverages expertise in chemistry and structure-based drug design to develop innovative small molecules aimed at overcoming resistance, minimizing adverse events, and addressing brain metastases [3].

Core Viewpoint - Nuvalent, Inc. has initiated a rolling New Drug Application (NDA) submission for zidesamtinib, a novel investigational ROS1-selective inhibitor, targeting TKI pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC), with completion expected in the third quarter of 2025 [1][2]. Group 1: Zidesamtinib Development - Zidesamtinib is designed to overcome limitations of existing ROS1 inhibitors and is intended to remain effective in tumors with resistance mutations, including G2032R [4]. - The drug is also formulated for central nervous system (CNS) penetration, aiming to improve treatment options for patients with brain metastases [4]. - Zidesamtinib has received breakthrough therapy designation for patients with ROS1-positive metastatic NSCLC previously treated with two or more ROS1 TKIs [4]. Group 2: Clinical Trial Insights - The ARROS-1 Phase 1/2 clinical trial is currently investigating zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors, with the Phase 1 portion focusing on safety and tolerability [5]. - The ongoing Phase 2 portion is designed for TKI-naïve and TKI pre-treated patients, with registrational intent [5]. Group 3: Regulatory Engagement - The FDA has accepted the NDA for zidesamtinib under the Real-Time Oncology Review (RTOR) program, allowing for earlier submission of efficacy and safety results [2]. - The company is actively engaging with the FDA regarding potential opportunities for line-agnostic expansion [2]. Group 4: Market Need - There is a significant need for new treatment options for patients with ROS1-positive NSCLC, especially those who cannot tolerate existing TKIs or have disease progression with brain metastases or resistance mutations [3].

Summary of Newvalent Conference Call Company Overview - Newvalent is a precision oncology company founded approximately seven years ago, focusing on innovative chemistry and structure-based drug design to develop better solutions for cancer patients [2][3] Core Focus Areas - The company targets clinically proven kinase targets, specifically in the ALK and ROS1 space, to address unmet medical needs in cancer treatment [3][10] - Newvalent is advancing two drugs towards potential approval: Zydasamtinib for ROS1 and Nelodelka for ALK [4] Drug Development Progress - Zydasamtinib: Top-line data presented in June, NDA submission initiated for pretreated ROS1 patients, with full data expected at the World Lung conference [4][24] - Nelodelka: Pivotal data presentation expected by year-end, with a Phase 3 ALCOZAR study initiated [4] Patient Advocacy and Community Engagement - Collaboration with patient advocacy groups for ALK and ROS1 has been beneficial, enhancing trial enrollment and community awareness [6][8] - These groups advocate for better treatment options, aligning their goals with Newvalent's mission [7] Unmet Medical Needs - In the ALK space, there are currently six approved therapies, but a significant need exists for a third-line treatment after patients progress on existing therapies [10][11] - CNS side effects are a major concern with current therapies, impacting patient quality of life and treatment adherence [12][14] Drug Efficacy and Tolerability - Newvalent aims to develop drugs that are effective against CNS disease and have fewer side effects compared to existing treatments [11][19] - Early data suggests that Zydasamtinib shows promising durability, with 93% of second-line ROS1 patients still in response after 1.5 years [20] Market Potential - Crizotinib, the current standard of care for ROS1, has global sales of approximately $400 million, but Newvalent believes there is significant room for improvement with Zydasamtinib [32] - The company draws parallels to the EGFR market, where Osimertinib significantly increased market size due to improved efficacy and tolerability [35] Future Strategies - Newvalent is focused on obtaining approvals for both previously treated and frontline settings for ROS1 patients, with ongoing discussions with regulatory bodies [30][27] - The company is also exploring the potential for its drugs in other solid tumors beyond lung cancer, aiming to drive more sequencing and testing [50] HER2 Program - Newvalent is developing MVL-330 for HER2 lung cancer, targeting exon 20 insertions with a focus on brain penetrance, which is a limitation of existing therapies [68] Conclusion - Newvalent is positioned to address significant unmet needs in the oncology space, particularly for ALK and ROS1 patients, with promising drug candidates and a strong focus on patient engagement and community collaboration [70]

About Nuvalent Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvale ...

