Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma

The new drug options for advanced melanoma include oncogene-targeted therapy (such as dabrafenib, trametinib and vemurafenib) and immune checkpoint blockade (such as pembrolizumab, nivolumab and ipilimumab). These drugs have shown remarkable efficacy and have regulatory approval for metastatic disease. However, most patients with advanced disease eventually progress. It is unknown if earlier treatment with systemic therapy after surgery improves long term survival or what is the optimal sequencing or combination of therapy. An efficient method of assessing drugs and combinations in humans is critical, particularly as combinations of molecularly targeted and/or immune therapies may have similar signals for efficacy in pre-clinical models, and recapitulation of the human immune system in animal models is limited. 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). Surgery remains the standard of care for resectable Stage III or IV melanoma, despite the recent drug therapy advances described above. The Food and Drug Administration (FDA) has recently expanded the approved use of ipilimumab to include a new use as adjuvant therapy for patients with resectable stage III / IV melanoma, to lower the risk of relapse following surgery. Neoadjuvant therapy in this group of patients may also result in improved survival rates and in the duration of local and distant disease control, with reduced surgical morbidity and the potential for early elimination of microscopic metastatic disease. There is an emerging and rapidly growing evidence base of the value of combining targeted and immunotherapies in a number of histological subtypes of cancers. The support for a potential synergy between the two treatment modalities has been established, as has the increased toxicity profile. Both single agent BRAF inhibitors and combined BRAF and MEK inhibitors induce a marked clonal T cell infiltrate in responding melanoma metastases early during treatment (day 7-15), which is transient, and is not present at progression. Concurrently, melanoma tumour antigen and the programmed death-ligand 1 (PDL1) expression increase early during treatment. It is unknown whether there is potential for converting a subset of patients who fail either immunotherapy or targeted therapy alone into long-term responders by treating with programmed cell death protein 1 (PD-1) inhibitors in conjunction with mitogen-activated protein kinases (MAPK) targeted therapies. Furthermore, it is unclear whether the PD-1 inhibitor would be best combined sequentially or concurrently with MAPK inhibitors. Mouse models have provided a clear rational for combining these treatments upfront, however there is no human tissue evidence to guide best combination strategies. The question of how best to maximize clinical outcome via concurrent versus sequential targeted and immune therapy may be explored efficiently in the human neoadjuvant setting, with detailed interrogation of multiple biopsies early during treatment. Immunological, proteomic and genetic features in tissue and blood provide an in vivo assessment of tumour responsiveness to therapy. This may enable more selective application of therapeutic agents to patients who are more likely to benefit. Such findings would improve the therapeutic index and cost effectiveness of these agents. Earlier systemic therapy prior to surgery also means earlier targeting of distant micrometastases that could become the source of future disease relapse. The rationale for this study design is therefore based on the hypothesis that one week of targeted therapy may be sufficient to induce an enhanced tumoral immunity to result in a higher pathological and clinical response using the 'Response Evaluation Criteria In Solid Tumors' (RECIST) guidelines when followed sequentially with pembrolizumab, than either pembrolizumab alone or the combination of targeted therapy and pembrolizumab upfront. The potential for toxicities that could affect adherence to the combined study treatments are recognised, as additive, overlapping or unforeseen adverse events may occur with the triple combination. The adverse event profiles and safety-related interruption to treatment will therefore be assessed in conjunction with the objective responses. 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 translational research performed on tissue biopsies and blood will provide mechanistic information to guide the selection of optimal combinations of therapies for phase 3 studies in the advanced and the adjuvant setting. This is a phase II, randomised, open label, three arm, parallel group, clinical trial of neoadjuvant combined targeted and immune therapy for patients with BRAF V600 mutant resectable stage III (bulky regional stage IIIB-D, but excluding in transit disease) melanoma. This translational study explores pathological and RECIST response rates for a 6-week duration of neoadjuvant therapy across 3 treatment arms. The key secondary outcomes to be measured include a detailed analysis of immunologic, proteomic and genetic biomarkers in tumour tissue and peripheral blood at weeks 1, 2 and 6 compared to baseline and correlated with clinical, metabolic and pathological response to neoadjuvant treatment, and relapse and overall survival to adjuvant treatment. In patients who relapse within 40 weeks of adjuvant treatment, further analysis of tumour tissue (if possible) will be undertaken. Relapse free and overall survival, surgical outcomes and adverse event profile will also be determined. Sixty patients will be randomised to one of three treatment groups in a 1:1:1 ratio, with 20 patients in each treatment arm: * "Sequential immunotherapy": Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 1 week, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 1, 3, and 6, then once every 3 weeks from week 6 for 50 weeks. * "Concurrent immunotherapy": Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 6 weeks then Pembrlizuamb alone for a further 46 weeks after surgery. * "Immunotherapy alone": Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks. Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation (i.e. V600D, V600K, V600R, V600M). Neoadjuvant treatment for all three arms will be administered for 6 weeks, followed by complete resection of tumour to no evidence of disease. 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 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 2 (EDT 2) * Week 6 - complete lymph node dissection specimen (POST) * At Relapse (RELAPSE) if applicable and available Surveillance of disease during the 6 week neoadjuvant period will be undertaken with surgical assessments and with ultrasounds of the affected lymph node basin.