Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFR hi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFR hi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFR hi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFR hi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.
Objective:To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma.Summary Background Data:Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear.Methods:In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection.Results:Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7–57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery.Conclusions:This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.
In resected high-risk melanoma (stage IIB/C-III) the risk of locoregional and/or distant recurrence is substantial and so far adjuvant therapies have been fairly unsuccessful. Interferon showed slight improvements in recurrence-free survival (RFS) but failed to convincingly improve overall survival (OS). In these patients, adjuvant therapy with treatments that show promising results in stage IV disease is arising. Studies using immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 agents reveal convincing RFS benefits. OS rates, however, are not mature yet in most studies. Only ipilimumab has shown an OS benefit but at a high cost of toxicity. Also in studies with adjuvant targeted therapy using BRAF and MEK inhibitors, ensuring results are reported regarding RFS. As possible toxicity cannot be ignored, it is crucial to identify patients who would benefit most from these adjuvant therapies. In patients with clinically detectable lymph node metastases, studies using neoadjuvant schedules of immunotherapy and targeted therapy have been performed. In phase I and II studies the most optimal schedule of combination immunotherapy was identified and further research on this front will follow in the coming years. Concluding, after decades of scarce options for patients with high-risk melanoma, recent developments in adjuvant therapy have changed the standard of care for these patients.
9587 Background: The aim of this study is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Methods: A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks. Results: Currently 20 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 17/18 (94%) patients resection was possible after neoadjuvant treatment, of which 16 (94%) were R0 resections. Median follow-up time is 28 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 94% and 2-year OS 82%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (20%) CR, 14 (70%) PR, 0 (0%) SD, 2 (10%) PD. Pathologic RR differed: 7 (35%) CR, 7 (35%) PR, 3 (15%) SD, 0 (0%) PD and in 3 patients (15%) no pathologic response was measured, since no resection was performed. Most patients (85%) experienced any toxicity, of which 50% was grade 1, 20% grade 2 and 3 patients (15%) experienced grade 3 toxicity. The most common reported toxicity was fever. Conclusions: Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 16/20 (80%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy. Clinical trial information: NTR4654.
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