First-line treatment for patients with advanced non–small-cell lung cancer (NSCLC) has traditionally been doublet chemotherapy. With the development of immunotherapy-based treatments, such as immune checkpoint inhibitors that target programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1), these therapies, with or without chemotherapy, have emerged as first-line treatment for patients with advanced NSCLC without a molecular driver. Immunotherapy treatment has led to significant overall survival (OS) improvement compared with standard chemotherapy, but primary and secondary treatment resistance still occurs. To understand the challenges faced when determining the best selection of second-line therapy, Insa and colleagues presented information on current standard of care for first-line therapy.
Immunotherapy that has conveyed survival benefit in highly PD-L1–expressing patients includes ipilimumab monotherapy, pembrolizumab monotherapy in patients with advanced NSCLC with ≥50% PD-L1 expression, and atezolizumab. The IMpower 110 trial demonstrated that atezolizumab monotherapy frontline treatment gave a significant improvement of OS when compared with platinum-based chemotherapy in advanced strong PD-L1–expressing NSCLC patients and is under review for this indication. Combination immunotherapy has also demonstrated efficacy in this patient population. Nivolumab plus ipilimumab in the phase 3 CheckMate-227 clinical trial demonstrated improvement in OS compared with chemotherapy, and tiragolumab and atezolizumab in the phase 2 CITYSCAPE trial gave trial participants clinically meaningful improvement in overall response rate and progression-free survival (PFS) compared with atezolizumab alone. Multiple clinic studies failed to show survival benefit of anti–PD-1 monotherapy in low and medium PD-L1–expressing populations. However, first-line chemotherapy combined with anti–PD-1/PD-L1 therapy and anti–PD-1 and anti–CTLA-4 doublet therapy does convey benefit.
Options available for second-line treatment were historically single-agent docetaxel, pemetrexed, or erlotinib, but these agents conveyed a poor clinical outcome. Currently, single-agent immunotherapy is the standard second-line choice, but now clinical trials are focusing on angiogenesis. The phase 3 REVEL clinical trial studied patients with stage IV NSCLC who progressed on first-line chemotherapy. Patients were randomized to receive docetaxel plus ramucirumab or placebo. The combination improved median OS, PFS, overall response rate, and disease control rate. Likewise, the phase 3 LUME-Lung 1 trial evaluated the addition of nintedanib to docetaxel, and patients with adenocarcinoma histology receiving this combination saw improved median PFS and prolonged OS. Retrospective studies have demonstrated the combination of chemotherapy and anti-angiogenics as second- or third-line treatment after immune checkpoint inhibitor therapy has conveyed survival benefits to patients receiving these treatments. These studies and others are demonstrating that the most appropriate treatment for second-line therapy for NSCLC patients is chemotherapy with or without anti-angiogenic agents. Immunotherapy rechallenge and new treatment combinations, including immunotherapy, cell-signaling inhibitors, or double immunotherapy, are promising approaches to overcoming prior or acquired resistance to first-line therapy.
Source
Insa A, Martín-Martorell P, Di Liello R, et al. Which treatment after first line therapy in NSCLC patients without genetic alterations in the era of immunotherapy? Crit Rev Oncol Hematol. 2022;169:103538.