Core Insights - Nuvalent, Inc. announced pivotal data for zidesamtinib, a novel ROS1-selective inhibitor, targeting advanced ROS1-positive non-small cell lung cancer (NSCLC) patients, which will be presented at the IASLC 2025 World Conference on Lung Cancer [1][2] - The company has initiated a rolling NDA submission for zidesamtinib, with the FDA agreeing to accept the NDA for the Real-Time Oncology Review pilot program, aiming for completion in Q3 2025 [2][3] Company Overview - Nuvalent, Inc. is a clinical-stage biopharmaceutical company focused on developing targeted therapies for cancer, specifically for clinically proven kinase targets [5][6] - The company leverages expertise in chemistry and structure-based drug design to create innovative small molecules that address treatment resistance and minimize adverse events [6] Product Details - Zidesamtinib is designed to be a brain-penetrant ROS1-selective inhibitor, effective against tumors that have developed resistance to existing ROS1 inhibitors, including those with treatment-emergent mutations [3][4] - The ARROS-1 Phase 1/2 clinical trial is investigating zidesamtinib in patients with advanced ROS1-positive NSCLC, with the Phase 1 portion focusing on safety and tolerability [4]

Table of Contents UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the quarterly period ended June 30, 2025 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____________ to _____________ Commission File Number: 001-40671 NUVALENT, INC. (Exact name of registrant as specified in its charter) Delawa ...

