1293MO Safety and efficacy of hypo- and conventionally fractionated thoracic radiotherapy plus durvalumab in elderly or frail NSCLC stage III patients unfit for chemotherapy: Interim results from the TRADE-hypo trial

Since patients with unresectable stage III NSCLC who are unfit for chemotherapy (CHT) due to age or frailty receive radiotherapy (RT) only, they do not have the opportunity to benefit from durvalumab consolidation after radiochemotherapy, raising the concern of undertreatment. Synergistic effects are expected when combining restored anti-tumor immune response elicited by immune checkpoint inhibition with an RT-induced increase in immunogenicity. The latter could be further boosted by hypofractionated RT, which might also be more practicable for the patient. TRADE-hypo (NCT04351256) is an open-label, allocated phase II trial addressing safety and efficacy of durvalumab (1.500 mg Q4W, max. 12 months) combined with either hypo- (55 Gy = 20 x 2.75 Gy, “HYPO”) or conventionally fractionated thoracic RT (60 Gy = 30 x 2 Gy, “CON”) in previously untreated NSCLC stage III patients unfit for CHT (planned n=88). A safety stop-and-go phase (6+6 design) in the HYPO-arm addressed the potential higher pneumonitis risk. An interim futility analysis was planned with 18 response-evaluable patients in each arm (after RT start, ≥1 dose durvalumab, ≥1 response assessment (RECIST1.1), futility rule ≤ 8 responses). By 11/2022, a total of 38 patients were enrolled (n=13 in HYPO, n=25 in CON). In the HYPO-arm, 2 pneumonitis grade ≥3 events occurred, resulting in permanent recruitment stop in this arm as per protocol. In the CON-arm, benefit-risk evaluation remained favorable, and the trial continued with recruitment into this arm only. Interim futility analysis was conducted in the CON-arm only and was positive with 11/18 patients achieving tumor response (5 stable, 2 progressive disease). An increased risk for pneumonitis was found in the HYPO-arm during the safety phase, leading to recruitment stop in this arm and continuation of TRADE-hypo with only the CON-arm. Interim futility analysis for the CON-arm was positive suggesting a benefit for the novel combination of durvalumab and thoracic RT for patients not suitable for CHT. Additional safety, efficacy, and biomarker data are expected for 05/25.