Durvalumab after radiotherapy in patients with unresectable stage III non-small-cell lung cancer ineligible for chemotherapy: the DUART phase II nonrandomized controlled study

Abstract

Background: Currently, patients with unresectable stage III non-small-cell lung cancer (NSCLC) ineligible for chemotherapy receive radiotherapy alone, with unsatisfactory results. DUART was a phase II single-arm trial of durvalumab in patients without progression after radiotherapy for unresectable stage III NSCLC.

Patients and methods: Patients were enrolled into parallel cohorts per radiotherapy dose (A: definitive; B: palliative) and received durvalumab (1500 mg every 4 weeks for up to 12 months). The primary endpoint was incidence of grade 3/4 possibly related adverse events (PRAEs) within 6 months of durvalumab initiation. Secondary endpoints included objective response rate, progression-free survival (PFS), and overall survival (OS). Exploratory circulating tumor (ctDNA) analyses utilized a targeted methylation assay (GRAIL, Inc.).

Results: As of 06 December 2023, 102 patients received durvalumab (cohort A: 53; cohort B: 49); 18.8%/73.3%/7.9% had Eastern Cooperative Oncology Group performance status 0/1/2 and median age was 79.0 years. Overall, 9.8% [95% confidence interval (CI) 4.8% to 17.3%] had grade 3/4 PRAEs within 6 months of durvalumab initiation. Median PFS (investigator assessed) was 9.2 months, with a 12-month landmark rate of 39.6%. Median OS was 21.1 months and the 12-month landmark rate was 64.7%. Patients who were ctDNA positive at cycle 1 or 7 had shorter PFS versus patients who were ctDNA negative at the same time point.

Conclusions: The safety profile of durvalumab after radiotherapy was consistent with PACIFIC (durvalumab after chemoradiotherapy). Efficacy across cohorts was encouraging. Some patients may achieve or maintain molecular remission with durvalumab even after palliative radiotherapy. Durvalumab following radiotherapy may be a potential treatment option in a frailer, older, chemotherapy-ineligible population.

Keywords: durvalumab; frail; non-small-cell lung cancer; radiotherapy; unresectable.

Figure 1

CONSORT diagram (all enrolled patients). Participant disposition as of data cut-off 6 December 2023. Enrolled patients are those who provided written informed consent. Patients who completed 12-month study treatment are those who reached the maximum doses of durvalumab.

Figure 2

Progression-free survival and overall survival. Kaplan–Meier curves for PFS and OS in (A, B) the safety analysis set, (C, D) cohort A (definitive radiotherapy), and (E, F) cohort B (palliative radiotherapy). PFS was defined as the time from the first dose of durvalumab to the first documented confirmed or unconfirmed disease progression or death (from any cause in the absence of progression) regardless of durvalumab discontinuation or receipt of another anticancer therapy before progression. Median follow-up duration for patients censored for PFS was 11.1 months (range <0.1-33.2 months) in the safety analysis set, 11.5 months (range <0.1-21.1 months) in cohort A, and 10.1 months (range <0.1-33.2 months) in cohort B. OS was defined as the time from the first dose of durvalumab to death from any cause. Median follow-up duration for patients censored for OS was 16.4 months (range 0.9-33.4 months) in the safety analysis set, 16.7 months (range 0.9-24.2 months) in cohort A, and 15.9 months (range 2.8-33.4 months) in cohort B. Tick marks indicate censored patients, and dashed lines indicate the landmark times. Some censoring may be obscured in the graphs if patients were censored around/at the same time point. Data cut-off 6 December 2023. CI, confidence interval; NC, not calculable; OS, overall survival; PFS, progression-free survival; RT, radiotherapy. ^aCalculated using the Kaplan–Meier technique; CI for medians based on the Brookmeyer–Crowley method; CI for landmark rates based on the Greenwood method.

Figure 3

Circulating tumour DNA analyses. ctDNA sample availability pre-dose at cycles 1, 2, and 7 of durvalumab (A). ctDNA dynamics among patients with evaluable samples at one or more time point (B, C). Kaplan‒Meier curves for PFS by ctDNA status at cycle 1 (D), cycle 2 (E), and cycle 7 (F). PFS was defined as the time from the first dose of durvalumab to the first documented confirmed or unconfirmed disease progression or death (from any cause in the absence of progression) regardless of durvalumab discontinuation or receipt of another anticancer therapy before progression. Tick marks indicate censored patients, and dashed lines indicate the landmark times. Some censoring may be obscured in the graphs if patients were censored around/at the same time point. Data cut-off 6 December 2023. C, cycle; CI, confidence interval; ctDNA, circulating tumor DNA; HR, hazard ratio; ITT, intent-to-treat; NC, not calculable; neg, negative; PFS, progression-free survival; pos, positive; ppm, parts per million; RT, radiotherapy; TMeF, tumor methylated fraction. ^aCalculated using the Kaplan–Meier technique; CI for medians based on the Brookmeyer–Crowley method using log–log transformation; CI for landmark rates based on the Greenwood method using log–log transformation. The HR and associated CI was calculated using a Cox proportional hazards model, while the P value was determined by the log-rank test.