Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

There was a 28% reduction in mortality. Patients who achieved a complete response (CR) or clearance of circulating tumor DNA (ctDNA) also experienced better outcomes.