[Nuvalent Highlights, Milestones, and Q2 2025 Financial Results](index=1&type=section&id=Nuvalent%20Highlights%20Pipeline%20and%20Business%20Achievements%2C%20Reiterates%20Key%20Anticipated%20Milestones%2C%20and%20Reports%20Second%20Quarter%202025%20Financial%20Results) Nuvalent highlighted pipeline and business achievements, reiterated key milestones, and reported Q2 2025 financial results - Nuvalent outlined pipeline and business achievements, reiterated key anticipated milestones, and reported second quarter 2025 financial results[3](index=3&type=chunk) - Initiated rolling NDA submission for zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC, targeting completion in **Q3 2025**[2](index=2&type=chunk)[4](index=4&type=chunk) - Initiated ALKAZAR Phase 3 randomized, controlled trial of neladalkib for front-line ALK-positive NSCLC[2](index=2&type=chunk)[4](index=4&type=chunk) - Topline pivotal data for neladalkib for TKI pre-treated patients with advanced ALK-positive NSCLC expected by **year-end 2025**[2](index=2&type=chunk)[4](index=4&type=chunk) - Jason Waters, MBA, promoted to Senior Vice President, Commercial, to build commercial infrastructure[2](index=2&type=chunk)[4](index=4&type=chunk) [Recent Pipeline Achievements and Anticipated Milestones](index=1&type=section&id=Recent%20Pipeline%20Achievements%20and%20Anticipated%20Milestones) This section details recent advancements in Nuvalent's ROS1, ALK, and HER2 programs and outlines key upcoming milestones [ROS1 Program (zidesamtinib)](index=1&type=section&id=ROS1%20Program) Nuvalent initiated a rolling NDA submission for zidesamtinib for TKI pre-treated ROS1-positive NSCLC, with target completion in Q3 2025, and the FDA accepted it into the RTOR pilot program - Rolling NDA submission for zidesamtinib, a novel ROS1-selective inhibitor, initiated for TKI pre-treated patients with advanced ROS1-positive NSCLC[5](index=5&type=chunk) - FDA accepted the NDA for participation in the Real-Time Oncology Review (RTOR) pilot program, facilitating an earlier start to the FDA's evaluation, with completion of the NDA submission targeted for **Q3 2025**[5](index=5&type=chunk)[6](index=6&type=chunk) - NDA submission is based on positive pivotal data from the global ARROS-1 Phase 1/2 clinical trial for TKI pre-treated patients, with preliminary data from the ongoing Phase 2 TKI-naïve cohort (104 patients enrolled as of June 16, 2025) also reported[6](index=6&type=chunk) [ALK Program (neladalkib)](index=2&type=section&id=ALK%20Program) The ALK program saw the initiation of the ALKAZAR Phase 3 trial for TKI-naïve ALK-positive NSCLC and anticipates pivotal data from the ALKOVE-1 trial for TKI pre-treated patients by year-end 2025 - Dosing of the first patient in ALKAZAR, a global Phase 3 randomized, controlled trial evaluating neladalkib for TKI-naïve ALK-positive NSCLC, has been announced[10](index=10&type=chunk) - Patients in ALKAZAR will be randomized 1:1 to receive neladalkib monotherapy or alectinib monotherapy, a front-line standard of care[10](index=10&type=chunk) - Pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC from the ALKOVE-1 Phase 1/2 trial are expected by **year-end 2025**[10](index=10&type=chunk) - Preliminary data from the Phase 2 exploratory cohort for patients with ALK-positive solid tumors beyond NSCLC will be presented at the ESMO Congress 2025 (October 17-21, 2025)[8](index=8&type=chunk)[10](index=10&type=chunk) [HER2 Program (NVL-330)](index=2&type=section&id=HER2%20Program) Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial for NVL-330 in HER2-altered NSCLC, focusing on safety, tolerability, dose determination, pharmacokinetics, and preliminary anti-tumor activity - Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial evaluating the overall safety and tolerability of NVL-330 for pre-treated patients with HER2-altered NSCLC[8](index=8&type=chunk) - Additional objectives of the HEROEX-1 trial include determination of the recommended Phase 2 dose, characterization of NVL-330's pharmacokinetic profile, and preliminary evaluation of anti-tumor activity[8](index=8&type=chunk) [Business Updates](index=2&type=section&id=Business%20Updates) This section provides updates on Nuvalent's leadership appointments and promotions, strengthening its commercial and strategic capabilities [Leadership Appointments and Promotions](index=2&type=section&id=Jason%20Waters%2C%20MBA%2C%20Promoted%20to%20Senior%20Vice%20President%2C%20Commercial) Nuvalent strengthened its commercial leadership with the promotion of Jason Waters to Senior Vice President, Commercial, and enhanced its board of directors with the appointment of Christy Oliger - Jason Waters, MBA, was promoted to Senior Vice President, Commercial, bringing over 20 years of biopharma experience, including 15 years in commercial oncology focused on product launches and commercialization[9](index=9&type=chunk)[11](index=11&type=chunk) - Christy Oliger was appointed to Nuvalent's board of directors, contributing over 30 years of commercial and business experience in the pharmaceutical and biotechnology industry, including senior leadership roles at Genentech[11](index=11&type=chunk) [Second Quarter 2025 Financial Results](index=3&type=section&id=Second%20Quarter%202025%20Financial%20Results) This section presents Nuvalent's financial performance for Q2 2025, including key metrics, consolidated statements of operations, and selected balance sheet data [Key Financial Highlights](index=3&type=section&id=Key%20Financial%20Highlights) Nuvalent's cash, cash equivalents, and marketable securities stood at **$1.0 billion** as of June 30, 2025, providing a runway into 2028, with a net loss of **$99.7 million** for Q2 2025 Q2 2025 Key Financials (in millions) | Metric | Q2 2025 (in millions) | | :----- | :-------------------- | | Cash, cash equivalents and marketable securities (as of June 30, 2025) | $1,005.6 | | R&D Expenses | $80.9 | | G&A Expenses | $23.7 | | Net Loss | $(99.7) | - Nuvalent continues to believe its existing cash, cash equivalents and marketable securities will be sufficient to fund its current operating plan into **2028**[4](index=4&type=chunk)[15](index=15&type=chunk) [Consolidated Statements of Operations](index=5&type=section&id=CONSOLIDATED%20STATEMENTS%20OF%20OPERATIONS) For Q2 2025, Nuvalent reported a net loss of **$99.7 million**, an increase from **$57.2 million** in Q2 2024, with R&D expenses significantly increasing to **$80.9 million** Consolidated Statements of Operations (Unaudited, in thousands) | Metric | Three Months Ended June 30, 2025 | Three Months Ended June 30, 2024 | Six Months Ended June 30, 2025 | Six Months Ended June 30, 2024 | | :------------------------------------ | :------------------------------- | :------------------------------- | :------------------------------- | :------------------------------- | | Research and development | $80,913 | $49,166 | $155,331 | $87,800 | | General and administrative | $23,658 | $15,984 | $44,052 | $29,938 | | Total operating expenses | $104,571 | $65,150 | $199,383 | $117,738 | | Loss from operations | $(104,571) | $(65,150) | $(199,383) | $(117,738) | | Total other income (expense), net | $5,063 | $8,154 | $15,450 | $16,643 | | Loss before income taxes | $(99,508) | $(56,996) | $(183,933) | $(101,095) | | Net loss | $(99,653) | $(57,166) | $(184,235) | $(101,648) | | Net loss per share (basic and diluted) | $(1.39) | $(0.88) | $(2.57) | $(1.58) | | Weighted average shares outstanding | 71,843,774 | 64,605,308 | 71,726,313 | 64,377,948 | [Selected Balance Sheet Data](index=6&type=section&id=SELECTED%20BALANCE%20SHEET%20DATA) As of June 30, 2025, Nuvalent reported cash, cash equivalents, and marketable securities of **$1.0 billion**, a decrease from **$1.1 billion** at December 31, 2024 Selected Balance Sheet Data (Unaudited, in thousands) | Metric | June 30, 2025 | December 31, 2024 | | :--------------------------------- | :-------------- | :---------------- | | Cash, cash equivalents and marketable securities | $1,005,598 | $1,118,302 | | Working capital | $944,463 | $1,078,428 | | Total assets | $1,040,543 | $1,141,752 | | Total liabilities | $100,801 | $71,960 | | Total stockholders' equity | $939,742 | $1,069,792 | [About Nuvalent](index=3&type=section&id=About%20Nuvalent) Nuvalent is a clinical-stage biopharmaceutical company focused on developing precisely targeted cancer therapies to overcome limitations of existing treatments - Nuvalent, Inc. is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome limitations of existing therapies for clinically proven kinase targets[3](index=3&type=chunk)[13](index=13&type=chunk) - The company leverages deep expertise in chemistry and structure-based drug design to develop innovative small molecules with the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses[13](index=13&type=chunk) - Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, and multiple discovery-stage research programs[13](index=13&type=chunk) [Forward-Looking Statements](index=3&type=section&id=Forward-Looking%20Statements) This section details Nuvalent's forward-looking statements, acknowledging inherent risks in drug development and commercialization - This press release contains forward-looking statements regarding Nuvalent's strategy, business plans, financial runway, expected timing of data announcements, NDA submissions, FDA product approvals, and clinical development programs for zidesamtinib, neladalkib, and NVL-330[14](index=14&type=chunk) - Drug development and commercialization involve a high degree of risk, and actual events or results may differ materially from those expressed or implied due to various factors, including clinical trial enrollment, unexpected data, regulatory approvals, costs, and intellectual property risks[16](index=16&type=chunk)[17](index=17&type=chunk) - Nuvalent explicitly disclaims any obligation to update any forward-looking statements[17](index=17&type=chunk) [Contacts](index=4&type=section&id=Investor%20Contact) This section provides contact information for investor relations and media inquiries - Investor Contact: Chelcie Lister, Nuvalent, Inc., clister@nuvalent.com[18](index=18&type=chunk) - Media Contact: Josie Butler, 1AB, josie@labmedia.com[18](index=18&type=chunk)

