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Updated Phase 1 data from ALKOVE-1 and ARROS-1 clinical trials to be presented at the ESMO Congress 2024
Durable activity of NVL-655 and zidesamtinib in heavily pre-treated patient populations supports ongoing Phase 2 investigation in earlier lines of treatment
Company plans to host a conference call on September 14, 2024 at 8:30 a.m. ET/2:30 p.m. CEST following oral presentations at ESMO
CAMBRIDGE, Mass., Sept. 9, 2024 /PRNewswire/ -- Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, today announced data from abstracts to be presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain, including updates from the Phase 1 portions of the ongoing ALKOVE-1 Phase 1/2 clinical trial of ALK-selective inhibitor NVL-655 and ARROS-1 Phase 1/2 clinical trial of ROS1-selective inhibitor zidesamtinib, and new preclinical data further characterizing the intracranial activity of zidesamtinib accepted for a poster session.
The Phase 1 data described in the abstracts will be updated in two oral presentations at ESMO and discussed during a live webcast and conference call with management on Saturday, September 14, 2024, at 8:30 a.m. ET/2:30 p.m. CEST, along with updates on the status of the global Phase 2 portions of both studies which are designed with registrational intent.
"Our development strategy has been anchored around our guiding hypothesis: that we could drive deep and durable responses for patients by creating precisely targeted therapies that address the limitations of currently available options. We believe the data from the fully enrolled Phase 1 portions of our ALKOVE-1 and ARROS-1 clinical trials continue to support the potential for our parallel lead programs to achieve this goal through addressing the combined challenges of treatment-emergent resistance, brain metastases, and off-target central nervous system (CNS) adverse events," said Christopher Turner, M.D., Chief Medical Officer of Nuvalent. "We are particularly encouraged by the durability of responses seen with both NVL-655 and zidesamtinib in these heavily pre-treated patient populations, which we believe has the potential to be differentiated and to translate into meaningful improvements in earlier lines of treatment."
"Complementary to our clinical updates at ESMO, we are pleased to also share new preclinical data that characterize the intracranial activity of our ROS1-selective inhibitor zidesamtinib in comparison to FDA-approved or investigational dual TRK/ROS1 inhibitors, which we believe supports the potential for zidesamtinib to deliver more durable intracranial responses while avoiding TRK inhibition," said Henry Pelish, Ph.D., Chief Scientific Officer at Nuvalent. "These data further add to the body of evidence that we believe supports the differentiated profile of zidesamtinib for patients with ROS1-positive NSCLC."
"At the outset of these programs, we set out to design best-in-class molecules that could deliver clinically meaningful outcomes for patients with ALK- or ROS1-positive NSCLC and eventually become the front-line standard of care. Our Phase 1 updates at ESMO are a critical milestone towards achieving our goal, with longer follow-up demonstrating that NVL-655 and zidesamtinib can drive deep and durable responses even in heavily pre-treated patients that have exhausted all other treatment options," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "These data support the ongoing Phase 2 investigation of NVL-655 and zidesamtinib in both TKI pre-treated and TKI naïve patients, and we look forward to providing further program updates during our conference call later this week."
Updated ALKOVE-1 Phase 1 Data
Title: Phase 1/2 ALKOVE-1 study of NVL-655 in ALK-positive solid tumorsPresentation Number: 1253OSession Category: Proffered paper sessionSession Title: NSCLC metastaticUpdated Presentation Date and Time: Saturday September 14, 2024, 9:30 – 9:40 a.m. CESTLocation: Barcelona Auditorium – Hall 2Presenter: Alexander Drilon, M.D. (Memorial Sloan Kettering Cancer Center, New York, USA)
Background: NVL-655 is a potent, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address key limitations of prior generation ALK TKIs (first generation (1G), second generation (2G) and third generation (3G)); it demonstrates preclinical activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations, while avoiding tropomyosin receptor kinase (TRK) inhibition, which is associated with neurologic toxicities.
