Nuvalent Highlights Presentation of Clinical Data at ESMO 2024 for Parallel Lead Programs for ROS1 and ALK-positive NSCLC and Accelerated Development Timelines By Investing.com

Up to date Section 1 dose-escalation information from ARROS-1 and ALKOVE-1 scientific trials proceed to help potential best-in-class profiles for zidesamtinib and NVL-655

Fast enrollment in Section 2 parts of the ARROS-1 and ALKOVE-1 scientific trials; Pivotal information from each ROS1 and ALK applications now anticipated in 2025

Initiation of ALKAZAR Section 3 randomized, managed trial of NVL-655 for treatment-naïve sufferers with superior ALK-positive NSCLC anticipated within the first half of 2025

Firm to host a convention name right now at 8:30 a.m. ET/2:30 p.m. CEST

CAMBRIDGE, Mass., Sept. 14, 2024 /PRNewswire/ — Nuvalent, Inc.  (Nasdaq: NUVL), a clinical-stage biopharmaceutical firm targeted on creating  exactly  focused therapies for clinically confirmed kinase targets in most cancers, right now highlighted the presentation of up to date information from the absolutely enrolled Section 1 dose-escalation parts of the continued ARROS-1 Section 1/2 scientific trial of zidesamtinib, a novel ROS1-selective inhibitor, and ALKOVE-1 Section 1/2 scientific trial of NVL-655, a novel ALK-selective inhibitor,   throughout two oral shows on the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.

As well as, the corporate introduced progress and supplied updates on the event technique and timelines for its parallel-lead applications zidesamtinib and NVL-655, together with its growth technique for tyrosine kinase inhibitor (TKI)-naïve ALK-positive non-small cell lung most cancers (NSCLC):

Section 2 portion of the ARROS-1 trial of zidesamtinib for TKI-naïve and TKI pre-treated sufferers with superior ROS1-positive NSCLC and different stable tumors: Between September 2023 and September 1, 2024, 227 sufferers have been enrolled within the ongoing single-arm, multi-cohort Section 2 portion of the ARROS-1 trial, which is designed with registrational intent. The corporate expects to report pivotal information from this trial in 2025.Section 2 portion of the ALKOVE-1 trial of NVL-655 for TKI-naïve and TKI pre-treated sufferers with superior ALK-positive NSCLC and different stable tumors: Between February 2024 and September 1, 2024, 229 sufferers have been enrolled within the ongoing single-arm, multi-cohort Section 2 portion of the ALKOVE-1 trial, which is designed with registrational intent for TKI pre-treated sufferers. The corporate additionally expects to report pivotal information from this trial in 2025.ALKAZAR Section 3 randomized, managed trial of NVL-655 for TKI-naïve sufferers with superior ALK-positive NSCLC: The Section 3 ALKAZAR trial can be a world, randomized, managed trial designed to judge NVL-655 versus the present customary of look after the remedy of sufferers with TKI-naïve ALK-positive NSCLC. Sufferers can be randomized 1:1 to obtain NVL-655 monotherapy or ALECENSA ® (alectinib) monotherapy, reflecting enter from collaborating physician-scientists and alignment with the U.S. Meals and Drug Administration (FDA). The corporate plans to provoke the ALKAZAR examine within the first half of 2025.

“The Section 1 parts of our ARROS-1 and ALKOVE-1 research have established preliminary scientific proof-of-concept for zidesamtinib and NVL-655 as selective, brain-penetrant, TRK-sparing TKIs which have the potential to maneuver up the remedy paradigm, as demonstrated by the preliminary security profile indicating favorable tolerability, and the sturdiness of responses noticed throughout affected person subsets offered right now at ESMO,” mentioned  Christopher Turner, M.D., Chief Medical Officer at Nuvalent.  “We imagine zidesamtinib and NVL-655 have the potential to not solely tackle clear medical wants within the third line the place no accredited therapies have demonstrated scientific profit, but in addition present differentiated choices within the second line  together with for sufferers who’ve skilled illness development resulting from CNS metastases or resistance mutations, and in the end ship deep, sturdy responses within the entrance line.”

