Abstract
BackgroundThe likelihood of a tumor recurrence in patients with T3-4N0–1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. As pathological complete responses (pCR) in resected specimens are seen in only a minority (28–38%) of patients following chemoradiotherapy, we designed the INCREASE trial (EudraCT-Number: 2019–003454-83; Netherlands Trial Register number: NL8435) to assess if pCR rates could be further improved by adding short course immunotherapy to induction chemoradiotherapy. Translational studies will correlate changes in loco-regional and systemic immune status with patterns of recurrence.Methods/designThis single-arm, prospective phase II trial will enroll 29 patients with either resectable, or borderline resectable, T3-4N0–1 NSCLC. The protocol was approved by the institutional ethics committee. Study enrollment commenced in February 2020.On day 1 of guideline-recommended concurrent chemoradiotherapy (CRT), ipilimumab (IPI, 1 mg/kg IV) and nivolumab (NIVO, 360 mg flat dose IV) will be administered, followed by nivolumab (360 mg flat dose IV) after 3 weeks. Radiotherapy consists of once-daily doses of 2 Gy to a total of 50 Gy, and chemotherapy will consist of a platinum-doublet. An anatomical pulmonary resection is planned 6 weeks after the last day of radiotherapy. The primary study objective is to establish the safety of adding IPI/NIVO to pre-operative CRT, and its impact on pathological tumor response. Secondary objectives are to assess the impact of adding IPI/NIVO to CRT on disease free and overall survival. Exploratory objectives are to characterize tumor inflammation and the immune contexture in the tumor and tumor-draining lymph nodes (TDLN), and to explore the effects of IPI/NIVO and CRT and surgery on distribution and phenotype of peripheral blood immune subsets.DiscussionThe INCREASE trial will evaluate the safety and local efficacy of a combination of 4 modalities in patients with resectable, T3-4N0–1 NSCLC. Translational research will investigate the mechanisms of action and drug related adverse events.Trial registrationNetherlands Trial Registration (NTR): NL8435, Registered 03 March 2020.
Highlights
The likelihood of a tumor recurrence in patients with T3-4N0–1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases
We estimated the grade 3–4 treatment related adverse events (trAE) associated with standard of care (SoC) in the present study to be approximately 65% and that this could rise to 75%, by adding ipilimumab (1x) and nivolumab (2x), which would still be comparable to the platinumetoposide arm of the PROCLAIM-study
Our study aims to explore this hypothesis and to characterize the changes in the tumor microenvironment (TME), tumor-draining lymph nodes (TDLN), and peripheral blood mononuclear cell (PBMC) prior to, and after induction therapy and after surgery
Summary
The likelihood of a tumor recurrence in patients with T3-4N0–1 non-small cell lung cancer following multimodality treatment remains substantial, mainly due distant metastases. In patients presenting with unresectable, non-metastatic locally advanced NSCLC, the administration of durvalumab (anti-PD-L1 antibody) consolidation for 12 months after definitive chemo-radiotherapy (CRT) has been shown to improve both overall and progression-free survival [5]. Multimodal strategies are recommended in the ESMO guidelines for fit patients with potentially resectable locally-advanced NSCLC [8] With this strategy, both the local tumor and regional lymph node metastases are targeted using chemo-radiotherapy and surgery, and any occult distant metastases by chemotherapy. Clinical outcomes have improved with the implementation of multi-multimodal strategies [9, 10], rates of distant metastases are still substantial, and pathological complete responses are seen in only a minority (28–38%) of patients [10,11,12,13]. Strategies to improve pathological complete response rates in this population may be useful as patients with < 10% of vital tumor after neoadjuvant therapy have been found to have an improved overall survival [10,11,12,13]
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