Total neoadjuvant therapy (TNT) has emerged as a promising treatment strategy for locally advanced rectal cancer (LARC), demonstrating higher pathological complete response (pCR) rates and enhanced disease-free survival. However, evidence specifically addressing high-risk LARC and the potential for organ-preserving approaches remains limited. The potential benefit of TNT may be further optimised when administered to patients with specific high-risk characteristics, associated with poor prognosis. The optimal TNT regimen for achieving favourable organ preservation and survival outcomes has not yet been established, as no studies have directly compared triplet-based induction chemotherapy with doublet-based TNT strategies. Consequently, there is considerable heterogeneity in the administration of chemotherapy within TNT regimens in clinical practice. This multicentre, parallel-arms, open-label, randomised, controlled, phase III trial will include 394 patients with non-metastasised, high-risk LARC, with WHO-performance status 0–1 and fit for FOLFOXIRI. High-risk LARC is defined as the presence of at least one of the following tumour characteristics: invasion of the mesorectal fascia (MRF) (i.e. T4b or evident invasion), extramural venous invasion (EMVI) grade IV, tumour deposits (TD), ≥ 2 enlarged lateral lymph nodes (LLN) (≥ 7 mm). Patients are informed about TNT versus chemoradiotherapy. Patients who will undergo TNT will be randomised 1:1 between 6 cycles of FOLFOXIRI, followed by chemoradiotherapy (25 × 2 or 28 × 1.8 Gy) or 4 cycles CAPOX/6 cycles FOLFOX, followed by chemoradiotherapy. Patients either undergo surgery or enter a watch-and-wait approach after neoadjuvant treatment. A watch-and-wait approach is considered in case of a clinical complete response (cCR), determined maximal 26 weeks after start of treatment. The primary outcome is complete response rate (i.e. pCR or sustained cCR at 1 year). The main secondary outcomes are disease-free survival, overall survival, regrowth rate, radicality, toxicity and completion rate of neoadjuvant treatment, treatment related toxicity, quality of life, and post-operative morbidity. Patients who are eligible and undergo neoadjuvant chemoradiotherapy, will be asked to participate in the observational cohort. This protocol describes the MEND-IT II study, which compares complete response rates (pCR and cCR) between FOLFOXIRI-based and CAPOX/FOLFOX-based TNT in a homogeneous high-risk LARC population. The results of this study may contribute to optimise neoadjuvant treatment strategies and tailored treatment. Overview of Medical-Scientific Research in the Netherlands (OMON): NL-011486. Clinicaltrials.gov: NCT07472868.

Abstract Background The introduction of (m)FOLFIRINOX and gemcitabine-nab-paclitaxel has changed the perspective for patients with locally advanced pancreatic cancer (LAPC). Consequently, in experienced centres 23% of patients with LAPC undergo a resection with 5-year overall survival (OS) rates of up to 25%. In the Netherlands, the nationwide resection rate for LAPC remains low at 8%. The PREOPANC-4 program aims for a nationwide implementation of the international multidisciplinary best-practice to improve patient outcome. Methods Nationwide program implementing the international multidisciplinary best-practice for LAPC. In the training phase, multidisciplinary and surgical webinars are given by 4 international experts, leading to a clinical protocol, followed by surgical off-site and on-site proctoring sessions. In the implementation phase, the clinical protocol will be implemented in all centres, including a nationwide expert panel (2022–2024). Healthcare professionals will be trained in shared decision-making. Consecutive patients diagnosed with pathology-proven LAPC (i.e., arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion [DPCG criteria]) are eligible. Primary outcomes are median and 5-year OS from diagnosis, resection rate, in-hospital/30-day mortality and major morbidity (i.e., Clavien-Dindo grade ≥ IIIa), and radical resection (R0) rate. Secondary outcomes include quality of life, functioning, side effects, and patients’ healthcare satisfaction in all included patients. Outcomes will be compared with patients with borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX in the PREOPANC-2 trial (EudraCT: 2017–002036-17) and a historical cohort of patients with LAPC from the PACAP registry (NCT03513705). The existing prospective LAPC Registry and PACAP PROMs (NCT03513705) will be used for data collection. In qualitative interviews, treatment preferences, values, and experiences of LAPC patients, their relatives, and healthcare professionals will be assessed for the development of shared decision-making supportive tools. It is hypothesized that the program will double the nationwide LAPC resection rate to 16% with major morbidity < 50% and mortality ≤ 5%, and OS following resection similar to that observed in patients with BRPC. Discussion The PREOPANC-4 program aims to safely implement the international multidisciplinary best-practice for LAPC leading to benchmark outcomes for both short-term morbidity, mortality, and OS. Trial registration PREOPANC-4 program was registered at ClinicalTrials.gov (NCT05524090) on September 1, 2022.

BACKGROUND:Ipilimumab+nivolumab (IPINIVO) can induce durable responses in advanced melanoma, but many patients experience progression at some point. It is currently unknown to what extent these patients benefit from IPINIVO rechallenge. This study describes efficacy and safety of IPINIVO rechallenge. METHODS:Data from advanced melanoma patients rechallenged with IPINIVO after previous ipilimumab-containing treatment were retrieved from the nationwide Dutch Melanoma Treatment Registry. Patient characteristics, responses, survival, and safety were analyzed. RESULTS:Among 3.759 patients receiving ipilimumab-containing treatment, 73 received rechallenge IPINIVO. 41 received IPINIVO, 32 ipilimumab monotherapy (IPI) as initial therapy. Objective response to rechallenge IPINIVO was seen in 36.1% (initial IPINIVO) and 40.0% (initial IPI) of patients. Median progression-free survival after rechallenge was 2.8 months (initial IPINIVO) and 5.6 months (initial IPI), but reached 18.4 months for responders to rechallenge therapy. Grade ≥3 immune-related adverse events occurred in 40.5% (initial IPINIVO) and 38.7% (initial IPI) of patients. Objective responses to initial and rechallenge treatment were discordant in 48.6% (initial IPINIVO) and 53.3% (initial IPI) of patients. Fifteen patients (20.5%) responded to rechallenge therapy but not to initial treatment. CONCLUSIONS:Rechallenge IPINIVO after previous ipilimumab-based therapy had a considerable response rate, acceptable safety profile, and potential for a durable response.

AIM:Data on the effectiveness of encorafenib/binimetinib in melanoma patients with brain metastases (BMs) are limited. METHODS:All patients with BRAF V600-mutated melanoma and BMs treated with encorafenib/binimetinib between 2019 and 2022 in the Netherlands were included from the nationwide Dutch Melanoma Treatment Registry. Patients previously treated with other BRAF/MEK inhibitors were excluded. We analyzed objective response rates (ORR), progression-free survival (PFS), and overall survival (OS). Multivariable Cox regression identified factors associated with survival. Subgroup analyses included asymptomatic versus symptomatic BMs and line of treatment (first-line versus later-line). RESULTS:In total, 190 patients were included. Symptomatic BMs were present in 63 % of patients. Encorafenib/binimetinib was the first-line treatment in 64 % of all patients, while 36 % had prior immunotherapy. Overall, the ORR was 69.4 %, median PFS was 5.5 months (95 %CI 4.9-6.2), and median OS 11.9 months (95 %CI 10.0-15.7). Age ≥ 70, ECOG PS ≥ 2, symptomatic BMs, and elevated LDH were significantly associated with worse survival. Patients with prior immunotherapy had a median PFS of 6.9 months (95 %CI 4.3-9.6) and OS of 17.9 months (95 %CI 13.7-31.2), while this was 4.9 months (95 %CI 4.3-5.5) and 10.1 months (95 %CI 8.1-13.0) in treatment-naïve patients. Median PFS and OS in patients with asymptomatic versus symptomatic BMs were 6.1 months (95 %CI 4.9-9.8) and 20.5 (95 %CI 14.0-NA) versus 5.3 months (95 %CI 4.9-6.3) and 10.7 (95 %CI 8.9-13.7), respectively. CONCLUSIONS:Encorafenib/binimetinib has clinical activity in real-world melanoma patients with BMs. Their prognosis is determined by the presence of symptomatic BMs, age, ECOG PS, and LDH levels.

