Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

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Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

Cancers ◽

10.3390/cancers13246180 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6180

Author(s):

Maria Gracia-Hernandez ◽

Zuleima Munoz ◽

Alejandro Villagra

Keyword(s):

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Epigenetic Alterations ◽

Therapeutic Approaches ◽

Extrinsic Factors ◽

Epigenetic Drugs ◽

Epigenetic Modifiers ◽

Melanoma Patients

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients.

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Vitiligo-like Leukoderma as an Indicator of Clinical Response to Immune Checkpoint Inhibitors in Late-stage Melanoma Patients

10.21203/rs.3.rs-827134/v1 ◽

2021 ◽

Author(s):

Sofia Verkhovskaia ◽

Francesca Romana Di Pietro ◽

Simona Mastroeni ◽

Maria Luigia Carbone ◽

Damiano Abeni ◽

...

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cox Model ◽

Immune Therapy ◽

Group Analysis ◽

Favorable Outcome ◽

Clinical Benefits ◽

Melanoma Patients

Abstract Purpose. Although development of immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma have been described in melanoma patients and have been associated with a favorable outcome. This vitiligo-like leukoderma can also appear in melanoma patients undergoing immune therapies such as immune checkpoint inhibitors. However, no consensus exists about the relationship between vitiligo-like leukoderma onset and improved overall survival. Our study investigates the possible association between the onset of vitiligo-like leukoderma during immune checkpoint inhibitor treatment and a better prognosis.Methods. A non-concurrent cohort study was conducted by identifying retrospectively 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with checkpoint inhibitors in any line of treatment. Toxicities developed during therapy were evaluated. Results. Among the 280 study participants, 50% developed at least one type of toxicity, and vitiligo-like leukoderma was observed in 43 patients (15.4%). In the multivariate Cox model, a protective effect for mortality was observed for patients with vitiligo-like leukoderma development (HR = 0.23; 95% CI = 0.11-0.44, p <0.0001). In a sub-group analysis comprising only cutaneous melanoma in first line of treatment (N=153), occurrence of vitiligo-like leukoderma was also an independent predictor factor for duration of clinical benefits measured by time to the next treatment (HR:0.17; 95% CI:0.06-0.44). Conclusion. Our findings indicate that onset of vitiligo-like leukoderma during melanoma treatment could be a marker of favorable outcome in patients treated with immune checkpoint inhibitors.

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18F-BMS986192 PET imaging of PD-L1 in metastatic melanoma patients with brain metastases treated with immune checkpoint inhibitors. A pilot study.

Journal of Nuclear Medicine ◽

10.2967/jnumed.121.262368 ◽

2021 ◽

pp. jnumed.121.262368

Author(s):

Pieter H Nienhuis ◽

Ines F. Antunes ◽

Andor W.J.M. Glaudemans ◽

Mathilde Jalving ◽

David Leung ◽

...

Keyword(s):

Pilot Study ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Pet Imaging ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Melanoma Patients

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ctDNA as a noninvasive monitoring tool in metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9548 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9548-9548

Author(s):

Renata Varaljai ◽

Kilian Wistuba-Hamprecht ◽

Teofila Seremet ◽

Joey Mark Santiago Diaz ◽

Jeremie Nsengimana ◽

...

Keyword(s):

Metastatic Melanoma ◽

Disease Progression ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapy Monitoring ◽

Analytical Sensitivity ◽

Operating Characteristics ◽

Promising Alternative ◽

Melanoma Patients

9548 Background: The field of liquid biopsy provides a promising alternative to standard tissue biopsies. Previous work has shown that plasma circulating cell-free DNA (ctDNA) can reflect the heterogeneous spectrum of mutations in cancer including metastatic melanoma. Our project aimed to establish and statistically validate plasma-based assays for tumour load and therapy monitoring in melanoma. Methods: On a large cohort of stage III and stage IV melanoma patients (N = 96) who received signalling targeted or immune checkpoint inhibitors we showed that the most common oncogenic drivers of this disease such as the BRAFV600E, NRASQ61 and the TERTC250T and TERTC228T promoter mutations (termed TERTprom) can be analysed in ctDNA with highly sensitive droplet digital PCR technology (detection of mutant ctDNA down to 0.01% analytical sensitivity). Results: Our research has demonstrated that ctDNA (irrespective of the genotype) significantly correlates with tumour stage (P < 0.05). Using receiver operating characteristics (ROC) analyses thresholds were established for risk stratification and response prediction. Elevated ctDNA at baseline was a significant predictor of disease progression compared to elevated LDH or S100 in multivariable cox proportional hazards model (Hazard ratio [HR] 7.43, P = 0.05). During therapy, patients with low ctDNA load (below the ROC threshold) had significantly better radiological outcomes and prolonged progression free survival (PFS) compared to patients with high ctDNA load (P < 0.0001). Our findings were confirmed on an independent cohort of metastatic melanoma patients (N = 35) treated with immune checkpoint inhibitors, where also during therapy low ctDNA load correlated with prolonged PFS (P = 0.003). An added benefit of ctDNA was demonstrated in about 80% of the patients, where ctDNA analyses preceded the radiological diagnosis of response or relapse. Progression was detected in plasma ctDNA in average 3.5 months earlier as compared to routine imaging techniques. Finally, we demonstrated that the occurrence of NRASQ61 mutation in BRAFV600-inhibitor treated patients at therapy baseline was associated with treatment failure. The sub-clonal NRASQ61 mutation at therapy baseline was an independent predictor of shorter PFS (HR 2.69, P = 0.02) as compared to BRAFV600E patients without the NRASQ61 mutation at therapy baseline. Conclusions: In sum, our results support the value of ctDNA as a sensitive biomarker for real-time therapy monitoring and early detection of disease progression.

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