nuvalent催化剂预告：预计2025年上半年将公布关键的ROS1（齐德沙替尼）数据

Restricted - External NUVLOVERWEIGHTU.S. Small & Mid CapBiotechnologyPOSITIVEPrice TargetUSD 100.00Price (30-May-25)USD 74.61Potential Upside/Downside+34.0%Source: Bloomberg, Barclays ResearchU.S. Small & Mid Cap BiotechnologyPeter Lawson, DPhil (Oxon)+1 212 526 9445peter.lawson@barclays.comBCI, USAlexandre Bouilloux+1 212 526 9937alexandre.bouilloux@barclays.comBCI, USWei Cheng, PhD+1 212 526 5149wei.cheng@barclays.comBCI, US Key factors that help de-risk upcoming Pivotal data in 1H25:1.Encouraging Phase 1 data for zidesamtinib, withefficacytrending superior to standardof care.At ESMO 2024, Nuvalent presented encouraging Phase 1 data in heavily pre-treatedpatients with ORR of 44% (31/71) and mDOR not reached across all TKI pre-treated patients(n=71). Notably, in 3L+ setting, ORR was 41% and mDOR was 12.1 months — closely alignedwith current standard of care in the 2L setting where ORR for repotrectinib and lorlatinib is~40%, and mDOR is ~14 months. In 2L setting, ORR was 73% (8/11) and mDOR was notreached with none of the patients having progressed at the datacutoff.2.Emerging data suggests superior safety/tolerability profile vs. competitors.From theESMO data, we saw only one Grade 3 adverse event (weight gain) and no discontinuationsdue to TRAEs. Dose reduction due to TRAEs was observed in only 8% (8/104) of thepatients. In comparison, we note competitor ROS1 TKIs have shown dose reductions in therange of 20-40%. The overall safety profile was also consistent with avoidance of TRK-related neurotoxicity, which is a key limiting factor for standard-of-caredrugs (e.g., lorlatinib, entrectinib) which are all dual TRK/ROS1 inhibitors.3.Strong enrollment trends in both ROS1 and ALK clinical trials.Nuvalent has shownacceleration in the rate of enrollment across both ROS1 and ALK TKI programs, which in ourview underscores; 1) the continued unmet medical need in the space, and 2) the strongsafety/tolerability as well asefficacyprofile of Nuvalent's drugs (both zidesamtinib; ROS1inhibitor as well as neladalkib; ALK inhibitor) which we believe also helps de-risk upcomingpivotal data.Potential risks heading into the pivotal data in 1H25 and where we could be wrong:•Unexpected safety / tolerability signals, CNS-related tox and/or higher than expecteddiscontinuations.•Lower than expected clinical activity, and/or meaningfully reduced response rates.•Unexpected idiosyncratic toxicity.Prior Clinical Data for Zidesamtinib in ROS1-PositiveNon-Small Cell Lung CancerBackground on ROS1 inhibitors - current standard of care and limitations.ROS1 fusionsare oncogenic drivers in non-small cell lung cancer (NSCLC), resulting fromchromosomal rearrangements that create a chimeric gene encoding a constitutively activetyrosine kinase. This aberrant kinase activity leads to uncontrolled cellular proliferation andsurvival. ROS1 fusions are identified in up to 3% of NSCLC cases, predominantly inadenocarcinomas.Brain metastasesare a significant clinical challenge in ROS1-positiveNSCLC, with up to 40% of patients developing CNS involvement.There is currently no clear standard of care in 2L+ for ROS1-positive NSCLC. Drugs commonlyused includes FDA-approved therapiescrizotinib(Xalkori manufactured by Pfizer, approvedMarch 2016, which is also SOC in 1L ROS1+ NSCLC),entrectinib(Rozlytrek manufactured byRoche, approved August 2019) andrepotrectinib(Augtyro manufactured by Bristol Myers,approved November 2023). Although not specifically FDA-approved in 2L ROS1+NSCLC,lorlatinib(Lorbrena manufactured by Pfizer, approved November 2018) is included inNCCN guidelines for patients who progressed on crizotinib or ceritinib. 2 Figure 1 below highlights key limitations of current FDA-approved ROS1 inhibitors. Keylimitations include resistance mutations, lack of brain penetrance and activity, andoff-targetinhibition of TRK leading to CNS toxicity.•Resistance mutations.Approximately 40% of patients who progress on crizotinib have theROS1 G2032R mutation. In preclinical studies, Nuvalent's zidesamtinib has shown potency 1+order of magnitude higher against ROS1 G2032R compared to crizotinib, entrectinib,repotrectinib, lorlatinib and taletrectinib. Nuvalent's zidesamtinib has also shown IC50 <10nM against multiple other resistance mutations (AACR 2022).•Brain penetrance.Up to ~50% of patients who progress on crizotinib have brain metastases,and ~30% of ROS1+ lung cancer patients have brain metastases at diagnosis. Whileentrectinib and repotrectinib have better brain penetration compared to crizotinib, both alsoinhibit TRK which leads to CNS toxicity. Nuvalent's zidesamtinib has similar brain penetranceto lorlatinib (a highly brain penetrant TKI) and has shown the ability to spare TRK inhibition inpreclinical studies (WCLC 2022).•TRK inhibition.TRK inhibition in the CNS is implicated in multiple adverse events including:weight gain, cognitive impairment, sleep disturbances, ataxia, and mood disorders.Nuvalent's zidesamtinib has shown the ability to spare