Immune checkpoint inhibitors plus platinum-based chemotherapy compared to platinum-based chemotherapy with or without bevacizumab for first-line treatment of older people with advanced non-small cell lung cancer.
Lung cancer is a cancer of the elderly, with a median age at diagnosis of 71. More than one-third of people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) are special antibodies that target a pathway in the immune system called the programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway. These antibodies help the immune system fight cancer cells by blocking signals that cancer cells use to avoid being attacked by the immune system. ICIs have changed the treatment of people with lung cancer. In particular, for people with previously-untreated advanced non-small cell lung cancer (NSCLC), current first-line treatment now comprises ICIs plus platinum-based chemotherapy, rather than platinum-based chemotherapy alone, regardless of their PD-L1 expression status. However, as people age, their immune system changes, becoming less effective in its T cell responses. This raises questions about how well ICIs work in older adults.
To assess the effects of immune checkpoint inhibitors (ICIs) in combination with platinum-based chemotherapy compared to platinum-based chemotherapy (with or without bevacizumab) in treatment-naïve adults aged 65 years and older with advanced NSCLC.
We searched the Cochrane Lung Cancer Group Trial Register, CENTRAL, MEDLINE, Embase, two other trial registers, and the websites of drug regulators. The latest search date was 23 August 2023. We also checked references and searched abstracts from the meetings of seven cancer organisations from 2019 to August 2023.
We included randomised controlled trials (RCTs) that reported on the efficacy and safety of adding ICIs to platinum-based chemotherapy compared to platinum-based chemotherapy alone for people 65 years and older who had not previously been treated. All data emanated from international multicentre studies involving adults with histologically-confirmed advanced NSCLC who had not received any previous systemic anticancer therapy for their advanced disease.
We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival and treatment-related adverse events (grade 3 or higher). Our secondary outcomes were progression-free survival, objective response rate, time to response, duration of response, and health-related quality of life (HRQoL).
We included 17 primary studies, with a total of 4276 participants, in the review synthesis. We identified nine ongoing studies, and listed one study as 'awaiting classification'. Twelve of the 17 studies included people older than 75 years, accounting for 9% to 13% of their participants. We rated some studies as having 'some concerns' for risk of bias arising from the randomisation process, deviations from the intended interventions, or measurement of the outcome. The overall GRADE rating for the certainty of the evidence ranged from moderate to low because of the risk of bias, imprecision, or inconsistency. People aged 65 years and older The addition of ICIs to platinum-based chemotherapy probably increased overall survival compared to platinum-based chemotherapy alone (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70 to 0.88; 8 studies, 2093 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events may not differ between the two treatment groups (risk ratio (RR) 1.09, 95% CI 0.89 to 1.32; 1 study, 127 participants; low-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improves progression-free survival (HR 0.61, 95% CI 0.54 to 0.68; 7 studies, 1885 participants; moderate-certainty evidence). People aged 65 to 75 years, inclusive The addition of ICIs to platinum-based chemotherapy probably improved overall survival compared to platinum-based chemotherapy alone (HR 0.75, 95% CI 0.65 to 0.87; 6 studies, 1406 participants; moderate-certainty evidence). Only one study reported data for treatment-related adverse events (grade 3 or higher). The frequency of treatment-related adverse events probably increased in people treated with ICIs plus platinum-based chemotherapy compared to those treated with platinum-based chemotherapy alone (RR 1.47, 95% CI 1.02 to 2.13; 1 study, 97 participants; moderate-certainty evidence). The addition of ICIs to platinum-based chemotherapy probably improved progression-free survival (HR 0.64, 95% CI 0.57 to 0.73; 8 studies, 1466 participants; moderate-certainty evidence). People aged 75 years and older There may be no difference in overall survival in people treated with ICIs combined with platinum-based chemotherapy compared to platinum-based chemotherapy alone (HR 0.90, 95% CI 0.70 to 1.16; 4 studies, 297 participants; low-certainty evidence). No data on treatment-related adverse events were available in this age group. The effect of combination ICI and platinum-based chemotherapy on progression-free survival is uncertain (HR 0.83, 95% CI 0.51 to 1.36; 3 studies, 226 participants; very low-certainty evidence). Only three studies assessed the objective response rate. For time to response, duration of response, and health-related quality of life, we do not have any evidence yet.
