A Phase II Study of Neoadjuvant Pembrolizumab & Lenvatinib for Resectable Stage III Melanoma

New therapeutic strategies for melanoma come as a result of significant advances in the understanding of the immunomodulatory mechanisms and molecular biology. The resulting new therapeutic strategies include oncogene-targeted therapy and immune checkpoint blockade, and these are now approved therapies that have transformed the routine clinical management for patients with metastatic disease. However, most patients with advanced melanoma still die of their disease, and thus, there remains an urgent need to improve upon current therapies. Most patients with advanced disease eventually progress, and the question as to whether earlier treatment with systemic therapy after resection of all macroscopic melanoma (adjuvant therapy) improves long term survival is under investigation in melanoma and other solid malignancies. Furthermore, with the increased number of therapies utilised in melanoma, the question of optimal sequencing and selection of single or combination therapy remains unanswered.

Neoadjuvant clinical trials in patients with resectable but bulky stage III/IV melanoma allows for the rapid evaluation of drug activity in humans utilising multiple clinical endpoints (metabolic response with Positron Emission Tomography [PET], clinical response with Computed Tomography [CT] imaging, pathological response, relapse-free survival and overall survival) and translational endpoints (morphological, genetic and immunophenotyping of tumour and blood).

This trial will test the combination of pembrolizumab and lenvatinib as neoadjuvant and pembrolizumab as adjuvant therapy for twenty adult patients with histologically confirmed RECIST 1.1 measurable and resectable AJCC (8th edition) Stage IIIB, IIIC or IIID cutaneous or unknown primary melanoma.

The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 receptor, thus inhibiting its interaction with programmed cell death ligand 1 and programmed cell death ligand 2. Pembrolizumab is indicated for the treatment of patients across a number of indications because of its mechanism of action to bind the PD-1 receptor on the T cell.

Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is essential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptors play a major role in tumour angiogenesis. Lenvatinib is an oral potent multiple RTK inhibitor that selectively inhibits VEGF receptors. In clinical use, lenvatinib is one of the only inhibitors currently labelled with a mechanism of action as an inhibitor of not only VEGFRs but also fibroblast growth factor receptors, both of which are currently believed to very important for tumour angiogenesis. Tumour blood vessels are abnormal, both structurally and functionally, relative to those of non-malignant tissues. Normalizing the tumour vasculature with antiangiogenic agents could potentially be used to improve the effectiveness of immunotherapy, particularly immune checkpoint blockade. The evidence indicates that the potential benefit of such combinations will be manifested though modulation of both the tumour vasculature and the tumour immune microenvironment.

The development of combination therapy of lenvatinib and an anti-PD-1 antibody pembrolizumab is ongoing for various solid tumours. In addition to efficacy and safety endpoints, testing this combination in the neoadjuvant setting provides a valuable opportunity to investigate potential biomarkers and mechanisms of responsiveness, resistance, toxicity and relapse. Limiting the combination of drugs to the neoadjuvant period only, limits the toxicity that may be experienced by patients whilst maintaining an effective treatment regimen.

In many cancers, early stage diagnosis and early treatment offers the best chance of a prolonged recurrence free- and overall survival. In stage III/IV resectable melanoma, an opportunity exists to improve outcomes with the addition of neoadjuvant and adjuvant systemic therapy as an adjunct to surgery. Neoadjuvant clinical trials for resectable but bulky stage III/IV melanoma allows for the efficient and rapid evaluation of drug activity in humans utilising multiple clinical endpoints of metabolic, radiological and pathological response; relapse-free survival; overall survival. Recent clinical trials of neoadjuvant ipilimumab combined with nivolumab (OPACIN-NEO) and neoadjuvant dabrafenib combined with trametinib (NeoCombi) in resectable stage III melanoma showed that a pathological response (< 50% viable tumour at tumour bed in the former trial, and complete response in the latter) was associated with a longer relapse-free survival

The rationale for this study design is therefore based on the hypothesis that six weeks of combined pembrolizumab and lenvatinib may be sufficient to induce an enhanced tumoral immunity to result in a higher pathological and clinical response at the time of definitive surgery.

The clinical and translational findings from this study have the potential to inform rational decisions regarding combinations of treatment both in the metastatic and the adjuvant settings. This is a critical study to inform future practice and future phase 3 clinical trials. The neoadjuvant design provides an important opportunity to address critical translational endpoints from multiple blood draws and tissue biopsies during treatment. From this, the evaluation of potential biomarkers and mechanisms of responsiveness, resistance, toxicity and relapse is possible, beyond the traditional clinical, pathological and radiological parameters. Baseline and serial blood, and tissue samples will be analysed at MIA translational research facilities. The biomarker component of this study will require blood samples and core biopsies of tumour tissue at the following time points:

Baseline (PRE) Week 1 (EDT 1) Week 6 - complete lymph node dissection specimen (POST) At Relapse (RELAPSE) if applicable and available

Neoadjuvant treatment will be administered for 6 weeks, followed by complete resection of tumour to no evidence of disease. Surveillance of disease during the 6 week neoadjuvant period will be undertaken with surgical assessments and with ultrasounds of the affected lymph node basin. Surgery is followed by 46 weeks of pembrolizumab adjuvant therapy or until disease relapse, death, intolerable adverse drug reactions or by withdrawal of patient consent. After 52 weeks of the study treatment phase, patients will be followed 3 monthly for relapse (and progression, following relapse) and survival for 10 years.

The efficacy endpoints for this study have been used across the International Neoadjuvant Melanoma Consortium.