Best first-line therapy for people with advanced non-small cell lung cancer, performance status 2 without a targetable mutation or with an unknown mutation status.

Background: Most people who are newly diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. For these people, survival is determined by various patient- and tumor-related factors, of which the performance status (PS) is the most important prognostic factor. People with PS 0 or 1 are usually treated with systemic therapies, whereas people with PS 3 or 4 most often receive supportive care. However, treatment for people with PS 2 without a targetable mutation remains unclear. Historically, people with a PS 2 cancer are frequently excluded from (important) clinical trials because of poorer outcomes and increased toxicity. We aim to address this knowledge gap, as this group of people represents a significant proportion (20% to 30%) of the total population with newly diagnosed lung cancer.

Objectives: To identify the best first-line therapy for advanced lung cancer in people with performance status 2 without a targetable mutation or with an unknown mutation status.

Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 17 June 2022.

Selection Criteria: We included randomized controlled trials (RCTs) that compared different chemotherapy (with or without angiogenesis inhibitor) or immunotherapy regimens, specifically designed for people with PS 2 only or studies including a subgroup of these people.

Data Collection And Analysis: We used standard Cochrane methods. Our primary outcomes were 1. overall survival (OS), 2. health-related quality of life (HRQoL), and 3. toxicity/adverse events. Our secondary outcomes were 4. tumor response rate, 5. progression-free survival, and 6. survival rates at six and 12 months' treatment. We used GRADE to assess certainty of evidence for each outcome.

Main Results: We included 22 trials in this review and identified one ongoing trial. Twenty studies compared chemotherapy with different regimens, of which 11 compared non-platinum therapy (monotherapy or doublet) versus platinum doublet. We found no studies comparing best supportive care with chemotherapy and only two abstracts analyzing chemotherapy versus immunotherapy. We found that platinum doublet therapy showed superior OS compared to non-platinum therapy (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.57 to 0.78; 7 trials, 697 participants; moderate-certainty evidence). There were no differences in six-month survival rates (risk ratio [RR] 1.00, 95% CI 0.72 to 1.41; 6 trials, 632 participants; moderate-certainty evidence), whereas 12-month survival rates were improved for treatment with platinum doublet therapy (RR 0.92, 95% CI 0.87 to 0.97; 11 trials, 1567 participants; moderate-certainty evidence). PFS and tumor response rate were also better for people treated with platinum doublet therapy, with moderate-certainty evidence (PFS: HR 0.57, 95% CI 0.42 to 0.77; 5 trials, 487 participants; tumor response rate: RR 2.25, 95% CI 1.67 to 3.05; 9 trials, 964 participants). When analyzing toxicity rates, we found that platinum doublet therapy increased grade 3 to 5 hematologic toxicities, all with low-certainty evidence (anemia: RR 1.98, 95% CI 1.00 to 3.92; neutropenia: RR 2.75, 95% CI 1.30 to 5.82; thrombocytopenia: RR 3.96, 95% CI 1.73 to 9.06; all 8 trials, 935 participants). Only four trials reported HRQoL data; however, the methodology was different per trial and we were unable to perform a meta-analysis. Although evidence is limited, there were no differences in 12-month survival rates or tumor response rates between carboplatin and cisplatin regimens. With an indirect comparison, carboplatin seemed to have better 12-month survival rates than cisplatin compared to non-platinum therapy. The assessment of the efficacy of immunotherapy in people with PS 2 was limited. There might be a place for single-agent immunotherapy, but the data provided by the included studies did not encourage the use of double-agent immunotherapy.

Authors' Conclusions: This review showed that as a first-line treatment for people with PS 2 with advanced NSCLC, platinum doublet therapy seems to be preferred over non-platinum therapy, with a higher response rate, PFS, and OS. Although the risk for grade 3 to 5 hematologic toxicity is higher, these events are often relatively mild and easy to treat. Since trials using checkpoint inhibitors in people with PS 2 are scarce, we identified an important knowledge gap regarding their role in people with advanced NSCLC and PS 2.