FDA Grants Breakthrough Therapy Designation to NVL-655 for Pretreated ALK+ NSCLC

NVL-655 has received FDA breakthrough therapy designation for patients with pretreated ALK-positive non-small cell lung cancer.



The FDA has granted breakthrough therapy designation to the novel brain-penetrant ALK-selective TKI NVL-655 for the treatment of patients with locally advanced or metastatic ALK-positive non–small cell lung cancer (NSCLC) who have previously received 2 or more ALK TKIs.1

This regulatory decision was supported by early safety and efficacy data from the phase 1 portion of the first-in-human phase 1/2 ALKOVE-1 trial (NCT05384626). Preliminary findings presented in October 2023 demonstrated favorable tolerability with NVL-655 at a daily dose of 150 mg along with signals of antitumor activity in heavily pretreated patients with advanced ALK-positive NSCLC. The agent was active in patients who had received 1 or more second-generation TKIs plus lorlatinib (Lorbrena), those who were lorlatinib-naive, those with single and compound ALK resistance mutations, and those with central nervous system (CNS) metastases.2

At the August 8, 2023, data cutoff, the objective response rate (ORR) was 39% in response-evaluable patients with NSCLC (n = 51) treated across all dose levels. Notably, all of these were partial responses. Moreover, the ORR was 44% in a subset of 41 patients treated at dose levels of 50 mg daily or higher. Thirty-seven (67%) response-evaluable patients remained on treatment with NVL-655. Among these patients, the median duration of treatment was 3.4 months. All responders continued on treatment without disease progression.3

Enrollment in the phase 2 portion of ALKOVE-1 is ongoing, and updated data from the trial are anticipated to read out at a medical meeting in the second half of 2024.1

"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," Darlene Noci, ALM, chief development officer at Nuvalent, stated in a news 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."

NVL-655 was designed to maintain activity in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors. The agent was also optimized for CNS penetration and avoids the inhibition of TRK receptors, thereby potentially preventing TRK-related, off-target CNS adverse effects associated with dual TRK/ALK inhibitors. The agent previously received orphan drug designation from the FDA for ALK-positive NSCLC.1

ALKOVE-1 trial is a first-in-human dose escalation and expansion study investigating the safety, tolerability, and antitumor activity of NVL-655 in patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors with a documented ALK rearrangement.4

The phase 1 portion of the study comprised patients 18 years of age or older with ALK-positive NSCLC who previously received at least 1 ALK TKI and patients with other ALK-positive solid tumors who previously received at least 1 systemic anticancer therapy. Patients in this phase must have evaluable disease.

The phase 2 portion of the study enrolled patients onto 1 of 6 cohorts. All patients except those in cohort 2f were 18 years of age or older and required to have locally advanced or metastatic NSCLC with a documented ALK rearrangement. In cohort 2f, patients must be at least 12 years of age; weigh more than 40 kg; and have confirmed locally advanced or metastatic solid tumors with a documented ALK rearrangement or activating ALK mutation. All patients in phase 2 must have measurable disease according to RECIST 1.1 criteria.

The primary objectives in phase 1 were to evaluate the overall safety and tolerability of NVL-655, determine the recommended phase 2 dose (RP2D) of the agent, and, if applicable, identify the maximum tolerated dose (MTD). In phase 2, the primary end point is ORR per Blinded Independent Central Review. Secondary end points include duration of response, time to response, progression-free survival, overall survival, and clinical benefit rate.

In the Phase 1 portion of ALKOVE-1, patients received daily NVL-655 across 6 different dose levels: 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg. The MTD was not reached, and the RP2D was determined to be 150 mg once daily.2


  1. Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-655. News Release. Nuvalent. May 16, 2024. Accessed May 17, 2024.
  2. Nuvalent initiates the phase 2 portion of ALKOVE-1 clinical trial for patients with ALK-Positive NSCLC and other solid tumors. News Release. Nuvalent. February 12, 2024. Accessed May 17, 2024.
  3. Nuvalent reports preliminary phase 1 clinical data from ALKOVE-1 trial that support best-in-class potential of NVL-655 for patients with ALK-positive NSCLC. News Release. Nuvalent. October 13, 2023. Accessed May 17, 2024.
  4. A study of NVL-655 in patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1). Updated May 13, 2024. Accessed May 17, 2024.
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