NVL-655 Elicits Preliminary Activity, Safety in Heavily Pretreated, ALK+ Advanced NSCLC

Treatment with the novel, ALK-selective TKI NVL-655 generated responses and was well tolerated in heavily pretreated patients with ALK-positive, advanced non–small cell lung cancer (NSCLC), according to results from the phase 1, dose-escalation portion of the phase 1/2 ALKOVE-1 trial (NCT05384626).

Findings showed that evaluable patients treated across all dose levels (n = 51) experienced an objective response rate (ORR) of 39%. Sixteen patients achieved a confirmed partial response (PR), and 4 patients had unconfirmed PRs. Additionally, among evaluable patients treated with NVL-655 at 50 mg per day or higher (n = 41), the ORR was 44%.

Furthermore, at a data cutoff of August 8, 2023, 67% of response-evaluable patients remained on the study treatment with a duration of treatment of up to 12 months. The median duration of treatment of 3.4 months.

Notably, NVL-655 demonstrated favorable tolerability, and the preliminary safety profile was consistent for an agent designed to selectively target ALK and spare TRK.

"These preliminary data support the potential for NVL-655 as an ALK-selective inhibitor that may combine, for the first time, potent and selective targeting of diverse ALK fusions and secondary ALK resistance mutations, including single and compound mutations involving G1202R and I1171N, brain penetrance, and the avoidance of TRK inhibition that can be dose limiting,” Jessica J. Lin, MD, assistant professor of medicine at Harvard Medical School and attending physician at Massachusetts General Cancer Center in Boston, stated in a news release.

NVL-655 is a novel, brain-penetrant, ALK-selective inhibitor that was designed to address the ongoing unmet needs that exist with currently available ALK inhibitors, including treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse effects (AEs) related to TRK inhibition.

The first-in-human ALKOVE-1 trial is enrolling patients with ALK-positive advanced NSCLC and other ALK-positive solid tumors. The ongoing phase 1 portion of the study features patients 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.

As of data cutoff, 93 patients have been enrolled in the phase 1 portion, including 91 patients with ALK-positive NSCLC. Patients were treated with NVL-655 once per day across 6 different dose levels: 15 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg.

The primary end points are to establish the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of NVL-655. Additional end points include safety, tolerability, pharmacokinetics (PK), and preliminary antitumor effects and intracranial activity.

Among the 93 patients with ALK-positive NSCLC enrolled thus far, all had previously been administered a second-generation ALK TKI or lorlatinib (Lorbrena). Furthermore, 77% of patients had received 2 or more ALK TKIs, including a second-generation ALK TKI and lorlatinib, and 44% of the patients had received at least 3 ALK TKIs, including a second-generation ALK TKI and lorlatinib. Moreover, 46% of patients harbored a secondary ALK mutation, including 26% with any compound ALK mutation.

Additional data for response-evaluable patients showed that patients with any history of CNS metastases (n = 29) achieved an ORR of 52%. Patients with any ALK resistance mutation (n = 28) experienced an ORR of 54%, including an ORR of 56% for those patients with compound ALK mutations (n = 16) and 71% for those with ALK G1202R single or compound mutations (n = 17). Patients who received at least 3 prior ALK TKIs and prior chemotherapy (n = 19) achieved an ORR of 42%. In those who had not received prior lorlatinib and had prior treatment with at least 1 second-generation ALK TKI with or without a prior first-generation ALK TKI (n = 7) experienced an ORR of 71%.

Preliminary PK findings indicated that dose levels at or above 50 mg per day may provide increased coverage for both individual and combined ALK mutations within the CNS. Additionally, a preliminary pharmacodynamic analysis demonstrated NVL-655's ability to eliminate various ALK resistance mutation alleles over a broad range of doses.

Further safety data showed that the majority of treatment-related AEs (TRAEs) were low grade and manageable. The most common TRAEs observed in the safety-evaluable population (n = 93) included increased alanine transaminase (any-grade, 19%; ≥grade 3, 6%), increased aspartate transaminase (18%; 4%), and nausea (10%; 0%).

Furthermore, TRAEs led to treatment discontinuation in 2% of patients and dose reductions in 5% of patients.

One patient treated with 200 mg of NVL-655 per day experienced a dose-limiting toxicity of transient, asymptomatic grade 4 increased creatine phosphokinase. The MTD was not reached.

Upon determination of the RP2D, the trial is designed to transition to its phase 2 dose-expansion portion, which will evaluate the safety and activity of NVL-655 in several expansion cohorts.

"With today's data, Nuvalent has presented preliminary proof-of-concept data for both of its novel parallel lead programs in ROS1- and ALK-positive cancers in just over 5 years since the company's inception," James Porter, PhD, chief executive officer at Nuvalent, stated in the news release. "We believe this achievement is a testament to the dedication of the Nuvalent team and to our approach of collaboration with leading physician-scientists, identification of medical needs stemming from the limitations of existing therapies, and focused application of our innovative chemistry and deep expertise in structure-based drug design to develop precisely targeted therapies according to well-defined target product profiles."

Reference

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 October 13, 2023. https://investors.nuvalent.com/2023-10-13-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