Integration of EGFR Inhibition With Radiation-Based Multimodality Treatment in Stage III EGFR Mutant NSCLC

Abstract

<h3>Purpose/Objective(s)</h3> Patients with stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CRT) may not benefit from consolidation immune checkpoint inhibitors, and adjuvant EGFR tyrosine kinase inhibitor (TKI) treatment with osimertinib is now approved for stage IB-IIIA. Whether and how to integrate TKI into the treatment of unresectable or borderline resectable stage III disease is unclear. <h3>Materials/Methods</h3> Patients with stage III (AJCC 7th ed.) EGFR mutant NSCLC amenable to CRT ± surgery were enrolled onto an IRB-approved Phase II trial (clinicaltrials.gov registered) and received induction afatinib 40 mg QD x 2 months, either definitive or neoadjuvant CRT with cisplatin/pemetrexed, surgery if appropriate, and 2 years of adjuvant afatinib provided there was no primary progression during the induction phase. The trial was closed for slow accrual. The primary endpoint of objective response rate after induction TKI and early survival outcomes have been previously reported. This is a secondary analysis of recurrences and updated outcomes. <h3>Results</h3> Seventeen patients completed induction TKI and CRT ± surgery between 2012 and 2020. There were 74% females. Median age was 56 years (range, 34-75 years). Neoadjuvant and definitive median radiation doses were 54 Gy (range, 45-66 Gy) and 66.6 Gy (range, 63-72 Gy). Ten patients with biopsy confirmed N2 (n = 9) or N3 (n = 1) disease underwent surgery which showed a mediastinal sterilization rate of 60%. Adjuvant TKI was initiated in 14 patients including 1 case of off-protocol erlotinib. Three patients aborted TKI, 7 completed 2 years of TKI, 2 remained on TKI at last follow-up while 2 switched to other treatments after recurrence. Notably, of the 7 patients completing 2 years of TKI, 6 recurred after a median interval of only 3 months (range, 1-55 months) from the completion date. In total there were 11 recurrences. The dominant pattern of recurrence was distant with just 1 isolated local failure in a patient treated with definitive CRT. Five of 11 recurrences were CNS-only, all of which occurred after completion of adjuvant TKI at a median interval of 4 months. Four of these patients had intracranial disease control at last follow-up. No grade 3+ radiation treatment related toxic events were observed. With a median follow-up of 43.3 months for patients alive, median progression-free survival (PFS) and overall survival (OS) times were 32 months and not reached, respectively. 3-year PFS and OS rates were 31% (95% CI, 6-56%) and 69% (43-94%), respectively. <h3>Conclusion</h3> This trial highlights the efficacy of aggressive local therapy and the potential promise of TKI treatment for stage III EGFR mutant NSCLC though interpretations are limited by small sample size. One particular risk for patients was CNS-only recurrence suggesting that better CNS directed treatments and CNS surveillance strategies should be studied to increase cure rates in this unique, genotype-defined NSCLC population.