The 2024 European Society for Medical Oncology (ESMO) Congress took place from September 13 to 17 in Barcelona, Spain, where significant progress in lung cancer research was unveiled. Dr. Ben J. Solomon, from the Peter MacCallum Cancer Centre in Melbourne, Australia, shared the results of the biomarker analysis from the ALINA study. In an exclusive interview with Oncology Frontier, Professor Solomon discussed the efficacy, safety, and biomarker analysis of alectinib in ALK-positive non-small cell lung cancer (NSCLC) patients. He also highlighted the latest advancements in targeted therapies for ALK-positive and KRAS G12C-mutant NSCLC.

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Oncology Frontier: During ESMO 2024, the biomarker analysis results from the ALINA study were presented. Could you discuss the biomarkers for ALK-positive NSCLC patients who received adjuvant alectinib versus chemotherapy after surgery? (Abstract 1206MO)

Dr. Ben J. Solomon: Last year at ESMO, we presented the overall results of the ALINA study, which was the first positive trial examining adjuvant alectinib in resected ALK-positive NSCLC patients. The study showed a significant disease-free survival (DFS) benefit, with a hazard ratio (HR) of 0.24. This year at ASCO, we presented preliminary exploratory biomarker analysis results from the ALINA study. Tumor samples from patients were analyzed using the FoundationOne CDx platform. We primarily focused on the incidence of EML4-ALK fusion variants, as well as the co-occurrence of TP53, CDKN2A, CDKN2B, and MTAP mutations.

We found that EML4-ALK variants v1 and v3 were the most common, appearing in 37% and 33% of patients, respectively. Notably, alectinib showed consistent benefit across all ALK variants compared to chemotherapy, with similar efficacy regardless of the specific variant. Among other mutations, TP53 mutations were detected in 24% of patients, which is lower than the 41% found in metastatic ALK-positive NSCLC patients (as seen in the ALEX study). Patients with TP53 mutations had slightly poorer outcomes with alectinib than those with wild-type TP53, though the difference was not statistically significant. Interestingly, wild-type TP53 and TP53-mutant patients had similar outcomes with chemotherapy. Further analyses, including studies on circulating tumor DNA (ctDNA) and minimal residual disease (MRD), are ongoing.

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Oncology Frontier: Could you elaborate on the safety and efficacy of adjuvant alectinib versus chemotherapy in resected ALK-positive NSCLC patients?

Dr. Ben J. Solomon: The ALINA study assessed two years of adjuvant alectinib treatment in surgically resected stage Ib-IIIa ALK-positive lung cancer patients. The results showed a significant improvement in DFS compared to chemotherapy (four cycles of platinum-based chemotherapy), with an HR of 0.24. The median DFS for chemotherapy was 41 months, whereas the median DFS for alectinib had not yet been reached.

In terms of safety, alectinib was well-tolerated, with side effects consistent with its known toxicity profile in metastatic ALK-positive NSCLC. The most common adverse events were elevated creatine kinase, abnormal liver function tests, constipation, and myalgia. In contrast, the most frequent side effects with chemotherapy were nausea, vomiting, and bone marrow suppression.

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Oncology Frontier: Can you discuss the latest developments in targeted therapies for ALK-positive and KRAS G12C-mutant NSCLC?

Dr. Ben J. Solomon: Targeted therapies for ALK-positive NSCLC have made great strides. At ESMO 2024, results from a Phase I trial of NVL-655, a fourth-generation ALK inhibitor, were presented. This compound has shown strong preclinical activity and appears effective in patients with resistance to lorlatinib (Abstract 1253O). NVL-655 could represent a promising option for patients who are refractory to current ALK inhibitors.

Regarding KRAS G12C, in addition to the first-generation inhibitors adagrasib and sotorasib, significant progress has been made in developing new inhibitors. One particularly promising compound is divarasib, which has demonstrated a response rate of approximately 59% in KRAS G12C-mutant NSCLC, with a median progression-free survival (PFS) of 15 months (Abstract 616MO).