Durvalumab and Tremelimumab for Adjuvant Therapy of Resected NSCLC

Non-small Cell Lung Cancer Clinical Trial

Official title: Identification of Tumor Neoantigens During Immune Checkpoint Blockade in Resectable Non-Small Cell Lung Cancer (NSCLC)

Status Withdrawn

Clinical Trial Summary

Despite aggressive surgery and chemotherapy, the risk of lung cancer recurrence remains high in most patients. This study aims to determine if a novel immune therapy consisting of two drugs is feasible and potentially increases the chance of cure in lung cancer patients after surgery and standard chemotherapy. The immune-based therapy being given in this study consists of two medications named durvalumab and tremelimumab.

Clinical Trial Description

Lung cancer is the most common cancer and leading cause of cancer related death worldwide, accounting for more than 1.3 million deaths annually. The 5 year survival of clinical stage IIIA NSCLC, a technically curable lung cancer by surgery, chemotherapy +/- radiotherapy delivered in the perioperative setting, remains a modest 15%, with systemic recurrence occurring in the majority of patients. 5 year overall survival (OS) for patients with stage IB and II disease is also modest at 53% and 25% respectively.

The FDA approvals of T-cell checkpoint inhibitors, targeting programmed cell death-1 (PD-1) has changed the landscape of NSCLC. Although robust responses to anti-PD-1 can be observed, it is a small subset of patients with durable benefit. In phase 3 trials, the response rate to anti-PD- 1 is 19% with only ½ of these patients experiencing durable benefit. Even NSCLC tumors with high levels of PD-L1 have only a 30% response rate and combination immunotherapy has improved efficacy modestly.

Clinical trials in resectable lung cancer, have traditionally attempted to institute new agents in the adjuvant setting. However clinical endpoints take years of follow-up to ascertain. For example, The ANITA study was the most recent phase III study of adjuvant chemotherapy in NSCLC. In this study, results were published 12 years after study initiation. Thus, while OS remains the gold standard for assessment of benefit of adjuvant therapy, studies that are 12 years long are slow, expensive, and may yield results that are out of date by the time they are published. Thus the use of valid surrogate endpoints for OS is a high priority in NSCLC.

The potential for durable benefit in the advanced NSCLC setting has, not unexpectably, led to a foray with immune checkpoint blockade treatment into the adjuvant setting for resectable NSCLC. Randomized trials with durvalumab, pembrolizumab, and nivolumab are all underway.

However in the resected setting, adjuvant patients cannot be monitored radiologically for treatment response due to the absence of measurable disease thus requiring innovative in vitro and in vivo methods to study therapeutic response to immune checkpoint blockade. Encouragingly, as proof of concept, single-agent ipilimumab has demonstrated improved recurrence-free survival at 3 years in resected stage III melanoma compared to placebo leading to FDA approval in this setting. Less encouragingly, the hazard ratio favored the higher risk patients suggesting the benefit may be restricted to those tumors more apt to have residual disease and may represent the subset where benefit is most realized. Furthermore the data are not sufficiently mature to demonstrate an overall survival advantage nor is it known if this data can be extrapolated to NSCLC where responses are numerically lower.

Patients with resectable NSCLC will undergo surgical resection and bone marrow procurement at the same time. Tumor will be dissociated into single cell suspension and separated into viable cryopreserved tumor cells and tumor infiltrating lymphocytes will be expanded in media and high dose IL-2. Post-operatively, after recovery from surgical resection, patients will receive adjuvant treatment with chemotherapy as determined by the treating physician. Subsequently patients will receive adjuvant durvalumab for 12 doses and tremelimumab for 4 doses. Serial PBMCs will be obtained every 4 weeks during therapy. Primary resected tumor will undergo whole exome sequencing and RNA sequencing and clonal neoantigens will be predicted with established algorithms. Neoantigen specific T cell reactivity will be tested in autologous PBMCs with multimer (quantitative) and ICS (functional) assays. ;

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer

• NCT number: NCT03130764
• Study type: Interventional
• Source: Columbia University
• Status: Withdrawn
• Phase: Phase 2
• Start date: March 2017
• Completion date: November 30, 2017