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. Author manuscript; available in PMC: 2023 Jan 1.
Published in final edited form as: Clin Adv Hematol Oncol. 2022 Jan;20(1):47–55.

Neoadjuvant Therapy for Melanoma – New and Evolving Concepts

Derek J Erstad 1, Russell G Witt 1, Jennifer A Wargo 1,2
PMCID: PMC9103060  NIHMSID: NIHMS1798515  PMID: 35060962

Abstract

Effective systemic therapies including targeted BRAF/MEK inhibition and immune checkpoint blockade have significantly changed the treatment landscape for malignant melanoma. Specifically, there have been promising clinical trial findings associated with the use of neoadjuvant therapy for clinically node positive and oligometastatic disease, conditions that have historically been managed with upfront surgical resection when possible. This review focuses on the burgeoning field of neoadjuvant therapy for melanoma. We review the rationale for this treatment approach, summarize completed and ongoing neoadjuvant clinical trials, and contextualize these findings within the growing body of knowledge about targeted and immune checkpoint therapy. Finally, we discuss future directions for neoadjuvant trials in melanoma, with particular focus on biomarker development, treatment effect modification, novel therapeutic regimens, and evolving surgical indications for regional and oligometastatic disease.

Keywords: Neoadjuvant therapy, malignant melanoma, BRAF/MEK inhibition, immune checkpoint blockade

Introduction

Effective targeted BRAF/MEK inhibitors and immune checkpoint blockade have led to improved survival outcomes in malignant melanoma that are unprecedented in the history of modern cancer therapy.1,2 These medications were initially studied in metastatic disease and as adjuvant therapy, both with promising results, and their usage in the neoadjuvant context is now an expanding field of investigation.3 This review will focus on neoadjuvant therapy for melanoma and will include the rationale for this treatment approach, a summary of translational and clinical trial findings, and a discussion of future directions for treatment strategies.

Rationale for Neoadjuvant Therapy

There are multiple theoretical advantages associated with a neoadjuvant approach to systemic therapy, particularly for immune modulating treatments.4 From a surgical perspective, neoadjuvant therapies have the potential to downstage unresectable disease and allow for curative-intent operative resection. Furthermore, the rate of R0 resection might be improved with preoperative therapy, as has been shown with certain gastrointestinal epithelial malignancies.5 Neoadjuvant administration of systemic immunotherapy and targeted BRAF/MEK inhibition might also have greater efficacy compared to their respective usage in the adjuvant setting. For both, it is thought that the presence of tumor biomass may increase the probability of immunologic activation against tumor neoantigens.6 Finally, a neoadjuvant approach has the unique advantage of allowing for biologic response assessment to treatment.7 Post-treatment tissue evaluation provides a plethora of valuable information that can inform prognosis, decision making for additional therapy, and scientific discovery by providing information about the cellular and molecular effects of therapy on the tumor microenvironment.8 Thus, the neoadjuvant treatment approach is useful for evaluating treatment efficacy, for ascertaining mechanisms of disease resistance, and for biomarker development.

Despite these numerous potential advantages, there remain theoretical downsides to neoadjuvant therapy. First, this approach inevitably delays time to surgical resection, which is the current standard of care and the primary curative modality, carrying the risk that some patients will progress and become unresectable.9 Both targeted therapy and checkpoint blockade are associated with distinct and sometimes severe toxicities that could theoretically delay timing to surgery, preclude surgery altogether, or potentially complicate the surgical course due complications from drug toxicities. A summary of the theoretical advantages and disadvantages of neoadjuvant therapy are displayed in Table 1.

Table 1.

Neoadjuvant Therapy in Context

Advantages Disadvantages

  1. Tumor downstaging: increase resectability, negative margins

  2. Immunologic Priming: more tumor biomass may increase likelihood of neoantigen detection and response to IO

  3. Biologic assessment: pathologic response to therapy; surrogate endpoint

  4. Inform prognosis, guide adjuvant therapy

  5. Mitigate surgical intervention

  6. Study novel drugs, mechanisms of resistance, development of biomarkers

  1. Potential delay in standard of care surgery

  2. Risk of disease progression to unresectable state

  3. Treatment toxicity could impact surgical resection and outcomes
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Neoadjuvant Clinical Trials Investigating BRAF/MEK Combined Inhibition

The discovery of recurrent somatic driver mutations in cancer has led to the development of highly effective targeted therapies. In melanoma, activating mutations in BRAFV600 are present in approximately 50% of patients.10 BRAF encodes the gene for human B-raf, a serine/threonine kinase that functions downstream of the Ras proto-oncogene. Mutated B-raf inappropriately phosphorylates, and thereby activates, downstream kinases including MAPK/ERK, leading to inappropriate signaling through proliferative and anti-apoptotic gene expression programs.11 Initial forays into single-agent, targeted inhibition of B-raf with Vemurafenib and Dabrafenib in patients with BRAF-mutated metastatic melanoma was shown to improve survival, but progression frequently occurred after several months through MAPK reactivation.12,13 It was subsequently observed that combination inhibition of BRAF and MEK partially addressed issues of MAPK reactivation, resulting in more durable responses.14,15

Based on promising findings in metastatic disease, Amaria et al. performed a single-center, open-label, randomized phase 2 trial in which patients with surgically resectable, clinical stage III or oligometastatic stage IV BRAF-mutated melanoma were randomly assigned to standard of care upfront surgery with consideration of adjuvant therapy vs. perioperative dabrafenib and trametinib.16 Seven patients were assigned to standard of care and 14 patients to neoadjuvant therapy. The trial was stopped early due to significantly longer event-free survival (EFS) in the neoadjuvant therapy group (median EFS 19.7 vs 2.9 months; HR 0.016, p < 0.0001).

Shortly thereafter, the findings from the NeoCombi study were published.17 This was a single arm, open-label, phase 2 study in which patients with stage IIIB-C BRAF-mutated melanoma were treated with perioperative dabrafenib plus trametinib with surgical resection. Thirty-five patients enrolled, and a pathologic response was observed in 100% of cases, of which 17 (49%) had a complete pathologic response (pCR). There was no progression during the 12 weeks of neoadjuvant therapy. The 2-year RFS for the entire cohort was 43% and was 63% for patients who experienced a pCR. Taken together, the trials conducted by Amaria et al. and the NeoCombi study provided evidence for high rates of durable response with neoadjuvant targeted therapy.

