Combining the targeted agent alectinib with the immunotherapeutic agent atezolizumab is tolerable among patients with ALK-positive advanced non–small-cell lung cancer (NSCLC), according to findings (abstract 9009) from a small phase 1b safety and clinical activity trial presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
“The combination of alectinib and atezolizumab appears to have an acceptable safety profile,” reported lead study author Don-Wan Kim, MD, of the Seoul National University Hospital in Seoul, South Korea. “No new or unexpected safety findings were identified for either agent. These data confirm that alectinib and atezolizumab can be combined.”
ALK gene rearrangements are found in up to 5% of patients with advanced NSCLC. Alectinib is a highly selective ALK inhibitor and is a National Comprehensive Cancer Network (NCCN)-preferred, category 1 first-line therapy option for patients with ALK-positive NSCLC, Kim noted. Atezolizumab is a humanized monoclonal antibody that binds to programmed death ligand 1 (PD-L1) to disrupt programmed death 1 (PD-1)/PD-L1 signaling, a pathway used by tumor cells to inhibit immune T cells from attacking them.
“Atezolizumab improved overall survival in the second-line treatment of NSCLC in the phase III OAK study and is an approved treatment for patients with advanced NSCLC that progresses after platinum-based chemotherapy,” Kim said (hazard ratio [HR], 0.73; 95% CI, 0.62–0.87; P = .0003).
However, data are limited regarding atezolizumab treatment in patients with ALK-positive lung cancer, Kim noted.
“Combining the alectinib with atezolizumab has the potential to further improve efficacy for patients with advanced ALK-positive NSCLC,” he said. “Alectinib-induced tumor cell death may release antigens, broadening the potential antitumor T-cell response.”
To evaluate the safety and clinical activity of alectinib plus atezolizumab, Kim and colleagues performed a two-stage phase Ib clinical trial; stage 1 consisted of a safety evaluation with 7 treatment-naive patients with advanced ALK-positive NSCLC and Eastern Cooperative Oncology Group performance scores of 0–1, followed by a stage 2 expansion cohort of those 7 patients plus 14 other study participants. Stage 2 was undertaken after no dose-limiting toxicities were identified after 28 days in stage 1 at 600-mg oral alectinib twice daily with 1,200-mg intravenous atezolizumab every 3 weeks. ALK status, CD8+ T-cell counts, and PD-L1 expression were evaluated using immunohistochemical tests of tumor tissue.
All 21 patients experienced adverse events, 7 (33%) of which were serious, Kim reported. There were no grade 4 toxicities or patient deaths.
Twelve patients (57%) had grade 3 adverse events deemed to be treatment-related. Five patients (24%) discontinued atezolizumab and 3 (14%) discontinued alectinib. Grade 3 treatment-related toxicities included maculopapular or erythematous rash, alanine aminotransferase increase, dyspnea, pneumonitis, blood bilirubin increase, liver function test increase, aseptic meningitis, hyperbilirubinemia, and neutropenia.
The overall response rate was 85.7% (18 of 21 patients), but most cases were partial responses. Complete response was seen in two patients (9.5%) and partial responses were noted in 16 (76%); 2 had stable disease. One patient was unevaluable.
The median duration of response was 20.3 months.
“CD8+ T-cell count increases were observed post-alectinib in seven of nine paired biopsies, but there was no clear association with response,” Kim reported.
Additional follow-up is needed to determine the possible survival benefits of this investigational regimen, Kim concluded.
The study was funded by F. Hoffmann-La Roche, Ltd.