“We’re grateful for the robust investigator enthusiasm for our applications, exemplified by the accelerated Section 2 enrollment in our ARROS-1 and ALKOVE-1 trials. We now anticipate reporting pivotal datasets from each Section 2 trials in 2025,” mentioned Darlene Noci, A.L.M., Chief Growth Officer at Nuvalent. “With the announcement of our deliberate ALKAZAR randomized, managed Section 3 examine, we’re thrilled to additionally set up a possible registration path for TKI-naïve sufferers with superior ALK-positive NSCLC. Via our multi-pronged methods, our purpose is to carry potential best-in-class therapies that may transfer up the remedy paradigm to sufferers as effectively as potential. We look ahead to initiating the ALKAZAR examine within the first half of 2025.”

The ALKAZAR trial is designed to enroll roughly 450 sufferers with TKI-naïve ALK-positive NSCLC. The first endpoint is development free survival (PFS) primarily based on Blinded Impartial Central Evaluate (BICR). Secondary endpoints embody PFS primarily based on investigator’s evaluation, and BICR evaluation of goal response fee (ORR), intracranial goal response fee (IC-ORR), general survival (OS), and security.

“On the outset of this 12 months, we introduced our OnTarget 2026 working plan delineating our path in direction of a possible first approval in 2026 from our pipeline of novel kinase inhibitors. With right now’s updates, we’ve efficiently achieved all the supporting milestones  laid out for 2024 and imagine we are actually on observe to share pivotal datasets from each of our parallel-lead applications in 2025, a testomony to the tireless dedication of our crew,” mentioned James Porter, Ph.D., Chief Govt Officer at Nuvalent.  “I’m extremely happy with what we’ve completed to date and am optimistic in regards to the highway forward. With the muse of encouraging Section 1 proof-of-concept information, robust enrollment momentum in our world Section 2 trials, alignment with the FDA on the design of our Section 3 ALKAZAR examine, and the dedication of our confirmed crew, we’re assured in our potential to proceed advancing our applications in direction of our purpose of delivering them as rapidly as potential to the sufferers that want them.”

ARROS-1 Section 1 Replace at ESMO 2024

From January 2022 to August 2023, the Section 1 portion of ARROS-1 enrolled 104 sufferers (99 NSCLC, 5 different stable tumors). Sufferers obtained zidesamtinib orally at dose ranges starting from 25 to 150 mg as soon as day by day (QD), and 100 mg QD was chosen because the really helpful Section 2 dose (RP2D). No clinically important exposure-response relationships for security and efficacy have been noticed and information are reported throughout all doses.

The affected person inhabitants was closely pre-treated, with a median of three prior strains of remedy (vary 1 “ 11). 69% (72/104) of sufferers had ‰¥2 prior ROS1 TKIs, and 66% (69/104) had prior chemotherapy. Notably, 55% (57/104) of sufferers obtained prior lorlatinib and 21% (22/104) obtained prior repotrectinib, highlighting the differentiated nature of this inhabitants from prior trials of different ROS1 inhibitors. 52% (54/104) had historical past of CNS metastases, together with circumstances of illness development following remedy with the brain-penetrant TKIs lorlatinib and/or repotrectinib.

As of the closing date of July 1, 2024, 71 pre-treated sufferers with ROS1-positive NSCLC have been response-evaluable. The median follow-up for the all-treated inhabitants was 12.1 months (vary, 0.8 “ 29.4).

Remedy with zidesamtinib resulted in sturdy scientific responses (ORR by RECIST 1.1) throughout key subgroups of response-evaluable sufferers. As of the info closing date:

Within the subset of sufferers with confirmed ROS1 G2032R resistance mutation, the ORR was 72% (13/18) for repotrectinib-naïve sufferers.

IC-ORR was 50% (4/8) in intracranial response-evaluable sufferers with measurable CNS lesions, of which 7/8 sufferers had been beforehand handled with the brain-penetrant TKIs lorlatinib and/or repotrectinib. The mIC-DOR was not reached, with no CNS development noticed amongst confirmed CNS responders.

