Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study.

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy. METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent. RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891). CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

Outcome of adjuvant immunotherapy in a real-world nation-wide cohort of patients with melanoma.

BACKGROUND: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. METHODS: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). RESULTS: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. CONCLUSION: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.

PD-L1 is a biomarker of real-world clinical outcomes for anti-CTLA-4 plus anti-PD-1 or anti-PD-1 monotherapy in metastatic melanoma.

BACKGROUND: Metastatic melanoma (MM) is commonly treated with a combination of nivolumab and ipilimumab, regardless of tumor PD-L1 expression. METHODS: We conducted a population-based study including all patients with MM (except ocular melanoma) treated in Denmark with first-line combination therapy or anti-PD-1 monotherapy since January 2017. Baseline data including known prognostic characteristics were used in multivariable and propensity-matched score (PMS) analyses to assess progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) according to PD-L1 expression. RESULTS: We identified 1341 eligible patients, with known PD-L1 status for 1081 patients (43% PD-L1 ≥ 1%, 57% PD-L1 < 1%). PD-L1 ≥ 1% was an independent positive prognostic biomarker for survival in the overall cohort (MSS: HR 0.66, CI 0.52-0.83, p < 0.001). In the PMS PD-L1 ≥ 1% cohort, combination therapy showed similar clinical outcomes to monotherapy (PFS: HR 1.41, CI 0.94-2.11, p = 0.101; MSS: HR 1.21, CI 0.70-2.11, p = 0.49; OS: HR 1.17, CI 0.68-2.00, p = 0.567). In contrast, in the PMS PD-L1 < 1% and in the PMS PD-L1 < 1% BRAF WT cohorts, combination therapy improved PFS (respectively with HR 0.70, CI 0.53-0.93, p = 0.013; and HR 0.54, CI 0.37-0.78, p = 0.001), but did not reach statistically significant improvements of MSS (HR 0.72, CI 0.50-1.02, p = 0.065; and HR 0.79, CI 0.51-1.21, p = 0.278) or OS (HR 0.78, CI 0.56-1.08, p = 0.135; and HR 0.81, CI 0.54-1.21, p = 0.305) compared to monotherapy. CONCLUSION: Our findings support previous exploratory analyses of Checkmate-067, highlighting that improved clinical outcomes with combination therapy are not established in unselected patients with high (≥1%) tumor PD-L1 expression.

Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies.

BACKGROUND: The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. METHODS: In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria. RESULTS: We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. CONCLUSIONS: The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Health care and socioeconomic costs for long-term survivors after implementation of checkpoint-inhibitors and targeted agents for metastatic melanoma.

BACKGROUND: Real-life data on health care costs and loss of productivity after implementing new agents for metastatic melanoma are important to supplement model-based economic data. MATERIALS AND METHODS: All patients registered in the Danish Metastatic Melanoma Database (DAMMED) and the National Patient Registry in 2007-2011 were compared to 2012-2016 after the implementation of checkpoint inhibitors and targeted therapy. Health care costs, social transfer income (STI), and loss of productivity were calculated with a 2-step one model generalised linear regression (GLM) model. Medicine costs were calculated separately. RESULTS: In 2007-2011, 70 (15%) out of 464 patients were long-term survivors compared to 347 (32%) out of 1089 patients in 2012-2016. Total health care costs per patient year were significantly lower in the first treatment year (€41.457 versus €60.547, relative change (RC) 0.72, 95% confidence interval (CI) 0.56-0.94, p = 0.015) and without significant difference the second year in 2012-2016 compared to 2007-2011. Medicine costs per patient year increased the first (€85.464 versus €26.339, RC 3.39, 95% CI 2.61-4.41, p < 0.001) and the second (€26.464 versus €11.150, RC 2.59, 95% CI 1.98-3.40, p < 0.001) year in 2012-2016 compared to 2007-2011. Productivity increased for long-term survivors in 2012-2016 in contrast to 2007-2011. CONCLUSION: Implementation of targeted therapy and checkpoint-inhibitors has increased medicine costs more than three-fold for long-term survivors. Total health care costs excluding medicine costs were significantly lower for long-term survivors the first and without change the second treatment year in 2012-2016 compared to 2007-2011. However, the number of treated patients increased which leads to an increase in overall total health care costs. Importantly, productivity increased for long-term survivors in 2012-2016.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma. Part 1: Diagnostics and prevention-Update 2023.

Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients.

European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma: Part 2. Treatment-Update 2023.

In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations were based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Multidisciplinary board decisions are mandatory for all patients with advanced cSCC, considering the risks of toxicity, the age and frailty of patients, and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with the best supportive care to improve symptom management and quality of life. The frequency of follow-up visits and investigations for subsequent new cSCC depends on underlying risk characteristics.

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.

Stage-Specific Risk of Recurrence and Death From Melanoma in Denmark, 2008-2021: A National Observational Cohort Study of 25 720 Patients With Stage IA to IV Melanoma.

Importance: To ensure optimal treatment and surveillance of patients with melanoma, knowledge of the clinical stage-specific risk of recurrence, mortality, and recurrence patterns across the American Joint Committee on Cancer Eighth Edition (AJCC8) substages is needed. Objective: To estimate stage-specific recurrence and melanoma-specific mortality rates, assess absolute stage-specific risks of recurrence and mortality, and describe stage-specific recurrence patterns, including conditional rates. Design: Retrospective cohort study of prospectively collected nationwide population-based registry data. Setting: Nationwide, population-based cohort study. Participants: The 25 720 Danish patients, 18 years or older, diagnosed with first-time stage IA to IV cutaneous melanoma between January 1, 2008, and December 31, 2019, were included and followed up from time of primary treatment until December 31, 2021. Exposures: First diagnosis of stage IA to IV cutaneous melanoma. Main Outcomes: Stage-specific cumulative incidence of recurrence and melanoma-specific mortality, melanoma-specific recurrence-free survival, and assessed absolute stage-specific risks of recurrence and melanoma-specific mortality. Secondary outcomes were stage-specific recurrence patterns, including conditional rates, and melanoma-specific survival. Results: We followed up 25 720 patients for a median of 5.9 years (95% CI, 58.9-59.3 years). Mean age was 59.1 years (95% CI, 58.9-59.3 years). Patients with stage IIB to IIC melanoma were older, had more comorbidities at diagnosis, and had the lowest rate of pathologic staging by sentinel node biopsy (81.6%-87.4%). A total of 10.6% of patients developed recurrence; first recurrence included distant recurrence, alone or with synchronous locoregional recurrence, in 56.6% of patients. We found a comparable risk of recurrence in stages IIIA and IIB (29.7% vs 33.2%) and in stages IIIB and IIC (35.9% vs 36.8%), respectively. Melanoma-specific mortality was comparable between stages IIIA and IIA (13.0% vs 13.6%) and between stages IIIB and IIB (18.4% vs 22.0%), respectively. These risk patterns persisted in cause-specific hazards models. Conclusions and Relevance: This nationwide, population-based cohort study found that the increasing stages of the current AJCC8 staging system do not accurately reflect an increasing risk of recurrence and mortality in melanoma. The high proportion of distant recurrences suggests that hematogenous spread is a more common metastatic pathway than previously assumed, and surveillance with routine functional/cross-sectional imaging should be considered for stages IIB to IV. Future efforts should be put toward developing new tools for risk stratification and determining the survival effect of routine imaging in surveillance.

Earlier Recurrence Detection Using Routine FDG PET-CT Scans in Surveillance of Stage IIB to IIID Melanoma: A National Cohort Study of 1480 Patients.

