Summary of Nuvalent Conference Call - October 01, 2025 Company Overview - **Company**: Nuvalent, Inc. - **Industry**: Oncology, specifically focused on targeted therapies for cancer treatment - **Foundation**: Established approximately seven years ago with expertise in chemistry and structure-based drug design [3][4] Key Programs and Developments - **Zetacentenib**: - Targeting ROS1-positive non-small cell lung cancer (NSCLC) - Recently completed its first New Drug Application (NDA) submission, marking a significant milestone for the company [5][6] - Received breakthrough designation, indicating a recognized medical need [10][27] - Clinical data shows a 93% response rate at 18 months for patients who progressed on prior therapies, indicating durable responses [14][22] - Demonstrated activity in the brain, addressing a critical need for CNS penetration [13][19] - **Nanodelcub**: - An ALK inhibitor for ALK-positive NSCLC - Pivotal data expected to be presented at ESMO, with top-line data anticipated by year-end [28][30] - Aimed at addressing the limitations of existing therapies like alectinib and lorlatinib, particularly in patients who have progressed on these treatments [33][34] - **NVL-330**: - Targeting HER2-altered NSCLC, specifically focusing on HER2 exon 20 insertions - Designed to have excellent brain penetration and a favorable safety profile [36][37] - Positioned as a potential treatment option for patients with HER2-driven cancers [38] Regulatory Interactions - **FDA Engagement**: - No significant changes reported in interactions with the FDA despite ongoing industry dynamics [6][7] - The company is committed to collaborating with the FDA to expedite drug approvals [10][25] Market Potential and Competitive Landscape - **Market Need**: - There is a clear medical need for effective treatments in the ROS1 and ALK spaces, as existing therapies have limitations [27][34] - The company is optimistic about the market potential for Zetacentenib, especially in light of competitor launches [27] Safety and Efficacy Considerations - **Safety Profile**: - Zetacentenib is noted for its favorable safety profile compared to other ROS1 TKIs, with only 2% of patients discontinuing due to adverse events [22][16] - Peripheral edema observed is common among TKIs and not necessarily indicative of tract inhibition [15][17] Upcoming Catalysts - **Future Updates**: - Pivotal data from the ALKOV1 study and updates on the HER2 program are expected in the next 6 to 12 months [40][41] Conclusion - Nuvalent is positioned as a leader in innovative oncology therapies, with promising data and regulatory progress for its key programs. The company is focused on addressing significant unmet medical needs in cancer treatment through targeted therapies.

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]