Zidesamtinib was well-tolerated with a preliminary security profile that was favorable and in step with its ROS1-selective, TRK sparing design. Among the many 104 handled sufferers in any respect doses, essentially the most frequent treatment-related adversarial occasions (TRAEs) have been oedema peripheral (19%), ALT enhance, AST enhance, and weight enhance (every 11%). Amongst these most frequent TRAEs, there was a single grade 3 occasion of weight enhance. No discontinuation resulting from TRAEs occurred. Dose reductions resulting from TRAEs occurred in 8% of sufferers. A most tolerated dose was not recognized.

The corporate believes these preliminary information show the potential for zidesamtinib to handle a medical want for the third-line remedy of ROS1-positive NSCLC the place no accredited therapies have demonstrated scientific profit, and to supply a differentiated possibility within the second line the place there additionally stays a medical want. Moreover, the corporate believes that these information in closely pre-treated sufferers may have the potential to translate to deep, sturdy responses within the front-line setting.

Additional investigation of zidesamtinib for each TKI-naïve and TKI pretreated sufferers with ROS1-positive NSCLC is underway within the Section 2 portion of the ARROS-1 scientific trial, designed with registrational intent. The corporate expects to report pivotal information in 2025.

ALKOVE-1 Section 1 Replace at ESMO 2024

From June 2022 to February 2024, the Section 1 portion of ALKOVE-1 enrolled 133 sufferers (131 NSCLC, 2 different stable tumors). Sufferers obtained NVL-655 orally at dose ranges starting from 15 to 200 mg QD, and 150 mg QD was chosen because the RP2D.

The affected person inhabitants was closely pre-treated, with a median of three prior strains of remedy (vary 1 “ 9). 46% (61/133) of sufferers had ‰¥3 prior ALK TKIs, and 56% (74/133) had prior chemotherapy. Notably, 84% (111/133) of sufferers obtained prior lorlatinib and 51% (68/133) had any secondary ALK resistance mutation together with 26% (34/133) with compound ( ‰¥2) ALK mutations, highlighting the differentiated nature of this inhabitants from prior trials of investigational ALK inhibitors. 56% (75/133) had historical past of CNS metastases, together with circumstances of illness development following remedy with the brain-penetrant TKI lorlatinib.

As of the closing date of June 15, 2024, 103 closely pre-treated sufferers with ALK-positive NSCLC handled throughout all doses have been response-evaluable, of whom 39 have been handled on the RP2D. The median follow-up for the all-treated inhabitants was 8.0 months (vary 0.2, 22.5).

Remedy with NVL-655 resulted in sturdy scientific responses (ORR by RECIST 1.1) throughout key subgroups of response-evaluable sufferers handled on the RP2D and throughout all dose ranges. As of the info closing date:

CNS responses have been noticed in sufferers with both measurable or unmeasurable CNS lesions throughout all doses, together with full intracranial responses in sufferers who beforehand obtained the brain-penetrant TKI lorlatinib. No CNS development was noticed amongst all confirmed CNS responders.

NVL-655 was well-tolerated with a preliminary security profile that was favorable and in step with its ALK-selective, TRK sparing design. Among the many 133 sufferers handled in any respect doses, essentially the most frequent TRAEs have been ALT enhance (34%), AST enhance (30%), constipation (16%), dysgeusia (13%), and nausea (12%). Amongst these most frequent TRAEs, 13% of sufferers skilled grade 3 ALT enhance, one affected person skilled grade 4 ALT enhance, and 9% of sufferers skilled grade 3 AST enhance. Transaminase elevations have been typically transient and reversible.

Discontinuations resulting from TRAEs occurred in 2% of sufferers and dose-reductions occurred in 15% of sufferers. A most tolerated dose was not recognized.

The corporate believes these preliminary information show the potential for NVL-655 to handle a medical want for the third-line remedy of ALK-positive NSCLC the place no accredited therapies have demonstrated scientific profit, and to supply a differentiated possibility within the second line. The continued Section 2 portion of the ALKOVE-1 scientific trial is designed with registrational intent for TKI pre-treated sufferers with ALK-positive NSCLC, and the corporate expects to report pivotal information in 2025.

Moreover, the corporate believes that these information in closely pre-treated sufferers may have the potential to translate to deep, sturdy responses within the front-line setting. The corporate plans to provoke the Section 3 randomized, managed, ALKAZAR examine with registrational intent for TKI-naïve sufferers within the first half of 2025.

