This is a randomized trial evaluating the efficacy and safety of sequential dual-agent immunotherapy and risk-adapted radiotherapy for patients with locally advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score of at least 50%. Participants will be randomized between two dual-agent immunotherapy regimens: durvalumab + monalizumab versus durvalumab + oleclumab.

Lung cancer is the leading cause of cancer-related death worldwide, with more than 1.5 million deaths per year. Non-small-cell lung cancer (NSCLC) represents more than 80% of lung cancers, and approximately one-third of NSCLC patients present with stage III disease. Locally advanced non-small cell lung carcinoma (LA-NSCLC) includes stage III NSCLC and unresectable stage II NSCLC. For several decades, standard treatment for patients with LA-NSCLC consisted of conventionally fractionated (1.8-2.0 Gy/day) radiotherapy to a total dose of approximately 60 Gy with concurrent chemotherapy. Based on the pivotal PACIFIC trial (NCT02125461), patients without disease progression after concurrent chemoradiotherapy are typically offered a one-year course of adjuvant durvalumab, which is an inhibitor of PD-L1. This "one-size-fits-all" approach has several limitations:

• Concurrent chemotherapy causes acute and subacute toxicities, which include esophagitis and pneumonitis. These adverse events impact patients' quality-of-life and can disrupt the planned treatment course, leading to increased risk of disease progression and death. Of note, approximately 25% of LA-NSCLC patients who receive chemoradiotherapy never initiate adjuvant durvalumab due to chemoradiotherapy toxicities or early disease progression. This is a major limitation of the PACIFIC approach, as immunotherapy is the most effective systemic therapy for NSCLC patients with high PD-L1 expression.
• Standard thoracic radiotherapy for LA-NSCLC delivers a uniform radiotherapy dose to the primary lung tumor and involved regional lymph nodes. Based on patterns-of-failure analyses and recent prospective trials, lower radiotherapy doses can be utilized to control small lung tumors and malignant lymph nodes. Unnecessary utilization of high-dose radiotherapy for small tumors and lymph nodes places patients at increased risk for the toxicities described above and can also cause cardiac toxicity and immunosuppression.
• For many patients, deferring immunotherapy for LA-NSCLC until after completion of chemoradiotherapy is problematic. As recently demonstrated in a randomized trial comparing preoperative immunotherapy to postoperative immunotherapy for melanoma, immunotherapy is most effective when utilized to treat intact tumors in patients with preserved immune systems. The current practice of employing regional lymph node irradiation prior to immunotherapy for LA-NSCLC appears to be particularly deleterious. As mentioned above, some LA-NSCLC patients who start treatment with chemoradiotherapy never reach the key phase of adjuvant immunotherapy.

To address the limitations described above and improve the safety and efficacy of LA-NSCLC therapy, Montefiore-Einstein has led a series of trials testing more personalized treatment approaches. The Selective Personalized RadioImmunotherapy for Locally Advanced NSCLC Trial (SPRINT, NCT03523702), tested a novel chemotherapy-free approach where 25 LA-NSCLC patients with PD-L1 TPS ≥ 50% were treated with three cycles of induction pembrolizumab, followed by a four-week course of risk-adapted and de-intensified thoracic radiotherapy based on restaging PET/CT, followed by consolidation pembrolizumab to complete a one-year treatment course. Patients with PD-L1 TPS < 50% could be enrolled and treated with standard concurrent chemoradiotherapy followed by standard adjuvant therapy.

Study participants will receive two cycles of dual-agent immunotherapy followed by a four-week course of risk-adapted radiotherapy, followed by up to ten cycles of dual-agent immunotherapy. Subjects who discontinue study therapy due to disease progression or treatment intolerance may receive additional therapy, at the discretion of the treating physicians.

Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) with PD 1 on T cells and CD80 (B7.1) on immune cells. It has been developed by AstraZeneca for use in the treatment of cancer. The mechanism of action for durvalumab is interference in the interaction of PD-L1 with PD 1 and CD80 (B7-1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in the restored proliferation of interferon-γ (IFN-γ). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell dependent mechanism. Based on these data, durvalumab is expected to stimulate the participant's antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody dependent cellular cytotoxicity and complement-dependent cytotoxicity.

