Laurent Greillier

Background The Geriatric Core Dataset (G-CODE) was developed to standardise geriatric assessment (GA) in older adults with cancer. This study aimed to develop and externally validate a mortality prediction score based on the G-CODE at 6-month (main endpoint), 12- and 24-month (secondary endpoints), in older patients with cancer. Methods Data came from two prospective French cohorts of cancer patients aged ≥70 referred for GA: the Elderly Cancer Patients (ELCAPA) cohort (training set) and the Geriatric Oncology Marseille (GOM) cohort (validation set). G-CODE items were evaluated using multivariate Cox regression analyses, with Akaike information criterion selection. Discrimination was assessed using time-dependent area under the receiver operator curve (tAUC) for 6-, 12-, and 24-month mortality. Results We included 950 and 766 patients in the training and validation sets (mean ± sd age: 83 ± 6 years/81 ± 6 years; men: 55%/59%; 6-month mortality: 27%/22%). The final G-CODE model highlighted five strong predictors of 6-month mortality: not having a caregiver, weight loss, comorbidities, an impaired 4-instrumental activities of daily living score, and an impaired timed-up-and-go test. The tAUCs of the model, including the G-CODE, age, cancer type, metastases, and treatment, were 82%, 78% and 80%. Conclusions The final G-CODE score (range: 0–17) accurately predicts 6-, 12-, and 24-month mortality. Clinical trial registration NCT02884375 (ClinicalTrials.gov).

Background: The sequential use of anti-programmed cell death (ligand)-1 [PD-(L)1] immune-checkpoint inhibitors (ICIs) followed by targeted tyrosine-kinase inhibitors (TKIs) for advanced non-small cell lung cancer (NSCLC) with oncogenic alterations raises questions about tolerance and efficacy. Recent study results suggested an increased risk of adverse events (AEs) with this sequence. Methods: Multicenter retrospective study on advanced NSCLC patients treated with ICIs followed by targeted therapies between 2015 and 2021. The primary endpoint was the rate of grade 3–5 adverse events (AEs). Main secondary endpoints were progression-free survival (PFS), time-to-treatment failure and overall survival (OS). Results: The analysis included 109 patients (most with EGFR, 30.3%; BRAF, 17.4%; MET exon-14, 17.4%; ALK, 10.1%; and RET, 6.4% gene alterations); 28/109, which is 25.7% of the patients, experienced grade 3/4 AEs and 4/109 (3.7%) experienced grade 5 AEs, leading to the definitive cessation of targeted therapy treatment in 14/32 (44%) of cases; higher grade 3–5 rates were observed with the dabrafenib–trametinib combination (12/16, 75%), capmatinib (4/8, 50%) and crizotinib (8/16, 50%). A last ICI-administration-to-targeted therapy-start interval of p = 0.001). In these sequential strategies, effectiveness of targeted therapies, in this second-line or later setting, appears to be lower than that in the published historical data. Conclusion: According to this analysis, sequential ICI–targeted therapy use for advanced NSCLC appeared to be associated with more grade 3–5 AEs.

Background: Advanced non-small cell lung cancer (NSCLC) is frequently associated with bone metastases, which complicate management and worsen prognosis. This study investigates the efficacy and safety of combining nivolumab (an immune checkpoint inhibitor) and denosumab (an anti-resorptive agent) in this setting.Methods: Multicenter, single-arm, phase 2 trial including advanced NSCLC with bone metastases. Patients received nivolumab (240 mg IV biweekly) and denosumab (120 mg SC monthly) as second-line therapy. The primary endpoint was the objective response rate (ORR).Results: Eighty-two patients were included between 8 November 2018 and 19 October 2021 with two years of follow up. The overall ORR was 12% (16% in PD-L1-positive patients, 8% in PD-L1-negative). Median progression-free survival (PFS) and overall survival (OS) were 1.75 and 8.36 months, respectively. Skeletal-related events occurred in 12% of patients, substantially lower than historical rates in chemotherapy-treated cohorts. Treatment was well-tolerated, with predominantly mild adverse events.Conclusions: This study did not demonstrate improved efficacy of nivolumab combined with denosumab. However, it provides prospective descriptive data on outcomes and skeletal-related events in a clinically relevant NSCLC population with bone metastases. Randomized studies are needed to determine the clinical value of bone-targeted therapies in the immunotherapy era.