Core Insights - Nuvalent, Inc. has initiated a rolling NDA submission for zidesamtinib targeting TKI pre-treated patients with advanced ROS1-positive NSCLC, aiming for completion in Q3 2025 [1][5] - The company has also started the ALKAZAR Phase 3 trial for neladalkib in TKI-naïve advanced ALK-positive NSCLC, with pivotal data expected by year-end 2025 [1][4] - Financial results for Q2 2025 show a net loss of $99.7 million, with R&D expenses at $80.9 million and G&A expenses at $23.7 million [10][15] Pipeline Achievements - The NDA submission for zidesamtinib is based on positive data from the ARROS-1 Phase 1/2 trial, which included 104 patients as of June 16, 2025 [5] - The ALKAZAR trial will randomize patients 1:1 to receive either neladalkib or alectinib, reflecting input from physician-scientists and regulatory agencies [4] - Preliminary data for neladalkib in ALK-positive solid tumors will be presented at the ESMO Congress 2025 [1][9] Business Updates - Jason Waters has been promoted to Senior Vice President, Commercial, to enhance the company's commercial strategy [2][10] - The company has a strong cash position of $1.0 billion as of June 30, 2025, expected to fund operations into 2028 [10][15] - Christy Oliger has been appointed to the board of directors, bringing over 30 years of experience in the pharmaceutical industry [10]

