Safe and effective systemic therapy for early-stage nonsmall-cell lung cancer

There has been a struggle to find effective therapies with warranted toxicity profiles for reducing the high rate of distant metastasis in people with early-stage non-smallcell lung cancer (NSCLC; 15-20% distant metastasis rate for T1-2N0).1 The NCIC CTG JBR.10 trial,2 ANITA trial,3 and CALGB 9633 trial4 all examined classic chemotherapy regimens, but they delivered substantial downside toxicity and did not consistently improve early-stage NSCLC outcomes and survival, leaving patients susceptible to relapse. In the Lancet, the results of the randomised controlled trial (RCT) by Joe Y Chang and colleagues5 in predominantly people with early-stage NSCLC (80%) show a potentially practice-changing approach using systemic immunotherapy after curative local treatment (stereotactic ablative radiotherapy [SABR]). Although this is only a phase 2 trial, the results are long-awaited, and finally support the much-needed use of effective and safe systemic therapy for early-stage disease. Until now, the National Comprehensive Cancer Network guidelines and other guidelines have had no systemic therapy recommendations for stage IA cancer and only selective use for patients with historically high-risk stage IB cancer. Although the overall survival data for Chang and colleagues'5 trial were not mature at the time of publication, the primary endpoint of 4-year event-free survival was significantly increased by adding four cycles of minimally toxic nivolumab in this moderately sized RCT at the MD Anderson Cancer Center. Specifically, 141 participants with local recurrence after T anyN anyM0 NSCLC (16%-24%) or newly diagnosed T1-3N0M0 (76%-84%) were randomly assigned as per the protocol to SABR cohort (n=75) or the SABR with immunotherapy (I-SABR) cohort (n=66) and received treatment. In general, both groups were well balanced. In the SABR group, the median age was 72 years (IQR 66-78), 55% were female, 85% were White, and 91% had previously been or were currently smokers; and in the I-SABR group, the median age was 72 years (IQR 66-75), 70% were female, 94% were White, and 89% had previously been or were currently smokers. With a 24% event-free survival improvement between the two groups across all recurrence patterns (distant metastasis and local, regional, and second primary cancers), nivolumab toxicity was low. There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab, with fatigue being the most common adverse event and an absence of grade 4-5 events. The Kaplan-Meier estimates showed an I-SABR treatment group plateau in event-free survival that did not decrease over time and was consistent