Introduction
Melanoma as a model system session
Neoadjuvant and adjuvant therapy for melanoma
Data comparison in adjuvant melanoma trials | ||||||
---|---|---|---|---|---|---|
Patient population | CM238 [60] | COMBI-AD [61] | KN054 [4] | |||
Completely resected stage IIIB/C or IV melanoma | Completely resected, BRAFV600E/K-positive stage IIIA/B/C melanoma | Completely resected stage IIIA/B/C melanoma | ||||
Treatment | Nivo | Lpi | Dab/Tram | Placebo | Pembro | Placebo |
N | 453 | 453 | 438 | 432 | 514 | 505 |
RFS HR | 0.65 (97.56% CI 0.51–0.83), P < 0.0001 | 0.47 (95% CI 0.39–0.58), P < 0.001 | 0.57 (98.4% CI 0.43–0.74), P < 0.001 | |||
1-year RFS rate (%) |
71
|
61
|
88
|
56
|
75
|
61
|
18-months RFS rate (%) | 66 | 53 | N/A | N/A | 71 | 53 |
3-years OS rate (%) | N/A | N/A | 86 | 77 | N/A | N/A |
Grade 3–5 TRAEs (%) |
14
| 46 |
31
| 5 |
15
| 3 |
DC rate due to AEs (%) |
10
| 43 |
26
| 3 |
14
| 2 |
Key points
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The use of interferon in the adjuvant setting has been superseded by checkpoint inhibitors and targeted agents that have moved from the metastatic to adjuvant setting.
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Anti-PD-1 therapy has shown greater efficacy and less toxicity than ipilimumab in the adjuvant setting.
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Adjuvant targeted therapy has also been shown to be effective in patients with completely resected BRAF-mutated melanoma, but toxicity is higher than with immunotherapy.
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Neoadjuvant therapy provides the opportunity to treat early in the disease course and is an area of active research interest with many trials ongoing.
Biomarkers in immunotherapy of melanoma: an update
Key points
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Two potential biomarkers for immunotherapy that are of interest are tumor mutational burden (TMB) and circulating tumor DNA (ctDNA).
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Certain cancer types, such as melanoma, have higher rates of high TMB tumors and high TMB is an independent predictor of response to immunotherapy.
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For patients with low TMB, studies to assess whether targeted agents may be more effective than immunotherapy are needed.
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Higher response to anti-PD-1 therapy has been reported in patients with undetectable ctDNA at baseline and in patients with significant reductions in ctDNA after starting treatment.
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It is not yet clear whether decrease in ctDNA levels during therapy or baseline level can serve as an important as a prognostic factor.
Mechanisms of targeted therapy resistance: from BRAF to NRAS mutant melanoma
Key points
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The convergence of multiple resistance mechanisms that reactivate (on drug) and hyper-activate (off drug) the MAPK pathway is a significant problem in treatment of melanoma.
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MEK inhibitors display marginal activity against NRAS mutant melanoma, likely due to both immunologic and tumor cell-intrinsic resistance.
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Anti-PD-1 therapy, despite innate resistance, may prime a subsequent MEK inhibitor response, suggesting that such sequencing paradigm may be broadly applicable to MAPK pathway-addicted cancers.
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Another strategy to overcome MAPK inhibitor resistance in melanoma involves exploitation of the MAPK inhibitor addiction phenotype. Discontinuation of the MEK inhibitor followed by addition of a PARP inhibitor to achieve regression of melanoma could represent one of the approaches.
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Next-generation MAPK inhibitors, such as dimeric RAF inhibitors, might be useful combinatorial partners to a MEK inhibitor across all MAPK-dependent subtypes of melanoma.
Clinical evidence emerging from radiation and immunotherapy
Key points
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Ionizing radiation targeted at lesions may help improve response to subsequent immunotherapy.
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The optimal dose and fractionation of radiation in combination with immunotherapy for the abscopal effect is yet unknown.
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Preclinical evidence suggests that the optimal effects of radiation and immune checkpoint blockade depend upon the dose per fraction of radiation used.
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Radiotherapy plus immune checkpoint inhibition can generate neo-epitopes that impart a memory effect.
Mechanisms of resistance and drivers of response session
Targeted therapy and immunotherapy: rational for combination and future perspectives
Key points
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Immunotherapy is slow-acting with the potential for long-term benefit while targeted therapy is fast-acting and promotes a rapid metabolic shutdown but with possible resistance.
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The immune signature is enriched in prognostic subgroups with a favourable response to BRAF and MEK inhibition, consistent with an immunosuppressive effect of oncogenic BRAF signalling on the tumor-host interaction.
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Blocking the MAPK signalling pathway results in changes in the TME that may mean tumor cells are more visible and hence more susceptible to immunotherapy.
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Several trials combining with an anti-PD-1/PD-L1 agent are ongoing with promising results.
Exosomes in melanoma
Key points
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Tumors produce and release a variety of extracellular vesicles, the smallest of which are exosomes, carriers of numerous receptors, ligands and factors that modulate functions of recipient cells.
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These tumor-derived exosomes (TEX) emerged as potential circulating biomarkers for parent tumor cells.
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Isolation of intact, biologically active exosomes from cancer patients’ plasma or other body fluids is now possible by mini-size exclusion chromatography.
