Key messages
• For people 65 years and older with advanced non-small cell lung cancer (NSCLC) who have not previously been treated for cancer, adding immunotherapy to chemotherapy prolongs life and extends the time before their cancer progresses. This finding comes from studies that mainly included people between 65 and 75 years old.
• We did not find these same beneficial effects of adding immunotherapy to chemotherapy in people over 75 years old.
What is advanced non-small cell lung cancer (NSCLC)?
NSCLC is one of two main types of lung cancer. About 80% to 85% of lung cancer cases are NSCLC. It mainly affects older people: diagnosis occurs at an average age of 71. NSCLC is usually detected when it is at the metastatic, or advanced, stage, which means cancer has spread beyond the original affected lung. At this stage, it can't be cured, but treatment can help to control it, and improve symptoms and quality of life.
How is NSCLC treated?
Treatment options vary, depending on the cancer stage, tumour characteristics, and other factors. Chemotherapy – powerful chemicals that kill cancer cells – has been the mainstay of lung cancer treatment. Immunotherapies are newer treatments that can help the immune system fight cancer. They have had positive results when combined with chemotherapy for people with advanced lung cancer. However, as people age, their immune system changes, becoming less effective at fighting cancer. This is called immunosenescence.
What did we want to find out?
We wanted to find out if, in this context of immunosenescence, immunotherapies are effective for people 65 years and older with advanced NSCLC, and what are the effects of intensifying chemotherapy-based treatment with the addition of immunotherapy.
What did we do?
We searched for studies that investigated the effect of giving chemotherapy plus immunotherapy versus chemotherapy alone to people 65 years and older with advanced NSCLC who had not previously had cancer treatment. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 17 studies with a total of 4276 people eligible for inclusion in this review. The studies compared immunotherapy plus chemotherapy to chemotherapy alone for people 65 years and older with previously untreated advanced NSCLC. Twelve of 17 studies included people older than 75 years, but this age group represented only 9% to 13% of all participants in the studies.
• For people 65 years and older, adding immunotherapy to chemotherapy prolonged life and extended the time before cancer progression, compared to chemotherapy alone. Both treatments had the same rate of toxic effects. Most of the people included in these studies were between 65 and 75 years old.
• For people 75 years and older, adding immunotherapy to chemotherapy may not prolong life or extend the time before cancer progression compared to chemotherapy alone.
What are the limitations of the evidence?
Our confidence in the evidence varied from moderate to very low, and was reduced because of concerns about how some of the studies were conducted. Only one study assessed some of the outcomes we were interested in. None of the studies assessed people's health-related quality of life.
How up to date is this evidence?
The evidence is current to 23 August 2023.
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.
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.