A recent literature review identifies promising therapeutic agents that have shifted the non-small cell lung cancer treatment paradigm.
Lung cancer is the leading cause of cancer mortality worldwide. Research is rapidly evolving regarding the treatment of non-small cell lung cancer (NSCLC) with biomarker-driven targeted therapy and immunotherapy using checkpoint inhibitors.
A review of phase III clinical trials, published in the Journal of Hematology & Oncology, has proposed NSCLC treatment algorithms based on emerging evidence.
Advancements in Adjuvant Therapies Transform NSCLC Treatment Landscape
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrated efficacy for improving disease-free survival (DFS) in patients with resected EGFR-mutant NSCLC in the ADAURA study. It reduced the risks of disease recurrence and death by 77% in stage II–IIIA patients and 73% in stage IB–IIIA patients. Osimertinib received regulatory approval as adjuvant therapy for patients with EGFR mutations. Conflicting results were observed in three phase III studies comparing first-generation EGFR-TKIs to chemotherapy.
Adjuvant Immunotherapy Outperforms Standard Treatment in NSCLC Trials
The programmed death ligand 1 (PD-L1) inhibitor atezolizumab demonstrated prolonged DFS compared to standard therapy in resected stage IB–IIIA NSCLC in the IMpower010 trial.
The KEYNOTE-091 trial revealed a longer median DFS with pembrolizumab than placebo as adjuvant treatment for resected stage IB–IIIA NSCLC. The FDA approved both immunotherapeutic agents for adjuvant treatment of stage IB–IIIA NSCLC.
In the CheckMate816 trial, neoadjuvant immunotherapy with nivolumab plus chemotherapy significantly improved the pathological complete response rate and event-free survival versus chemotherapy alone.
Durvalumab and Sugemalimab Demonstrate Efficacy in Treating Unresectable Stage III NSCLC
The PACIFIC trial compared consolidation therapy with durvalumab versus placebo after concurrent chemoradiotherapy and revealed substantial benefits in progression-free survival (PFS) and overall survival (OS) with durvalumab. The FDA approved durvalumab for treating unresectable stage III NSCLC following concurrent platinum-based chemoradiotherapy.
The Gemstone-301 study demonstrated the efficacy of sugemalimab in prolonging PFS, leading to its approval in China for unresectable stage III NSCLC after concurrent or sequential chemoradiotherapy.
The PACIFIC-R trial assessed durvalumab’s real-world effectiveness, achieving a median real-world PFS of 21.7 months and a 3-year OS rate of 63.2%.
Various Novel Agents Show Efficacy in Treating Advanced NSCLC
Recent evidence from various phase II NSCLC trials suggests that adding local consolidation therapy to systemic treatment for oligometastasis prolongs PFS and OS and may be curative for some patients, establishing a new treatment paradigm for oligometastatic NSCLC.
Advancements in KRAS-G12C-Targeted NSCLC Therapies
The KRAS oncogene is prevalent in lung adenocarcinomas. The KRAS-G12C variant has become a target for NSCLC treatment. Sotorasib demonstrated efficacy in a phase II trial and became FDA-approved as the first KRAS inhibitor. However, the phase III trial met PFS but not OS endpoints.
Adagrasib demonstrated similar benefits in another trial and became the second approved KRAS inhibitor. Unlike sotorasib, adagrasib additionally showed effectiveness in controlling intracranial disease.
Advances in HER2-Mutant NSCLC Treatment
The first-generation tyrosine receptor kinase inhibitors larotrectinib and entrectinib demonstrated efficacy in lung cancers, with notable response rates, prolonged PFS, and CNS activity.
Various anti-human epidermal growth factor receptor-2 (anti-HER2) therapies showed limited efficacy in NSCLC, with high toxicity. However, recent data regarding anti-HER2 antibody–drug conjugates is promising, particularly trastuzumab deruxtecan, which received accelerated approval for previously treated HER2-mutant NSCLC after showing favorable response rates and PFS and OS benefits in clinical trials.
Cemiplimab and Combinations Improve Survival in NSCLC
Immune checkpoint inhibitors are standard for oncogene-negative advanced NSCLC. Cemiplimab with chemotherapy demonstrated significant PFS and OS improvements versus chemotherapy alone. Toripalimab and sugemalimab with chemotherapy also improved survival outcomes. Combinations like tiragolumab plus atezolizumab and tremelimumab plus durvalumab with chemotherapy demonstrated efficacy in metastatic NSCLC. Atezolizumab plus chemotherapy demonstrated similar systemic and intracranial response rates. Conflicting data exists regarding patients with EGFR-mutant NSCLC and anti-angiogenic therapy.
Source:
Liu, S. M., Zheng, M., Pan, Y., Liu, S., Li, Y., & Wu, Y. (2023). Emerging evidence and treatment paradigm of non-small cell lung cancer. Journal of Hematology & Oncology, 16(1). https://doi.org/10.1186/s13045-023-01436-2