Neoadjuvant Clinical Trials Investigating Checkpoint Inhibitor Therapy

It has long been known there exists a dynamic interaction between the immune system and malignant melanoma. Standard of care systemic therapies historically included cytokine infusions with Interferon-alpha (IFNa) and Interleukin-2 (IL-2), both of which were designed to stimulate anti-tumor immune activation, though often with prohibitive inflammatory side-effects. Immune checkpoint blockade had a revolutionary impact in melanoma because these medications were highly effective, easy to administer, and exhibited side effect profiles that were generally less severe than for cytokine infusions and adoptive cell therapies.

Checkpoint inhibition was initially studied in advanced melanoma, where it was demonstrated that PD-1 checkpoint blockade provided superior survival outcomes compared to CTLA-4 inhibition.2,18 Subsequent adjuvant trials for high-risk, resectable melanoma were a natural next step as there was a historic precedent for adjuvant therapy with cytokine infusions, and this approach still allowed for standard of care upfront surgery. There have been several notable checkpoint blockade trials in the adjuvant space. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial was a phase 3 double-blind trial evaluating adjuvant pembrolizumab vs. placebo in patients with stage III melanoma.19 1,019 patients were treated with complete lymph node dissection followed by randomization to receive pembrolizumab vs. placebo for one year. The 3-year RFS for immunotherapy treatment was 63.7% vs. 44.1% for placebo, while the 3.5-year distant metastasis-free survival (DMFS) was 65% and 49%, respectively.20 KEYNOTE-054 thus provided evidence for a survival benefit with checkpoint blockade compared to close observation. CheckMate 238 was another adjuvant phase 3 double-blind trial for resected stage IIIB-IV melanoma that directly compared nivolumab versus ipilimumab.21 Recent long-term follow up was reported, and 4-year RFS for nivolumab was 51.7% vs. 41.2% for ipilimumab, while there was no difference in OS (77.9% vs. 76.6%, respectively).22 This trial corroborated the finding in advanced disease that PD-1 inhibition provided a more significant treatment effect than CTLA4 blockade in melanoma.18,21,23 More recently, preliminary results for the CheckMate 915 trial were presented at the American Association for Cancer Research (AACR) Annual Meeting 2021.24 This was an Australian trial with an intent-to-treat design that randomized over 1,800 patients with stage III-IV melanoma to adjuvant combination ipilimumab plus nivolumab vs. nivolumab alone. Unexpectedly, there was no difference in 2-year RFS between the treatment arms (64.6% for combination therapy and 63.2% for monotherapy).

Given this background, multiple neoadjuvant trials have been implemented and reported over the last 5 years. The Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) study was a seminal clinical trial that investigated combination checkpoint blockade with ipilimumab and nivolumab in both adjuvant and perioperative contexts.6 This was a phase 1B trial in which patients were randomized to either 12 weeks of adjuvant therapy or 6 weeks of neoadjuvant plus six weeks of adjuvant therapy. Nine of 10 patients in both arms experienced grade 3/4 toxicities when dosed at ipilimumab 3 mg/kg and nivolumab 1 mg/kg.6 The 4-year EFS was 80% for perioperative therapy and 60% for adjuvant therapy, while the 4-year overall survival (OS) was 90% and 70%, respectively.25

Another groundbreaking neoadjuvant trial in melanoma was conducted by Amaria et al., which was published concomitantly with the OpaCIN study findings. In this trial, the authors investigated neoadjuvant PD-1 monotherapy with nivolumab (3mg/kg) for four doses versus combination nivolumab (1mg/kg) plus ipilimumab (3mg/kg) for three doses in patients with high-risk, resectable melanoma.9 Twenty-three patients were enrolled (n = 12 monotherapy, n = 11 combination therapy), and the trial was stopped early due to disease progression that prohibited subsequent surgery in two patients receiving nivolumab monotherapy. Combination therapy was associated with high objective response rate (ORR) (73%) and pCR rate (45%), though there was high associated toxicity (73% grade 3 adverse events). In contrast, nivolumab monotherapy was associated with only a modest ORR (25%) and pCR rate (25%), though only 8% of patients experienced a grade 3 toxicity. There were no significant differences in survival outcome measures (RFS, DMFS, and OS), though this analysis was limited by small sample sizes. The authors performed extensive translational analyses of tumor samples to identify signatures of response, and they identified higher CD8+ tumor infiltrate, increased tumor cell PD-L1 expression, and greater presence of lymphoid markers in responders vs. non-responders. They also identified a higher rate of T-cell clonality in responders, as previously described.26

Shortly thereafter, Huang et al. investigated the impact of a single dose of pembrolizumab 3 weeks prior to surgical resection.8 In this study, 27 patients with stage IIIB-IV melanoma treated with surgical resection were enrolled, and 8/27 (29.6%) exhibited a major or complete pathologic response after a single dose. One-year DFS was 63%, though no patients with complete/major responses had recurred by the study endpoint. Similar to the study by Amaria et al., a higher quantity of CD8+ tumor infiltrate was associated with better response to checkpoint blockade.

Finally, findings from the OpaCIN trial inspired the subsequent OpaCIN-neo trial, which was a phase 2b study investigating optimal dosing for combination ipilimumab plus nivolumab neoadjuvant therapy for stage III melanoma.27 In this trial, 86 patients were randomized to three different treatment arms with different dosing regimens, and the investigators observed that the optimal combination, as evidenced by minimal toxicity and maximal effect, was two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every three weeks intravenously. Rozeman et al. recently published long-term survival data, and the overall 2-year RFS for all three treatment arms was 84% but was 97% for patients with an observed pathologic response vs. only 36% for non-responders.25

Neoadjuvant vs. Adjuvant Immunotherapy for Melanoma

It remains unknown whether neoadjuvant therapy is superior to adjuvant therapy, or vice versa. To date, no phase 3 clinical trials comparing these approaches have been completed to provide more clarity on the topic. The Southwest Oncology Group (SWOG) S1801 is an ongoing phase 2 clinical trial investigating survival outcome measures for patients with stage III-IV resectable melanoma treated with neoadjuvant vs. adjuvant pembrolizumab (PD-1 inhibitor).28 Results for this head-to-head comparison have not yet been published. Cross-trial comparisons are inherently limited, though cautious interpretation of completed studies does suggest a trend in favor of neoadjuvant therapy. Considering the aforementioned clinical trials, on aggregate adjuvant therapy was associated with an RFS of approximately 50-65% at 2-4 years of follow up. In contrast, neoadjuvant studies provided evidence of more durable responses, with recurrence-free intervals ranging from 80-84% at 1-4 years of follow up.