Convention Name Data

Following oral shows on the ESMO Congress 2024 in Barcelona, Spain, administration will host a reside webcast and convention name on Saturday, September 14, 2024 at 8:30 a.m. ET/2:30 p.m. CEST.

To entry the decision, register on-line right here  for the reside webcast or dial +1 (800) 836-8184 (home) or +1 (646) 357-8785 (worldwide) at the very least 10 minutes previous to the beginning time and ask to be joined to the Nuvalent name. Accompanying slides and a reside video webcast can be obtainable within the Traders part of the Nuvalent web site at  https://traders.nuvalent.com/occasions. A replay and accompanying slides can be archived on the Nuvalent web site for 30 days.

About Zidesamtinib and the ARROS-1 Section 1/2 Medical Trial

Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the intention to beat limitations noticed with at the moment obtainable ROS1 inhibitors. Zidesamtinib is designed to stay energetic in tumors which have developed resistance to at the moment obtainable ROS1 inhibitors, together with tumors with treatment-emergent ROS1 mutations similar to G2032R. As well as, zidesamtinib is designed for central nervous system (CNS) penetrance to enhance remedy choices for sufferers with mind metastases, and to keep away from inhibition of the structurally associated tropomyosin receptor kinase (TRK) household. Collectively, these traits have the potential to keep away from TRK-related CNS adversarial occasions seen with twin TRK/ROS1 inhibitors and to drive deep, sturdy responses for sufferers throughout all strains of remedy. Zidesamtinib has obtained breakthrough remedy designation for the remedy of sufferers with ROS1-positive metastatic non-small cell lung most cancers (NSCLC) who’ve been beforehand handled with 2 or extra ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

Zidesamtinib is at the moment being investigated within the ARROS-1 trial (NCT05118789), a first-in-human Section 1/2 scientific trial for sufferers with superior ROS1-positive NSCLC and different stable tumors. The finished Section 1 portion enrolled ROS1-positive NSCLC sufferers who beforehand obtained at the very least one ROS1 TKI, or sufferers with different ROS1-positive stable tumors who had been beforehand handled. The Section 1 portion of the trial was designed to judge the general security and tolerability of NVL-520, with extra targets together with dedication of the really helpful Section 2 dose (RP2D), characterization of the pharmacokinetic profile, and analysis of preliminary anti-tumor exercise. The continued world, single arm, open label Section 2 portion is designed with registrational intent for TKI naïve and TKI pre-treated sufferers with ROS1-positive NSCLC.

About NVL-655 and the ALKOVE-1 Section 1/2 Medical Trial

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the intention to beat limitations noticed with at the moment obtainable ALK inhibitors. NVL-655 is designed to stay energetic in tumors which have developed resistance to first-, second-, and third-generation ALK inhibitors, together with tumors with single or compound treatment-emergent ALK mutations similar to G1202R. As well as, NVL-655 is designed for central nervous system (CNS) penetrance to enhance remedy choices for sufferers with mind metastases, and to keep away from inhibition of the structurally associated tropomyosin receptor kinase (TRK) household. Collectively, these traits have the potential to keep away from TRK-related CNS adversarial occasions seen with twin TRK/ALK inhibitors and to drive deep, sturdy responses for sufferers throughout all strains of remedy. NVL-655 has obtained breakthrough remedy designation for the remedy of sufferers with regionally superior or metastatic ALK-positive non-small cell lung most cancers (NSCLC) who’ve been beforehand handled with 2 or extra ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.  

NVL-655 is at the moment being evaluated within the Section 2 portion of the ALKOVE-1 Section 1/2 scientific trial, a first-in-human examine of NVL-655 in sufferers with superior ALK-positive NSCLC and different stable tumors (NCT05384626). The finished Section 1 portion enrolled ALK-positive NSCLC sufferers who beforehand obtained at the very least one ALK TKI and sufferers with different ALK-positive stable tumors who had been beforehand handled with at the very least one prior systemic anticancer remedy. The first targets have been to find out the really helpful Section 2 dose (RP2D) and if relevant, the utmost tolerated dose (MTD) of NVL-655 in sufferers with ALK-positive stable tumors. Further targets included characterization of the general security, tolerability, and pharmacokinetic profile, and analysis of the preliminary anti-tumor exercise of NVL-655. The continued world, single arm, open label Section 2 portion is designed with registrational intent for TKI pre-treated sufferers with ALK-positive NSCLC and to allow preliminary investigation for sufferers with ALK-positive NSCLC who’re TKI naïve.

