A Study Evaluating The Combination of Immunotherapy With Radiotherapy in Non-Small Cell Lung Cancer

Inclusion Criteria:

* Disease-Related Criteria

  * Patients must have histologically or cytologically confirmed metastatic or recurrent non-small cell lung cancer (NSCLC) with progression on prior immunotherapy
  * The patient's disease is eligible for SOC treatment with immunotherapy or chemotherapy.
  * Patients must have measurable disease per RECIST v1.1, defined as at least one lesion that can be accurately measured in at least one dimension with longest diameter ≥10 mm (or ≥15 mm short axis for lymph nodes) by CT or MRI
  * Patients must have at least one lesion that meets criteria for hypofractionated ablative RT treatment:
  * Tumor volume 0.25 cc to 65 cc (approximately ≤5 cm maximal dimension)
  * Located in sites amenable to ablative RT (see radiotherapy section for specific anatomic criteria)
  * Note: Tumors \>65 cc may be partially treated to 65 cc volume
  * Prior/Concurrent Therapy Criteria
  * Patients must have received exactly ONE prior line of anti-PD-1 or anti-PD-L1 therapy for non-small cell lung cancer. This therapy may have been given as:
  * Monotherapy
  * In combination with chemotherapy
  * In combination with another immunotherapy such as CTLA-4 inhibition
  * In combination with a targeted therapy, such as adagrasib
  * Special Cases for Neoadjuvant/Adjuvant Immunotherapy:
  * If patient received neoadjuvant, adjuvant, or consolidation anti-PD-1/PD-L1 therapy for Stage I-III disease and progressed ≤365 days from initiation (Cycle 1 Day 1), this counts as the single allowed therapy for advanced disease
  * If patient progressed \>365 days from neoadjuvant/adjuvant therapy initiation, this does NOT count as therapy for advanced disease, and patient must have received subsequent anti-PD-1/PD-L1 therapy for Stage IV or recurrent disease
  * Patients with the following sensitizing mutations are ineligible, given known poor response to immunotherapy: EGFR, ALK, ROS1, RET, NTRK, HER2.
  * Patients with the following sensitizing mutations must have previously received at least one of the appropriate targeted therapies, in addition to prior immunotherapy: BRAF, KRAS, MET. Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria is also met.
* Clinical/Laboratory Criteria

  * Age ≥18 years
  * ECOG Performance Status 0-2 (see Appendix A)
  * Participants must be able to safely receive the investigational drug combination and the investigator's choice of standard of care regimens described in Section 5.1 (Agent Administration), per the current FDA-approved package inserts, treating investigator's discretion, and institutional guidelines.
  * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  * Because radiation and chemotherapy are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Both men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of immunotherapy, radiation, and/or chemotherapy administration.
  * Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Patients with history of (non-infectious) pneumonitis requiring corticosteroids.
* Patients with evidence of interstitial lung disease.
* Patients with uncontrolled intercurrent illness.
* Pregnant women are excluded from this study. Radiation is considered Class X and chemotherapy such as docetaxel are considered Class D agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with radiation, immunotherapy, and chemotherapy breastfeeding should be discontinued if the mother is participating in the study.

Radiation-Specific Exclusions

* Patients who have received prior radiation to any of the planned treatment sites (\>10% dose overlap)
* Patients with lesions in locations not amenable to safe ablative RT delivery, including:
* Esophagus or stomach directly involved by tumor (unless dose constraints can be met)
* Small bowel or colon directly involved by tumor (unless dose constraints can be met)
* Spinal cord lesions with \<3 mm clearance between epidural disease and spinal cord