To date, durvalumab has been given to thousands of participants as part of ongoing studies either as monotherapy or in combination with other anticancer agents.

Durvalumab is approved in some countries as monotherapy for unresectable Stage III NSCLC (following chemoradiation therapy), and in combination with chemotherapy for extensive stage small cell lung cancer and for locally advanced or metastatic biliary tract cancer. Durvalumab is approved as monotherapy in unresectable hepatocellular carcinoma in Japan. Durvalumab is also approved when administered in combination with tremelimumab for unresectable hepatocellular carcinoma, and also in combination with tremelimumab plus chemotherapy for participants with metastatic NSCLC without epidermal growth factor receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) mutations.

A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing errors. Given the expectation of similar pharmacokinetic (PK) exposure and variability, AstraZeneca considered it feasible to switch to fixed dosing regimens.

A fixed dose of 1500 mg durvalumab administered q4w is to be used for all participants with a body weight greater than 30 kg. Currently, the use of a fixed dose of 1500 mg durvalumab, administered both in combination with chemotherapy and as monotherapy, is approved for treatment of extensive stage small cell lung cancer. Additionally, the 1500 mg fixed dose is approved in some regions as monotherapy for unresectable stage III NSCLC.

For participants in this study, who will have locally advanced NSCLC with high PD-L1 expression, durvalumab is expected to be among the most effective systemic treatment options to reduce the risk of disease progression and death. The researchers believe that initiation of durvalumab prior to receipt of thoracic radiotherapy, which will take place in this study, will yield greater benefits than what is observed when durvalumab is planned as adjuvant therapy after chemoradiotherapy. One reason is that durvalumab may be more effective when given to patients with intact immune systems. Chemoradiotherapy is known to cause lymphopenia, which has been associated with reduced efficacy of immunotherapy and inferior clinical outcomes. Additionally, administration of durvalumab prior to radiotherapy can reduce participants' thoracic disease burden, which will reduce the required extent of thoracic irradiation and should reduce the risk of acute and long-term treatment toxicity.

Monalizumab is a humanized mAb of the IgG4 subtype that specifically binds and inhibits Cluster of Differentiation 94 (CD94)/NK cell protein group 2 A(NKG2A). Engagement of NKG2A, a receptor found on both the natural killer and CD8+ T cells, culminates in inhibition of immune cell effector functions. As a heterodimer with CD94 on the cell surface, NKG2A can recognize the non-classical major histocompatibility complex molecules, human leukocyte antigen (HLA)-E expressed by antigen presenting cells. HLA-E has been shown to be overexpressed in various tumor types, including lung cancer. This overexpression functions as a negative prognostic factor in the lung carcinoma. These findings suggest that unleashing NK cell and CD8+ T cell activity by inhibiting NKG2A/HLA-E binding in lung cancer may contribute to stronger anti-tumor immunity.

Oleclumab is a human IgG1λ mAb that selectively binds to and inhibits the ectonucleotidase activity of CD73. Oleclumab inhibits the production of adenosine and inorganic phosphate from adenosine monophosphate (AMP) by CD73. Adenosine creates an immunosuppressive tumor microenvironment by impairing the proliferation of effector cytotoxic cells and promoting generation of immunosuppressive regulatory T cells, myeloid derived suppressor cells and tumor associated macrophages. In NSCLC, high expression of CD73 has been associated with poor prognosis.

The addition of monalizumab to adjuvant durvalumab after chemoradiotherapy, as well as the addition of oleclumab to adjuvant durvalumab after chemotherapy, for patients with LA-NSCLC improved PFS rates in the COAST trial (NCT03822351). PACIFIC-9 trial (NCT05221840) is an ongoing confirmatory phase III study testing the same approaches. The combination of durvalumab and monalizumab, as well as the combination of durvalumab an oleclumab, were tested as neoadjuvant therapies before surgery in the NeoCOAST trial (NCT03794544), where these combination therapies each numerically improved pathologic response rates compared to durvalumab alone. Of note, results from both COAST and NeoCOAST suggest that the additions of monalizumab to durvalumab, and of oleclumab to durvalumab, did not increase toxicity rates. There, existing data support testing monalizumab in combination with durvalumab, and oleclumab in combination with durvalumab, as induction therapies before definitive radiotherapy and as consolidation therapies after radiotherapy, to reduce the extent of thoracic irradiation required and improve local and distant disease control.