It is also interesting to note that combination CTLA4 plus PD-1 inhibition was shown to provide an additive effect in advanced disease (CheckMate067) and as neoadjuvant therapy (Amaria et al.), but not in the adjuvant context (CheckMate 915). The biologic underpinnings of these differences in treatment efficacy require further investigation, though one noticeable difference is that tumor biomass is present at the time of checkpoint inhibitor treatment for advanced disease and neoadjuvant therapy, unlike for adjuvant treatment. It is conceivable that dual checkpoint blockade might have greater impact when immunologic exposure to neoantigens is theoretically more plentiful. In support of this argument, it was observed in the OpaCIN and OpaCIN-neo trials that neoadjuvant therapy was associated with greater expansion of tumor-resident T cell clones compared to adjuvant therapy.27

Treatment Response Biomarkers Drive the Next Generation of Neoadjuvant Trials

Despite the excitement and promise of checkpoint blockade for the treatment of metastatic melanoma, only about half of patients will have an objective response to combination therapy, while even lower response rates are observed with single agents.2 There are multiple ongoing efforts to better understand the biologic determinants of treatment response, and this work could have two pragmatic implications for clinical care. First, improved pre-treatment response prediction would allow for more accurate prognostication and could inform management decisions, e.g. surveillance frequency. Second, this work could lead to the development of personalized therapeutic regimens that are designed to optimize treatment effect.

One important avenue of investigation involves assessment of pathologic tumor response, which has been shown to correlate with RFS and OS for both targeted inhibition and immunotherapy. Interestingly, the degree of pathologic response, and its association with outcome measures, appears to differ based on treatment type.29 Among patients treated with neoadjvuant BRAF/MEK inhibition, evidence of pCR was associated with superior survival outcomes, while those who had a near-complete response or partial response behaved more similar to non-responders over time. Conversely, for patients treated with immunotherapy, partial and near complete responses behaved similar to complete responders with very few recurrences during the observation period. While no patients with a pCR to immunotherapy have recurred to date, recurrence has been observed for patients with targeted therapy who similarly had a complete response. These findings indicate that that pathologic response, of any degree, is a more sensitive marker of durable response for immunotherapy than for targeted BRAF/MEK inhibition.

Several studies have also investigated the relationship between pathologic response and preoperative clinicopathologic traits in the hope of identifying pre-treatment prognostic markers. Menzies et al. recently evaluated pathologic response and survival of 192 stage III melanoma patients treated with neoadjuvant therapy.29 In this study, there were no significant associations observed in BRAF/MEK inhibitor-treated patients, and for immunotherapy, only the treatment regimen, combination vs. monotherapy checkpoint blockade, was significant on multivariable analysis. Post-hoc analysis of participants in the OpACIN-Neo trial support these findings, as there was no association between tumor ulceration, size, or PD-1 expression and pathologic response to therapy.27 These studies capture the current state of knowledge, which is that it remains difficult to predict who will have a good response to neoadjuvant therapy based on pretreatment clinical factors.

Technological advances, particularly next generation sequencing, have allowed for deeper investigations into the biologic determinants of response to neoadjuvant therapy for melanoma. By transcriptomic analysis, Interferon-gamma (IFN-y) expression has been shown to associate with pathologic response to checkpoint blockade. IFN-y is a cytokine produced by activated T cells, NK cells, and NK T cells, which has multiple effects on immune signaling resulting in an inflammatory state that is critical to the innate immune response.30 With respect to the tumor microenvironment, INF-y has been shown to stimulate expression of HLA proteins, theoretically supporting neoantigen presentation and immune cell recruitment. However, IFN-y also co-stimulates inhibitory signals including PD-L1 and PD-L2, and this combination of immunologic stimulation and dampening represents a complex interplay that is not fully understood. Nonetheless, the presence of INF-y signaling has been associated with a reduced risk of relapse, and thus it may have empiric value as a predictor of immunotherapy response.6 A recent post-treatment analysis of 65 patients from the OpaCIN-neo trial confirmed that high IFN-y gene expression was significantly associated with the degree of pathologic response and the risk of relapse.25 In this study, the authors observed an association between EFS and tumor mutational burden (TMB). However, no correlation between TMB and IFN-y expression was observed, though patients who exhibited both high TMB and IFN-y signaling had a 100% rate of partial pathologic response and zero recurrences at 2 years. Conversely, presence of both low TMB and low IFN-y signaling was associated with a 2-year EFS rate of only 49% in comparison to 83% or greater for all other combinations in which at least one biomarker (TMB or IFN-y expression) was elevated.25

Translational discovery of IFN-y expression in the TME inspired the DONIMI trial, a biomarker driven, multicenter phase 1b trial evaluating Domatinostat, Nivolumab, and Ipilimumab in IFN-y signature-low and IFN-y signature-high stage III melanoma.31 Domatinostat is a selective class I histone deacetylase inhibitor (HDACi) that is thought to potentially stimulate IFN-y gene expression. The intention of this trial is to convert pre-treatment IFN-y low tumors to an IFN-y high phenotype in order to enhance tumor response.