BACKGROUND: The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with positron emission tomography-computed tomography with fluorodeoxyglucose (FDG PET-CT) in a nationwide, population-based surveillance program. This study aimed to determine the impact of surveillance with routine FDG PET-CT on hazard, cumulative incidence, and absolute risk of overall, locoregional, and distant recurrence detection in patients with stage IIB to IIID cutaneous melanoma. METHODS: This retrospective, population-based, nationwide cohort study used prospectively collected data from five national health registries to compare hazard, cumulative incidence, and absolute risk of recurrence in patients with cutaneous melanoma diagnosed in 2008-2010 (cohort 1, followed with clinical examinations) and patients with cutaneous melanoma diagnosed in 2016-2017 (cohort 2, followed with clinical examinations and routine FDG PET-CT at 6, 12, 24, and 36 months). RESULTS: The study included 1480 patients with stage IIB to IIID cutaneous melanoma. Cumulative incidences of overall and distant recurrence were higher in cohort 2, with a peak difference at three years (32.3 % vs 27.5 % and 25.8 % vs. 18.5 %, respectively). The hazard of recurrence was higher in cohort 2 during the first two years, with hazard rates for overall and distant recurrence of 1.16 (95 % confidence interval [CI], 0.93-1.44) and 1.51 (95 % CI, 1.16-1.96), respectively. The patterns persisted in absolute risk estimates. CONCLUSIONS: Patients with stage IIB to IIID melanoma followed with routine FDG PET-CT had a 51 % increased hazard of distant recurrence detection within the first two years of surveillance. Future studies must determine whether this earlier recurrence detection translates into improved survival.

Seasonal variation in effect of anti-PD-1 initiation on overall survival among patients with advanced melanoma.

Melanoma is a highly immunogenic cancer, and circannual rhythms influence the activity of the immune system. We retrospectively collected information on all cases with metastatic melanoma (ocular melanoma excluded) that initiated treatment with BRAF-inhibitor-based therapy (BRAFi) or anti-PD-1 monotherapy (PD-1). Cases were divided in two groups based on treatment initiation in the summer half-year (April to September) or winter half-year (October to March). We collected a total of 1054 (BRAF-i) and 1205 (PD-1) patient cases. Median follow-up was 39.7 (BRAFi) and 47.5 (PD-1) months. We did not observe differences in outcomes across patients who were treated in summer versus winter in the BRAFi cohort. Furthermore, we did not observe significant differences in ORR, CRR, and PFS in the PD-1 cohort. However, in patients with BRAF wild-type disease of the PD-1 cohort, treatment initiation in summer was associated with an improved OS (mOS 39.7 months [summer] versus 21.3 months [winter]; HR 0.70, 95% CI 0.57-0.86, p = .0007). This result remained robust to multivariable proportional hazards adjustment (HR 0.70, 95% CI 0.57-0.87, p = .001). Initiation of immunotherapy in summer is associated with prolonged survival in patients with BRAF wild-type melanoma living in Denmark.

European consensus-based interdisciplinary guideline for melanoma. Part 1: Diagnostics: Update 2022.

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed with dermatoscopy. If a melanoma is suspected, a histopathological examination is always required. Sequential digital dermatoscopy and full body photography can be used in high-risk patients to improve the detection of early melanoma. Where available, confocal reflectance microscopy can also improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the American Joint Committee on Cancer classification. Thin melanomas up to 0.8 mm tumor thickness do not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC onwards whole-body examinations with computed tomography (CT) or positron emission tomography CT (PET-CT) in combination with brain magnetic resonance imaging are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to define the frequency and extent of examinations. A stage-based follow-up scheme is proposed which, according to the experience of the guideline group, covers the optimal requirements, but further studies may be considered. This guideline is valid until the end of 2024.

European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2022.

A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on the systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to 2-cm safety margins. Sentinel lymph node dissection shall be performed as a staging procedure in patients with tumor thickness ≥1.0 mm or ≥0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions in stage III/IV patients should be primarily made by an interdisciplinary oncology team ("tumor board"). Adjuvant therapies can be proposed in stage III/completely resected stage IV patients and are primarily anti-PD-1, independent of mutational status, or alternatively dabrafenib plus trametinib for BRAF mutant patients. In distant metastases (stage IV), either resected or not, systemic treatment is always indicated. For first-line treatment particularly in BRAF wild-type patients, immunotherapy with PD-1 antibodies alone or in combination with CTLA-4 antibodies shall be considered. In stage IV melanoma with a BRAF-V600  E/K mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy. In patients with primary resistance to immunotherapy and harboring a BRAF-V600  E/K mutation, this therapy shall be offered as second-line therapy. Systemic therapy in stage III/IV melanoma is a rapidly changing landscape, and it is likely that these recommendations may change in the near future.

