Personalized Radiotherapy for Individualized Treatment Strategies and Monitoring (PRISM)

Cohort-Specific Rationale

COHORT A (ES-SCLC Personalized ultrahypofractionated stereotactic ablative radiotherapy (PULSAR) Thoracic Tumor):

Chemoimmunotherapy with 4-6 cycles of platinum/etoposide and PD-L1 (Programmed Death-Ligand 1 protein) inhibition has become the standard systemic therapy for extensive stage small cell lung cancer (ES-SCLC), based on modest but significant OS (overall survival) benefits seen with the addition of either atezolizumab or durvalumab to chemotherapy in the IMpower133 and CASPIAN trials, respectively. However, outcomes remain poor with median OS of only 12.3 months. Notably, consolidative thoracic RT (radiotherapy) was not allowed either trial. This contrasts with prior signal for potential benefit for addition of thoracic RT to standard chemotherapy in ES-SCLC in the CREST trial, though this was not duplicated the RTOG 0937. Encouraging preliminary safety data has been published for addition of hypofractionated thoracic RT to single agent PD-1 inhibition after response to induction chemotherapy (6% grade 3 toxicity), but toxicities with doublet immune checkpoint blockade (ipilimumab/nivolumab) and RT showed a nearly 20% rate of high grade AEs (adverse events). This has led to an ongoing cooperative study (NRG LU007) seeking to define the impact of consolidative thoracic RT given with atezolizumab following induction chemotherapy. In the interim, while use of thoracic RT consolidation in ES-SCLC remains supported as a standard of care by guidelines, its implementation is variable. Particularly important open question involve timing for synergy/additivity with immune checkpoint blockade and cytotoxic therapy, minimization of target size for safety, and tailoring of dose according to patient need given significant competing risks for extra-thoracic progression and tolerance. In seeking to address this, this study notes that small cell lung cancer generally shrinks rapidly with each cycle of chemoimmunotherapy. Delivering a "pulse" of RT to the thoracic disease immediately prior to cycles 2-6 of chemoimmunotherapy may result in faster tumor response and reduction of overall treatment target size. Moreover, prolongation of time between doses enables observation of response, which would allow investigators to withhold further RT dose in those unlikely to benefit due to extra-thoracic progression or exceptional early response of thoracic disease.

COHORT B (Brain metastasis PULSAR):

Brain metastases from solid tumors affect nearly 30% of patients who die of cancer and present an increasing challenge for management as patients live longer with improved systemic therapies. Treatment often includes radiotherapy, increasingly delivered as stereotactic radiosurgery (SRS) to spare normal brain. For larger lesions or those near sensitive areas, fractionated stereotactic radiation therapy (FSRT) delivered in up to 5 treatments is used to reduce swelling and late injury. Prolongation of the duration between fSRT treatments from days to weeks further has enabled adjustments of the treatment target to tumor size changes over treatment, further reducing healthy brain exposure without sacrifice in tumor control (7). UT Southwestern has expanded upon this modified fSRT approach with PULSAR. Based upon observed kinetics of response, the predominant PULSAR approach has been to deliver treatments in two "pulses" given as 3 fractions every other day, 3-4 week break, and then 2 final fractions every other day. In the initial experience (n=109 treated lesions), PULSAR demonstrated favorable efficacy and tolerability in treating brain metastases (2-year 90% local control and <10% grade 3 toxicity), when compared to historical fSRT reports especially for larger >=2cm lesions. PULSAR for brain metastases thus shows high potential to address larger tumors and to individualize RT dose/intensity, especially in the setting of increasing numbers of central nervous system (CNS)-active systemic agents.

In particular, with longer patient survivals, there remains a critical need to reduce the risk of toxicity and edema by de-escalating dose in addition to target size. The best 'biomarker' for such de-escalation appears to be early radiographic response, with published work strongly correlating a >=20% lesion volume reduction by 3-months to improved local control. Notably, such reductions are commonly seen in time for decision making in the PULSAR approach, with the collected data previously showing a median 38% reduction in larger tumors (>=2cm) during treatment. Specifically, ~50% of patients achieve a 25% reduction by pulse 2. In this cohort, the study will assess whether a more conservative >=25% tumor volume at interim imaging of PULSAR can be used to omit the second "pulse" for "responders," while retaining high control rates.

COHORT C (Pre-op Sarcoma PULSAR):

Pre-operative radiotherapy is an integral component of treatment for large (>5cm), high grade, extremity and trunk soft tissue sarcomas. Recent developments in this disease include the use of preoperative stereotactic body radiotherapy (SBRT) and the addition of concurrent immunotherapy (IO) to standard long course RT. The SARC032 trial demonstrated that pembrolizumab together with preoperative conventionally fractionated RT improved disease-free survival (DFS) in patients with STS. There was a statistically significant improvement in disease-free survival, with a hazard ratio of 0.61 (90% CI 0.39-0.96), and a 2-year disease-free survival rate of 67% versus 52% in the control group. This is the first trial in decades to improve outcomes for patients with STS and has established a new standard of care. With respect to SBRT, multiple single institution phase II clinical trials have evaluated dose and fractionation schemes of 30-40 Gy in 5 fractions with excellent local control but concern for increases in late toxicities, including wound complications and long bone fractures.

In general, SBRT is an attractive approach to the treatment of STS due to its relative "radioresistance" and low alpha-beta ratio. However, its optimization remains a need in regard to reducing complication risk and refining the target size, leading to its use primarily at high-volume sarcoma centers. Notably, though the sarcoma field has moved towards hypofractionated RT, no study has combined SBRT with IO. This is the natural next step in the evolution of the preoperative paradigm and a ripe opportunity to introduce PULSAR for patients with extremity and truncal STS. PULSAR allows for better synergy with IO compared to conventional RT as it doesn't impede the immune response with daily fraction delivery. In addition, PULSAR may improve the late toxicities seen with recent SBRT regimens by allowing for normal tissue repair in between pulses. Lastly, by delivering this treatment in a spaced-out fashion, real time information regarding tumor response can be obtained via multi-parametric MRI (mpMRI) prior to each pulse, and final tumor imaging responses can be further validated by pathologic assessment of the resected specimen.

COHORT D (Resectable HNSCC PULSAR/SAbR):

Despite recent technological advances, outcomes for HPV-negative locally advanced head and neck squamous cell carcinoma (HNSCC) remain suboptimal, with high rates of recurrence and significant treatment-related morbidity. Neoadjuvant immunotherapy represents a promising strategy to improve oncologic and functional outcomes by addressing micrometastatic disease earlier, increasing pathologic response rates, and potentially de-escalating subsequent treatment. KEYNOTE-689 recently demonstrated that perioperative immunotherapy improves event-free survival in resectable HNSCC, underscoring a potential role for neoadjuvant therapy. However, more than 10% of patients treated with neoadjuvant immunotherapy did not receive curative-intent surgery, and of those who went to resection, fewer than 10% had a major pathologic response.

Building on this foundation, integration of novel radiotherapy paradigms with immunotherapy may further increase response and ultimately long-term outcomes. There have already been several phase I trials combining neoadjuvant stereotactic ablative radiotherapy (SAbR) with immunotherapy, which have shown the paradigm's safety and feasibility along with a major pathologic response rate around 75%. In this context, PULSAR is a tantalizing concept as it allows time for repair of normal tissue and tumor response, enabling adaptation of radiation plans to ongoing anatomic and biologic changes in the tumor. In this study, we will assess the feasibility of neoadjuvant adaptive radiotherapy (either PULSAR or standard SAbR) paired with immunotherapy.