Updates on lung neuroendocrine neoplasm classification - Vocino Trucco - 2024 - Histopathology

Adjuvant Durvalumab Does Not Improve Survival In Completely Resected NSCLC

After complete resection of early-stage non-small cell lung cancer (NSCLC) and optimal chemotherapy, adjuvant durvalumab did not improve disease-free survival versus placebo in the international, double-blind, phase 3 BR.31 trial.

Adjuvant chemotherapy improves 5 year survival in completely resected stage I-IIB NSCLC; however, approximately 60% of patients still relapse and die of disease1. Adjuvant immunotherapy with atezolizumab recently demonstrated improvement in disease-free survival (DFS) with limited benefit on overall survival2.

The PD-L1 inhibitor durvalumab has proven efficacy as a peri-operative regimen in resectable NSCLC3. The Canadian Cancer Trials Group (CCTG) BR.31 trial (NCT02273375), conducted in 269 centers across 19 countries, aimed to evaluate the benefit of adjuvant durvalumab in early-stage, completely resected NSCLC. The primary endpoint was DFS in patients with PD-L1 greater than or equal to 25% EGFR–/ALK. Glenwood Goss, MD, from Ottawa Hospital, in Canada, presented the results4.

After optional adjuvant chemotherapy (in 85% of participants), 1,415 participants (stage I-IIIA) were randomly assigned to receive adjuvant durvalumab or placebo. After a median follow-up of 60 months, the primary endpoint was not met. Median DFS was 66.9 months (95% CI 57.6–NR) versus 60.2 months (95% CI 47.7–NR) in the durvalumab arm and placebo arm (HR 0.90; P=0.624). In addition, no benefit of adjuvant durvalumab was demonstrated in participants with PD-L1 greater than or equal to 1% EGFR–/ALK–, nor in PDL all-comers/EGFR–/ALK–. Safety data were in line with results from previous trials.

Based on these outcomes, Prof. Goss concluded that "after complete resection and optimal chemotherapy, adjuvant durvalumab does not improve DFS versus placebo."

Medical writing support was provided by Marten Dooper.

Copyright ©2024 Medicom Medical Publishers

Adjuvant Durvalumab Therapy Improves Survival In Limited-stage Small Cell Lung Cancer

1. In this randomized controlled trial, adjuvant therapy with durvalumab led to improved overall and progression-free survival compared to placebo in patients with limited-stage small cell lung cancer (SCLC). 

2. Durvalumab had a tolerable safety profile, with a comparable incidence of adverse effects to the placebo group. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Small cell lung cancer is an aggressive form of cancer, in which one-third of patients present with limited-stage disease. The longest survival is achieved with concurrent chemoradiotherapy. These patients, however, often have disease relapse within two years and have limited five-year survival. Advances in systemic treatment for limited-stage SCLC have not progressed over the decades. However, more recent studies have suggested that adjuvant therapy with a high-affinity human IgG1 monoclonal antibody, called durvalumab, that binds programmed death ligand 1 could help prolong disease-free survival in patients with non-small cell lunger cancer who have undergone concurrent chemoradiotherapy. This randomized controlled trial evaluated the efficacy and safety of durvalumab, with or without tremelimumab—a monoclonal antibody targeting the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitory receptor on T cells—as adjuvant therapy in patients with limited-stage SCLC who remained progression-free following chemoradiotherapy. Patients were randomized to receive durvalumab, durvalumab plus tremelimumab, or a placebo. Durvalumab significantly improved overall survival and progression-free survival compared to placebo. The incidence of adverse effects in patients treated with durvalumab was comparable to those receiving placebo, indicating a tolerable safety profile. However, limitations of the study include insufficient statistical power for subgroup analyses and the underrepresentation of Black patients.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three randomized controlled trial assessed whether durvalumab, with or without tremelimumab, improved survival outcomes in patients with limited-stage SCLC after standard chemoradiotherapy. Adult patients with histologically or cytologically documented limited-stage SCLC who had not had progression after definitive chemoradiotherapy and who had a World Health Organization performance status score of zero or one were eligible. Patients with a history of pneumonitis of grade two or higher or with unresolved toxic effects of chemoradiotherapy were excluded from participation. A total of 730 patients were randomly assigned in a 1:1:1 ratio to either the durvalumab group that received 1500mg of durvalumab plus tremelimumab-matched placebo every 4 weeks for 4 doses (n=264), the durvalumab-tremelimumab group that received 1500mg of durvalumab plus 75mg of tremelimumab every 4 weeks for 4 doses (n=200), or the placebo group that received durvalumab-matched placebo plus tremelimumab-matched placebo every 4 weeks for 4 doses (n=266). The two primary outcomes were overall survival and progression-free survival when comparing the durvalumab group to the placebo group. Results from this trial found that durvalumab therapy led to significantly longer overall survival than placebo. Durvalumab also resulted in significantly longer progression-free survival. The incidence of adverse events was 24.4% in the durvalumab group and 24.2% in the placebo group. Overall, results from this randomized controlled trial found that adjuvant therapy with durvalumab resulted in significantly longer overall and progression-free survival compared to placebo in patients with limited SCLC after standard chemoradiotherapy. Durvalumab was also found to have a tolerable safety profile.

Image: PD

©2024 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.

Research Digest: Perioperative Pembrolizumab And Overall Survival In Early-stage NSCLC

A second interim analysis of the KEYNOTE-671 trial has shown that adding perioperative pembrolizumab to neoadjuvant chemotherapy for early-stage non-small-cell lung cancer (NSCLC) is effective and safe. This combination of medication showed significant overall survival benefit for patients who lived longer without cancer progression, recurrence or death and increased health-related quality of life.

This follows the results of the first interim analysis which found that adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage NSCLC but did not improve overall survival.

The global phase 3 trial was undertaken at 189 medical centres between May 2018 and Dec 2021 and involved 797 participants. All participants were 18 or older and had resectable stage II, IIIA, or IIIB (N2) NSCLC.

Patients were randomly assigned to one of two medication groups, with 397 undertaking treatment with pembrolizumab: four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every three weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every three weeks).

The control group had four cycles of neoadjuvant placebo (administered intravenously every three weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every three weeks).

Groups were stratified based on disease stage, levels of the PD-L1 protein in cancer cells, lung cancer types and geographical regions. Researchers compared rates of overall survival and event-free survival between the two groups.

At 36 months, overall survival rates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (95% CI 58–69) in the placebo group. Median event-free survival was 47.2 months in the pembrolizumab group and 18.3 months in the placebo group.

Serious side effects (grade 3–5) were more common in the pembrolizumab group (45%) compared to the placebo group (38%). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group.

The authors concluded that the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was beneficial in patients with resectable, early-stage NSCLC due to significant overall survival benefits and the manageable safety profile, supporting its use in this patient group.

ReferenceSpicer, J et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2024; Sept. 28: DOI: 10.1016/S0140-6736(24)01756-2.

---