Immune infiltrates are another potential marker of susceptibility to checkpoint blockade. Post-treatment analysis of tumor samples from the OpaCIN-neo trial revealed that quantity of immune cell infiltrate was associated with the degree of pathologic response.25 In this study, the authors also reported that increased circulating levels of vascular endothelial growth factor receptor 2 (VEGFR-2), CX3CL1, and PD-L2 after neoadjuvant therapy were associated with non-responders. VEGF signaling is thought to have multiple pro-tumor functions, including inhibition of effector T cell function, abrogation of immune cell trafficking to the TME, suppression of antigen presentation by dendritic cells, and stimulation of myeloid derived suppressor cells and regulatory T cells.32-35 Based on these findings, the Neo PeLe trial is a phase II study of neoadjuvant pembrolizumab and lenvatinib for stage III melanoma. Lenvatinib is a multiple RTK inhibitor that selectively inhibits VEGF receptors, including VEGFR-2.36 Similar to the DONIMI trial, the goal of this study is to increase immunotherapy susceptibility among non-responders.

The Impact of the Gut Microbiome

Our understanding of the complex interplay between gut microbiota and the immune system is still in its infancy, but several seminal studies have implicated the microbiome in the response to immune-based therapies. The intestines contain the largest reservoir of lymphocytes in the human body, and continuous communication between bacteria and immune cells, primarily contained in Peyer’s patches in the lamina propria of the intestinal wall, influences both local and systemic immune activation states. Alterations in the diversity and abundance of gut bacterial species have been associated with multiple diseases with immunologic underpinnings, including inflammatory bowel disease, hepatic steatohepatitis, and various types of cancer. In 2015, it was shown in preclinical melanoma models that variation in the quality and quantity of gut bacterial species influences susceptibility to checkpoint blockade.37,38 These studies inspired a series of clinical investigations that corroborated such findings in melanoma patients treated with immunotherapy.39-42 In each case, it was found that patterns in the microbiome could be linked to “responder” and “non-responder” states, though the patterns were variable between studies. It is not fully understood why there has been limited overlap in microbiome signatures between studies, though it may be partly related to technical considerations such as sequencing pipelines and differences in patient populations.43

Nonetheless, the gut microbiome has been identified as a novel target for cancer therapy, both as a means for disease prevention and for effect modification of immunotherapy. Thus, work is ongoing to identify consortia of bacteria that enhance immune response in the setting of checkpoint blockade. In addition, there are active clinical trials investigating interventions and behaviors that influence microbial diversity, including diet, exercise, and the use of antibiotics.44,45 Delivery of therapeutic microbiota is an area of active investigation, including fecal microbial transplant (FMT) and biotherapeutics comprised of one or multiple strains of bacteria. Although obstacles remain, it might be possible in the future to sample the stool of melanoma patients to contextualize their baseline microbial signature as immunotherapy responder vs. non-responder status. Then by means such as dietary changes, an “off the shelf” biotherapeutic, or fecal transplant, it may be possible to convert patients to responder states prior to initiation of checkpoint blockade.

Combination Targeted BRAF/MEK Inhibition Plus Immunotherapy

Although targeted therapy is not mechanistically thought of as an immune-modulating therapy, It has been previously shown in both preclinical animal models and patient samples that targeted BRAF/MEK inhibition is associated with multiple immunologic changes in the TME, the majority of which are immune activating. These changes include increased expression of antigen presenting machinery (major histocompatibility complex proteins), increased presentation of immune-stimulating melanocyte differentiation antigens, and infiltration of cytotoxic (CD8+) T cells without a concomitant rise in immune suppressive cells.46-48 Given these immunologic changes incurred with targeted therapy, there might be an additive effect with combined checkpoint blockade.

There is precedent for combination BRAF/MEK plus checkpoint blockade in studies of advanced melanoma. The Keynote-022 trial was a phase II multicenter, double-blinded clinical trial for patients with metastatic or unresectable BRAF-mutated melanoma who were randomized to treatment with dabrafenib and trametinib plus pembrolizumab or placebo.49,50 PFS at 24 months was 41% for combination therapy vs. 16% for BRAF/MEK therapy. Median OS was not reached for combination therapy and was 26.3 months for BRAF/MEK therapy.49 Triplet therapy consisting of pembrolizumab plus targeted BRAF/MEK inhibition was associated with a higher incidence of treatment related adverse events. The study did not achieve statistical significance for the prespecified primary endpoint of progression-free survival.

More recently, the COMBI-i trial was a placebo-controlled, phase 3 clinical trial investigating spartalizumab, an anti-PD-1 antibody, vs. placebo in combination with dabrafenib and trametinib for patients with BRAF-mutated advanced melanoma.51 There was no difference in the primary endpoint of PFS between treatment arms, though some beneficial trends were observed with the addition of anti-PD-1 therapy. Objective response rates were 68.5% for the spartalizumab arm vs. 64.2% for the placebo arm.

Finally, a third study, the IMspire150 trial, was a phase III multicenter, double-blinded, randomized controlled trial investigating atezolizumab, an anti-PD-L1 antibody, vs. placebo plus cobimetinib and vemurafenib for advanced and locally unresectable melanoma.52 The primary endpoint of this study was PFS, which was found to be significantly increased by investigator assessment with combination checkpoint and BRAF/MEK therapy (15.1 vs 10.6 months, p = 0.025). There was no difference on overall survival with limited duration of follow up.

In summary, it remains to be determined whether the combination of immune checkpoint blockade plus BRAF/MEK inhibition provides a survival advantage. As more checkpoint inhibitors and targeted therapies are developed, identifying the optimal combinations and dosing regimens remains an area of active investigation, particularly given the high toxicity profile of combination therapy. Further investigation of this therapeutic strategy in the neoadjuvant space is required to determine its potential benefit.

Evolving Indications for Surgical Intervention with Neoadjuvant Therapy

The advent of highly effective neoadjuvant therapies comes with new questions about the role of surgery for locally advanced and metastatic disease. With regard to regional nodal disease, the German Dermatologic Cooperative Oncology Group-Selective Lymphadenectomy Trial (DeCOG-SLT) and Multicenter Selective Lymphadenectomy Trial II (MSLT-II) provided supporting evidence for observation rather than therapeutic lymph node dissection for clinical node negative, sentinel node positive melanoma.53,54 For patients with clinical node positive disease, the standard of care remains therapeutic lymph node dissection. However, for patients with clinically positive nodes who experience an objective response to neoadjuvant checkpoint blockade, there is often no evidence of residual malignancy on pathologic analysis of the surgical specimen.27 This observation provided the inspiration for the personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab (PRADO) trial for resectable stage III melanoma.55 In this study, which is an extension cohort of the OpaCIN-neo trial, patients with clinical node positive melanoma were treated with 2 cycles of ipilumumab and nivolumab after fiducial marker placement in the index lymph node (ILN), which was defined as the largest node with pathologically confirmed metastatic disease. Resection of the ILN was performed at 6 weeks after initiation of neoadjuvant therapy, and patients with a major pathologic response in the ILN underwent no further intervention, patients with a partial response were treated with completion lymph node dissection, and patients with no response were treated with node dissection followed by adjuvant nivolumab. This trial is ongoing with long-term survival outcomes pending. Findings from this study may set new precedent to further limit the indications for therapeutic lymphadenectomy.

