Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

Review - The impact of pharmacogenetics on the outcome of immune checkpoint inhibitors.

The development of immune checkpoint inhibitors (ICIs) has a tremendous effect on the treatment options for multiple types of cancer. Nonetheless, there is a large interpatient variability in response, survival, and the development of immune-related adverse events (irAEs). Pharmacogenetics is the general term for germline genetic variations, which may cause the observed interindividual differences in response or toxicity to treatment. These genetic variations can either be single-nucleotide polymorphisms (SNPs) or structural variants, such as gene deletions, amplifications or rearrangements. For ICIs, pharmacogenetic variation in the human leukocyte antigen molecules has also been studied with regard to treatment outcome. This review presents a summary of the literature regarding the pharmacogenetics of ICI treatment, discusses the most important known genetic variations and offers recommendations on the application of pharmacogenetics for ICI treatment.

Suitability of tumor-associated antibodies as predictive biomarker for response to immune checkpoint inhibitors in patients with melanoma: a short report.

In 2019, Fässler et al showed in this journal that the presence of tumor-associated antibodies correlated with response to immune checkpoint inhibitor treatment in patients with metastatic melanoma. The results of this study suggested that tumor-associated antibodies directed against melanocyte-differentiation antigens and the cancer-germline antigen NY-ESO-1 should be further investigated as candidate biomarkers for response to immune checkpoint inhibitors. The aim of the current study was to validate and extend these previous findings. Therefore, we examined the correlation between serum levels of tumor-associated antibodies and tumor response after treatment with immune checkpoint inhibitors in patients with metastatic melanoma.All patients included in this prospective study were diagnosed with advanced stage melanoma and treated with nivolumab or pembrolizumab monotherapy. Blood samples were collected before and during treatment. Serum levels of tumor-associated antibodies against the melanocyte differentiation antigen Melan-A and the cancer germline antigens NY-ESO-1, MAGE-C2, MAGE-A6 and ROPN1B were measured at baseline and during treatment. Differences between responders and non-responders were assessed using the Mann-Whitney U-test, and differences between different overall survival categories with the Kruskal-Wallis test. P values ≤0.05 were considered significant.Serum samples of 58 patients with advanced melanoma with long-term follow-up (>3 years) were collected. In contrast to the findings of Fässler et al, for all antibodies tested, we found no significant differences between serum levels of responders and non-responders before or during treatment with immune checkpoint inhibitors. In addition, no significant differences were found in serum levels of tumor-associated antibodies for different overall survival groups.Although our study included a larger and more mature cohort of patients with longer follow-up, we could not externally validate the findings of Fässler et al In addition, we were not able to identify other cancer germline antigens as predictive biomarkers of response to immune checkpoint inhibitors in patients advanced melanoma. Based on the results of the present study, clinical applicability of tumor-associated antibodies directed against tumor antigens as predictive biomarkers for immune checkpoint inhibitors in patients with advanced melanoma is not feasible.

The course of C-peptide levels in patients developing diabetes during anti-PD-1 therapy.

INTRODUCTION: Immune checkpoint inhibitor (ICI) associated diabetes is a harmful adverse event (AE) in patients with cancer following anti-programmed (cell) death protein-1 (PD-1) treatment. There are no available biomarkers able to predict this AE. The primary aim of this study was to investigate C-peptide levels as potential predictor for the occurrence of ICI-related diabetes. The secondary aim was to describe the presence of islet autoantibodies and course of pancreatic enzymes in patients with and without ICI-related diabetes. METHODS: From a total of 1318 patients with cancer who started anti-PD-1 treatment 8 cases and 16 controls were studied in this nested case-control study. C-peptide levels, islet autoantibodies, and pancreatic enzymes were measured in prospectively collected blood serum. RESULTS: In cases versus controls, median C-peptide levels were comparable at baseline and before toxicity or at the corresponding time point in controls. No patient had C-peptide levels below reference range before toxicity onset. Two out of eight patients in the ICI-related diabetes group had positive islet autoantibodies, whereas one out of 16 patients in the control group had positive islet autoantibodies. Pancreatic enzymes were elevated before diabetes onset in one patient (13%) and in one control (6%) at the corresponding time point. CONCLUSIONS: In patients developing ICI-related diabetes, changes in C-peptide levels, islet autoantibody positivity, and pancreatic enzymes before ICI-related diabetes onset seem comparable to patients without ICI-related diabetes. (NTR: NL6828).

Associations between patient and disease characteristics and severe adverse events during immune checkpoint inhibitor treatment: An observational study.

