NVL-655 Earns FDA Breakthrough Therapy Designation in ALK-Positive NSCLC

3D rendered medical illustration of male anatomy with lung cancer: © Sebastian Kaulitzki- stock.adobe.com

• NVL-655 is a novel tyrosine kinase inhibitor (TKI) developed for patients with ALK-positive non-small cell lung cancer (NSCLC).
• Breakthrough therapy designation helps to expedite the development and review of agents that treat serious or life-threatening conditions.
• The agent is being investigated in the phase 1/2 ALKOVE-1 study (NCT05384626).

The FDA has granted a breakthrough therapy designation to NVL-655, a novel brain-penetrant ALK-selective TKI for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who have received 2 or more ALK TKIs.¹

"Today's announcement of FDA breakthrough therapy designation for NVL-655 marks another important milestone for our ALK program and the second breakthrough designation granted to our pipeline of novel kinase inhibitors this year," said Darlene Noci, ALM, chief development officer at Nuvalent, in a press release. "Our team is committed to expeditiously advancing NVL-655 in recognition of the continued need for innovation for patients with ALK-positive NSCLC who have exhausted available therapies. We expect to provide an update from the ALKOVE-1 trial of NVL-655 at a medical meeting in the second half of this year."

The designation is supported by preliminary safety and activity findings of NVL-655 in the intent-to-treat population from the phase 1 portion of the ALKOVE-1 trial.

About ALKOVE-1

ALKOVE-1 is a phase 1/2 dose-escalation and -expansion study with an estimated enrollment of 470 patients with NSCLC and other ALK-mutated solid tumors.² The primary end points of phase 1 are dose-limiting toxicities and recommended phase 2 dose, and primary end points for phase 2 are objective response rate and incidence of treatment-emergent adverse events. Secondary end points include pharmacokinetics, duration of response, clinical benefit rate, time to response, progression-free survival, overall survival, and quality of life.

In phase 1, patients are receiving NVL-655 delivered orally daily. In phase 2, there are 6 cohorts:

• Patients with locally advanced or metastatic NSCLC with an ALK rearrangement who have received a prior second-generation ALK TKI, including ceritinib (Zykadia), alectinib (Alecensa), or brigatinib (Alunbrig). Patients can have received up to 2 prior lines of chemotherapy or immunotherapy.
• Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement, who have received 2 to 3 prior ALK TKIs, including crizotinib (Xalkori), ceritinib, alectinib, brigatinib, or lorlatinib (Lorbrena). Patients can have received up to 2 prior lines of chemotherapy or immunotherapy.
• Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have only received lorlatinib as an ALK TKI therapy. Patients can have received up to 1 prior lineof chemotherapy or immunotherapy before lorlatinib.
• Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who have never received ALK TKI therapy but can have received up to 1 prior line of chemotherapy and/or immunotherapy.
• Patients with locally advanced or metastatic NSCLC harboring an ALK rearrangement who are not eligible for other phase 2 cohorts.
• Patients with other solid tumors harboring an ALK rearrangement or activating ALK mutation, who have received at least 1 prior systemic anticancer therapy.

Enrollment in the phase 2 portion is ongoing,¹ and the estimated study completion date is March 2026.²

REFERENCES:

1. Nuvalent receives US FDA breakthrough therapy designation for NVL-655. News release. Nuvalent. May 16, 2024. Accessed May 17, 2024. https://tinyurl.com/4hrthsx5

2. A study of NVL-655 in patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1). ClinicalTrials.gov. Updated May 13, 2024. Accessed May 17, 2024. https://clinicaltrials.gov/study/NCT05384626