2138 - A Phase II Randomized Clinical Trial (MC1623) of Concurrent Chemotherapy and Standard (60-66 Gy) vs. High (72 Gy) Dose Proton Beam Therapy (PBT) for Patients with Unresectable, Stage II/III Non-Small

T. T. W. Sio¹, N. Y. Yu¹, M. M. Voss², T. B. Daniels³, W. Liu¹, M. R. Buras⁴, Y. Rong⁵, T. A. DeWees⁶, J. Stoker⁷, V. Ernani⁸, S. E. Beamer⁹, K. K. Sakata¹⁰, M. Bues¹, S. Ravanbakhsh¹¹, R. Tao¹², H. R. Paripati¹³, X. Ding¹⁴, J. DCunha¹¹, K. L. Swanson¹⁰, and S. E. Schild¹; ¹Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, ²Department of Quantitative Health Sciences, Mayo Clinic, Phoenix, AZ, ³NYU Langone Health, New York, NY, ⁴Department of Qualitative Health Sciences, Section of Biostatistics, Mayo Clinic, Scottsdale, AZ, ⁵Department of Radiation Oncology, Mayo Clinic AZ, Phoenix, AZ, ⁶Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Duarte, CA, ⁷Mayo Clinic, Phoenix, AZ, ⁸Medical Oncology, Mayo Clinic Arizona, Phoenix, AZ, ⁹Department of Thoracic Surgery, Mayo Clinic, Phoenix, AZ, ¹⁰Pulmonary Medicine, Mayo Clinic Arizona, Phoenix, AZ, ¹¹Cardiothoracic Surgery, Mayo Clinic Arizona, Phoenix, AZ, ¹²Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, ¹³Department of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, ¹⁴Mayo Clinic Arizona, Phoenix, AZ

Purpose/Objective(s): NRG 0617 established that the standard dose of photon RT for unresectable NSCLC is 60 Gy in 30 fractions. However, no dose-escalating trials have been reported for modern active-scanning PBT. A signal-seeking Phase II randomized study (MC1623) was designed and conducted to address this. Materials/Methods: A single-institutional study was performed. Inclusion criteria included patient (pt)’s age = 18 years; tissue confirmation of NSCLC; PFT’s FEV1 = 1 L; unresectable or medically inoperable stage II-III; ECOG PS 0-1; acceptable labs for concurrent chemo; and curative intent. Exclusion criteria included weight loss = 10%; M1 cancer; uncontrolled illnesses; active second malignancy; and prior RT that would overlap with planned PBT. A brain MRI was required. The original design was to randomize pts into 60 Gy/30 fractions (fx) vs. 66 Gy/33 fx vs. 72 Gy/36 fx arms in a 1:1:1 fashion. Contouring included generations of GTV, iGTV, and CTV’s. SFO/MFO optimization methods were used for PBT. The primary endpoint was progression-free survival (PFS) improvement, with secondary endpoints being overall survival (OS), adverse events, locoregional and distant failure rates.

Results: Accrual was slower than expected, and the 66-Gy arm was first closed, followed by the entire study. Between Aug 2017 and June 2021, 20 pts met inclusion criteria (originally planned for 48 pts). 1 pt was denied by insurance for PBT; 2 (11%) withdrew their consent after randomization. The final analysis consisted of 17 pts. 2 (12%) pts were randomized to the 66-Gy arm, and they were included with the other 8 pts (60 Gy) as standard-dose arm. 7 (41%) pts received 72 Gy (high-dose). The Mayo Prognostic scores for comorbidities were balanced (P=0.89). The mean age was 76.4 (standard) vs. 74.2 years (P=0.50); 8 (47%) were male. 13 (77%) smoked in the past. 8 (47%) pts had squamous cell carcinoma; 8 (50%) pts had T3/4 tumors, and 14 (82%) with N2 nodes. At the end of follow-up (median 1.86 years), 6 pts were alive, and 11 deaths had occurred. There was no difference in progression-free (2.04 vs. 0.94 years, P=0.71) nor overall (3.05 vs. 2.36 years, P=0.74) survivals, for standard vs high dose arms, respectively. Female gender appeared to favor PFS (P=0.03), and no nodal involvement for improved OS (P=0.08). There was 1 pt with grade 3 pneumonitis in standard-dose arm, and 1 pt each with grade 3 myocardial infraction and pulmonary fibrosis in high-dose arm. A competing risk analysis is being planned.

Conclusion: While the study was too small to statistically determine a benefit of one dose arm vs. the other, numerically, there appeared no clear advantage to 72-Gy dose escalation in terms of PFS and OS which could be verified in a larger randomized trial. NRG 1308 should clarify if PBT is superior to photon-based RT. With standard use of immunochemotherapy in addition to CRT for locally advanced NSCLC, the increased chance of cardiopulmonary toxicities may be lessened with better tissue-sparing PBT. This, too, will require further prospective studies.