Nuvalent announces updated preliminary data from ALKOVE-1 trial

Nuvalent announced updated preliminary data from the Phase 1 dose-escalation portion of its ongoing ALKOVE-1 Phase 1/2 clinical trial of NVL-655 for patients with advanced ALK-positive non-small cell lung cancer, or NSCLC, and other solid tumors. These data will be presented at the 35th AACR-NCI-EORTC, or ANE, Symposium in Boston, Massachusetts. NVL-655 is a novel brain-penetrant ALK-selective tyrosine kinase inhibitor, or TKI, created with the aim to simultaneously overcome the clinical challenges of emergent treatment resistance, brain metastases, and off-target central nervous system, or CNS, adverse events associated with tropomyosin receptor kinase, or TRK, inhibition that may limit the use of currently available ALK TKIs. As of the enrollment and data cut-off date of August 8 for the preliminary data, 93 patients have been enrolled in the Phase 1 portion of the ALKOVE-1 trial across six evaluated dose levels of NVL-655 ranging from 15 mg once daily to 200 mg QD. Enrollment in the Phase 1 portion of the trial is ongoing. Preliminary activity data as of the cut-off date were available from 51 heavily pre-treated response-evaluable NSCLC patients. The objective response rate, or ORR, by RECIST 1.1 was 39% of patients treated at all doses, of which all were partial responses. In the subset of 41 patients treated at dose levels of 50 mg QD or higher, the ORR was 44%. To evaluate key target characteristics of NVL-655, activity was examined in subgroups of the 51 response-evaluable patients treated at all doses, including: patients with any history of CNS metastases; patients with any ALK resistance mutation, including those with compound ALK mutations and those with ALK G1202R single or compound mutations; the most heavily pre-treated of patients, after receiving greater than or equal to three prior ALK TKIs including at least one 2nd generation ALK TKI plus lorlatinib, and prior chemotherapy and lorlatinib-naive patients who had received at least one 2G +/- 1G ALK TKI. Preliminary pharmacokinetic, or PK, analyses were available for dose levels 15 mg QD to 150 mg QD. Treatment with NVL-655 resulted in exposure above target efficacy thresholds in both the periphery and in the CNS. These preliminary PK data suggest that dose levels of 50 mg QD and above may provide increased coverage of single and compound mutations in the CNS. Preliminary pharmacodynamic analysis showed that NVL-655 induced clearance of diverse ALK resistance mutation alleles across a wide dose range. As of the cut-off date for the preliminary data, 67% of response-evaluable patients remained on treatment with NVL-655 with duration of treatment up to 12 months. All patients with tumor response continued on treatment without disease progression. NVL-655 was well-tolerated with a preliminary safety profile that was favorable and consistent with its ALK-selective, TRK sparing design.