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.