The diagnostic accuracy and clinical impact of FDG-PET/CT follow-up for patients on adjuvant immunotherapy for high-risk malignant melanoma.

OBJECTIVE: The benefit of FDG-PET/CT in follow-up of patients treated with adjuvant immunotherapy after resection of high-risk malignant melanoma (MM) is debated. This study evaluated the diagnostic accuracy and clinical impact of FDG-PET/CT for diagnosing MM recurrence during the first year after surgery. METHODS: We retrospectively included 124 patients with resected high-risk MM, who received adjuvant immunotherapy and follow-up FDG-PET/CT. Clinical information and AJCC-8 stage was obtained from patients' medical records. Recurrence was verified by biopsy/progression on a subsequent scan leading to change of treatment. Non-recurrence was assumed when no metastases were observed until the subsequent follow-up scan. Incidence of recurrence, sensitivity, specificity, positive and negative predictive values (PPV and NPV) were outcome measures. RESULTS: Incidence rate of MM recurrence was 0.27 [95% CI 0.17-0.37] per person-year during the first-year. Recurrence was detected in 13 patients (10%) at 3-month FDG-PET/CT, in 10 patients (8.1%) at 6 months, 1 patient (0.8%) at 9 months, 3 patients (2.4%) at 12 months. The overall sensitivity, specificity, PPV, and NPV were 97% [86-99], 82% [78-86], 39% [29-50], and 99% [98-99], respectively. The PPV trended towards higher values as disease stage increased. At the 3-month scan, the majority of actions derived from positive findings were surgery or earlier expedition of the subsequent follow-up scan. CONCLUSION: The high rate of recurrence in patients with high-risk MM treated with adjuvant immunotherapy emphasizes the need for follow-up. The potential harm by a moderately low specificity reflecting a high number of false-positive results must be weighed against the benefit of early detection of recurrence.

Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA).

PURPOSE: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone. METHODS: ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population. RESULTS: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported. CONCLUSION: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy.

Impact of patient-reported outcomes on symptom monitoring during treatment with checkpoint inhibitors: health-related quality of life among melanoma patients in a randomized controlled trial.

INTRODUCTION: In a randomized controlled trial, we previously investigated if melanoma patients receiving checkpoint inhibitors had fewer severe immune-related adverse events (irAEs) when they reported symptoms using electronic patient-reported outcomes (ePRO) with triggered alerts as an add-on to standard care, compared to standard care alone. The aim of this study is to examine between-group differences in health-related quality of life (HRQoL) and associations between irAEs severity and HRQoL. METHODS: The study population of 138 patients completed the EuroQol EQ-5D-5L Index and FACT-M questionnaires at baseline and weeks 24 and 48. We analyzed HRQoL from all patients who completed at least one questionnaire. Missing FACT-M items were imputed following existing guidelines. RESULTS: There was no difference in HRQoL at baseline as measured EQ-5D-5L between the intervention and the control group. Between baseline and 48 weeks, mean EQ-5D-5L scores were unchanged among patients in the intervention group (p = 0.81) but decreased significantly among patients in the control group (p = 0.03). Consequently, patients in the intervention group had higher mean scores than those in the control group (p = 0.05) at 48 weeks. Mean FACT-M scores did not differ significantly between the two groups at any of the time points. There were observed no between-group differences in mean EQ-5D-5 and mean FACT-M scores between patients with severe irAEs and patients who had none. CONCLUSION: Melanoma patients receiving CPIs who self-reported irAEs using ePRO with triggered alerts as a supplement to standard care maintained their HRQoL compared to patients who received standard care alone. Patients in the intervention group had a significantly better HRQoL measured by EQ-5D-5L than controls 48 weeks after baseline. The results suggest that including ePRO in standard care increases melanoma patients´ well-being. Further and larger studies are needed to confirm this finding and examine the impact of severe irAEs on cancer patients' HRQoL. TRIAL REGISTRATION: Clinicaltrials.gov NCT03073031 Registered 8 March 2017, Retrospectively registered https://clinicaltrials.gov/ .

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study.

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30-40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

BACKGROUND: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. METHODS: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. RESULTS: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. CONCLUSIONS: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.