AIM: With increasing use of immune checkpoint inhibitors (ICIs) more patients will develop severe and potentially life-threatening immune-related adverse events (irAEs). So far, predictive models for the occurrence of grade ≥3 irAEs are lacking. Therefore, we analysed associations between patient and disease characteristics, and the occurrence of grade ≥3 irAEs. METHODS: Patients with cancer who were treated with anti-PD-1 (+/-anti-CTLA-4) between July 2015 and February 2020, and who were prospectively included in the MULTOMAB-trial, were eligible for this cohort study. Time to and occurrence of grade ≥3 irAEs according to CTCAE v5.0 were retrospectively registered. The associations between patient and disease characteristics and irAE occurrence were analysed using the competing risk cox-regression model of Fine and Gray. Analyses were performed separately in patients treated with monotherapy (anti-PD-1) and combination therapy (anti-PD-1 + anti-CTLA-4). Subgroup analyses were performed in tumour types with the highest number of patients; melanoma and NSCLC. RESULTS: Out of 641 patients, 106 patients (17%) experienced grade ≥3 irAEs. None of the analysed factors were associated with grade ≥3 irAE occurrence in the monotherapy (n = 550) or the combination therapy (n = 91) groups, nor in the subgroup analyses. Of interest, none of the patients with NSCLC with a WHO performance status of 0 (n = 34) experienced grade ≥3 irAEs. Most common NSCLC histology types were adenocarcinoma (n = 99/55%) and squamous cell carcinoma (n = 39/22%). CONCLUDING STATEMENT: This study shows that patient and disease characteristics are not able to predict the occurrence of serious AEs in patients treated with ICIs.

Experiences of resuming life after immunotherapy and associated survivorship care needs: a qualitative study among patients with metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved the overall survival of patients with metastatic melanoma. It is unclear how the growing group of metastatic melanoma survivors resume their lives after treatment, and which needs they have regarding survivorship care (SSC). OBJECTIVES: To gain an in-depth understanding of metastatic melanoma survivors' experiences of resuming life after ICIs and their associated SSC needs. METHODS: A qualitative study was conducted among 20 patients with metastatic melanoma in whom ICIs had been discontinued after ongoing tumour response. One focus group (n = 9) was held, which was complemented by 11 individual interviews. Purposive sampling was used to select a variable sample in terms of sex, age, time since discontinuation of ICIs, and perceived impact of the disease. A topic guide was used to structure the (group) interviews, which were transcribed verbatim and analysed in a thematic content analysis, using several phases of coding. RESULTS: In resuming life after ICIs, the prognosis switch often caused mixed feelings among patients, mainly because of the uncertainty about the future. Demands and expectations from self and others, persistent complaints and new problems in different life domains often make it challenging to proceed with life as it was prior to metastatic cancer. Patients indicated they needed to find a new balance, which included learning to cope with uncertainty and a changed perspective on life and close relationships. In terms of SSC needs, patients particularly stressed the need for more tailored patient information, available at one location. In addition, they emphasized the need to know who to turn to in case of questions and indicated the need for psychosocial support, also for their close relatives. CONCLUSIONS: Metastatic melanoma survivors face various challenges in resuming life after ICIs and are left with several unmet SSC needs. Efforts should be focused on offering psychosocial supportive care in addition to medical care, from diagnosis onwards, taking into account the patient's close relatives. A single point of contact and personalized survivorship care plan (SCP) could be of added value in guiding them through the patient journey, which is, given its multidisciplinary nature, particularly important in melanoma care. What is already known about this topic? Since the introduction of immune checkpoint inhibitors (ICIs) the overall survival of patients with metastatic melanoma has improved significantly, leading to a growing group of melanoma survivors. Melanoma survivors may face various problems and challenges in resuming life after treatment, which may be associated with unmet survivorship care (SSC) needs. An in-depth understanding of their experiences with resuming life and the associated SSC needs is currently lacking. What does this study add? Metastatic melanoma survivors experience various challenges after immunotherapy, from the uncertain prognosis switch to the struggle of finding a new balance in life. Besides negative aspects, such as complaints in different life domains, the patient journey is often accompanied by positive outcomes, for example a changed perspective on life. They stress the need for tailored patient information and broader supportive care, also for their close relatives. What are the clinical implications of this work? In addition to medical care, efforts should be focused on offering psychosocial supportive care, including return-to-work issues, from diagnosis onwards, ideally taking into account the patient's close relatives. To guide them through the patient journey, a single point of contact and a personalized survivorship care plan (SCP) could be of added value. The latter is particularly important in melanoma care, given its multidisciplinary nature.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors.

BACKGROUND: Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I-III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting. METHODS: Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs). RESULTS: 588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and -1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(Vd; 0.34). A significant inverse CL-OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07-2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade >3 irAEs (p=0.70). CONCLUSIONS: High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on Vd). A strong inverse CL-OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.

The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.

INTRODUCTION: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma. PATIENTS AND METHODS: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation. RESULTS: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences. CONCLUSION: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.

Dutch Oncology COVID-19 consortium: Outcome of COVID-19 in patients with cancer in a nationwide cohort study.

AIM OF THE STUDY: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. METHODS: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. RESULTS: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). CONCLUSION: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered.