Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achieving high-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aim of this study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-related adverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK. Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durable response to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression. HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEs and survival. HRQoL data was compared with two norm-based datasets. Results Eighty-four metastatic melanoma survivors were eligible and 87% (N = 73) completed the SF-36. ICI-related toxicity of any grade occurred in 92% of patients and 43% had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients required steroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyond steroids. Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical role functioning and general health compared with the normative population. There was a trend towards inferior scores in patients with previous exposure to ipilimumab compared with those never exposed to ipilimumab. Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicity and experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population's unique survivorship needs.
Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM.
Understanding the evolutionary pathways to metastasis and resistance to immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present the most comprehensive intra-patient metastatic melanoma dataset assembled to date as part of the PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI non-responders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one of the patients. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.
The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number sample trees. Supplementary figure 6: MEDICC tree of all exome samples demonstrating that samples cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all samples. Supplementary figure 13: Number of samples per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for samples with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk samples from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of samples for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of samples for which RNA-seq was performed faceted by tissue site.</p>
<div>Abstract<p>Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found <i>KIT</i> extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, <i>MYC</i> amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.</p>Significance:<p>Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.</p></div>
<div>Abstract<p>Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found <i>KIT</i> extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, <i>MYC</i> amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.</p>Significance:<p>Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.</p></div>
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number sample trees. Supplementary figure 6: MEDICC tree of all exome samples demonstrating that samples cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all samples. Supplementary figure 13: Number of samples per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for samples with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk samples from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of samples for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of samples for which RNA-seq was performed faceted by tissue site.</p>
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