Methods: The global ALKOVE-1 Phase 1 (NCT05384626) enrolled patients with pretreated advanced ALK-positive solid tumors. Key objectives were selection of a recommended Phase 2 dose (RP2D), safety, and efficacy (RECIST 1.1, investigator assessment).
Results: As of the data cut-off date of March 23, 2024, 133 patients (131 NSCLC, 2 other) received NVL-655 (15-200 mg orally once daily (QD)) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-8) prior anticancer therapies and included:
A maximum tolerated dose was not reached. 150 mg QD was selected as the RP2D, providing favorable safety, activity and exposure exceeding targeted efficacy thresholds for ALK resistance mutations. The most common treatment-related adverse events (TRAEs) were ALT increase (33%), AST increase (29%), constipation (15%), nausea (12%) and dysgeusia (11%); 2% discontinued due to TRAEs.
ALK+ NSCLC response-evaluable (± chemo) | ORR at all doses, % (n/n) | Median DOR, months (m), (95% CI) | % DOR > 6 m (95% CI) | ORR at 150 mg, % (n/n) |
All | 38% (39/103) | 9.2 (6.9, NE) | 79 %(56, 91) | 39% (15/38)* |
≥3 prior ALK TKI inc. 2G and lorlatinib | 37% (16/43) | 7.7 (5.6, NE) | 79 %(37, 95) | 38% (6/16) |
lorlatinib-naïve (≥1 2G ± 1G) | 53% (9/17) | NR (3.5, NE) | 83 %(27, 97) | 57% (4/7) |
ALK mutation | 55% (30/55) | 14.4 (6.9, NE) | 86 %(63, 95) | 57% (12/21) |
G1202R | 76% (22/29) | 14.4 (6.9, NE) | 88 %(60, 97) | 83% (10/12) |
prior lorlatinib | 49% (23/47) | 14.4 (6.9, NE) | 83 %(56, 94) | 50% (8/16) |
compound (≥2) mut. | 58% (15/26) | 14.4 (5.1, NE) | 80 %(50, 93) | 78% (7/9) |
lorlatinib-naïve (≥1 2G ± 1G) | 88% (7/8) | NR (NE, NE) | 100 %(100, 100) | 80% (4/5) |
NE, not estimable; NR, not reached *13/15 responses ongoing (DOR range 1.1 – 9.0 m) | ||||
CNS activity, including complete resolution of CNS metastases in lorlatinib-experienced patients, was observed.
Conclusions: NVL-655 demonstrated encouraging efficacy and durability in heavily pretreated ALK-positive NSCLC patients, including patients who exhausted available therapies (including lorlatinib), with ALK single and compound resistance mutations, and with CNS metastases. Safety was favorable, consistent with the ALK-selective, TRK-sparing design. Phase 2 enrollment is ongoing with registrational intent for previously treated patients.
Updated ARROS-1 Phase 1 Data
Title: Phase 1/2 ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumorsPresentation Number: 1256MOSession Category: Mini oral sessionSession Title: NSCLC metastaticUpdated Presentation Date and Time: Saturday September 14, 2024, 10:25 – 10:30 a.m. CESTLocation: Santander Auditorium – Hall 5Presenter: Benjamin Besse, M.D., Ph.D. (Institut Gustav Roussy, Villejuif, France)
Background: Zidesamtinib is a brain-penetrant, TRK-sparing, highly selective ROS1 TKI with activity against diverse ROS1 fusions and resistance mutations including G2032R.
Methods: The global ARROS-1 Phase 1 (NCT05118789) enrolled patients with heavily pretreated advanced/metastatic ROS1-positive solid tumors. Key objectives were selection of the RP2D and evaluation of safety and efficacy (RECIST 1.1, investigator assessment).
