3662 - A Phase II Study of Single Fraction Induction Spatially Fractionated Radiation Therapy SFRT Prior Neoadjuvant Chemotherapy/Immunotherapy for Patients with Resectable Non-Small Cell Lung Cancer

Purpose/Objective(s):

Spatially fractionated radiation therapy (SFRT) may enhance the pathological response when used as an induction prior to neoadjuvant chemo-immunotherapy in NSCLC. Irradiation of the tumor incites a robust inflammatory response. Thus, converting a tumor into an immunogenic hub that functions as an in-situ vaccine through various coordinated actions, including the exposure of tumor-associated antigens, the induction of immunogenic cell death, and the cross-priming of antigen-specific T cells. Phase III trials of chemo-IO achieved 17-24% of pCR, yet outcomes remain suboptimal. Patients achieving pCR consistently demonstrate significantly improved OS and EFS compared with those with incomplete or major pathological responses, underscoring the need to enhance pCR rates. In the palliative setting, retrospective SFRT data demonstrated high one-year local control (83%) with acceptable toxicity (grade =3 toxicity 13%). Conversely, the LU005 randomized trial showed no benefit when radiation was given concurrently with immunotherapy, highlighting the importance of timing. This study will evaluate whether induction SFRT can serve as an immune-priming bridge to improve systemic therapy pCR rates in resectable NSCLC.

Materials/Methods:

Eligible patients must have histologically confirmed NSCLC with primary tumor measuring at least 4cm in diameter. Participants will receive one fraction of SFRT with dose variations from 1500-1800 cGy using an alpha/beta of 10 equal to an equivalent dose in 2 Gy fractions (EQD2) of 3100-4200 cGy and biologic equivalent doses (BEDs) ranging from 37.50-50 Gy. Participants will have a week of holiday treatment to give the immune system time to mount a response to the effects of SFRT before starting a 1:1 ratio of fixed-dose IO-platinum base chemotherapy every 3 weeks at the discretion of the medical oncologist.

Primary endpoint: Pathological complete response Secondary endpoints: Frequency of treatment related adverse events (TRAEs), major pathologic response (MPR; - =10% residual viable tumor), 1-year progression free survival (PFS), 1-year overall survival (OS) and correlative immune analyses (CD4+/CD8+ ratio and VEGF production)

Results:

Trial in progress, pending activation following PRMC and IRB review

Conclusion:

This study will evaluate whether induction SFRT can augment the efficacy of neoadjuvant chemo-IO in resectable NSCLC. By shifting RT from a concurrent role to an immune-priming strategy, this trial aims to define optimal sequencing for integrating RT and IO.

Clinical Timeline:

Biopsy and Diagnosis	Screening and Baseline	5 - 10 days	POST SFRT research labs (Prior to cycle 1 only)
	Pre-SFRT Research labs	SFRT	Chemotherapy/Immunotherapy	Imaging: CT and/or PET scans	Surgeon Evaluation	Surgical Resection
			Standard of care (q3 weeks)	3 weeks (+/- 1week) post Chemo-IO		pCR Evaluation