Immune checkpoint inhibition (ICI) with anti-CTLA-4 and/or anti-PD-1 antibodies is standard treatment for metastatic melanoma. Anti-PD-1 (pembrolizumab, nivolumab) and anti-PD-L1 antibodies ...(atezolizumab, durvalumab, and avelumab) have been approved for treatment of several other advanced malignancies, including non-small-cell lung cancer (NSCLC); renal cell, and urothelial carcinoma; head and neck cancer; gastric, hepatocellular, and Merkel-cell carcinoma; and classical Hodgkin lymphoma. In some of these malignancies approval was based on the detection of biomarkers such as PD-L1 expression or high microsatellite instability.
We review the current status of prognostic and predictive biomarkers used in ICI for melanoma and other malignancies. We include clinical, tissue, blood, and stool biomarkers, as well as imaging biomarkers.
Several biomarkers have been studied in ICI for metastatic melanoma. In clinical practice, pre-treatment tumor burden measured by means of imaging and serum lactate dehydrogenase level is already being used to estimate the likelihood of effective ICI treatment. In peripheral blood, the number of different immune cell types, such as lymphocytes, neutrophils, and eosinophils, as well as different soluble factors, have been correlated with clinical outcome. For intra-tumoral biomarkers, expression of the PD-1 ligand PD-L1 has been found to be of some predictive value for anti-PD-1-directed therapy for NSCLC and melanoma. A high mutational load, particularly when accompanied by neoantigens, seems to facilitate immune response and correlates with patient survival for all entities treated by use of ICI. Tumor microenvironment also seems to be of major importance. Interestingly, even the gut microbiome has been found to correlate with response to ICI, most likely through immuno-stimulatory effects of distinct bacteria. New imaging biomarkers, e.g., for PET, and magnetic resonance imaging are also being investigated, and results suggest they will make early prediction of patient response possible.
Several promising results are available regarding possible biomarkers for response to ICI, which need to be validated in large clinical trials. A better understanding of how ICI works will enable the development of biomarkers that can predict the response of individual patients.
Immune checkpoint inhibitors (ICI) have improved survival of patients with metastatic melanoma but can induce autoimmunologic side effects. Ye et al. report a retrospective analysis that further ...supports the finding that these are biomarkers for patients' clinical benefit. Thereby, patients with immune-related adverse events show a differential gene expression in chemokine-mediated signalling.
Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by ...inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Aim
The recent introduction of long axial field-of-view (LAFOV) PET/CT scanners has yielded very promising results regarding image quality and sensitivity in oncological patients. We, herein, aim to ...determine an appropriate acquisition time range for the new long axial field of view Biograph Vision Quadra PET/CT (Siemens Healthcare) using low dose
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FFDG activity in a group of melanoma patients.
Methodology
Forty-nine melanoma patients were enrolled in the study. All patients underwent total body PET/CT from the top of the head through the feet in two bed positions (field-of-view 106 cm) after i.v. injection of 2.0 MBq/kg
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FFDG. The PET images of the first bed position (head to upper thigh; PET-10) were reconstructed and further split into 8-min (PET-8), 6-min (PET-6), 5-min (PET-5), 4-min (PET-4), and 2-min (PET-2) duration groups. Comparisons were performed between the different reconstructed scan times with regard to the visual evaluation of the PET/CT scans using the PET-10 images as reference and by calculating the 95%-CI for the differences between different time acquisitions. Moreover, objective evaluation of PET/CT image quality was performed based on SUV calculations of tumor lesions and background, leading to calculation of liver signal-to-noise ratio (SNR), and tumor-to-background ratio (TBR).
Results
A total of 60 scans were evaluated. Concerning visual analysis, 49/60 (81.7%) PET-10 scans were pathological, while the respective frequencies were 49/60 (81.7%) for PET-8 (95%-CI: − 0.0602–0.0602), 49/60 (81.7%) for PET-6 (95%-CI: − 0.0602–0.0602), 48/60 (80%) for PET-5 (95%-CI: − 0.0445–0.0886), 46/60 (76.7%) for PET-4 (95%-CI: − 0.0132–0.1370), and 45/60 (75%) for PET-2 (95%-CI: 0.0025–0.1593). In 18 PET-10 scans, the extent of metastatic involvement was very large, rendering the accurate calculation of
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FFDG-avid tumor lesions very complicated. In the remaining 42 PET-10 scans, for which the exact calculation of tumor lesions was feasible, a total of 119 tumor lesions were counted, and the respective lesion detection rates for shorter acquisitions were as follows: 97.5% (116/119) for PET-8 (95%-CI: 0–1), 95.0% (113/119) for PET-6 (95%-CI: 0–1), 89.9% (107/119) for PET-5 (95%-CI: 0–2), 83.2% (99/119) for PET-4 (95%-CI: 1–2), and 73.9% (88/119) for PET-2 (95%-CI: 2–4). With regard to objective image quality evaluations, as a general trend, the reduction of acquisition time was associated with a decrease of liver SNR and a decrease of TBR, although in lesion-based analysis the change in TBR and tumor SUV
mean
values was non-significant up to 6 and 5 min acquisitions, respectively.
Conclusions
In melanoma, low-dose LAFOV PET/CT imaging is feasible and can reduce the total scan time from head to upper thigh up to 5 min providing comparable diagnostic data to standard lengths of acquisition. This may have significant implications for the diagnostic work-up of patients with melanoma, given the need for true whole-body imaging in this type of cancer.
Abstract Background Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 ...receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. Conclusion Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this ...phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma.
After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety.
At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval CI, 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.
As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).
The cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) antibody ipilimumab was the first drug that was shown to improve the survival of patients with metastatic melanoma.1 Although the proportions ...of patients who achieved a response were low (only 10–20%), approximately 20% of patients achieved long-term tumour control.2 These findings gave rise to hopes of being able to even cure patients with advanced melanoma. ...an individualised first-line treatment decision should be made for every patient based on their clinical situation. ...the long-term follow-up results from the KEYNOTE-006 study show the potential of pembrolizumab for long-term tumour control.
The liver is the most preferential initial site of metastasis for uveal melanoma (mUM), and this preference is associated with rapid mortality in mUM patients. Despite the significant clinical ...benefits of Immune checkpoint inhibitors (ICIs) in metastatic cutaneous melanoma patients, ICIs have shown little to no benefit in mUM patients. A potential reason for this inefficiency of ICI could be partly devoted to the involvement of the liver itself, thanks to its rich source of growth factors and immunosuppressive microenvironment. Uveal melanoma cells show increased expression of a transmembrane protein called cMET, which is known as the sole receptor for the Hepatocyte growth factor (HGF). Hyperactivation of cMET by HGF contributes to mUM development, and the liver, being the major source of HGF, may partially explain the metastasis of uveal melanoma cells to the liver. In addition, cMET/HGF signaling has also been shown to mediate resistance to ICI treatment, directly and indirectly, involving tumor and immune cell populations. Therefore, targeting the cMET/HGF interaction may enhance the efficacy of immunotherapeutic regimes for mUM patients. Hence in this minireview, we will discuss the rationale for combining cMET inhibitors/antibodies with leading immune checkpoint inhibitors for treating mUM. We will also briefly highlight the challenges and opportunities in targeting cMET in mUM.
Abstract Background Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade ...of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. Methods and findings In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Conclusion Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options ...for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
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