Anti-PD-1: When to Stop Treatment.

PURPOSE OF REVIEW: Emerging data indicate that immune checkpoint blockade (ICB) in patients with metastatic melanoma can be stopped electively or at the time of toxicity with an acceptable risk for progression. However, the optimal treatment duration remains to be defined. We review published data on treatment duration, outcome after treatment discontinuation, and treatment re-introduction in patients with metastatic melanoma. RECENT FINDINGS: Published studies indicate that disease control can be maintained after discontinuation of ICB therapy. Discontinuation of therapy in responders decreases the risk for treatment-related adverse events and lowers the financial burden of ICB. With the limitation of the limited and heterogenous available published data, elective treatment discontinuation after 1 year of treatment appears safe with an acceptable risk of disease progression. The depth of response is currently the best predictor of prolonged response. The metabolic response on 18F-FDG-PET/CT is expected to gain importance, especially for partial responders.

Early discontinuation of PD-1 blockade upon achieving a complete or partial response in patients with advanced melanoma: the multicentre prospective Safe Stop trial.

BACKGROUND: The introduction of programmed cell death protein 1 (PD-1) blockers (i.e. nivolumab and pembrolizumab) has significantly improved the prognosis of patients with advanced melanoma. However, the long treatment duration (i.e. two years or longer) has a high impact on patients and healthcare systems in terms of (severe) toxicity, health-related quality of life (HRQoL), resource use, and healthcare costs. While durable tumour responses have been observed and PD-1 blockade is discontinued on an individual basis, no consensus has been reached on the optimal treatment duration. The objective of the Safe Stop trial is to evaluate whether early discontinuation of first-line PD-1 blockade is safe in patients with advanced and metastatic melanoma who achieve a radiological response. METHODS: The Safe Stop trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 200 patients with advanced and metastatic cutaneous melanoma and a confirmed complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumours (RECIST) v1.1 will be included to early discontinue first-line monotherapy with nivolumab or pembrolizumab. The primary objective is the rate of ongoing responses at 24 months after discontinuation of PD-1 blockade. Secondary objectives include best overall and duration of response, need and outcome of rechallenge with PD-1 blockade, and changes in (serious) adverse events and HRQoL. The impact of treatment discontinuation on healthcare resource use, productivity losses, and hours of informal care will also be assessed. Results will be compared to those from patients with CR or PR who completed 24 months of treatment with PD-1 blockade and had an ongoing response at treatment discontinuation. It is hypothesised that it is safe to early stop first-line nivolumab or pembrolizumab at confirmed tumour response while improving HRQoL and reducing costs. DISCUSSION: From a patient, healthcare, and economic perspective, shorter treatment duration is preferred and overtreatment should be prevented. If early discontinuation of first-line PD-1 blockade appears to be safe, early discontinuation of PD-1 blockade may be implemented as the standard of care in a selected group of patients. TRIAL REGISTRATION: The Safe Stop trial has been registered in the Netherlands Trial Register (NTR), Trial NL7293 (old NTR ID: 7502), https://www.trialregister.nl/trial/7293 . Date of registration September 30, 2018.

Validation of a clinicopathological and gene expression profile model for sentinel lymph node metastasis in primary cutaneous melanoma.

BACKGROUND: The Clinicopathological and Gene Expression Profile (CP-GEP) model was developed to accurately identify patients with T1-T3 primary cutaneous melanoma at low risk for nodal metastasis. OBJECTIVES: To validate the CP-GEP model in an independent Dutch cohort of patients with melanoma. METHODS: Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible. The CP-GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA). Using the pathology result of SLNB as the gold standard, performance measures of the CP-GEP model were calculated, resulting in CP-GEP high risk or low risk for nodal metastasis. RESULTS: In total, 210 patients were included in the study. Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma. Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively. Overall, the CP-GEP model had a negative predictive value (NPV) of 90·5% [95% confidence interval (CI) 77·9-96.2], with an NPV of 100% (95% CI 72·2-100) in T1, 89·3% (95% CI 72·8-96·3) in T2 and 75·0% (95% CI 30·1-95·4) in T3 melanomas. The CP-GEP indicated high risk in all T4 melanomas. CONCLUSIONS: The CP-GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis. In this validation cohort, the CP-GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.

Seasonal variation of anti-PD-1 outcome in melanoma-Results from a Dutch patient cohort.

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment.

Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry.

BACKGROUND: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy. METHODS: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS. RESULTS: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44). CONCLUSION: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment.

The genomic and transcriptomic landscape of advanced renal cell cancer for individualized treatment strategies.

Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was investigated to identify putative actionable variants and signatures. In this prospective multicenter study (NCT01855477), whole-genome sequencing (WGS) data of locally advanced and metastatic tissue biopsies and matched whole-blood samples were collected from 91 patients with histopathologically confirmed RCC. WGS data were analyzed for small somatic variants, copy-number alterations and structural variants. For a subgroup of patients, RNA sequencing (RNA-Seq) data could be analyzed. RNA-Seq data were clustered on immunogenic and angiogenic gene expression patterns according to a previously developed angio-immunogenic gene signature. In all patients with papillary and clear cell RCC, putative actionable drug targets were detected by WGS, of which 94% were on-label available. RNA-Seq data of clear cell and papillary RCC were clustered using a previously developed angio-immunogenic gene signature. Analyses of driver mutations and RNA-Seq data revealed clear differences among different RCC subtypes, showing the added value of WGS and RNA-Seq over clinicopathological data. By improving both histological subtyping and the selection of treatment according to actionable targets and immune signatures, WGS and RNA-Seq may improve therapeutic decision making for most patients with advanced RCC, including patients with non-clear cell RCC for whom no standard treatment is available to data. Prospective clinical trials are needed to evaluate the impact of genomic and transcriptomic diagnostics on survival outcome for advanced RCC patients.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition.

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.

Cost-effectiveness of adjuvant systemic therapies for patients with high-risk melanoma in Europe: a model-based economic evaluation.

BACKGROUND: The introduction of adjuvant systemic treatment has significantly improved recurrence-free survival in patients with resectable high-risk melanoma. Adjuvant treatment with immune checkpoint inhibitors and targeted therapy, however, substantially impacts health care budgets, while the number of patients with melanoma who are treated in the adjuvant setting is still increasing. To evaluate the socioeconomic impact of the three adjuvant treatments, a cost-effectiveness analysis (CEA) was carried out. MATERIALS AND METHODS: Data were obtained from the three pivotal registration phase III clinical trials on the adjuvant treatment of patients with resected high-risk stage III in melanoma (KEYNOTE-054, CheckMate 238, and COMBI-AD). For this CEA, a Markov model with three health states (no evidence of disease, recurrent/progressive disease, and death) was applied. From a societal perspective, different adjuvant strategies were compared according to total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. To evaluate model uncertainty, sensitivity analyses (deterministic and probabilistic) were carried out. RESULTS: In the adjuvant setting, total costs (per patient) were €168 826 for nivolumab, €194 529 for pembrolizumab, and €211 110 for dabrafenib-trametinib. These costs were mainly determined by drug acquisition costs, whereas routine surveillance costs varied from €126 096 to €134 945. Compared with routine surveillance, LYs improved by approximately 1.41 for all therapies and QALYs improved by 2.02 for immune checkpoint inhibitors and 2.03 for targeted therapy. This resulted in incremental cost-effectiveness ratios of €21 153 (nivolumab), €33 878 (pembrolizumab), and €37 520 (dabrafenib-trametinib) per QALY gained. CONCLUSIONS: This CEA compared the three EMA-approved adjuvant systemic therapies for resected stage III melanoma. Adjuvant treatment with nivolumab was the most cost-effective, followed by pembrolizumab. Combination therapy with dabrafenib-trametinib was the least cost-effective. With the increasing number of patients with high-risk melanoma who will be treated with adjuvant treatment, there is an urgent need to reduce drug costs while developing better prognostic and predictive tools to identify patients who will benefit from adjuvant treatment.

Trends in survival and costs in metastatic melanoma in the era of novel targeted and immunotherapeutic drugs.

BACKGROUND: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs. MATERIALS AND METHODS: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis. RESULTS: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million. CONCLUSION: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma.

Survival outcomes of patients with advanced melanoma from 2013 to 2017: Results of a nationwide population-based registry.

BACKGROUND: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice. METHODS: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616). Because the proportional hazards assumption was violated, a multivariable Cox model restricted to the first 6 months and a multivariable landmark Cox model from 6 to 48 months were used to assess overall survival (OS) of cases without missing values. The 2017 cohort was excluded from this analysis because of the short follow-up time. RESULTS: Median OS of the 2013 and 2016 cohort was 11.7 months (95% confidence interval [CI]: 10.4-13.5) and 17.7 months (95% CI: 14.9-19.8), respectively. Compared with the 2013 cohort, the 2016 cohort had superior survival in the Cox model from 0 to 6 months (hazard ratio [HR] = 0.55 [95% CI: 0.43-0.72]) and in the Cox model from 6 to 48 months (HR = 0.68 [95% CI: 0.57-0.83]). Elevated lactate dehydrogenase levels, distant metastases in ≥3 organ sites, brain and liver metastasis and Eastern Cooperative Oncology Group performance score of ≥1 had stronger association with inferior survival from 0 to 6 months than from 6 to 48 months. BRAF-mutated melanoma had superior survival in the first 6 months (HR = 0.50 [95% CI: 0.42-0.59]). CONCLUSION(S): Prognosis for advanced melanoma in the Netherlands has improved from 2013 to 2016. Prognostic importance of most evaluated factors was higher in the first 6 months after diagnosis. BRAF-mutated melanoma was only associated with superior survival in the first 6 months.

Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib.

