Personalized RadiotherapyPersonalized Radiotherapy for Individualized Treatment Strategies and Monitoring (PRISM)

PULSAR with online adaptive planning to 7-10 Gy per fraction for up to 3 pulses directed at the bulkiest sites of disease in the thorax before infusion days (window: D-1 to D-4; optimal D-1) of three cycles of chemoimmunotherapy. The first radiotherapy pulse must be delivered before chemoimmunotherapy cycle 4. The three "pulses" of radiotherapy ideally should be given with consecutive cycles of systemic therapy. Radiotherapy can be suspended if a complete clinical response is reached before all 3 pulses are delivered. Chemoimmunotherapy will be given per standard of care

PULSAR will be delivered in a 2 "pulse" strategy:

1: Deliver fSRT/SRS every other day (minimum 48 hour separation between treatments, minimum 1 treatment per week;begin and complete within 60 days of registration) for 3 fractions. Pulse 1 must begin and complete within 60 days of registration; 2) Repeat treatment planning MRI will be performed after 4 weeks (window: +/-1 weeks) after fraction 3 and volumetric response assessment made; 3) Pulse 2 is omitted in those with >=25% volumetric size reduction response. In others, pulse 2 will deliver fSRT/SRS every other day (minimum 48 hour separation between treatments, minimum 1 treatment per week). Pulse 2 may deliver higher dose per fraction within Section 4.1.3.4 specifications (Table 6), rationale for this would be for addressing lesions that either due to large size or proximity to critical structures could only be treated to a lower dose range in pulse 1. Pulse 2 must begin 4 weeks (+/-1 weeks) after end of Pulse 1.

Patients will receive pembrolizumab infusion every 3 weeks for three doses starting the day after the first pulse of radiation and then synchronizing the day after the administration of each pulse of radiation. Adjuvant pembrolizumab may be given at physician discretion per standard of care. External beam radiation will be delivered to a dose of 24 Gy in pulses of 8 Gy each once every 3 weeks over a total of 9 weeks. Surgery will be performed 3-6 weeks after cycle 3 of immunotherapy.

Random PULSAR or SAbR,by site.PULSAR:Each pulse of radiotherapy(RT)(8Gy)given to primary tumor/involved nodes using online adaptive RT plan.RT given 1-7 days before each pembrolizumab cycle,total of 3 pulses,3 weeks apart.Before 3rd pulse,repeat MRI \& PET simulation done.SAbR:Each fraction of RT(8 Gy)given to primary tumor/nodes using online adaptive RT plan.Total of 3 fractions of RT over 2 weeks,then 3 cycles of pembrolizumab done every 3 weeks.Both arms:adjuvant RT determined on surgical pathology \& risks of recurrence.Factors in primary tumor for adjuvant RT:pathologic T3/T4,positive/close(defined as <3 mm)margins,lymphovascular invasion/perineural invasion.Factors in neck for adjuvant RT: >1 lymph node,lymph nodes >3 cm. Independent decision to treat primary site/lymph(either primary site/lymph treated based on criteria.)For adjuvant RT,primary site dose:60Gy in 30 fractions.Involved nodals:60Gy in 30 fractions.Uninvolved nodals:54Gy in 30 fractions.

Radiographic response-adapted thoracic tumor radiotherapy given as single doses ('pulses') before standard of care chemoimmunotherapy cycles. Adaptive Changes Allowed: Tumor target (size/shape), # of doses (reduction) Adaptive Changes Allowed: Tumor target (size/shape), # of doses (reduction)

Fractionated stereotactic radiosurgery (SRS, 5 doses total) for brain metastasis given in two "pulses" (3 fractions + 2 fractions) with second pulse adapted to interim radiographic response Adaptive Changes Allowed: Omission of 2nd "pulse" in >=25% responders or tumor target size/shape change in remainder

Pre-operative PULSAR with immunotherapy for localized soft tissue sarcoma Adaptive Changes Allowed: Tumor target (size/shape)

Neoadjuvant immunotherapy \& radiation given as either PULSAR (3 "pulses") or SAbR (3 fractions) prior to resection for HNSCC Adaptive Changes Allowed: Tumor and nodal target (size/shape)