The Phase 3 E4512 Trial in ALK+ NSCLC: Insights From the IASLC WCLC Plenary скачать в хорошем качестве

The Phase 3 E4512 Trial in ALK+ NSCLC: Insights From the IASLC WCLC Plenary

David Gerber, MD, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, joined Lung Cancers Today at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer (WCLC) to share insights on the phase 3 ECOG-ACRIN E4512 trial. The trial, which evaluated if adjuvant treatment with crizotinib could improve disease-free survival (DFS) in patients with surgically resected ALK-positive non-small cell lung cancer (NSCLC), was presented by Dr. Gerber during the first IASLC Presidential Symposium of the meeting. “We saw no difference in the disease-free survival between adjuvant crizotinib and observation in ALK-positive resected non-small cell lung cancer,” Dr. Gerber told Lung Cancers Today, noting that this held true across subgroups according to patient sex, cancer stage, and if patients had received post-operative radiation therapy. With a median follow-up of 58.3 months, the study showed that the median DFS was 72.8 months among the patients receiving neoadjuvant crizotinib, more than 3 months shorter than the median DFS of 75.1 months among patients undergoing observation (hazard ratio [HR], 1.06; 90% CI, 0.63–1.77; P=0.86). The primary endpoint of the phase 3 E4512 trial was DFS, with secondary end points of overall survival and safety. The median OS was not reached in patients receiving crizotinib or undergoing observation (HR, 0.49; 90% CI, 0.18–1.37; P=0.26). “There's been very few survival events or deaths in either arm to date,” Dr. Gerber said. “It's very, very immature data, but we don't see any meaningful difference to date in terms of overall survival.” Safety results showed that around one-third (34%) of patients receiving crizotinib had grade 3 treatment-related adverse events, including diarrhea in 6% and edema in 4%. One patient had a stroke, which was a grade 4 event. Nearly one-quarter (22%) of patients required dose reductions, with 25% discontinuing treatment because of toxicity. “What struck me about this trial was that toxicity was the reason for people stopping treatment in over one-quarter of cases,” Dr. Gerber said. “That’s considerably more than we see in terms of what proportion of patients stop crizotinib due to toxicity in trials of crizotinib in metastatic lung cancer.” Dr. Gerber shared his hypotheses on why treatment was discontinued due to toxicity in this proportion of patients. “When people take adjuvant crizotinib, they may be taking it for longer than they take it in metastatic disease… the longer you take a drug, the more likely you’ll have symptoms from cumulative toxicity over time,” he said. “And we just have to wonder, is there a difference in not only a patient's motivation, but a medical oncologist's motivation, a treating physician motivation, to continue taking a drug if it's metastatic lung cancer, where you know if you stop it, the cancer's eventually going to start growing, versus a post-operative setting, where you as an individual patient and you as an individual physician, aren't quite sure what is the actual efficacy of what you're doing in real time.” About the Phase 3 ECOG-ACRIN E4512 trial The trial enrolled 166 patients with resected stage IIA–IIIB ALK-positive NSCLC, as confirmed by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS). “Our target enrollment was 168, but we stopped enrollment at the point when the US Food and Drug Administration approved adjuvant alectinib,” Dr. Gerber explained. To be eligible for the phase 3 E4512 trial, patients were required to have negative surgical margins, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no prior therapy with an ALK inhibitor. However, patients remained eligible for the study if they received adjuvant chemotherapy and post-operative radiation. “The E4512 trial was very open-ended in terms of what the surgery requirements were,” he said. “For example, there was no specific surgical procedure required, no specific lymph node sampling and adjuvant chemotherapy and post operative radiation therapy. Both were allowed before starting treatment but were not required.” Study investigators randomized patients to undergo observation or receive crizotinib 250 mg twice daily for up to two years, or “until disease recurrence or unacceptable toxicity.”