SINDAS these patients.

Top Line: The long-awaited full pub of the SINDAS trial is here.

The Study: Spoiler alert, the trial was closed early after the first prespecified interim analysis at 68% accrual (n=133) because of the clear survival benefit in the experimental arm. As a reminder, patients receiving upfront first-generation EGFR-TKI (e.g. erlotinib) for EGFR-mutated non-small cell lung cancer (NSCLC) with ≤5 de novo synchronous mets and 0 brain mets were randomized across five Chinese centers to +/- the addition of upfront ablative radiation to all sites of disease in conjunction with initiation of systemic therapy. Two important things to note here. Radiation was delivered, upfront, to both the primary site (including N2-3 disease in over half of enrollees) in addition to all sites (again, as many as 5) of metastatic disease. Even still, all radiation (including to primary tumor / nodes) was delivered in no more than 5 fractions to what many would consider a modest total dose of 25-40 Gy “generally utilizing the maximum dose that did not exceed 5-fraction dose tolerances to adjacent organs-at-risk.” As in initial abstract reporting, the full manuscript reports median progression-free survival was improved from 12.5 → 20.2 months with the addition of radiation. Delving more into individual lesion control, at a median follow-up of two years, crude local control was 55% with TKI alone and >90% with the addition of radiation. Before radiation haters can question the inherent utility of this outcome, let’s jump to the real headline. Median overall survival was significantly prolonged from 17.4 months → 25.5 months with the addition of radiation. What might critics point to next? The survival curves in both arms are so impressive as to be almost too impressive, outshining those with locally-advanced NSCLC and even rivaling those with inoperable early-stage NSCLC. Not to mention everything we know about the importance of escalating radiation doses goes out the window considering this was achieved with as little as 25Gy/5 to extensive mediastinal disease. Could EGFR-TKIs be potentiating radiation…? All we can do is point to the survival curves and speculate. Finally, questions remain as to how this applies in the setting of brain mets or the more-commonly used newer-gen EGFR-TKIs of today (e.g. osimertinib).

TBL: Five or fewer radiation treatments to all sites of de novo oligometastatic disease (5 or fewer mets) deserves discussion for patients receiving EGFR-targeted therapy for NSCLC. | Wang, JNCI 2022