Alectinib Shows Activity in ALK-Rearranged Advanced Solid Tumors

Alectinib (Alecensa) demonstrated antitumor activity for patients with advanced solid tumors with ALK rearrangements other than non­–small cell lung cancer (NSCLC), but not for those with ALK mutations and amplifications, according to results presented at the 2022 American Association for Cancer Research Annual Meeting.¹

Investigators in the phase 2 MyPathway basket study (NCT02091141) observed 3 partial responses (PRs) and 3 patients with stable disease (SD) lasting for more than 4 months out of the 10 patients with ALK rearrangements. However, 11 patients with ALK mutations or amplifications had no response to alectinib therapy.

“ALK rearrangements are oncogenic drivers found in around 5% of advanced NSCLC,” Fulda Meric-Bernstam, MD, chair of the department of investigational cancer therapeutics, the Phase I Program at the University of Texas MD Anderson Cancer Center, medical director of precision oncology decision support, and the Nellie B. Connally Chair in breast cancer research, stated in her presentation. “Alectinib is a potent ALK inhibitor that has demonstrated superiority in PFS over crizotinib [Xalkori] in advanced ALK-positive NSCLC.”

The ALK cohort of the study included 21 total patients with ALK rearrangements, gene amplifications, or mutations who had no satisfactory alternative treatment options for advanced solid tumors. The median age was 63 years, and they had a median of 2 prior lines of therapy.

The most common cancer in the cohort was colorectal cancer in 5 patients, followed by uterine cancer in 4 patients. Other tumor types included ovarian, esophageal, and skin cancer.

Patients received 600 mg oral alectinib twice a day. They were reevaluated every 8 weeks for 24 weeks, then every 12 weeks afterward until disease progression or unacceptable toxicity. The primary end point was investigator-assessed objective response rate (ORR), and secondary end points included disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), and safety.

At the data cut-off date of January 20, 2022, the ALK rearrangement subgroup had an ORR of 30% (95% CI, 6.7%-65.2%) and a DCR of 60% (26.2%-87.8%). There were no patients with SD of 4 or fewer months, and 3 reports of progressive disease (PD), while 1 patient’s assessment was unavailable. In the group of other ALK alterations, the ORR was 0%, and there were 3 patients with SD of greater than 4 months, 1 with SD of 4 or fewer months, and 7 who had PD, for a DCR of 27.3% (95% CI, 6.0%-61.0%).

In those with ALK-rearranged tumors, the median DOR was 6.6 months (95% CI, 6.0-not estimable [NE]). The median PFS was 8.2 months (95% CI, 1.7-13.6) in this group versus only 1.8 months (95% CI, 1.1-5.5) for tumors with other ALK alterations. However, the median OS was lower for patients with ALK rearrangements, at 14.1 months (95% CI, 5.2-NE) versus 20.5 months (95% CI, 5.7-NE).

The 3 patients with PRs had melanoma, papillary urothelial carcinoma, and colon adenocarcinoma. The patient with papillary urothelial carcinoma had an additional ALK D1529N mutation, but the other 2 responders had only ALK rearrangement.

The safety profile was as expected for alectinib, with common treatment-related adverse events (AEs) including nausea (23.8%), peripheral edema (23.8%), fatigue (19.0%), anemia (14.3%), and myalgia (14.3%). Six patients (28.6%) had a dose interruption and 3 (14.3%) had a dose reduction due to treatment-emergent AEs, but no patients needed to stop treatment due to AEs. Additionally, no patients died due to treatment-emergent AEs.

These safety data were consistent with those of the randomized phase 3 ALEX study (NCT02075840) of alectinib in patients with NSCLC.² In the ALEX study, alectinib showed superior PFS and a higher 5-year OS rate versus crizotinib in patients with ALK-positive NSCLC.

According to Merc-Bernstam, investigators in the MyPathway study monitored the partner genes in ALK fusions, other ALK mutations, and co-mutations to identify biomarkers that might predict response or resistance to alectinib.¹ ALK rearrangements are also being studied as a cohort of the phase 2 TAPISTRY platform study (NCT04589845) of patients with locally advanced or metastatic solid tumors at the same dosage and using a similar study design.

“Cancers in this study that had ALK mutations or amplifications alone were not responsive, but I should highlight that we did not know if all of these mutations were activated, and further, some of these mutations now have been defined to be resistance mutations to ALK inhibitors.” Meric-Bernstam said. “Although this is a small number of patients, alectinib appears active in patients with advanced solid tumors with ALK rearrangements.”

_References:

_{1. Swanton C, Friedman CF, Sweeney CJ, et al. Activity and safety of alectinib for ALK-altered solid tumors from MyPathway. Presented at: American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT032.}

_{2. Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol. 2020;31(8):1056-1064. doi:10.1016/j.annonc.2020.04.478}