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Clinical Trial
. 2024 Jul 5;29(7):609-618.
doi: 10.1093/oncolo/oyae107.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC

Allison E B Chang  1 , Andrew J Piper-Vallillo  2 , Raymond H Mak  3 , Michael Lanuti  4 , Alona Muzikansky  5 , Julia Rotow  6 , Pasi A Jänne  6 , Mari Mino-Kenudson  7 , Scott Swanson  8 , Cameron D Wright  4 , David Kozono  3 , Paul Marcoux  6 , Zofia Piotrowska  1 , Lecia V Sequist  1 , Henning Willers  9
Affiliations
Clinical Trial

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC

Allison E B Chang et al. Oncologist. .

Abstract

Background: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC.

Patients and methods: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population.

Results: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths.

Conclusion: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Keywords: EGFR-mutant; lung cancer; oncogenes; radiation oncology; stage III; surgical oncology.

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Conflict of interest statement

A.C.: none. A.P.V.: Sanofi-Genzyme and Takeda (consulting). R.M.: ViewRay (Advisory Board, consulting, research funding), AstraZeneca (Advisory Board), Varian Medical Systems (Consulting) Sio Capital Management (Consulting), Novartis (Honorarium). M.L.: none. A.M.: none. J.R.: consulting fees or honoraria from Amgen, AstraZeneca, BioAtla, BMS, Daiichi Sankyo, Genentech, G1 Therapeutics, Guardant Health, Janssen, Jazz Pharmaceuticals, Sanofi-Genzyme, Summit Therapeutics and Takeda; contracted for research (institutional) with: AstraZeneca, BioAtla, Blueprint Medicines, Enliven Therapeutics, EpimAb Biotherapeutics, LOXO Oncology, ORIC. P.A.J.: grants: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Puma Technology, Revolution Medicines, and Takeda Oncology; royalties and patents: LabCorp; consulting fees: AbbVie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai Pharmaceutical Co., Daiichi Sankyo, Duality, Eisai, Eli Lilly, Frontier Medicines, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta, and Voronoi. Stock or stock options: Gatekeeper Pharmaceuticals. M.M.K.: AstraZeneca, Pfizer, Repare, Boehringer Ingelheim, Sanofi, AbbVie, Daiichi Sankyo (consultancy), Elsevier (royalties). S.S.: none. C.W.: none. D.K.: Genentech/Roche (consultancy), RefleXion (honorarium). P.M.: none. Z.P.: served as a consultant and/or received honoraria from Eli Lilly, Boehringer Ingelheim, Bayer, Sanofi/Genzyme, C4 Therapeutics, Janssen, Takeda, Cullinan Oncology, Daiichi Sankyo Europe GmbH, Lilly, AstraZeneca, Taiho Pharmaceutical, Blueprint Medicines; received institutional research funding from Novartis, ARIAD/Takeda, Spectrum Pharmaceuticals, AstraZeneca, Cullinan Oncology, Daiichi Sankyo Europe GmbH, AbbVie, Janssen Oncology, Blueprint Medicines, GlaxoSmithKline/Tesaro; serves on a data safety monitoring committee for Genentech/Roche; and has received travel support from Janssen and AstraZeneca. L.V.S.: received institutional research funding from AstraZeneca, Novartis, and Delfi Diagnostics, and is involved in a clinical demonstration project funded by GRAIL and Point 32 Health. H.W.: none.

Figures

Figure 1.
Figure 1.
Modified CONSORT diagram.
Figure 2.
Figure 2.
Efficacy. (A) Individual patient RECIST response after 2 months of induction afatinib (n = 19). ND denotes lack of measurable disease by RECIST. Circles denote patients who were thought to be unresectable at study entry, but had dramatic responses to therapy and underwent surgery. Note: RECIST responses were not confirmed with a second scan as patients proceeded directly to chemoradiotherapy. ORR, objective response rate. (B) Distribution of pathologic response at time of surgery (n = 10 patients). Major pathologic response was defined as <10% residual tumor cells. (C) Progression-free survival of cohort. (D) Overall survival of cohort.
Figure 3.
Figure 3.
Patterns of disease progression. (A) Right: the longitudinal course of all 19 patients is depicted by horizontal bars of varying length. Periods of deviation from protocol-defined therapy are noted with a checkered bar; these deviations included continuation of consolidation afatinib beyond the predefined 2-year period or off-protocol consolidation erlotinib. Left: colored boxes denote T-stage, N-stage, resectability at diagnosis, RECIST response category after induction afatinib, surgical disposition, pathologic response at time of surgery (major pathological response is <10% residual tumor cells, pCR is pathological complete response), completion of 2 years of consolidation afatinib, and recurrence isolated to the central nervous system (CNS). (B) Progression-free survival after stopping consolidation afatinib (n = 12, includes only those patients who received consolidation afatinib and no other consolidation TKI off-protocol). (C) Distribution of site of first recurrence (n = 19, ITT group).
Figure 4.
Figure 4.
Adverse events per CTCAE version 4.0.
See this image and copyright information in PMC

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