Nuvalent (NASDAQ:NUVL) executives highlighted ongoing regulatory milestones for the company’s lead oncology programs and discussed commercialization strategy, pipeline plans, and financial positioning during a conference fireside chat.
Company focus and lead programs
Chief Executive Officer Jim Porter described Nuvalent as a company built around deep chemistry and structure-based drug design expertise, with an emphasis on clinically validated kinase targets. Porter said the company works closely with physicians to understand limitations of existing therapies—such as target coverage, central nervous system (CNS) activity, and tolerability—and then applies “innovative chemistry” to address those gaps.
- ROS1: The FDA accepted Nuvalent’s NDA for zidesamtinib in TKI-pretreated ROS1-positive non-small cell lung cancer (NSCLC), with a PDUFA date of Sept. 18. Balcom said commercial readiness efforts are underway to support a potential U.S. launch later this year. The company also plans to submit data to support a potential indication expansion in TKI-naïve ROS1 in the second half of the year.
- ALK: Nuvalent completed a pre-NDA meeting with the FDA for NVL-655 in TKI-pretreated ALK-positive NSCLC and is on track to submit an NDA in the first half of the year. The company is also progressing the phase 3 ALCAZAR study in TKI-naïve ALK.
- HER2: Nuvalent continues advancing a phase 1b/2 study in HER2-altered NSCLC.
- Additional pipeline: Management reiterated guidance to disclose a new development candidate by year-end.
ROS1 filing strategy and differentiation
On the path toward a broader, line-agnostic ROS1 label, management described how follow-up requirements influenced timing. Porter said prior ROS1 precedents involved following patients for 12 months post-response, but Nuvalent aligned with the FDA on six months post-response for the previously treated setting, supporting the company’s earlier submission. For the frontline (TKI-naïve) cohort, Porter said the company had enrolled 104 patients as of June of last year—more than required—and kept enrollment open due to enthusiasm, while prioritizing longer follow-up. The company reiterated plans to submit frontline data in the second half of this year for FDA consideration of a line-agnostic extension.
Asked about competitive dynamics, including taletrectinib gaining momentum in the U.S., Porter said Nuvalent’s program has been guided by physician priorities: activity against the original ROS1 fusion and ROS1 resistance mutations, CNS penetration for brain metastases, and high selectivity for ROS1 to improve tolerability. Porter characterized zidesamtinib as the “first and only” drug with that combination of attributes and said trial enrollment was rapid due to enthusiasm for the differentiated profile.
Porter also pointed to clinical performance he described as durable responses across treatment lines, strong activity in patients with ROS1 mutations, and deep responses in CNS disease, including what he called high CNS complete response rates.
ALK regulatory approach, durability claims, and safety management
For NVL-655 in ALK-positive NSCLC, Porter said the company has breakthrough designation and is pursuing a previously treated label supported by single-arm data. He described a “straightforward” case in the third-line setting, where he said available options perform poorly, and then focused on the second-line setting where lorlatinib is standard of care.
Porter said lorlatinib has a 7–9 month duration of response in second line, and he asserted Nuvalent is seeing greater durability. He said that in patients who have not yet received lorlatinib, the company is seeing “60+%” of patients still in response at 1.5 years, which he characterized as “alectinib-like durability” in second line. Porter argued that this pattern—durability improving rather than worsening in later lines—speaks to NVL-655’s activity against ALK mutations, CNS activity, and tolerability, allowing patients to remain on therapy longer.
On how investors might gauge FDA receptivity to a broader label during review, Porter said his understanding is that FDA labeling decisions are typically made at the time of approval, based on the data package and the landscape then in place. He added the company may gain insights during the process, but what it will communicate “to be determined.”
Porter also addressed liver function test (LFT) elevations observed in the ALK program, describing transaminase elevations as common across kinase inhibitors and across approved ALK TKIs. He said these events are often transient, reversible, occur early, are typically low grade, and asymptomatic, and are generally managed with dose interruption or reduction. Nuvalent did not break down the transaminase data between treatment-naïve and all patients, he said, but added that discontinuations due to transaminase elevations were a “small single-digit” percentage.
Regarding a phase 3 protocol change, Porter said Nuvalent added a couple more blood draws early in treatment to help physicians identify and manage liver enzyme spikes and avoid prematurely discontinuing patients. The goal, he said, is to preserve long-term benefit by ensuring early transient signals do not disrupt dosing unnecessarily.
Commercial strategy: building ex-U.S. capabilities
Porter said the company’s strategy has evolved from seeking an ex-U.S. partner—while commercializing in the U.S. itself—to pursuing a plan to “go it alone” globally. He cited evolving macro issues around pricing and the value of maintaining optionality and flexibility through full ownership. He also emphasized that ALK and ROS1 are established global markets, that the company believes it has “the best drugs” for these markets, and that enrollment and expanded access demand have been strong across geographies.
Management said Nuvalent has not disclosed specific ex-U.S. regulatory timelines, but noted that ARROS-1, ALKOVE-1, and ALCAZAR are global studies and that global registration strategies are in place. Porter added the company is recruiting for a head of international and has been working with consultants for roughly the last year and a half to understand and build the necessary infrastructure.
Balcom said Nuvalent ended the past year with approximately $1.4 billion in cash, providing operating runway “into 2029.” He said he would not commit that the entire ex-U.S. build is fully funded within the current cash balance, while noting the company’s guidance does not include potential product revenues.
Market sizing discussion and pipeline outlook
Porter said the company’s recent market opportunity slides were intended to be illustrative—using peak sales for current standards of care and today’s pricing to show how longer time on therapy could expand market size. He suggested the ROS1 market could grow to resemble today’s ALK market (which he described as “$2+ billion”) and that the ALK market could grow toward today’s EGFR market, which he said is roughly “2–3 times” larger.
On geographic mix, Porter said ALK and ROS1 historically have had a high share of sales outside the U.S. (he cited 65%–70% for the category), though he said Nuvalent is not yet providing a specific forecast.
Discussing whether ALK and ROS1 alone can support global infrastructure, Porter said he believes they are sufficient in the near term, while also describing them as the “tip of the spear” for a broader pipeline.
On the HER2 program (NVL-330), Balcom said Nuvalent is following the data and wants to ensure it can “tell a clear story,” without providing a specific timing commitment for disclosure yet. Porter outlined what the company aims to demonstrate clinically—safety, activity, durability, and brain penetration—arguing that CNS activity is important as patients live longer and face higher risk of CNS disease across solid tumors. Porter also said Nuvalent plans to announce a fourth program by year-end, adding that the candidate has already been discovered.
About Nuvalent (NASDAQ:NUVL)
Nuvalent, Inc (NASDAQ:NUVL) is a clinical-stage precision oncology company focused on the discovery, development and commercialization of targeted therapies for patients with genetically defined cancers. Founded in 2019 and headquartered in San Diego, California, Nuvalent applies structure-guided drug design to develop small molecule inhibitors that address key oncogenic drivers. The company’s research platform integrates insights from cancer biology, medicinal chemistry and translational science to create therapies with differentiated selectivity and potency against validated targets.
Nuvalent’s lead pipeline candidates include NVL-520, a highly selective RET inhibitor designed to minimize off-target effects, and NVL-655, a potent covalent inhibitor targeting KRAS G12D mutations.