Background: CheckMate-743 trial results led to nivolumab+ipilimumab becoming the standard first-line therapy for unresectable pleural mesothelioma (uPM), but real-world (rw) long-term follow-up evidence remains limited.Methods: This updated nationwide retrospective analysis of rw-efficacy and -safety of that combination therapy for uPM in a French early-access program (Meso-Immune) included progression-free survival (rw-PFS), overall survival (rw-OS), objective response rate (ORR) and immune-related adverse events (irAEs). Post-progression efficacies of second- and third-line therapies were also assessed.Results: Among 204 uPM patients (median age 75 years) included, histology was epithelioid for 152 (75%) and non-epithelioid for 52 (25%), 55% had breast-cancer-1-associated protein-1 (BAP1) loss. At median 30-month follow-up, median rw-(m)PFS (95% CI) lasted 6.3 (5.3–7.9) months, with 13.8% mPFS rate. For the 117 (75%) and 67 (89%) patients given, respectively, second-/third-line therapies: median rw-mPFS2/3 lasted 6.9 (6.1–8.2)/3.1 (2.6–5.3) months and ORR2 reached 28.2% (20.0–37.6%). mOS lasted 20.2 (17.6–23.0) months, with 25% of patients alive at 30 months; it was longer for epithelioid vs non-epithelioid uPM patients (22.3 vs. 14.3 months). BAP1 loss did not impact PFS or OS. irAEs occurred in 69% of patients: grade ≥3 for 35.6%, including 6.4% grade 5. Toxicities necessitated treatment discontinuation for 39% and hospitalization for 34%.Conclusions: This rw-analysis showed that combination nivolumab+ipilimumab for uPM provided long-term durable clinical benefit, comparable to CheckMate-743, despite an older population, with subsequent therapies retaining efficacy, especially for epithelioid subtype. These findings support first-line nivolumab+ipilimumab standard-of-care and underscore the need to improve beyond second-line strategies.

Background: Advanced non-small cell lung cancer (NSCLC) is frequently associated with bone metastases, which complicate management and worsen prognosis. This study investigates the efficacy and safety of combining nivolumab (an immune checkpoint inhibitor) and denosumab (an anti-resorptive agent) in this setting.Methods: Multicenter, single-arm, phase 2 trial including advanced NSCLC with bone metastases. Patients received nivolumab (240 mg IV biweekly) and denosumab (120 mg SC monthly) as second-line therapy. The primary endpoint was the objective response rate (ORR).Results: Eighty-two patients were included between 8 November 2018 and 19 October 2021 with 2 years follow up. The overall ORR was 12% (16% in PD-L1-positive patients, 8% in PD-L1-negative). Median progression-free survival (PFS) and overall survival (OS) were 1.75 and 8.36 months, respectively. Skeletal-related events occurred in 12% of patients, substantially lower than historical rates in chemotherapy-treated cohorts.Treatment was well-tolerated, with predominantly mild adverse events.Conclusions: This study did not demonstrate improved efficacy of nivolumab combined with denosumab. However, it provides prospective descriptive data on outcomes and skeletal-related events in a clinically relevant NSCLC population with bone metastases. Randomized studies are needed to determine the clinical value of bone-targeted therapies in the immunotherapy era.

PURPOSE: Adjuvant immunotherapy improved patient outcomes in two trials in completely resected non–small cell lung cancer (NSCLC), but with conflicting primary end point results. The Canadian Cancer Trials Group BR.31 trial evaluated adjuvant durvalumab in completely resected early-stage NSCLC. METHODS: Following resection of stage IB (≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer 7th Edition) and optional adjuvant chemotherapy, patients were randomly assigned 2:1 to durvalumab 20 mg/kg or placebo 20 mg/kg once every 4 weeks for 12 cycles. Random assignment was stratified by stage, extent of nodal dissection, tumor cell (TC) PD-L1 expression, adjuvant chemotherapy use, and center. The primary end point was investigator-assessed disease-free survival (DFS). Secondary outcomes included overall survival (OS), adverse events, and quality of life. The primary analysis was in the subgroup with cancers that had a PD-L1 TC expression ≥25%, no common activating EGFR mutations ( EGFR –), and no ALK gene rearrangements ( ALK –). Secondary analyses in hierarchical order included DFS in the subgroup whose tumors were EGFR–/ALK– with PD-L1 TC ≥1%, followed by all patients whose tumors were EGFR–/ALK–, followed by OS in the same primary and secondary subgroups in the same hierarchical order. RESULTS: Of 1,415 patients randomly assigned, 1,219 (86%) had EGFR–/ALK– tumors: 815 randomly assigned to durvalumab and 404 to placebo. With a median follow-up of 60 months, there were no differences in DFS between patients assigned durvalumab (316) versus placebo (161) in the primary population (stratified hazard ratio [HR], 0.93 [95% CI, 0.71 to 1.25]; P = .64) or in the secondary populations. Grade 3 to 4 adverse events were higher in durvalumab-treated patients (D = 26% v P = 20%). CONCLUSION: Adjuvant durvalumab following complete resection was not associated with improvement in DFS compared with placebo in EGFR –/ ALK – NSCLC, regardless of PD-L1 status.

This article reviews key second-line regimens recommended in major guidelines for treatment of patients with extensive-stage small cell lung cancer with platinum-sensitive relapse (chemotherapy-free interval ≥90 days), focusing on recent prospective clinical trials and post hoc analyses.