For this study, participants will undergo standard evaluations, including biopsy and PD-L1 testing, staging positron emission tomography/computed tomography (PET/CT), and laboratory studies, before treatment. PET/CT will be performed after induction immunotherapy for biologic response assessment and to aid with radiotherapy planning. CT will be performed after radiotherapy and then approximately every three months throughout the first year of study participation. Subsequent tumor assessments will follow institutional standards. Safety will be assessed throughout using Common Terminology Criteria for Adverse Events (CTCAE).

The researchers believe that, for patients with locally advanced NSCLC with PD-L1 tumor proportion score of at least 50%, sequential treatment with dual-agent immunotherapy and risk-adapted radiotherapy will be safe and effective. The specific hypothesis that will be tested as the primary objective of this study is that induction dual-agent immunotherapy will yield response rates that are higher than what had been observed in a previous trial with single-agent immunotherapy. These response rates will be assessed using Fludeoxyglucose (18F)-positron emission tomography (FDG-PET) imaging, as response on PET to induction therapy was identified as a powerful predictor of long-term clinical outcomes in the previous trial.

Inclusion Criteria:

1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.

2. Patient is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations, including follow-up.

3. Age > 18 years at time of study entry

4. Body weight ≥35 kg

5. Life expectancy of at least 12 weeks

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

7. Previously untreated, pathologically proven NSCLC and one of the following stages:

   1. American Joint Committee on Cancer (AJCC) version 8 Stage II disease, medically or technically unresectable
   2. AJCC version 8 Stage III disease
   3. Recurrent disease after curative-intent treatment for early-stage NSCLC, with current disease burden that would qualify as AJCC version 8 stage II-III

8. PD-L1 testing performed using an FDA-approved immunohistochemical assay and demonstrating tumor proportion score (TPS) of at least 50%.

9. Whole body PET/CT within 42 days prior to study entry demonstrating at least one hypermetabolic pulmonary lesion or thoracic lymph node.

10. MRI of the brain or head CT with contrast within 42 days prior to study entry.

11. PFTs within 42 days of study entry are recommended but not required.

12. Adequate normal organ and marrow function as defined below:

Hemoglobin ≥9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L Platelet count ≥75 × 109/L Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with Gilbert's syndrome.

Serum albumin ≥ 3.0 g/dL AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal Measured creatinine clearance >40 mL/min or Calculated creatinine clearance >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.

• Males: (Weight in kg) x (140 - Age) ÷ (72 x serum creatinine in mg/dL)
• Females: (Weight in kg) x (140 - Age) x 0.85 ÷ (72 x serum creatinine in mg/dL)

Exclusion Criteria:

1. Participation in another clinical study with an investigational product during the last 3 months

2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study

3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy, with these exceptions:

   1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
   2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment on this study may be included after consultation with the Study Physician.

4. Any concurrent chemotherapy, Intraperitoneal (IP) chemotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

5. History of another primary malignancy except for

   1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
   2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   3. Adequately treated carcinoma in situ without evidence of disease

6. History of leptomeningeal carcinomatosis

7. Prior radiotherapy that would preclude safe delivery of radiotherapy as specified in this study.

8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first planned dose of IP.

9. History of allogenic organ transplantation.

10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with celiac disease controlled by diet alone

11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent

12. History of grade 3 or greater edema (e.g., peripheral, pulmonary)

13. History of venous thrombosis within the past 3 months prior to the planned first dose of study treatment. Note: Subjects with thrombosis due to mechanical obstruction by the tumor that is found incidentally and is asymptomatic and does not require therapy may be enrolled at the investigator's discretion and should be closely monitored.

14. Cardiac or peripheral vascular disease meeting any of the following criteria:

    1. History of myocardial infarction in the prior 12 months
    2. History of stroke or transient ischemic attack requiring medical therapy

15. Congestive heart failure ≥ Class 3 based on New York Heart Association Functional Classification

16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)

17. History of active primary immunodeficiency

18. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening.

    1. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible.
    2. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

19. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).

20. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP.

22. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.

23. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

24. Patients who have received prior anti-PD-1 or anti PD-L1 therapy:

    1. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
    2. All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    3. Must not have experienced a ≥Grade 3 immune related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    4. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.