Compared to platinum-based chemotherapy alone, adding ICIs to platinum-based chemotherapy probably leads to higher overall survival and progression-free survival, without an increase in treatment-related adverse events (grade 3 or higher), in people 65 years and older with advanced NSCLC. These data are based on results from studies dominated by participants between 65 and 75 years old. However, the analysis also suggests that the improvements reported in overall survival and progression-free survival may not be seen in people older than 75 years.
Orillard E
，Adhikari A
，Malouf RS
，Calais F
，Marchal C
，Westeel V
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《Cochrane Database of Systematic Reviews》
Decoding KRAS mutation in non-small cell lung cancer patients receiving immunotherapy: A retrospective institutional comparison and literature review.
KRAS mutation the most common molecular alteration in advanced non-small cell lung cancer (NSCLC) and is associated with an unfavourable prognosis, largely due to the lack of targeted therapeutic options for the majority of the KRAS mutated isoforms. The landscape of NSCLC treatment has expanded with the introduction of immune checkpoint inhibitors (ICIs). Nonetheless, data regarding the efficacy of ICI in NSCLC patients harbouring KRAS mutations are conflicting. This study aimed to compare clinical outcomes of ICIs in advanced NSCLC with different isoforms of KRAS mutations.
A retrospective study was conducted on 143 patients with advanced NSCLC harbouring different KRAS mutation and treated with immune checkpoint inhibitors (ICI) between December 2020 and July 2022 at "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan. Log-rank and Cox Hazard methods were used for survival analysis.
We evaluated 143 patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS mutations. The most common mutation was G12C (41 %), followed by G12V (23.7 %) and G12D (11.8 %). The G12C mutation was notably associated with a higher incidence of bone metastases (42 %). Immunotherapy was administered as monotherapy in 54.5 % of cases, while 69 % received it as part of a first-line combination with chemotherapy. Co-mutations were detected in 52 % of patients, with Q61 (63 %) and G12C (58 %) being the most prevalent. Among these, 24 % had STK11 co-mutations, and 29 % had TP53 co-mutations. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed across different KRAS subtypes. The longest OS was seen in patients with Q61 (46.5 months), 13X (31.8 months), and G12C (28.7 months). The highest overall response rate (ORR) of 73 % was observed in the G12D group, particularly with the combination of chemoimmunotherapy, where stable disease was the most common outcome at 40 %. The median duration of response (DOR) was 7.4 months across both treatments. The longest DOR was seen in the G12V group at 10.2 months, with no significant difference between treatments. In contrast, the shortest DOR was in the G12A group, with 1.54 months in those treated with combination therapy compared to 2.57 months with single-agent therapy. Regarding co-mutations, patients with STK11 co-mutations had a higher median OS than those without (39.7 vs. 26.1 months), but this was not statistically significant (p = 1). Similarly, TP53 co-mutations were associated with a lower median OS (19.1 vs. 26.1 months, p = 0.7), though this too was not statistically significant. Importantly, bone metastases emerged as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.81, p < 0.001), regardless of KRAS subtype or co-mutation status.
KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.
Urtecho SB
，Provenzano L
，Spagnoletti A
，Bottiglieri A
，Pircher C
，Massa G
，Sposetti C
，Proto C
，Brambilla M
，Occhipinti M
，Mazzeo L
，Beninato T
，Leporati R
，Giani C
，Cavalli C
，Serino R
，Prina MM
，Bassetti A
，Nasca V
，di Mauro RM
，Abate A
，Manglaviti S
，Dumitrascu AD
，Liberti GD
，Cassano TS
，Ganzinelli M
，Wu S
，Garassino MC
，de Braud FGM
，Russo GL
，Prelaj A
... -
《-》
Nivolumab plus ipilimumab versus carboplatin-based doublet as first-line treatment for patients with advanced non-small-cell lung cancer aged ≥70 years or with an ECOG performance status of 2 (GFPC 08-2015 ENERGY): a randomised, open-label, phase 3 study.
Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2.
This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361.
The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group.
The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study.
Bristol-Myers Squibb.
Léna H
，Greillier L
，Cropet C
，Bylicki O
，Monnet I
，Audigier-Valette C
，Falchero L
，Vergnenègre A
，Demontrond P
，Geier M
，Guisier F
，Hominal S
，Locher C
，Corre R
，Chouaid C
，Ricordel C
，GFPC 08–2015 ENERGY investigators
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ResearchGate
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