While neoadjuvant therapy may lead to narrowed surgical indications for resectable, regional disease, it might also expand indications for unresectable locally advanced and metastatic melanoma. Blankenstein et al. recently published their findings from the REDUCTOR trial, which was a prospective, single arm, phase II trial investigating the downstaging potential of neoadjuvant BRAF/MEK inhibition for unresectable regionally advanced and oligometastatic melanoma.56 This trial enrolled 21 patients with stage IIIc melanoma, of which 18 (86%) were treated with surgical resection, and an R0 resection was achieved in 17 of 18 patients with a median RFS of 9.9 months. The findings from this trial reveal the potential of neoadjuvant BRAF/MEK inhibition to downstage unresectable disease. By inference, it is conceivable that the extent of downstaging and rate of durable response might be even better with checkpoint blockade or combination targeted inhibition and checkpoint blockade.

Conclusion

The advent of effective systemic therapies with targeted BRAF/MEK inhibition and immune checkpoint blockade has drastically changed the treatment landscape for melanoma, particularly the prospect of neoadjuvant therapy for locally advanced and metastatic disease. While preliminary trial data is very supportive for the use of neoadjuvant therapy for stage III/IV melanoma, there are multiple active lines of investigation designed to further optimize its application, which we have described in this review and summarized in Table 2. Going forward, it is likely that neoadjuvant therapy will increasingly be utilized with expanded indications, and hopefully more durable responses.

Table 2.

Future Directions of Neoadjuvant Trials.

Redefining Surgical Indications

  • Mitigating unnecessary lymphadenectomy in neoadjuvant responders (PRADO Trial)55

  • Downstaging unresectable disease (REDUCTOR Trial)56
Optimizing Treatment Response

  • Stimulating Responder Transcriptomic Signature (IFN-y high) with HDACi and IFN therapy31,57

  • Stimulating Responder Gut Microbiome Signature with diet, FMT, biotherapeutics44,45

  • Abrogating Non-Responder Signature (Circulating VEGF2) with Anti-VEGF therapy36
Novel Treatment Combinations

  • Combination BRAF/MEK plus immune checkpoint blockade58

  • Combination immune checkpoint blockade plus viral oncolysis59

  • Trialing novel checkpoint and targeted inhibitors
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FMT, fecal microbiota transplantation; HDACi, histone deacetylase inhibitor; IFN, interferon; VEGF, vascular endothelial growth factor.

Footnotes

Conflicts of Interest:

J.A.W. is an inventor on a US patent application (PCT/US17/53.717) relevant to the current work; reports compensation for speaker’s bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, MedImmune, and Bristol-Myers Squibb (BMS); serves as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline (GSK), BMS, Merck, Biothera Pharmaceuticals, and Micronoma.

Financial Disclosures:

There are no financial relationships related to the design or execution of this study.