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Melanoma-derived exosomes (MTEX) carry melanoma-associated antigens that are not detectable in exosomes produced by normal cells.
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The ability to isolate functional MTEX and to assess for melanoma-associated antigens or other molecular or genetic markers of the tumor will facilitate testing of the role of MTEX as liquid biopsies in melanoma.
Intestinal ecosystem and immunity against melanoma
Key points
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Dysbiosis of the intestinal flora may influence the outcome of cancer immunotherapy and it has been shown that the anti-tumor efficacy of CTLA-4 blockade is supported by gut bacteria, with T cell responses specific for Bacteroides spp. associated with improved efficacy.
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Antibiotics may inhibit the clinical benefit of anti-PD-1 or anti-PD-L1 treatment in patients with advanced cancer.
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Enhanced systemic and anti-tumor immunity was suggested in patients who responded to checkpoint inhibitors with a favourable gut microbiome and in germ-free mice receiving fecal transplants from responders.
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Studies to assess the role of the microbiome in melanoma are now ongoing with the hope that microbiome modulation may become an important modality in cancer therapy.
Tumor and host factors regulating immunotherapy efficacy
Key points
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The T cell-inflamed and non-inflamed TME represents two categories of immune escape.
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Activity of anti-PD-1 is associated with a T cell-inflamed TME signature at baseline and the T cell-inflamed TME serves as an approximate predictive biomarker for response to anti-PD-1-based immunotherapies.
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Mechanisms of human TIL apoptosis should be investigated to develop new potential therapeutic strategies for T cell-inflamed tumors.
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Molecular mechanisms that mediate the presence or absence of the T cell-inflamed TME are being elucidated using parallel genomics platforms.
Intratumoral immunotherapy a weapon beyond a “mass” destruction
Key points
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Ongoing studies are evaluating oncolytic intratumoral immunotherapy in combination with checkpoint inhibition.
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Oncolytic virus demonstrating promising clinical findings include HF10, a bioselected replication-competent oncolytic virus derived from HSV-1, and coxsackievirus A21 (CVA21).
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An intralesional agent, PV-10, which contains an injectable formulation of rose bengal disodium, is being assessed in combination with pembrolizumab.
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Intratumoral plasmid IL-12 with electroporation has shown promising activity in patients and good tolerability.
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Intralesional therapy may promote the release and presentation of tumor-derived antigens, thereby turning tumors from an immunologically ‘cold’ to ‘hot’ status and so providing potential synergy with checkpoint blockade.
Emerging strategies session
Translational research in the therapeutic landscape for metastatic melanoma
Key points
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In addition to NGS, a multitude of other cutting-edge technologies are also involved in translational research, including single-cell mass cytometry/imaging mass cytometry, fast drug-testing, deep drug, genomics and transcriptomics.
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Many examples of translational research indicate its fundamental role in helping guide therapy.
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A clinical goal of translational research is a multi-system predictive model to guide treatment decision-making in metastatic melanoma.
Role of adrenergic stress reversal in melanoma therapy
Key points
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Adrenergic signalling promotes tumor growth and metastasis.
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Norepinephrine (NE) signalling through β-adrenergic receptors on T cells is highly immunosuppressive, but its role in cancer has been largely unexplored.
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In preclinical studies, reducing adrenergic stress by physiologic reduction of NE signalling improved anti-PD-1 efficacy, while combining β-blockade with anti-PD-1 therapy had a synergistic inhibitory effect on tumor growth while anti-PD-1 alone had no impact.
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Several retrospective studies have suggested that the incidental use of β-blockers is beneficial to cancer patients.
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Based on these findings, a phase IB/II study of propranolol with fixed-dose pembrolizumab in patients with unresectable stage III and stage IV melanoma has been initiated.
Advancing the understanding and treatment of melanoma CNS metastases
Key points
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Targeted agents and immunotherapies have demonstrated significant benefits in patients with metastatic disease but patients with active brain metastases have typically been excluded from large trials.
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Three recent studies in patients with melanoma brain metastases have provided promising results (COMBI-MB, CheckMate 204 and the Anti-PD1 Brain Collaboration studies).
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Combination therapy with ipilimumab plus nivolumab is better than single-agent PD-1 therapy and represents a new standard of care for patients with asymptomatic brain metastases not requiring steroids.
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Targeted therapy of combined BRAF and MEK inhibition offers rapid responses and initial disease control, including in patients on steroids but most responses are ≤ 6 months and around half of patients have intracranial before extracranial progression.
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Next steps include further investigation of different combinatorial approaches, treatment options after failure on ipilimumab plus nivolumab or dabrafenib plus trametinib.
STING agonism and type I interferon to augment immunotherapy
Key points
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Given that a T cell-inflamed TME may serve as a predictive biomarker for response to immunotherapies, how do we treat non-T cell-infiltrated tumors?
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STING agonists may provide a means to deliberately initiate innate immune inflammation to promote an endogenous T cell response in non-T cell-inflamed tumors.
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Intratumoral administration of the STING agonist, MK-1454, resulted in complete tumor regression and enhances the efficacy of anti-PD-1 therapy in mouse syngeneic models and showed encouraging efficacy and an acceptable safety profile in combination with pembrolizumab in patients with advanced solid tumors or lymphoma.
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Tumor-targeted or systemic STING agonism may be the ideal partner for combination cancer therapeutic development.