NVL-655 Shows Strong Efficacy in Heavily Pretreated ALK+ NSCLC

The novel ALK inhibitor NVL-655 demonstrated encouraging activity in heavily pretreated patients with advanced ALK-positive non–small cell lung cancer (NSCLC), including in those who were previously treated with lorlatinib (Lorbrena), according to findings from the phase 1 ALKOVE-1 study (NCT05384626) presented at the 2024 ESMO Congress.¹

Of those with evaluable efficacy data across all doses (n = 103), the overall response rate (ORR) was 38%. In those treated at the recommended phase 2 dose (RP2D; n = 39), the ORR was 38%. For patients specifically with the G1202R ALK resistance mutation (n = 32), the ORR was 69% across all doses (22 of 32) and 71% at the RP2D (10 of 14). The median duration of response (DOR) across all doses was 14.4 months, with 78% having a DOR of 6 months or longer. At the RP2D, the DOR was not yet reached with all patients responding beyond 6 months.

"Durable responses were observed in a heavily pretreated population, including in patients who previously progressed on lorlatinib and in those whose cancers harbored single or compound ALK resistance mutations," lead investigator Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center, said during a presentation of the results. "Durable intracranial responses were also observed, including [central nervous system (CNS)] partial responses after prior lorlatinib. And with this encouraging activity, we look forward to further investigating the drug in less heavily pretreated patients."

In preclinical studies, NVL-655 had potent activity against ALK-driven cell lines, including in single ALK mutations, compound mutations of 2 or more, and EML4-ALK fusions. Additionally, the agent avoids other targets like TRK, Drilon noted, and has a high level of brain penetrance, which in preclinical data was higher than lorlatinib. Based on a preliminary assessment of findings from the study, the FDA granted the agent a breakthrough therapy designation in May 2024. This designation was for those who received 2 or more prior ALK TKIs.²

"You'll see that relative to prior first-, second-, and third-generation ALK TKIs, NVL-655 is more potent in various ALK fusion–positive cell lines," said Drilon. "NVL 655 was designed to avoid TRK inhibition seen with drugs like lorlatinib that is associated with neurological side effects."

The dose escalation portion of the study exploring several doses was completed and an expansion cohort was opened. Overall, the phase 1 portion of the study enrolled 133 patients, with efficacy evaluable for 103 patients. Patients in the study received doses ranging from 15 mg to 200 mg daily, with a maximum tolerated dose not reached. The 150-mg daily dose was selected as the RP2D, based on various factors such as plasma levels that reached threshold levels in the patients treated at this dose level. Including the expansion cohort, 52 patients were treated with the RP2D.¹

In the RP2D-dose group, the median age of patients was 59 years with two-thirds of patients being female (67%). ECOG performance status was 0 (46%) and 1 (54%), and most patients were non-smokers (69%). More than half of patients (60%) had a history of brain metastases at baseline and all had an ALK fusion, with secondary ALK mutations being single (29%), compound (25%), or ALK G1202R (29%). The median number of prior therapies was 4 (range, 1-8) and half (50%) had received 3 or more prior ALK TKIs with all patients having received a second-generation or better TKI. Fifty-eight percent of patients had received prior chemotherapy. The most common prior TKIs were second-generation agents (94%), with 85% of patients also receiving lorlatinib.

"Compared to other ALK TKI studies, ALKOVE-1 has tested NVL-655 in a unique, primarily post-lorlatinib, and heavily pretreated setting," noted Drilon.

In patients treated with prior lorlatinib plus 1 or more other agent (n = 85), the ORR was 35% in both the RP2D group and in the full study population (11 of 31 and 30 of 31, respectively). In those with compound ALK mutations in this group (n = 28), the ORR was 54% across all doses (15 of 28) and 64% in the RP2D cohort (7 of 11). The DOR in this group was 9.2 months across all doses and 75% of patients had a DOR of longer than 6 months. At the RP2D, the DOR was not yet reached, and all patients continue to respond beyond 6 months.

In those with lorlatinib-naive disease (n = 17), the ORR was 53% across all doses (9 of 17) and 57% at the RP2D (4 of 7). In those with 1 or more ALK mutation (n = 8), the ORR was 88% across all doses (7 of 8) and was 80% at the RP2D (4 of 5). The DOR was not yet reached in this group across all doses and in the RP2D arm, with 88% of patients responding for greater than 6 months across all doses and all still responding with the RP2D.

"It's helpful to think about this data in 2 major subgroups, in the first population of lorlatinib pretreated patients, for which no TKI is currently approved," Drilon said. "It is equally useful to examine the second population of patients who are lorlatinib-naive."

Patients specifically with ALK resistance mutations also had durable responses, Drilon noted. In patients with ALK resistance mutations regardless of prior treatment (n = 30), the DOR was 14.4 months across all doses with 85% responding for 6 months or more. In the RP2D cohort for this group (n = 12), the DOR was not yet reached with 100% having a DOR of 6 months or more.

In those with compound ALK mutations specifically, all of which received prior lorlatinib, the median DOR was 14.4 months across all doses with 80% responding beyond 6 months. In this group, the DOR was not yet reached with the RP2D and 100% of patients responding beyond 6 months. In those who were lorlatinib-naive, across all dose levels (n = 7) and the RP2D (n = 4), responses remained ongoing with all patients responding longer than 6 months.

Intracranial ORR was seen in 50% of those who were lorlatinib naive (1 of 2) and for 15% of those who received prior lorlatinib (2 of 13). Additionally, there were 31% of patients with confirmed CNS lesions (4 of 13) who had unconfirmed intracranial ORRs but discontinued treatment in the absence of CNS activity before follow-up. "No CNS progression was noted among confirmed CNS responders, including patients who previously received lower lorlatinib," Drilon noted.

In updated safety, most treatment-related adverse events (TRAEs) were grade 1 and 2 in severity across all dose levels. The discontinuation rate due to a TRAE was 2% and a dose reduction was required for 15% of patients. The most common TRAEs were ALT increase (34%) and AST increase (30%). Grade 3 AST was seen in 13% of patients with 1 patient experiencing a grade 4 event. Grade 3 AST increase was seen in 9% of patients, with no grade 4 events. Other common TRAEs were all grade 1 and 2 in severity, with the most common being constipation (16%), dyspepsia (13%), and nausea (12%).

"All of these events were generally transient and reversible," Drilon added. "This profile shown here is consistent with the drug’s design that avoids TRK-related neurotoxicity."

The phase 2 portion of ALKOVE-1 continues to enroll for both patients with TKI-naive disease and those who received prior TKI exposure. The primary end point of the phase 2 arm is ORR by blinded independent central review with secondary end points focused on DOR, progression-free survival, and other response and safety measures. The study is enrolling across 54 locations and is targeting enrollment of 470 individuals across both phase 1 and 2 (NCT05384626).

References

1. Drilon AE, Lin JJ, Johnson ML, et al. Phase I/II ALKOVE-1 Study of NVL-655 in ALK-positive (ALK+) Solid Tumours. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1253O.
2. Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-655. News Release. Nuvalent. May 16, 2024. Accessed September 14, 2024. https://investors.nuvalent.com/2024-05-16-Nuvalent-Receives-U-S-FDA-Breakthrough-Therapy-Designation-for-NVL-655