References

  • 1.Curti BD, Faries MB. Recent Advances in the Treatment of Melanoma. N Engl J Med 2021;384(23):2229–2240. DOI: 10.1056/NEJMra2034861. [DOI] [PubMed] [Google Scholar]
  • 2.Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, Cowey CL, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hogg D, Hill A, Marquez-Rodas I, Haanen J, Guidoboni M, Maio M, Schoffski P, Carlino MS, Lebbe C, McArthur G, Ascierto PA, Daniels GA, Long GV, Bastholt L, Rizzo JI, Balogh A, Moshyk A, Hodi FS, Wolchok JD. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019;381(16):1535–1546. DOI: 10.1056/NEJMoa1910836. [DOI] [PubMed] [Google Scholar]
  • 3.Amaria RN, Menzies AM, Burton EM, Scolyer RA, Tetzlaff MT, Antdbacka R, Ariyan C, Bassett R, Carter B, Daud A, Faries M, Fecher LA, Flaherty KT, Gershenwald JE, Hamid O, Hong A, Kirkwood JM, Lo S, Margolin K, Messina J, Postow MA, Rizos H, Ross MI, Rozeman EA, Saw RPM, Sondak V, Sullivan RJ, Taube JM, Thompson JF, van de Wiel BA, Eggermont AM, Davies MA, International Neoadjuvant Melanoma Consortium m, Ascierto PA, Spillane AJ, van Akkooi ACJ, Wargo JA, Blank CU, Tawbi HA, Long GV. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol 2019;20(7):e378–e389. DOI: 10.1016/S1470-2045(19)30332-8. [DOI] [PubMed] [Google Scholar]
  • 4.Liu J, Blake SJ, Yong MC, Harjunpaa H, Ngiow SF, Takeda K, Young A, O'Donnell JS, Allen S, Smyth MJ, Teng MW. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer Discov 2016;6(12):1382–1399. DOI: 10.1158/2159-8290.CD-16-0577. [DOI] [PubMed] [Google Scholar]
  • 5.Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Faris JE, Zhu AX, Goyal L, Lillemoe KD, DeLaney TF, Fernandez-Del Castillo C, Ferrone CR, Hong TS. Total Neoadjuvant Therapy With FOLFIRINOX Followed by Individualized Chemoradiotherapy for Borderline Resectable Pancreatic Adenocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 2018;4(7):963–969. DOI: 10.1001/jamaoncol.2018.0329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, Krijgsman O, van den Braber M, Philips D, Broeks A, van Thienen JV, Mallo HA, Adriaansz S, Ter Meulen S, Pronk LM, Grijpink-Ongering LG, Bruining A, Gittelman RM, Warren S, van Tinteren H, Peeper DS, Haanen J, van Akkooi ACJ, Schumacher TN. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24(11):1655–1661. DOI: 10.1038/s41591-018-0198-0. [DOI] [PubMed] [Google Scholar]
  • 7.Krishnamoorthy M, Lenehan JG, Maleki Vareki S. Neoadjuvant Immunotherapy for High-Risk, Resectable Malignancies: Scientific Rationale and Clinical Challenges. J Natl Cancer Inst 2021. DOI: 10.1093/jnci/djaa216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Huang AC, Orlowski RJ, Xu X, Mick R, George SM, Yan PK, Manne S, Kraya AA, Wubbenhorst B, Dorfman L, D'Andrea K, Wenz BM, Liu S, Chilukuri L, Kozlov A, Carberry M, Giles L, Kier MW, Quagliarello F, McGettigan S, Kreider K, Annamalai L, Zhao Q, Mogg R, Xu W, Blumenschein WM, Yearley JH, Linette GP, Amaravadi RK, Schuchter LM, Herati RS, Bengsch B, Nathanson KL, Farwell MD, Karakousis GC, Wherry EJ, Mitchell TC. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med 2019;25(3):454–461. DOI: 10.1038/s41591-019-0357-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Amaria RN, Reddy SM, Tawbi HA, Davies MA, Ross MI, Glitza IC, Cormier JN, Lewis C, Hwu WJ, Hanna E, Diab A, Wong MK, Royal R, Gross N, Weber R, Lai SY, Ehlers R, Blando J, Milton DR, Woodman S, Kageyama R, Wells DK, Hwu P, Patel SP, Lucci A, Hessel A, Lee JE, Gershenwald J, Simpson L, Burton EM, Posada L, Haydu L, Wang L, Zhang S, Lazar AJ, Hudgens CW, Gopalakrishnan V, Reuben A, Andrews MC, Spencer CN, Prieto V, Sharma P, Allison J, Tetzlaff MT, Wargo JA. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018;24(11):1649–1654. DOI: 10.1038/s41591-018-0197-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Cancer Genome Atlas N. Genomic Classification of Cutaneous Melanoma. Cell 2015;161(7):1681–96. DOI: 10.1016/j.cell.2015.05.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949–54. DOI: 10.1038/nature00766. [DOI] [PubMed] [Google Scholar]
  • 12.Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, Group B-S. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507–16. DOI: 10.1056/NEJMoa1103782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr., Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380(9839):358–65. DOI: 10.1016/S0140-6736(12)60868-X. [DOI] [PubMed] [Google Scholar]
  • 14.Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367(18):1694–703. DOI: 10.1056/NEJMoa1210093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015;372(1):30–9. DOI: 10.1056/NEJMoa1412690. [DOI] [PubMed] [Google Scholar]
  • 16.Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, Glitza IC, Cormier J, Hwu WJ, Tawbi HA, Patel SP, Lee JE, Gershenwald JE, Spencer CN, Gopalakrishnan V, Bassett R, Simpson L, Mouton R, Hudgens CW, Zhao L, Zhu H, Cooper ZA, Wani K, Lazar A, Hwu P, Diab A, Wong MK, McQuade JL, Royal R, Lucci A, Burton EM, Reddy S, Sharma P, Allison J, Futreal PA, Woodman SE, Davies MA, Wargo JA. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018;19(2):181–193. DOI: 10.1016/S1470-2045(18)30015-9. [DOI] [PubMed] [Google Scholar]
  • 17.Long GV, Saw RPM, Lo S, Nieweg OE, Shannon KF, Gonzalez M, Guminski A, Lee JH, Lee H, Ferguson PM, Rawson RV, Wilmott JS, Thompson JF, Kefford RF, Ch'ng S, Stretch JR, Emmett L, Kapoor R, Rizos H, Spillane AJ, Scolyer RA, Menzies AM. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF(V600) mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol 2019;20(7):961–971. DOI: 10.1016/S1470-2045(19)30331-6. [DOI] [PubMed] [Google Scholar]
  • 18.Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbe C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017;377(14):1345–1356. DOI: 10.1056/NEJMoa1709684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol 2020;38(33):3925–3936. DOI: 10.1200/JCO.20.02110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, Haydon AM, Meshcheryakov A, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Di Giacomo AM, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan PC, van Akkooi ACJ, Krepler C, Ibrahim N, Marreaud S, Kicinski M, Suciu S, Robert C, Group EM. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22(5):643–654. DOI: 10.1016/S1470-2045(21)00065-6. [DOI] [PubMed] [Google Scholar]
