Thoracic Radiotherapy and Inhibition of PD-1 and LAG-3 for Locally Advanced Non-Small Cell Lung Cancer

Determine anti-tumor efficacy by characterizing response rates on positron emission tomography (PET) following three cycles of induction immunotherapy with cemiplimab and fianlimab without chemotherapy for locally advanced non-small cell lung cancer (LA-NSCLC).

Non-small cell lung cancer (NSCLC) represents more than 80% of lung cancers, and approximately 35% of NSCLC patients present with stage III disease. Standard treatment for patients with locally advanced NSCLC, which may be defined as American Joint Committee on Cancer (AJCC) stage III disease or unresectable stage II disease, typically consists of conventionally fractionated (1.8-2.0 Gray (Gy) per day) radiotherapy (RT) to a total dose of approximately 60 Gy with concurrent chemotherapy. Based on the PACIFIC trial (NCT02125461), patients without disease progression after concurrent chemoradiotherapy are typically offered a one-year course of the adjuvant PD-L1 inhibitor durvalumab, regardless of PD-L1 tumor proportion score (TPS). Recent results from the PACIFIC-2 trial (NCT03519971) failed to demonstrate a survival benefit of adding concurrent durvalumab to chemoradiotherapy, and therefore the PACIFIC regimen of adjuvant immunotherapy following chemoradiation remains the standard of care for unresectable LA-NSCLC.

Based on the PACIFIC trial standard, both the RT and systemic therapy utilized to treat LA-NSCLC patients in standard of care follow a non-biomarker selected "one-size-fits-all" approach in the US. In advanced NSCLC, however, patients with high PD-L1 TPS score (≥ 50%) benefit more from the immune checkpoint inhibitors pembrolizumab, atezolizumab, and cemiplimab compared to cytotoxic chemotherapy alone, and single agent immunotherapy (IO) has become a first-line standard of care for such patients. Omitting chemotherapy from the treatment of LA-NSCLC patients with high PD-L1 expression who will receive IO is a logical step. On the other hand, patients with low PD-L1 TPS score (\< 50%) benefit less from single agent IO in advanced NSCLC, and IO is typically offered together with chemotherapy. Given the poor response to IO for patients with low PD-L1 TPS expression, the investigator team believes that combination IO plus chemotherapy could be particularly beneficial in the low-TPS LA-NSCLC setting.

Induction (also referred to as neoadjuvant) IO before RT for LA-NSCLC has several potential advantages. For example, the native tumor functioning as an in-situ vaccine in the neoadjuvant setting, with an intact lymphatic system and unirradiated nodal status, could promote optimal immune priming. Indeed, neoadjuvant IO has shown impressive efficacy in both deficient mismatch repair (dMMR) rectal cancer and melanoma. For early-stage NSCLC, this approach is highlighted in recent neoadjuvant trials of immune checkpoint inhibition in combination with chemotherapy for resectable NSCLC, such as CheckMate 816 (NCT02998528), Keynote-671 (NCT03425643), and NADIMII (NCT03838159). Furthermore, results from the PACIFIC trial and real-world data show that approximately 25% of LA-NSCLC patients started on chemoradiotherapy never receive consolidation durvalumab, and approximately 50% of patients started on consolidation durvalumab do not complete the intended year of treatment. Thus, administering induction IO may be particularly advantageous for LA-NSCLC patients to enhance IO treatment delivery.

SPRINT (NCT03523702) was a multi-institutional Phase II trial where biomarker-selected (PD-L1 TPS ≥ 50%) LA-NSCLC patients were treated with 3 cycles of induction pembrolizumab to reduce the extent of thoracic RT, and cytotoxic chemotherapy was omitted from the treatment regimen. Patients with PD-L1 TPS \< 50% received standard concurrent chemoradiotherapy (chemoRT) followed by standard adjuvant treatment, to serve as a non-randomized comparator for evaluating toxicities and clinical outcomes. Following induction, PD-L1 TPS ≥ 50% patients received PET-based dose-painted RT according to a novel and personalized approach that was studied in two prior trials (NCT02073968, NCT03481114) that can decrease toxicities by utilizing shortened courses of RT and reducing doses administered to small tumors and nodes. Based on these studies, PET response to induction IO using PERCIST criteria may serve as a useful prognostic factor to identify LA-NSCLC patients more likely to respond to novel IO regimens at an earlier time point in treatment (prior to administration of RT). This observation is also supported by prior prospective and retrospective studies showing that response on PET rather than CT may be a better predictor of survival for NSCLC patients receiving IO. Furthermore, early identification of IO response provides added insight to a tumor's unique immune biology that could be used to individualize subsequent RT, IO, and/or chemotherapy treatment plans. Overall, SPRINT demonstrated high treatment efficacy with limited toxicity and introduces PET response to induction IO as a novel endpoint that allows for early assessment of treatment activity, and which could potentially serve as a new paradigm in LA-NSCLC interventional studies.

