Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Eroglu, Zeynep; Eatrides, Jennifer; Naqvi, Syeda Mahrukh Hussnain; Kim, Young‐Chul; Rich, Jeani; Babacan, Nalân Akgül; Brohl, Andrew S.; Markowitz, Joseph; Sarnaik, Amod A.; Zager, Jonathan S.; Sondak, Vernon K.; Messina, Jane L.

doi:10.1111/pcmr.12813

Cited by 13 publications

(13 citation statements)

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“…It will also be critical to consider patient eligibility criteria for combination trials, and determine at what stage to assign patients to a CDK4/6i combination. Upfront CDK4/6i combinations, including alternative scheduling regimens, might prove both efficacious and biologically insightful in the neoadjuvant setting, where both ICI and BRAF/MEK-targeted therapies have already shown some success 59 , 60 . Given BRAFi+MEKi-mediated tumor cell death induces a T cell response, upfront co-treatment with CDK4/6i may be used to opportunistically improve the quality of this immune response early on.…”

Section: Closing Remarksmentioning

confidence: 99%

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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CDK4/6 inhibitors (CDK4/6i) were developed as a cancer therapeutic on the basis of their tumor-intrinsic cytostatic potential, but have since demonstrated profound activity as immunomodulatory agents. While currently approved to treat hormone receptor-positive breast cancer, these inhibitors are under investigation in clinical trials as treatments for a range of cancer types, including melanoma. Melanoma is a highly immunogenic cancer, and has always been situated at the forefront of cancer immunotherapy development. Recent revelations into the immunotherapeutic activity of CDK4/6i, therefore, have significant implications for the utility of these agents as melanoma therapies. In recent studies, we and others have proven the immunomodulatory effects of CDK4/6i to be multifaceted and complex. Among the most notable effects, CDK4/6 inhibition induces transcriptional reprogramming in both tumor cells and immune cells to enhance tumor cell immunogenicity, promote an immune-rich tumor microenvironment, and skew T cell differentiation into a stem-like phenotype that is more amenable to immune checkpoint inhibition. However, in some contexts, the specific immunomodulatory effects of CDK4/6i may impinge on anti-tumor immunity. For example, CDK4/6 inhibition restricts optimal T cells expansion, and when used in combination with BRAF/MEK-targeted therapies, depletes immune-potentiating myeloid subsets from the tumor microenvironment. We propose that such effects, both positive and negative, may be mitigated or exacerbated by altering the CDK4/6i dosing regimen. Here, we discuss what the most recent insights mean for clinical trial design, and propose clinical considerations and strategies that may exploit the full immunotherapeutic potential of CDK4/6 inhibitors.

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Section: Closing Remarksmentioning

confidence: 99%

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

2022

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“…Alternatively, BRAF/MEK inhibition can be associated with rapid tumor response and in our study, was chosen in cases where surgeons perceived that a significant reduction in tumor burden could potentially reduce surgical morbidity. 18 Recently, the DREAMseq study (NCT02224781) examining the sequence of therapy for patients with metastatic melanoma (ICI or targeted as frontline) was stopped by the data safety monitoring committee because overall survival overwhelmingly favored use of ICI therapy first. 19 Although the patient population in the DREAMseq study is different from patients eligible for NT, DREAMseq data may support use of ICI therapy over targeted therapy as preferred choice for NT.…”

Section: Discussionmentioning

confidence: 99%

Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice

et al. 2022

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Objective: To determine the feasibility and impact of neoadjuvant therapy (NT) in patients who present with advanced melanoma amenable to surgical resection. Summary Background Data: Given current effective systemic therapy for melanoma, the use of NT is being explored in patients with advanced melanoma with disease amenable to surgical resection. Methods: Prospective data from 3 institutions was obtained in patients with clinically evident Stage III/IV melanoma who underwent NT. The primary objective was to compare recurrence-free survival between patients who had pathologic complete response (pCR) to those with persistent disease. Results: NT was offered to 45 patients, with 43 patients initiating various NT regimens including PD-1 antagonist (PD-1) therapy (N = 16), PD-1 plus ipilimumab (N = 10), BRAF/MEK inhibitor therapy (N = 14), a combination of those three (N = 1), and talimogene laherparepvec (TVEC) (N = 2). Thirty-two (74.1%) patients underwent surgery whereas 11 patients did not undergo surgery for these reasons: clinical CR (N = 7), progressive disease not amenable to resection (N = 3), and ongoing therapy (N = 1). 12 of 32 patients (37.5%) had pCR with these therapies: PD-1 (N = 4), PD-1 plus ipilimumab (N = 2), BRAF/MEK (N = 4), combination (N = 1), and TVEC (N = 1). At median followup of 16.4 months there was only 1 recurrence in the pCR group and patients with a pCR had significantly improved recurrence-free survival compared to patients without pCR (p = 0.004). Conclusions: Despite variability in NT regimens across institutions, NT for melanoma is feasible and associated with improved prognosis in patients who achieve a pCR. Maximizing rates of pCR could improve prognosis for patients with advanced melanoma.

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“…It is only defined that achievement of pCR correlates with melanoma PD-L1 expression, CD8+ T-cell infiltration, and a higher number of Ki67-positive melanoma cells at baseline [ 30 ]. Several issues remain in question, including the optimal duration of neoadjuvant BRAF inhibition prior to surgery, the role of adjuvant therapy, whether imaging response correlates with pathologic response, whether pathologic response correlates with RFS and OS, and if responses can inform post-operative treatment decisions [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…In survival analysis after a median of 43-month follow-up, only one patient who achieved a pCR and eight without a pCR recurred. These authors concluded that patients with a pCR had significantly improved RFS and OS in patients with residual tumors [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Technically unresectable melanoma refers to cases for whom surgical resection is not possible without unacceptable functional impairment; as well as cases macroscopically resectable, but of high-volume or multifocal disease, which bears a high likelihood of residual micro-or macroscopic disease after surgery; or finally, those with encasement of vital structures and cases in which increased risk of major adverse events during surgery is anticipated [ 11 , 14 ]. Patients with borderline resectable melanoma are those with a primary or recurrent disease with advanced regional infiltration that makes surgical resection challenging [ 15 ]. In general, resection of more advanced disease is associated with increased perioperative morbidity and may lead to incomplete surgical resection.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma

Czarnecka

Ostaszewski

Borkowska

et al. 2021

Cancers

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Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.

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Neoadjuvant BRAF‐targeted therapy in regionally advanced and oligometastatic melanoma

Cited by 13 publications

References 30 publications

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?

Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice

Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma

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