  • 21.Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob JJ, Butler MO, Middleton MR, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar RR, Smylie M, Meyer N, Mortier L, Atkins MB, Long GV, Bhatia S, Lebbe C, Rutkowski P, Yokota K, Yamazaki N, Kim TM, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto PA, CheckMate C. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017;377(19):1824–1835. DOI: 10.1056/NEJMoa1709030. [DOI] [PubMed] [Google Scholar]
  • 22.Ascierto PA, Del Vecchio M, Mandala M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Marquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21(11):1465–1477. DOI: 10.1016/S1470-2045(20)30494-0. [DOI] [PubMed] [Google Scholar]
  • 23.Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, Hwu WJ, Weber JS, Gangadhar TC, Joseph RW, Dronca R, Patnaik A, Zarour H, Kefford R, Hersey P, Zhang J, Anderson J, Diede SJ, Ebbinghaus S, Hodi FS. Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. J Clin Oncol 2018;36(17):1668–1674. DOI: 10.1200/JCO.2017.75.6270. [DOI] [PubMed] [Google Scholar]
  • 24.Long Georgina V S D, Vecchio Michele Del, Larkin James, Atkinson Victoria, Schenker Michael, Pigozzo Jacopo, Gogas Helen J., Dalle Stéphane, Meyer Nicolas, Ascierto Paolo A., Sandhu Shahneen, Eigentler Thomas, Gutzmer Ralf, Hassel Jessica C., Robert Caroline, Carlino Matteo, Di Giacomo Anna Maria, Butler Marcus O, Muñoz-Couselo Eva, Brown Michael P., Rutkowski Piotr, Haydon Andrew, Grob Jean-Jacques, Schachter Jacob, Queirolo Paola, Menzies Alexander, Re Sandra, Bas Tuba O., De Pril Veerle, Tenney Daniel, Tang Hao, Weber Jeffrey S.. Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915). American Association for Cancer Research (AACR) Annual Meeting2021. [Google Scholar]
  • 25.Rozeman EA, Hoefsmit EP, Reijers ILM, Saw RPM, Versluis JM, Krijgsman O, Dimitriadis P, Sikorska K, van de Wiel BA, Eriksson H, Gonzalez M, Torres Acosta A, Grijpink-Ongering LG, Shannon K, Haanen J, Stretch J, Ch'ng S, Nieweg OE, Mallo HA, Adriaansz S, Kerkhoven RM, Cornelissen S, Broeks A, Klop WMC, Zuur CL, van Houdt WJ, Peeper DS, Spillane AJ, van Akkooi ACJ, Scolyer RA, Schumacher TNM, Menzies AM, Long GV, Blank CU. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma. Nat Med 2021;27(2):256–263. DOI: 10.1038/s41591-020-01211-7. [DOI] [PubMed] [Google Scholar]
  • 26.Roh W, Chen PL, Reuben A, Spencer CN, Prieto PA, Miller JP, Gopalakrishnan V, Wang F, Cooper ZA, Reddy SM, Gumbs C, Little L, Chang Q, Chen WS, Wani K, De Macedo MP, Chen E, Austin-Breneman JL, Jiang H, Roszik J, Tetzlaff MT, Davies MA, Gershenwald JE, Tawbi H, Lazar AJ, Hwu P, Hwu WJ, Diab A, Glitza IC, Patel SP, Woodman SE, Amaria RN, Prieto VG, Hu J, Sharma P, Allison JP, Chin L, Zhang J, Wargo JA, Futreal PA. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med 2017;9(379). DOI: 10.1126/scitranslmed.aah3560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Rozeman EA, Menzies AM, van Akkooi ACJ, Adhikari C, Bierman C, van de Wiel BA, Scolyer RA, Krijgsman O, Sikorska K, Eriksson H, Broeks A, van Thienen JV, Guminski AD, Acosta AT, Ter Meulen S, Koenen AM, Bosch LJW, Shannon K, Pronk LM, Gonzalez M, Ch'ng S, Grijpink-Ongering LG, Stretch J, Heijmink S, van Tinteren H, Haanen J, Nieweg OE, Klop WMC, Zuur CL, Saw RPM, van Houdt WJ, Peeper DS, Spillane AJ, Hansson J, Schumacher TN, Long GV, Blank CU. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol 2019;20(7):948–960. DOI: 10.1016/S1470-2045(19)30151-2.. [DOI] [PubMed] [Google Scholar]
  • 28.A Study to Compare the Administration of Pembrolizumab After Surgery Versus Administration Both Before and After Surgery for High-Risk Melanoma.
  • 29.Menzies AM, Amaria RN, Rozeman EA, Huang AC, Tetzlaff MT, van de Wiel BA, Lo S, Tarhini AA, Burton EM, Pennington TE, Saw RPM, Xu X, Karakousis GC, Ascierto PA, Spillane AJ, van Akkooi ACJ, Davies MA, Mitchell TC, Tawbi HA, Scolyer RA, Wargo JA, Blank CU, Long GV. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med 2021;27(2):301–309. DOI: 10.1038/s41591-020-01188-3. [DOI] [PubMed] [Google Scholar]
  • 30.Ikeda H, Old LJ, Schreiber RD. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002;13(2):95–109. DOI: 10.1016/s1359-6101(01)00038-7. [DOI] [PubMed] [Google Scholar]
  • 31.Multicenter Phase 1b Trial Testing the Neoadjuvant Combination of Domatinostat, Nivolumab and Ipilimumab in IFN-gamma Signature-low and IFN-gamma Signature-high RECIST 1.1-measurable Stage III Cutaneous or Unknown Primary Melanoma.
  • 32.Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, Hagemann IS, Lal P, Feldman MD, Benencia F, Coukos G. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20(6):607–15. DOI: 10.1038/nm.3541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, Prieto PA, Miller JP, Bassett RL, Gopalakrishnan V, Wani K, De Macedo MP, Austin-Breneman JL, Jiang H, Chang Q, Reddy SM, Chen WS, Tetzlaff MT, Broaddus RJ, Davies MA, Gershenwald JE, Haydu L, Lazar AJ, Patel SP, Hwu P, Hwu WJ, Diab A, Glitza IC, Woodman SE, Vence LM, Wistuba II, Amaria RN, Kwong LN, Prieto V, Davis RE, Ma W, Overwijk WW, Sharpe AH, Hu J, Futreal PA, Blando J, Sharma P, Allison JP, Chin L, Wargo JA. Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. Cancer Discov 2016;6(8):827–37. DOI: 10.1158/2159-8290.CD-15-1545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92(11):4150–66. (https://www.ncbi.nlm.nih.gov/pubmed/9834220). [PubMed] [Google Scholar]
  • 35.Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2013;73(2):539–49. DOI: 10.1158/0008-5472.CAN-12-2325. [DOI] [PubMed] [Google Scholar]
  • 36.A Phase II Study of Neoadjuvant Pembrolizumab & Lenvatinib for Resectable Stage III Melanoma.