Core Viewpoint - Nuvalent, Inc. has initiated the ALKAZAR Phase 3 trial to evaluate neladalkib for TKI-naïve patients with advanced ALK-positive non-small cell lung cancer (NSCLC), comparing it to the standard of care, ALECENSA® [1][2] Group 1: Clinical Trial Details - The ALKAZAR trial aims to enroll approximately 450 TKI-naïve patients, with a 1:1 randomization to receive either neladalkib or alectinib [2] - The primary endpoint of the trial is progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR), with several secondary endpoints including overall survival and intracranial response metrics [2][3] Group 2: Neladalkib Profile - Neladalkib is designed to address treatment limitations of existing ALK inhibitors, particularly for patients with brain metastases and resistance mutations [5] - The drug has received breakthrough therapy designation for patients with locally advanced or metastatic ALK-positive NSCLC previously treated with two or more ALK tyrosine kinase inhibitors [5] Group 3: Company Overview - Nuvalent, Inc. focuses on developing targeted therapies for cancer, leveraging expertise in chemistry and structure-based drug design [6][7] - The company is advancing a pipeline that includes investigational candidates for ROS1-positive, ALK-positive, and HER2-altered NSCLC, along with multiple discovery-stage research programs [7]

Pipeline Programs and Milestones - Nuvalent is advancing parallel lead programs for ROS1+ and ALK+ NSCLC in global clinical development, with potential for first FDA approval in 2026[4] - The company plans to report pivotal data for TKI pre-treated ROS1+ NSCLC from the ARROS-1 trial in 1H 2025 and complete rolling NDA submission in Q3 2025[14] - Topline pivotal data for TKI pre-treated ALK+ NSCLC from the ALKOVE-1 trial is anticipated by year-end 2025, with ALKAZAR Phase 3 trial for TKI-naïve ALK+ NSCLC planned to initiate in early 2H 2025[14, 205] - NVL-330 for HER2-altered NSCLC is in Phase 1a/1b investigation, with additional discovery research programs ongoing[12, 205] Zidesamtinib (NVL-520) for ROS1+ NSCLC - In TKI pre-treated ROS1+ NSCLC patients, the ORR was 44% (51/117), with 78% (95% CI: 62, 88) DOR ≥ 12 months and 62% (95% CI: 28, 84) DOR ≥ 18 months[73] - In patients with prior crizotinib or entrectinib only ± chemotherapy, the ORR was 51% (28/55), with 93% (95% CI: 74, 98) DOR ≥ 12 months and 93% (95% CI: 74, 98) DOR ≥ 18 months[80] - Zidesamtinib demonstrated CNS activity, with an IC-ORR of 48% (27/56) in any prior ROS1 TKI ± chemotherapy and 85% (11/13) in prior crizotinib only ± chemotherapy[90] - The safety profile of zidesamtinib was generally well-tolerated, with peripheral edema reported in 36% of patients, constipation in 17%, blood CPK increased in 16%, fatigue in 16%, and dyspnea in 15%[96] - In TKI-naïve patients with ROS1+ NSCLC, the ORR was 89% (31/35), with 96% (95% CI: 76, 99) DOR ≥ 6 months and 96% (95% CI: 76, 99) DOR ≥ 12 months[103] Neladalkib (NVL-655) for ALK+ NSCLC - In a heavily pre-treated ALK+ solid tumor population, 51% had any secondary ALK mutation, 26% had a compound ALK mutation, and 56% had a history of CNS metastasis[140, 141] - In all NSCLC response evaluable patients, across all doses, the ORR was 38% (39/103), with a mDOR of 144 months and 78% DOR > 6 months[149] - In patients with any ALK resistance mutation at RP2D, the ORR was 55% (12/22), with a mDOR not reached and 100% DOR > 6 months[158] - The preliminary safety profile of neladalkib was consistent with its ALK-selective design, with ALT increased in 34% of patients, AST increased in 30%, constipation in 16%, dysgeusia in 13%, and nausea in 12%[166] Market Overview - The combined worldwide sales for ALK and ROS1 TKIs in 2024 were approximately $31 billion[27]