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Efficacy of Durvalumab After Chemoradiotherapy in Patients With Limited-Stage Small Cell Lung Cancer
TAKE-HOME MESSAGE
- In this phase III, double-blind, placebo-controlled trial, patients with limited-stage small cell lung cancer were randomized to receive durvalumab 1500 mg, durvalumab plus tremelimumab, or placebo and were followed for up to 24 months. Indeed, durvalumab was associated with a significantly higher overall survival than placebo and increased progression-free survival. Certain adverse effects (such as severe pneumonitis) occurred more frequently in the durvalumab group.
- As immune checkpoint inhibitors are gaining increased importance in the treatment of patients with cancer, this study suggests the potential of durvalumab in the treatment of patients with small cell lung cancer, which confers a particularly high mortality rate.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy.
METHODS
In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded.
RESULTS
A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group.
CONCLUSIONS
Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).
Additional Info
Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer
N. Engl. J. Med 2024 Oct 10;391(14)1313-1327, Y Cheng, DR Spigel, BC Cho, KK Laktionov, J Fang, Y Chen, Y Zenke, KH Lee, Q Wang, A Navarro, R Bernabe, EL Buchmeier, JW Chang, Y Shiraishi, SS Goksu, A Badzio, A Shi, DB Daniel, NTT Hoa, M Zemanova, H Mann, H Gowda, H Jiang, S SenanFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
ADRIATIC is a phase III trial in limited-stage small cell lung cancer (SCLC) evaluating the impact of adjuvant durvalumab with or without tremelimumab in patients without progression after chemoradiotherapy.
Cheng and co-investigators report in The New England Journal of Medicine a first interim analysis with durvalumab versus placebo. Overall survival (OS) and progression-free survival (PFS) were the two primary endpoints. Radiotherapy fractionation and prophylactic cranial irradiation were left to the investigator's decision. A total of 264 patients were randomized to durvalumab and 266 to placebo, planned for a 24-month duration. The results of combination therapy with durvalumab and tremelimumab (200 patients) are still blinded. In terms of the patient population for this interim analysis, 87.4% of patients presented with stage III disease and 53.8% received prophylactic cranial irradiation. In the durvalumab arm, 66.5% of patients (vs 73.6% in the placebo arm) discontinued treatment due to disease progression or adverse events.
OS was improved with durvalumab compared with placebo (HR, 0.73; P = .01), with a 24-month OS rate of 68.0% versus 58.5%, a 36-month OS rate of 56.5% versus 47.6%, and an estimated median OS of 55.9 versus 37.3 months.
PFS was also significantly improved with durvalumab compared with placebo (HR, 0.76; P = .02), with an 18-month PFS rate of 48.8% versus 36.1%, a 24-month PFS rate of 46.2% versus 34.2%, and a median PFS duration of 16.6 versus 9.2 months.
In terms of tolerance, grade 3 to 4 serious adverse events occurred at a similar rate in both arms (~24%). Additional toxicity possibly attributable to durvalumab was consistent with what was reported in previous trials.
The overall results of this interim analysis are important for nonmetastatic SCLC, a disease for which no progress has been reported over the past 30 years. The improved OS and PFS by adding immunotherapy after concurrent chemoradiotherapy raises questions on the effect of using a new immunotherapy-based therapeutic approach. In fact, despite the difference in lung cancer histology between the ADRIATIC and PACIFIC trials, durvalumab in both subtypes provides an improvement in outcomes.
Durvalumab added after chemoradiotherapy could be a new standard of care for limited-stage SCLC.
Further trials, however, should be undertaken, including an earlier use of immunotherapy in combination with chemoradiation. The search for prognostic and predictive factors of efficacy should also be encouraged to better define patient profiles for better personalization.