  • 37.Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084–9. DOI: 10.1126/science.aac4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350(6264):1079–84. DOI: 10.1126/science.aad1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103. DOI: 10.1126/science.aan4236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108. DOI: 10.1126/science.aao3290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, Koh AY. Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients. Neoplasia 2017;19(10):848–855. DOI: 10.1016/j.neo.2017.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97. DOI: 10.1126/science.aan3706. [DOI] [PubMed] [Google Scholar]
  • 43.Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy. Nat Med 2019;25(3):377–388. DOI: 10.1038/s41591-019-0377-7. [DOI] [PubMed] [Google Scholar]
  • 44.Effect of Diet on the Immune System in Patients With Stage III-IV Melanoma Receiving Immunotherapy, DIET Study.
  • 45.The Impact of an Antibiotic (Cefazolin) Before Surgery on the Microbiome in Patients With Stage I-II Melanoma.
  • 46.Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, Ferrone CR, Flaherty KT, Lawrence DP, Fisher DE, Tsao H, Wargo JA. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70(13):5213–9. DOI: 10.1158/0008-5472.CAN-10-0118. [DOI] [PubMed] [Google Scholar]
  • 47.Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, Mitra D, Boni A, Newton LP, Liu C, Peng W, Sullivan RJ, Lawrence DP, Hodi FS, Overwijk WW, Lizee G, Murphy GF, Hwu P, Flaherty KT, Fisher DE, Wargo JA. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res 2013;19(5):1225–31. DOI: 10.1158/1078-0432.CCR-12-1630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, Haynes NM, Kinross K, Yagita H, Koya RC, Graeber TG, Ribas A, McArthur GA, Smyth MJ. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest 2013;123(3):1371–81. DOI: 10.1172/JCI66236. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 49.Ferrucci PF, Di Giacomo AM, Del Vecchio M, Atkinson V, Schmidt H, Schachter J, Queirolo P, Long GV, Stephens R, Svane IM, Lotem M, Abu-Amna M, Gasal E, Ghori R, Diede SJ, Croydon ES, Ribas A, Ascierto PA, team K-i. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J Immunother Cancer 2020;8(2). DOI: 10.1136/jitc-2020-001806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Ascierto PA, Ferrucci PF, Fisher R, Del Vecchio M, Atkinson V, Schmidt H, Schachter J, Queirolo P, Long GV, Di Giacomo AM, Svane IM, Lotem M, Bar-Sela G, Couture F, Mookerjee B, Ghori R, Ibrahim N, Moreno BH, Ribas A. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med 2019;25(6):941–946. DOI: 10.1038/s41591-019-0448-9. [DOI] [PubMed] [Google Scholar]
  • 51.Dummer R, Lebbe C, Atkinson V, Mandala M, Nathan PD, Arance A, Richtig E, Yamazaki N, Robert C, Schadendorf D, Tawbi HA, Ascierto PA, Ribas A, Flaherty KT, Pakhle N, Campbell CD, Gusenleitner D, Masood A, Brase JC, Gasal E, Long GV. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat Med 2020;26(10):1557–1563. DOI: 10.1038/s41591-020-1082-2. [DOI] [PubMed] [Google Scholar]
  • 52.Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Manikhas GM, Yan Y, Huang KC, Uyei A, McNally V, McArthur GA, Ascierto PA. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF(V600) mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;395(10240):1835–1844. DOI: 10.1016/S0140-6736(20)30934-X. [DOI] [PubMed] [Google Scholar]
  • 53.Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, Jahkola T, Bowles TL, Testori A, Beitsch PD, Hoekstra HJ, Moncrieff M, Ingvar C, Wouters M, Sabel MS, Levine EA, Agnese D, Henderson M, Dummer R, Rossi CR, Neves RI, Trocha SD, Wright F, Byrd DR, Matter M, Hsueh E, MacKenzie-Ross A, Johnson DB, Terheyden P, Berger AC, Huston TL, Wayne JD, Smithers BM, Neuman HB, Schneebaum S, Gershenwald JE, Ariyan CE, Desai DC, Jacobs L, McMasters KM, Gesierich A, Hersey P, Bines SD, Kane JM, Barth RJ, McKinnon G, Farma JM, Schultz E, Vidal-Sicart S, Hoefer RA, Lewis JM, Scheri R, Kelley MC, Nieweg OE, Noyes RD, Hoon DSB, Wang HJ, Elashoff DA, Elashoff RM. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017;376(23):2211–2222. DOI: 10.1056/NEJMoa1613210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer NH, Berking C, Sunderkotter C, Kaatz M, Schatton K, Lehmann P, Vogt T, Ulrich J, Herbst R, Gehring W, Simon JC, Keim U, Verver D, Martus P, Garbe C, German Dermatologic Cooperative Oncology G. Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node. J Clin Oncol 2019;37(32):3000–3008. DOI: 10.1200/JCO.18.02306. [DOI] [PubMed] [Google Scholar]
  • 55.Blank CU, Reijers ILM, Pennington T, Versluis JM, Saw RP, Rozeman EA, Kapiteijn E, Veldt AAMVD, Suijkerbuijk K, Hospers G, Klop WMC, Sikorska K, Hage JAVD, Grunhagen DJ, Spillane A, Rawson RV, Wiel BAVD, Menzies AM, Akkooi ACJV, Long GV. First safety and efficacy results of PRADO: A phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. Journal of Clinical Oncology 2020;38(15_suppl):10002–10002. DOI: 10.1200/JCO.2020.38.15_suppl.10002. [DOI] [Google Scholar]
  • 56.Blankenstein SA, Rohaan MW, Klop WMC, van der Hiel B, van de Wiel BA, Lahaye MJ, Adriaansz S, Sikorska K, van Tinteren H, Sari A, Grijpink-Ongering LG, van Houdt WJ, Wouters M, Blank CU, Wilgenhof S, van Thienen JV, van Akkooi ACJ, Haanen J. Neoadjuvant Cytoreductive Treatment with BRAF/MEK Inhibition of prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single Arm, Open-label Phase II Trial. Ann Surg 2021. DOI: 10.1097/SLA.0000000000004893. [DOI] [PubMed] [Google Scholar]
  • 57.Tarhini A, Lin Y, Lin H, Rahman Z, Vallabhaneni P, Mendiratta P, Pingpank JF, Holtzman MP, Yusko EC, Rytlewski JA, Rao UNM, Ferris RL, Kirkwood JM. Neoadjuvant ipilimumab (3 mg/kg or 10 mg/kg) and high dose IFN-alpha2b in locally/regionally advanced melanoma: safety, efficacy and impact on T-cell repertoire. J Immunother Cancer 2018;6(1):112. DOI: 10.1186/s40425-018-0428-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma.
  • 59.Neo-adjuvant T-VEC + Nivolumab Combination Therapy for Resectable Early Metastatic (Stage IIIB/C/D-IV M1a) Melanoma With Injectable Disease.

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