Based on this experience, the investigator team believes that the SPRINT treatment approach (induction IO followed by RT and consolidation IO) can be used to investigate other novel IO combinations for biomarker-selected LA-NSCLC. One such immune target is lymphocyte activation gene 3 (LAG3), which is expressed by various immune cells, and regulates effector T-cell activation and responses. LAG-3 inhibition restores the effector function of exhausted T cells, enhancing their ability to attack tumor cells. In addition, LAG-3's inhibitory effects on T cells appear distinct from those of PD-L1, serving as a potential rationale for combining LAG-3 and PD-1/PD-L1 inhibition. In metastatic melanoma, the RELATIVITY-047 trial (NCT03470922) showed that combination PD-1 and LAG-3 blockade with nivolumab and relatlimab, respectively, improves progression-free survival (PFS) compared to nivolumab alone with a favorable toxicity versus nivolumab plus the CTLA-4 inhibitor ipilimumab. These findings suggest that combination PD-1 and LAG-3 inhibition may have potential utility for treatment of other malignancies, such as NSCLC. Furthermore, a Phase I study of cemiplimab and fianlimab in unresectable stage IIIB-C or IV NSCLC (NCT03005782) showed that the combination demonstrated clinical activity with a similar safety profile compared to cemiplimab alone. Given the promising findings observed in SPRINT, RELATIVITY-047, and NCT03005782, the research team believes that dual immune checkpoint blockade with the PD-1 inhibitor cemiplimab plus the LAG-3 inhibitor fianlimab administered before and after thoracic RT, as per the SPRINT approach, has valuable therapeutic potential for LA-NSCLC patients.

Treatment will be administered in three phases as detailed in this registration: (1) three cycles of induction IO, with histology-specific platinum doublet chemotherapy (PDC) added for subjects with PD-L1 TPS \<50%; (2) thoracic RT (with concurrent PDC recommended for subjects with PD-L1 TPS \<50%); (3) 13 cycles of consolidation IO.

Eligibility Criteria:
Inclusion Criteria:

* Previously untreated and biopsy-proven NSCLC, with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection or stereotactic radiotherapy for early-stage disease is allowed)

  * AJCC version 8 Stage II disease, medically or technically unresectable
  * AJCC version 8 Stage III disease, eligible for non-surgical treatment
* Determination of PD-L1 expression on pretreatment tumor specimen using a clinically validated assay
* Eligible for standard nonsurgical treatment for Stage III NSCLC, i.e., chemotherapy and concurrent RT followed by adjuvant durvalumab
* Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic pulmonary lesion(s) and/or thoracic lymph node(s)
* MRI of the brain or head CT with contrast within 42 days prior to study entry
* PFTs within 42 days of study entry
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Adequate end-organ function for study therapy, as per clinician assessment and including:

  * Hemoglobin ≥ 9.0 g/dL
  * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (\> 1500 per mm3)
  * Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
  * Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
  * AST (SGOT)/ALT (SGPT), and alkaline phosphatase ≤ 2.5 x institutional upper limit of normal (ULN)
  * Serum creatinine clearance \>30 mL/min by the Cockcroft-Gault formula (as below) or by 24-hour urine collection for determination of creatinine clearance: (except for patients planned to receive pemetrexed, in which case serum creatinine clearance needs to \>45 ml/min)

    * Males: Weight (kg) x (140 - Age) ÷ (72 x serum creatinine (mg/dL))
    * Females: 0.85 x Weight (kg) x (140 - Age) ÷ (72 x serum creatinine (mg/dL))
* A female participant is eligible to participate if she is not pregnant (see Exclusion Criteria), not breastfeeding, and at least one of the following conditions applies:

  * Not a woman of childbearing potential (WOCBP) as defined in the Appendix
  * A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 6 months (180 days) after the last dose of study treatment with cemiplimab and fianlimab
  * A WOCBP who agrees to follow the contraceptive guidance in the Appendix and for at least 6 months after the last dose of chemotherapy or as specified in FDA prescribing labels (e.g. 14 months after the last dose of cisplatin)
* A male participant must agree to use contraception during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period
* The participant (or legally acceptable representative if applicable) provides written informed consent for the trial

Exclusion Criteria:

* Presence of known sensitizing epidermal growth factor (EGFR) mutation or anaplastic lymphoma kinase (ALK) fusion

  o Determination of EGFR/ALK mutation status is required for non-squamous cell carcinoma histologies and recommended for squamous cell carcinoma
* Prior therapy with an anti-PD-1, anti-PD-L1, or LAG-3 inhibitor
* Patient currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
* Active malignancy other than lung cancer that (1) requires active treatment other than hormonal therapy and (2) is deemed by the treating physicians to be likely to affect the patient's life expectancy
* A history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Known history of myocarditis
* Troponin T (TnT) or troponin I (TnI) \> 2x institutional ULN at baseline. Patients with TnT or TnI levels between \> 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \> 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on the medical judgement in the patient's best interest
* Known active Bacillus Tuberculosis (TB)
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Pregnancy, assessed with urine pregnancy test within 72 hours prior to study treatment allocation. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test is required. If more than 72 hours elapse between screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative
* Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment
* History or current evidence of significant (CTCAE grade ≥2) local or systemic infection (e.g., cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication
* Active infection requiring therapy
* Uncontrolled infection with HIV, Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection

  * Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards
  * Patients with known hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug
  * Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by polymerase chain reaction (PCR) either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted
  * Patients with HIV or hepatitis must be reviewed by a qualified specialist (e.g., infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial
* Diagnosis of immunodeficiency or ongoing chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
* Known hypersensitivity to the active substances or to any of the excipients
* Received a live vaccine within 30 days of planned start of study medication o Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing