Results from two phase 3 lung cancer clinical trials by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) were presented at the 2025 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, in September. Their findings have immediate implications for clinical practice, warranting their inclusion in the Presidential Symposium plenary program of the meeting.

The trial summaries are below, along with interpretations shared by ECOG-ACRIN Therapeutic Studies Program Chair Suresh S. Ramalingam, MD, executive director of the Winship Cancer Institute of Emory University and the Roberto C. Goizueta Chair in Cancer Research at Emory University School of Medicine.

Operable ALK+ Lung Cancer

About one in 25 patients with non-small cell lung cancer (NSCLC) have tumors that harbor the anaplastic lymphoma kinase (ALK) fusion gene. Although there is no cure, targeted treatments, such as crizotinib, are helping patients with ALK-positive (ALK+) NSCLC live longer. Crizotinib was the first tyrosine kinase inhibitor (TKI) approved by the US Food and Drug Administration (FDA) in 2013 to treat patients with metastatic ALK+ NSCLC. In E4512, ECOG-ACRIN evaluated crizotinib for its potential to improve survival in operable, early-stage disease. The study enrolled 166 of 168 planned participants through the ALCHEMIST program before the trial was halted in 2024, following the FDA's approval of another ALK inhibitor, alectinib, as adjuvant treatment for these patients.

Participants in E4512 had resected stage 2A-3B ALK+ NSCLC, negative margins, and ECOG performance status 0-1. Pre-operative therapy or prior treatment with an ALK inhibitor were not allowed. Adjuvant chemotherapy and post-operative radiation therapy were allowed. Patients were randomized to receive either observation or crizotinib 250 mg twice daily until recurrence, unacceptable toxicity, or for up to 2 years. The primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS) and safety. 

At a median follow-up of 58.3 months, median DFS was 72.8 months with crizotinib versus 75.1 months with observation. Median OS was not reached in either arm. Among 85 patients on crizotinib, 34% had grade 3 treatment-related adverse events, and one patient had a grade 4 treatment-related stroke. The median duration of crizotinib treatment was 13.5 months (range 3.4-23.9 months). Nearly one-quarter (22%) required dose reductions, and 25% discontinued crizotinib due to toxicities. 

Dr. Ramalingam: “While the results failed to document a role for crizotinib in early-stage NSCLC, the availability of subsequent generations of ALK inhibitors with a favorable tolerability profile and better activity in the brain provides hope for improving patient outcomes. In fact, a study with alectinib, a second-generation ALK TKI, demonstrated improved disease-free survival in early-stage NSCLC when given as adjuvant therapy. One of the reasons E4512 failed to show benefit for crizotinib could be due to its limited efficacy against brain metastasis, a common problem in patients with ALK-positive NSCLC.”

To learn more, watch a trial presentation video with lead investigator David Gerber, MD (UT Southwestern), in Lung Cancers Today and review WCLC Abstract PL02.18.

Inoperable Lung Cancer

For patients with locally advanced, inoperable NSCLC (stage 3), the standard therapy involves concurrent administration of platinum-based chemotherapy and radiation therapy (CRT). Then, patients whose disease has not progressed following CRT receive 1 year of immunotherapy with durvalumab, approved by the FDA in 2018 (based on the results of the PACIFIC trial). Since then, other studies have suggested that combining durvalumab with CRT may enhance effectiveness. The EA5181 trial was conducted to address whether adding durvalumab to the CRT phase could result in improved patient outcomes.

The trial enrolled 662 patients with previously untreated, inoperable stage 3A-3C NSCLC or those with mediastinal node recurrence after prior surgery. Patients were randomized to receive either concurrent durvalumab with CRT (Arm A) or CRT alone (Arm B). Patients in both arms who completed CRT without progression or significant toxicity were assigned to 1 year of durvalumab consolidation (Arm C). Overall survival (OS) was the primary endpoint. Secondary endpoints were objective response rates (ORR), PFS, recurrence patterns (local versus distant), and toxicity.

The trial completed enrollment well ahead of the projected dates. At a median follow-up of 29.9 months, 277 patients in Arms A (82.7%) and B (84.7%) started Arm C. The most common chemotherapy regimen was carboplatin/paclitaxel (85.6%). The proportions of participants receiving all treatment cycles in Arms A and B were 93.7% and 94.0%, respectively. The median OS was 41.5 months (Arm A) versus 39.4 months (Arm B). Disease progression was reported in 45.4% of Arm A/C patients and 44.0% of Arm B/C patients. Median PFS was 15.5 months versus 16.8 months, respectively. The overall response rates (complete and partial) were 51.3% (Arm A) and 47.1% (Arm B). There were no significant differences in grade 3-5 or grade 2-5 cardiac/pulmonary events between Arms A and B. Local recurrences were 55.9% and 49.6% in Arms A and B, respectively. Radiation in-field recurrences were noted in 28.6% (Arm A) and 28.4% (Arm B).

Dr. Ramalingam: “These results argue against the use of concurrent PD-1 blockade with chemoradiotherapy and confirm the role of durvalumab in the consolidation setting for locally advanced NSCLC. There was no evidence of higher toxicity with concurrent durvalumab; these data suggest that the lack of improved efficacy is attributable to mechanistic aspects of combined PD-1 blockade with radiotherapy in lung cancer.”

To learn more, watch a trial presentation video with lead investigator John M. Varlotto, MD (Marshall University) in The ASCO Post and review WCLC Abstract PL03.06.