The ASCENT trial: A phase II study of neoadjuvant afatinib, chemoradiation and surgery for stage III EGFR mutation-positive NSCLC.

8544 Background: The stage III NSCLC paradigm now includes immunotherapy (IO), but advanced EGFR-mutant (EGFR+) pts typically don’t respond to IO. In 2011 we began a phase II trial of neoadjuvant afatinib (NeoAfat) and standard of care (SOC) curative intent treatment for EGFR+ stage III NSCLC, NCT01553942. We present an interim analysis given the evolving SOC landscape. Methods: EGFR+ stage III pts amenable to curative-intent chemoradiation (CRT) ± surgery were treated with NeoAfat 40mg po QD x2mo, then concurrent CRT: cisplatin 75mg/m2 + pemetrexed 500mg/m2 IV q3wk up to 4 cycles and 3D conformal RT or IMRT personalized to tumor size, site, operability. Surgery and adjuvant afatinib (AdjAfat) x2yr were optional. Primary outcome was objective response rate (ORR) to NeoAfat. Results: 13 pts were treated (10F/3M); med age 56 (range 34-75). EGFR mutations: del19 (n = 9); L858R (n = 4). Stage: operable IIIA (n = 7); inoperable IIIA/B (n = 6). NeoAfat ORR = 69% (95% CI 39-91); 5 (38%) pts dose reduced NeoAfat. All pts proceeded to CRT with pre-op med RT dose of 54 Gy (range 45-66; n = 7), definitive med dose of 65 Gy (range 63-72; n = 6). 5 (71%) of the 7 surgical pts had major (4) or complete (1) pathologic response. 7 (54%) pts started AdjAfat at med dose of 30mg QD; 4 completed 2yr, 2 aborted early, 1 ongoing . Key grade 3/4 toxicities: rash 5), diarrhea (5), esophagitis (3), nausea (3), pneumonitis (2 gr 3) and febrile neutropenia (1); no treatment-related deaths. With med follow-up of 24.1 mo (range 5.0-64.2), 6 (46%) pts have recurred; including 4/6 inoperable pts, 2/7 who had surgery, 1/5 with major path response (CNS-only recurrence). Med PFS is 34.6 mo (95% CI 12.6-NR). 2-yr OS is 85% (95% CI 33-98). Conclusions: Neo-adjuvant afatinib achieves high ORR and major surgical path responses, and doesn’t impair receipt of SOC, curative CRT ± surgery in EGFR+ stage III NSCLC. Feasibility of NeoAfat exceeds AdjAfat in stage III setting. The prolonged PFS compares favorably to PACIFIC IO arm; more data is needed about optimal strategy for stage III EGFR+ pts. ASCENT is still ongoing, but it and similar randomized RTOG 1306 have accrued slowly, highlighting the challenge of studying curative approaches in genotype-defined subgroups. Clinical trial information: NCT01553942.