About Nuvalent

Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical firm targeted on creating exactly focused therapies for sufferers with most cancers, designed to beat the restrictions of present therapies for clinically confirmed kinase targets. Leveraging deep experience in chemistry and structure-based drug design, we develop progressive small molecules which have the potential to beat resistance, reduce adversarial occasions, tackle mind metastases, and drive extra sturdy responses. Nuvalent is advancing a sturdy pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung most cancers, and a number of discovery-stage analysis applications.

Ahead-Trying Statements

This press launch incorporates forward-looking statements throughout the that means of the Personal Securities Litigation Reform Act of 1995, as amended, together with, with out limitation, implied and specific statements concerning Nuvalent’s technique, enterprise plans, and focus; the scientific growth applications for zidesamtinib and NVL-655; the anticipated timing of reporting information readouts from Nuvalent’s scientific trials of zidesamtinib and NVL-655; the design and timing of the ALKAZAR trial, together with alignment with the FDA concerning the design of the trial; the potential scientific results of zidesamtinib and NVL-655; the potential of Nuvalent’s pipeline applications, together with zidesamtinib and NVL-655; the implications of information readouts and shows; Nuvalent’s analysis and growth applications for the remedy of most cancers; and dangers and uncertainties related to drug growth. The phrases “could,” “would possibly,” “will,” “may,” “would,” “ought to,” “count on,” “plan,” “anticipate,” “intention,” “purpose,” “intend,” “imagine,” “count on,” “estimate,” “search,” “predict,” “future,” “challenge,” “potential,” “proceed,” “goal” or the adverse of those phrases and related phrases or expressions are supposed to establish forward-looking statements, though not all forward-looking statements comprise these figuring out phrases. Drug growth and commercialization contain a excessive diploma of danger, and solely a small variety of analysis and growth applications lead to commercialization of a product. You shouldn’t place undue reliance on these statements or the scientific information offered.

Any forward-looking statements on this press launch are primarily based on administration’s present expectations and beliefs and are topic to quite a few dangers, uncertainties, and essential components that will trigger precise occasions or outcomes to vary materially from these expressed or implied by any forward-looking statements contained on this press launch, together with, with out limitation: dangers that Nuvalent could not absolutely enroll the ARROS-1, ALKOVE-1 or ALKAZAR trials or that enrollment will take longer than anticipated; sudden considerations that will come up from extra information, evaluation, or outcomes obtained throughout preclinical research or scientific trials; the danger that outcomes of earlier scientific trials might not be predictive of the outcomes of later-stage scientific trials; the danger that information from our scientific trials might not be enough to help registration and that Nuvalent could also be required to conduct a number of extra research or trials previous to in search of registration of our product candidates; dangers that Nuvalent could not obtain the targets and milestones set forth in its OnTarget 2026 working plan; the incidence of adversarial security occasions; dangers that the FDA, European Medicines Company or different international regulators could not approve our potential merchandise on the timelines we count on, or in any respect; dangers of sudden prices, delays, or different sudden hurdles; dangers that Nuvalent could not have the ability to nominate drug candidates from its discovery applications; the direct or oblique affect of public well being emergencies or world geopolitical circumstances on the timing and anticipated timing and outcomes of Nuvalent’s scientific trials, technique, and future operations, together with the ARROS-1, ALKOVE-1 and ALKAZAR trials; the timing and end result of Nuvalent’s deliberate interactions with regulatory authorities; and dangers associated to acquiring, sustaining, and defending Nuvalent’s mental property. These and different dangers and uncertainties are described in larger element within the part entitled “Danger Elements” in Nuvalent’s Quarterly Report on Kind 10-Q for the quarterly interval ended June 30, 2024, in addition to any prior and subsequent filings with the Securities and Alternate Fee. As well as, any forward-looking statements symbolize Nuvalent’s views solely as of right now and shouldn’t be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to replace any forward-looking statements.