BACKGROUND: Because sunitinib can induce extensive necrosis in metastatic renal cell cancer (mRCC), we examined whether criteria defined by Choi might be valuable to predict early sunitinib efficacy. METHODS: Computed tomography was used for measurement of tumour lesions in mm and lesion attenuation in Hounsfield units (HUs). According to Choi criteria partial response (PR) was defined as > or =10% decrease in size or > or =15% decrease in attenuation. RESULTS: A total of 55 mRCC patients treated with sunitinib were included. At first evaluation, according to the Response Evaluation Criteria in Solid Tumours (RECIST) 7 patients had PR, 38 stable disease (SD), and 10 progressive disease (PD), whereas according to Choi criteria 36 patients had PR, 6 SD and 13 PD. Median tumour attenuation decreased from 66 to 47 HUs (P< or =0.001). In patients with PR, Choi criteria had a significantly better predictive value for progression-free survival and overall survival (both Ps<0.001) than RECIST (P=0.685 and 0.191 respectively). The predictive value for RECIST increased (P=0.001 and <0.001 respectively), when best response during treatment was taken into account. CONCLUSION: Choi criteria could be helpful to define early mRCC patients who benefit from sunitinib, but the use of these criteria will not change the management of these patients.

Impact of the coronavirus disease 2019 pandemic on cancer treatment: the patients' perspective.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has inevitable consequences for medical care of patients without COVID-19. To assess the impact of this pandemic on oncological care, a nationwide survey was conducted among patients with cancer in the Netherlands. METHODS: The patients' perspective on oncological care was investigated using an online survey between March 29th 2020 and April 18th 2020. The survey consisted of 20 questions on four topics: patients' characteristics, contact with the hospital, consequences of the COVID-19 pandemic and concerns about COVID-19. RESULTS: Five thousand three hundred two patients with cancer completed this nationwide survey. Overall, 30% of patients reported consequences for their oncological treatment or follow-up. In the majority of cases, this resulted in conversion from hospital visit to consultation by phone or video. The most frequently adjusted treatments were chemotherapy (30%) and immunotherapy (32%). Among patients with delay and discontinuation of treatment, 55% and 63% of patients, respectively, were (very) concerned about these consequences of the COVID-19 pandemic. Consequences were independent of regional differences in COVID-19 incidence. However, patients in regions with high COVID-19 incidence were significantly more concerned. CONCLUSION: This is the first study investigating perspectives of patients with cancer during the COVID-19 pandemic. The study demonstrates the significant impact of the COVID-19 crisis on oncological care, indicating the need for psycho-oncological support during this pandemic.

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer.

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand-foot syndrome and a combination of grade 1-2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity.

Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules.

BACKGROUND: Distinguishing malignant thyroid nodules in patients with follicular cytology by fine-needle aspiration (FNA) remains problematic. The large majority of thyroid nodules (> 85%) are overtreated. Therefore, a clear need exists to develop more accurate initial diagnostic tests for follicular thyroid nodules. Galectin-3 is the most recent promising marker to aid discrimination between benign and malignant thyroid lesions; however, this biomarker can be absent in follicular malignancies. AIMS: This study was undertaken to determine whether additional biomarkers can help to discriminate between benign and malignant thyroid nodules. METHODS: Surgical specimens of 36 patients with benign (n = 12) and malignant (n = 24) thyroid nodules showing follicular cytology were assessed by immunohistochemistry for the expression of galectin-3 and novel biomarkers. RESULTS: Expression of hexokinase III (HK III) (P = 0.000) cyclin A (P = 0.002) and galectin-3 (P = 0.003) differed significantly between benign and malignant thyroid nodules. HK III had a sensitivity of 79% [95% confidence interval (CI) 60-91] and a specificity of 100% (95% CI 76-100) in predicting malignancy. Galectin-3 had a sensitivity of 79% (95% CI 56-91) and a specificity of 75% (95% CI 47-91) in predicting malignancy. Combining HK III, cyclin A and galectin-3 in a parallel test increased the sensitivity to 96% (95% CI 80-99) while the specificity remained at a high level of 75% (95% CI 47-91). Leave-one-out cross-validation demonstrated a stable predictive validity of a model based on HK III, cyclin A and galectin-3. CONCLUSIONS: In this study, we have demonstrated that in addition to galectin-3, HK III and cyclin A profiles could be important biomarkers in predicting malignancy in follicular thyroid nodules. The use of these biomarkers may allow an accurate preoperative diagnosis of thyroid cancer, which can be cost saving and may avoid serious morbidity such as vocal cord paralysis. The value of the suggested biomarkers warrants further evaluation in a large prospective study on cytological samples of follicular thyroid nodules.

Verapamil-induced erythermalgia.

Erythermalgia is a rare clinical syndrome characterised by intermittent, usually symmetrical burning pain, warmth and dermal erythema of the extremities with an amelioration of discomfort by cooling of the extremity. In this report, we describe a patient with erythermalgia caused by long-term verapamil use. After discontinuing the verapamil, the symptoms improved dramatically within two weeks.