Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting?

Abstract

BackgroundThe combination of BRAF and MEK inhibitors represents the standard of care treatment for patients with metastatic BRAF-mutated melanoma, notwithstanding the high frequency of emergent resistance. Moreover, therapeutic options outside clinical trials are scarce when patients have progressed after both targeted therapy and therapy with immune checkpoint inhibitors. In this article, we report our experience with targeted therapy rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy.MethodsFour patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitors after progression with targeted therapy and subsequent immunotherapy (checkpoint inhibitors).ResultsTwo patients (one of them was heavily pretreated) had partial response over 36 months (with local treatment on oligoprogression disease) and 10 months, respectively. A third patient with multisite visceral disease and high serum levels of lactate dehydrogenase had a short-lived clinical benefit rapidly followed by massive progression of disease (early progressor). The fourth patient, currently on treatment with BRAF/MEK inhibitors, is showing a clinical benefit and radiological stable disease over 3 months of therapy. Adverse events were manageable, similar to those reported during the first targeted therapy; the treatment was better tolerated at rechallenge compared with the first treatment by two out of four patients.

Management challenges and therapeutic strategies for metastatic melanoma – a case report

“…The fourth patient currently on treatment with BRAF/MEK inhibitors showed clinical benefit and radiological stable disease for over 3 months. 17 Furthermore, the 5-year update of part 1 of the CO-LUMBUS trial further supports the use of combination treatment with BRAF and MEK inhibitors for advanced BRAF V600-mutant melanoma. This update demonstrated benefits in terms of progression-free survival and overall survival, reaffirming the role of this combination therapy as a standard of care.…”

Trametinib-Resistant Melanoma Cells Displaying MITFhigh/NGFRlow/IL-8low Phenotype Are Highly Responsive to Alternating Periods of Drug Withdrawal and Drug Rechallenge

“…In several preclinical studies performed using drug-naïve melanomas, various drug-tolerant subpopulations have been identified as a part of the response to BRAF V600 /MEK inhibition [33], including a subpopulation of MITF low /NGFR high cells [34][35][36]. While melanoma cell response to targeted therapeutics and their withdrawal after short exposure to drugs is a frequent subject of investigation (for example, [14,37]), reports on alterations induced by drug holiday and drug rechallenge in preclinical models of stable melanoma resistant to BRAF V600 /MEK inhibitors [18][19][20][21][22][23][24][25] or in melanoma patients who developed resistance [38][39][40][41][42][43][44] are limited. In this long-term study, we focused on two distinct trametinib-resistant melanoma cell lines exerting either a differentiation phenotype (MITF high ) or de-differentiation phenotype (MITF low ).…”

Intermittent treatment of BRAF V600E melanoma cells delays resistance by adaptive resensitization to drug rechallenge

“…On one hand, two recent phase II trials revealed worse progression-free survival in patients with melanoma treated intermittently with dabrafenib + trametinib or vemurafenib + cobimetinib compared with those treated with continuous therapy, with no difference in overall survival ( 38 , 39 ). On the other hand, retrospective and prospective studies of dozens of patients who progress on BRAF or MEK inhibitor have reported that more than one-third show a second clinical response after a drug holiday period ( 27 , 33 – 37 ). Preclinical studies using xenografts have been mixed as well.…”

“…Preclinical studies with patient-derived xenograft (PDX) melanomas or xenografts from established human melanoma cell lines showed that intermittent dosing can delay drug resistance and tumor growth compared with continuous dosing ( 29 – 32 ). Clinical reports and a phase 2 clinical trial have shown dozens of cases where patients with melanoma develop resistance and progress when treated with BRAF or MEK1/2 inhibitors continuously, but then show further response when retreated after a drug holiday period ( 32 – 37 ). By contrast, phase 2 trials of intermittent dosing with BRAF and MEK inhibitor combinations showed worse progression-free survival and no difference in overall survival compared with continuous treatment ( 38 , 39 ).…”