Nuvalent Initiates the Phase 2 Portion of ALKOVE-1 Clinical Trial for Patients with ALK-Positive NSCLC and other Solid Tumors
Alignment with
Phase 2 Designed with Registrational Intent for TKI Pre-Treated Patients with ALK-Positive NSCLC and Enables Preliminary Evaluation in the TKI-naïve Setting
NVL-655 is a novel brain-penetrant ALK-selective tyrosine kinase inhibitor (TKI) created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse events associated with inhibition of the structurally-related tropomyosin receptor kinase (TRK) family that may limit the use of currently available ALK TKIs.
In the Phase 1 portion of ALKOVE-1, six dose levels (15 mg to 200 mg QD) of NVL-655 were evaluated in heavily pre-treated patients with ALK-positive solid tumors, and a maximum tolerated dose was not reached. The RP2D of 150 mg QD maintained steady state plasma levels above target efficacy thresholds (ALK wild type fusions and ALK single and compound mutations in both the periphery and in the CNS).
"The transition of our NVL-655 program into Phase 2 advances a second, parallel opportunity towards our goal of bringing potential best-in-class therapies to patients as efficiently as possible," said
"With today's announcement, we've delivered on the first of the key 2024 milestones laid out in our
ALKOVE-1 Phase 2 Design
The Phase 2 portion of the ALKOVE-1 trial will be conducted globally across
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TKI Pre-Treated ALK-Positive NSCLC
- 2 – 3 Prior TKIs: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2-3 prior ALK TKIs. Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
- 1 Prior 2G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have received 1 prior second-generation (2G) ALK TKI (ceritinib, alectinib, or brigatinib). Up to 2 prior lines of chemotherapy and/or immunotherapy are allowed.
- 1 Prior 3G TKI: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received lorlatinib (third-generation, 3G) as the only prior ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy received prior to lorlatinib is allowed.
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TKI-Naïve ALK-Positive NSCLC
- Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who are naïve to ALK TKI therapy. Up to one prior line of chemotherapy and/or immunotherapy is allowed.
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Other
- Other ALK-Positive NSCLC: Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, not eligible for other Phase 2 cohorts.
- Other ALK-Positive Solid Tumors: Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received ≥1 prior systemic anticancer therapy, or for whom no satisfactory standard therapy exists.
Additional details can be found on www.clinicaltrials.gov (NCT05384626).
Selection of NVL-655 RP2D
The selection of 150 mg QD as the RP2D for NVL-655 was supported by the FDA based on clinical data from the Phase 1 dose escalation portion of the ALKOVE-1 trial. The company believes that the preliminary Phase 1 data support the opportunity for NVL-655 as a potential best-in-class therapy that may be able to move up the treatment paradigm for patients with ALK-positive NSCLC.
The selection was based on the following considerations:
- The dose level of 150 mg QD maintained steady state plasma levels above target efficacy thresholds (ALK wild type fusions and ALK single and compound mutations in both the periphery and in the CNS).
- Favorable tolerability of NVL-655 was observed at the 150 mg QD dose level, continuing to suggest the potential for a highly ALK-selective, TRK sparing safety profile.
- Early anti-tumor activity was observed in ALK-positive NSCLC patients across a broad range of doses, including 150 mg QD. Objective responses (RECIST 1.1) were observed in heavily pre-treated patients including patients who had received one or more second-generation TKIs (alectinib, brigatinib, or ceritinib) plus lorlatinib, patients who were lorlatinib-naïve, patients with ALK single and compound resistance mutations, and patients with CNS metastases.
Preliminary Phase 1 data were presented in
About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with both single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received orphan drug designation for ALK-positive non-small cell lung cancer (NSCLC) and is currently being investigated in the ALKOVE-1 clinical trial (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.
About
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2024: Execute on Global Registrational Strategies
- Progress the Phase 2 portion of the ARROS-1 trial of NVL-520 in patients with advanced ROS1-positive NSCLC with registrational intent;
- Initiate the Phase 2 portion of the ALKOVE-1 trial of NVL-655 in patients with advanced ALK-positive NSCLC, including cohorts in pretreated patients with registrational intent;
- Launch the front-line development strategy for its ALK program;
- Present interim data from the ongoing ARROS-1 and ALKOVE-1 clinical trials at medical meetings; and,
- Initiate the Phase 1 trial for its HER2 program.
- 2025: First Pivotal Data
- 2026: First Approved Product
About
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding
Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: risks that
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