Results: As of the data cut-off date of March 12, 2024, 104 patients (99 NSCLC, 5 other) received zidesamtinib (25-150 mg orally QD) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-11) prior anticancer therapies including any ROS1 TKI (99%), and included:
100 mg QD was selected as the RP2D with no observed dose relationships for safety or efficacy. No dose-limiting toxicity or discontinuation due to TRAE occurred. TRAE led to dose reduction in 5.8%. Most common TRAEs were peripheral edema (18%) and transaminase increase (12%); TRAEs were grade ≥3 in 7.7%.
73 patients with ROS1-positive NSCLC were response-evaluable:
# Prior ROS1 TKIs ± Chemo | ORR | Median DOR, months (m) (95% CI) | % DOR > 6m (95% CI) | % DOR > 12m (95% CI) |
Any prior ROS1 TKI (range: 1-4) | 38% (28/73*) | NR (10.2, NE) | 85 %(64, 94) | 69 %(45, 84) |
Repo-naïve | 45% (25/55*) | NR (10.2, NE) | 91 %(69, 98) | 74 %(48, 89) |
≥2 | 36% (19/53*) | 15.8 (6, NE) | 79 %(53, 92) | 62 %(35, 80) |
Repo-naïve | 42% (16/38*) | NR (6.4, NE) | 88 %(59, 97) | 68 %(38, 85) |
1 (crizotinib) | 64% (7/11) | NR (NE, NE) | All ongoing (range, 1.8+ - 22.8+m) | |
NE, not estimable; NR, not reached. *2 complete responses (CRs), ongoing with DOR 16.6+ and 23.5+m Median follow-up for response evaluable patients 9.4m (range, 0.8 – 25.8m) | ||||
In patients with known ROS1 G2032R, ORR was 65% (11/17) with a median duration of response (mDOR) of 15.8m (6, NE) among repo-naïve patients and ORR was 38% (3/8) among repo-pretreated patients. In patients with measurable intracranial (IC) metastases and ≥2 prior ROS1 TKIs (all with prior lorlatinib and/or repo), IC-ORR was 57% (4/7), and IC-DOR range was 1.9+ - 17.3+m with no IC progression.
Conclusions: Zidesamtinib demonstrated encouraging efficacy and durability in patients with pretreated ROS1-positive NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS metastases. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Phase 2 enrollment is ongoing with registrational intent in patients with TKI-naïve and pre-treated ROS1-positive NSCLC.
Preclinical Intracranial Activity of Zidesamtinib
Title: Profiling of Zidesamtinib and Other ROS1 Inhibitors in an Intracranial CD74-ROS1 G2032R Preclinical Model
Presentation Number: 8PAbstract Number: 4811
Onsite Poster Display Date:Sunday September 15, 2024Presenter: Anupong Tangpeerachaikul (Nuvalent, Inc., Cambridge, Massachusetts, United States)
Introduction. TKIs crizotinib, entrectinib, and repotrectinib (US only) are approved for the treatment of ROS1-positive non-small cell lung cancer. Depth and durability of responses can be limited by the ROS1 G2032R resistance mutation and brain metastases, identified in ~40% and ~50% of patients, respectively, after disease progression on crizotinib. ROS1-selective TKI zidesamtinib and dual-TRK/ROS1 TKIs repotrectinib and taletrectinib have reported clinical activity against ROS1 G2032R and intracranial activity, with different adverse event profiles. In this study, we compared these three TKIs in a preclinical ROS1 G2032R brain tumor model.
Methods. Ba/F3 CD74-ROS1 G2032R luciferase cells were implanted in the brain of Balb/c nude mice. Mice were orally treated with TKIs for 25 days QD or twice daily (BID). Brain tumors were monitored 1 – 2 times per week by bioluminescence imaging (BLI). At the endpoint, plasma and brain samples were collected for pharmacokinetics analyses.
Results. Zidesamtinib (3 mg/kg BID) suppressed CD74-ROS1 G2032R brain tumors to
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