What this trial measures

• COHORT A-assess safety of addition of PULSAR radiotherapy to thoracic tumor in ES-SCLC alongside chemoimmunotherapy, while making preliminary/exploratory assessments of disease response and dosimetric benefit to PULSAR5 years

  Primary objective will be to report safety of PULSAR with chemoimmunotherapy for extensive stage small cell lung cancer. Accrual goal will be 15 patients.Study is interested in precise estimates of safety as well as outcome variability that will aid in the planning of larger, sufficiently powered efficacy trial. Sample size of 15 patients will allow for relative precision in conclusions regarding safety outcome.Namely,if 4 out of 15 patients enrolled are observed as having grade 3+ cardiopulmonary acute toxicity,the 95% CI for that rate would be (7.95%-55.10%) using an Exact (Clopper-Pearson) binomial confidence interval. Descriptive statistics according to variable type (continuous, categorical) will be used for reporting the cohort characteristics. Primary endpoint of pre-defined high grade toxicities will be reported as a categorical percentage.Disease control(time to event variables) will be reported by Kaplan-Meier estimates.

• COHORT B-assesses ability to de-escalate dose in good responders by imaging using rule-based imaging-response guided omission of 2nd "pulse" of PULSAR fractionated SRS (fSRS) for brain metastases5 years

  Sample size comparing local control \& toxicity with prior PULSAR data(which didn't dose de-escalate based on response)to ensure high control rate is preserved.Using two-tailed test with alpha of 0.05 \& power of 0.8,estimated sample size to detect difference in 1-yr local failure rates between pSRT \& fSRT.Stats according to variable type(continuous,categorical)used for reporting primary endpoint of proportion of patients de-escalated \& endpoints.To evaluate local control \& toxicity(late CNS),competing risk regression \& calculated cumulative incidence,with death as competing risk will be performed.Gray's test will be used to assess statistical significance.OS analyzed using Kaplan-Meier method using survival,log-rank test employed to compare survival distributions.To account for clustered data,where patients may have multiple brain metastases treated,repeated analyses for CRR using crrSC(R package)will be performed.

• COHORT C- assess the rate of MWC in a novel approach of immunotherapy with concurrent PULSAR.5 years

  Descriptive analyses will summarize the number and proportion of patients with MWCs, exact 95% confidence intervals, timing of MWCs relative to surgery, severity, management required, attribution to treatment, and whether each event occurred within the irradiated field. Given the small sample size and feasibility-oriented objective, analyses will be primarily descriptive rather than powered for formal hypothesis testing. Exploratory outcomes, including progression-free survival, pathologic response, immune correlates, and other clinical endpoints, will be summarized descriptively to inform future study design.

• COHORT D-assess the proportion of patients who proceed to curative intent resection following neoadjuvant therapy.5 years

  The primary endpoint is feasibility of the neoadjuvant radiotherapy and immunotherapy paradigm, defined as the proportion of patients who proceed to curative-intent surgical resection. Feasibility will be evaluated separately for each treatment arm, with particular focus on the PULSAR-IO arm. For each arm, the observed proportion proceeding to surgery will be summarized along with Exact (Clopper-Pearson) binomial confidence intervals. Feasibility will be declared if at least 90% of patients in the treatment arm proceed to curative-intent surgery. No formal hypothesis testing or between-arm comparisons are planned for the primary feasibility endpoint.