The landmark PACIFIC trial has led to the current standard of care for LA-NSCLC which is chemoradiation followed by consolidation immunotherapy. However, approximately 50% of these patients are unable to receive the PACIFIC regimen due to treatment-related toxicity, being unfit for chemoradiotherapy or developing early disease progression. Two other significant studies (KEYNOTE 024 and Checkmate 227) have demonstrated that immunotherapy can be more effective and of fewer severe adverse events than chemotherapy in LANSCLC.

 Increasing number of studies support the potential synergy between radiation and immunotherapy. As a result, there is growing interest in chemotherapy-free approaches utilizing radiotherapy and immunotherapy for the treatment of LA-NSCLC. Several Phase I/II trials utilizing immunotherapy in combination with radiotherapy and without chemotherapy as curative-intent treatment for LA-NSCLC have confirmed the feasibility and safety. Radiation type, dose and fractionation are being studied for this chemotherapy-free approach. Proton radiation could be used in chemotherapy-free regimens to further reduce toxicity. While ongoing phase I/II trials continue to investigate chemotherapy-free treatment of LA-NSCLC utilizing radiotherapy and immunotherapy, the medical community is considering randomized phase III trials to further explore this promising treatment strategy.