AIM:BRAF/MEK inhibitor induction therapy (BRAF/MEK-i) followed by ipilimumab/nivolumab (IPI/NIVO) did not show benefit over upfront IPI/NIVO in unselected advanced melanoma patients in clinical trial setting. We investigated BRAF/MEK-i in subgroups of patients with advanced melanoma and poor prognostic characteristics. METHODS:Patients with BRAF-mutant advanced melanoma treated with BRAF/MEK inhibitors (<120 days) followed by planned switch to IPI/NIVO or upfront IPI/NIVO between 2016 and 2023 were included from the nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and overall survival (OS) were analyzed in propensity score-matched cohorts and subgroups (LDH 250-500 and >500U/L, symptomatic and asymptomatic brain metastases (BMs), liver metastases, ≥ 3 metastatic sites, and ECOG PS ≥ 2). RESULTS:We included 709 patients (187 BRAF/MEK-i and 522 upfront IPI/NIVO). In the matched cohort (n = 280), median PFS and OS were not statistically significantly different: 6.5 (95 %CI 5.3-8.1) and 20.0 (95 %CI 17.2-35.3) months for BRAF/MEK-i vs. 6.6 (95 %CI 4.3-11.3) and 54.0 (95 %CI 21.7-64.4) months for upfront IPI/NIVO. Upfront IPI/NIVO showed significantly improved PFS compared to BRAF/MEK-i for asymptomatic BMs (median 9.4 months (95 %CI 6.3-28.2) vs. 4.8 months (95 %CI 4.1-5.3); p < 0.01), and significantly improved OS for asymptomatic BMs (median 60.4 months (95 %CI 39.1-NR) vs. 16.2 months (95 %CI 11.7-31.8); p < 0.01), liver metastases (median 49.8 months (95 %CI 32.1-60.3) vs. 14.1 months (95 %CI 12.1-20.5); p < 0.01), LDH 250-500 U/L (median 52.7 months (95 %CI 35.1-NR) vs. 20.1 months (95 %CI 13.9-35.5); p = 0.03), and ≥ 3 metastatic sites (median 54.0 months (95 %CI 39.1-NR) vs. 16.7 months (95 %CI 13.8-24.8); p < 0.01). CONCLUSIONS:BRAF/MEK-i showed no significant benefit over upfront IPI/NIVO in matched and stratified analyses according to prognostic characteristics.

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.

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.

Introduction Adjuvant chemotherapy improves survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). The decision to initiate chemotherapy involves both patient and physician factors, decision-specific criteria, and contextual considerations. This study aimed to assess medical oncologists' views on adjuvant chemotherapy following pancreatic resection for PDAC. Methods An online survey and case vignette study were distributed to medical oncologists via the Dutch Pancreatic Cancer Group (DPCG), International Hepato-Pancreato-Biliary Association (IHPBA) and related networks. Results A total of 91 oncologists from 14 countries participated, 46% of whom treated more than 40 new PDAC patients annually, with a median experience of 15 years. Significant discrepancies were noted in their recommendations for adjuvant chemotherapy across case vignettes. In patients over 70, 17% advised against chemotherapy, while 31% said age was not a factor. Oncologists with less than 10 years of experience and those in non-academic settings were less likely to recommend adjuvant therapy. While 87% agreed mFOLFIRINOX is the preferred adjuvant treatment, consensus on individual cases was lacking. The recommended interval between surgery and chemotherapy ranged from 3 to 26 weeks, with varying reasons for withholding treatment, primarily due to postoperative recovery and performance status. Conclusions Our study revealed substantial variation among oncologists in counseling on adjuvant chemotherapy after PDAC resection. This emphasizes the need for more patient involvement in decision-making and improving shared decision-making.

Background Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy.Methods The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life.Discussion From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response.Trial registration ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

Background Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. Methods This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 150 mg/m 2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m 2 ). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. Discussion The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Trial registration Clinical Trials: NCT04927780. Registered June 16, 2021.

Checkpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies, assessing their health-state utilities is essential and can be used for the calculation of quality-adjusted life years and for cost-effectiveness analyses. Therefore, we evaluated the health-state utilities in long-term advanced melanoma survivors. Health-state utilities were evaluated in a cohort of advanced melanoma survivors 24–36 months (N = 37) and 36-plus months (N = 47) post-ipilimumab monotherapy. In addition, the health-state utilities of the 24–36 months survivor group were assessed longitudinally, and utilities of the combined survival groups (N = 84) were compared with a matched control population (N = 168). The EQ-5D was used to generate health-state utility values, and quality-of-life questionnaires were used to establish correlations and influencing factors of utility scores. Health-state utility scores were similar between the 24–36 months’- and the 36-plus months’ survival group (0.81 vs 0.86; p = .22). In survivors, lower utility scores were associated with symptoms of depression (β = − .82, p = .022) and fatigue burden (β = − .29, p = .007). Utility scores did not significantly change after 24–36 months of survival, and the utilities of survivors were comparable to the matched control population (0.84 vs 0.87; p = .07). Our results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores.

Abstract Background The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. Methods This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. Discussion This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. Trial registration Clinicaltrials.gov: NCT04838496 , registered on 02–04-2021 Netherlands Trial Register: NL9790. Protocol version Version 3 dd 11–4-2022.

There is limited evidence on the validity of using EQ-5D in advanced melanoma. We assessed validity and responsiveness of the EQ-5D-3L and EQ-5D-5L in patients with advanced melanoma. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry (data cut-off May 2020). Patients either completed the EQ-5D-3L (included 2014 to mid-2016) or the EQ-5D-5L (included from mid-2016). We compared content and construct validity by EQ-5D dimension. Discriminatory performance was assessed using Shannon entropy. We assessed responsiveness for health states progression-free (PF) and progressive disease (PD) and discriminant validity for known-groups (good/intermediate and poor prognosis). Health state utilities were estimated using random-effects models to account for panel data. A total of 415 and 744 patients completed 1040 and 2657 EQ-5D-3L and EQ-5D-5L questionnaires, respectively. The average age was 61 years and 59% was male. The EQ-5D utility was higher for 3L (0.836 [95%CI:0.821-0.852]) compared to 5L (0.797 [95%CI:0.785-0.810]). Proportion at the ceiling of the scale was larger in 3L than in 5L in all dimensions and largest in the dimension selfcare (93% vs. 90%); the difference was most pronounced in the dimension pain (63% vs. 41%). Shannon entropy showed better discriminatory performance in 5L than in 3L across all dimensions. Of the patients that could be linked with clinical data, 538 received systemic treatment in clinical practice. Both EQ-5D-versions were responsive to changes in health with higher utility scores in progression-free health states (PF-3L:0.844 [95%CI:0.821-0.868] and PF-5L: 0.808 [95%CI:0.790-0.825]) than in progressive disease health states (PD-3L:0.785 [95%CI:0.740-0.829] and PD-5L:0.755 [95%CI:0.727-0.784]). Similarly, both EQ-5D-versions discriminated between good/intermediate (3L:0.861 [95%CI:0.836-0.886]; 5L:0.811 [95%CI:0.791-0.831]) and poor prognosis (3L:0.772 [95%CI:0.718-0.826]; 5L:0.754 [95%CI:0.715-0.793]). Although the EQ-5D-5L has better discriminatory performance than the EQ-5D-3L, both are responsive to changes in health and discriminate between known-groups and thus appear valid for use in advanced melanoma.

Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. CAIRO5 was designed to find the optimal induction regimen. We present results of pts with left-sided and RAS/BRAFV600E wild-type tumour. Pts were randomised between FOLFOX/FOLFIRI (patient preference) plus either bevacizumab (arm A) or panitumumab (arm B) up to 12 cycles. Prior systemic or local therapy for metastases was not allowed. (Un)resectability of CRLM was assessed by a liver expert panel of surgeons and radiologists, at baseline by predefined criteria and every 2 months thereafter by individual opinion. Primary endpoint was progression-free survival (PFS). Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal) and choice of irinotecan vs oxaliplatin. 256 events were required to detect a hazard ratio (HR) of 0.70 for PFS with 80% power and 2-sided log-rank test at 5% assuming a median PFS of 11.6 months in arm A. 236 pts (118 in each arm) were included in 43 Dutch sites from November 2014 until closure due to futility in March 2022. 6 ineligible pts were excluded. Median follow up was 44 months. Main characteristics were (arm A/B): median age 59/60, male 61/63%, synchronous CRLM 88/92%, prior adjuvant chemotherapy 4/3%, median number of CRLM 12/12. With 197 events, median PFS in arm A vs B was 10.6 vs 10.3 months (stratified HR 1.12, 95% CI 0.84-1.50, p=0.44). Response rate (RR) was 52% vs 76% (p<0.01). Median depth of response (DOR) was 33% vs 49% (p<0.01). R0/1 resection ± ablation rate was 58% vs 56% (p=0.79). Grade ≥3 toxicity occurred in 52% vs 69% (p=0.01), Clavien Dindo grade ≥3 surgical complications in 21% vs 14% (p=0.30). In first-line treatment of pts with initially unresectable CRLM and left-sided and RAS/BRAFV600E wild-type tumour there is no difference in median PFS between the addition of either bevacizumab or panitumumab to FOLFOX/FOLFIRI. The addition of panitumumab significantly increases RR and DOR but this does not translate in an increased local therapy rate of CRLM.

Introduction Predicting checkpoint inhibitors treatment outcomes in melanoma is a relevant task, due to the unpredictable and potentially fatal toxicity and high costs for society. However, accurate biomarkers for treatment outcomes are lacking. Radiomics are a technique to quantitatively capture tumor characteristics on readily available computed tomography (CT) imaging. The purpose of this study was to investigate the added value of radiomics for predicting durable clinical benefit from checkpoint inhibitors in melanoma in a large, multicenter cohort.Methods Patients who received first-line anti-PD1 ± anti-CTLA4 treatment for advanced cutaneous melanoma were retrospectively identified from nine participating hospitals. For every patient, up to five representative lesions were segmented on baseline CT and radiomics features were extracted. A machine learning pipeline was trained on the radiomics features to predict durable clinical benefit, defined as stable disease for more than six months or response per RECIST 1.1 criteria. This approach was evaluated using a leave-one-center-out cross validation and compared to a model based on previously discovered clinical predictors. Lastly, a combination model was built on the radiomics and clinical model.Results A total of 620 patients were included, of which 59.2% experienced durable clinical benefit. The radiomics model achieved an area under the receiver operator characteristic curve (AUROC) of 0.607 [95%CI 0.562-0.652], lower than that of the clinical model (AUROC=0.646 [95%CI 0.600-0.692]). The combination model yielded no improvement over the clinical model in terms of discrimination (AUROC=0.636 [95%CI 0.592-0.680]) or calibration. The output of the radiomics model was significantly correlated with three out of five input variables of the clinical model (p < 0.001).Discussion The radiomics model achieved a moderate predictive value of durable clinical benefit, which was statistically significant. However, a radiomics approach was unable to add value to a simpler clinical model, most likely due to the overlap in predictive information learned by both models. Future research should focus on the application of deep learning, spectral CT derived radiomics and a multimodal approach for accurately predicting benefit to checkpoint inhibitor treatment in advanced melanoma.### Competing Interest StatementAvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Roche, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer and Sanofi and has received speaker honoraria from BMS and Novartis. JdG has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, Novartis. PJ has a research collaboration with Philips Healthcare and Vifor Pharma. MBS has consultancy/advisory relationships with Pierre Fabre, MSD and Novartis. EK has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly, Bayer, EISAI and Ipsen, and received research grants not related to this paper from Bristol Myers Squibb and Pierre Fabre. PD has consultancy/advisory relationships with Paige, Pantarei and Samantree paid to the institution and research grants from Pfizer, none related to current work and paid to institute. KS has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, AbbVie and received honoraria from Novartis, MSD and Roche and research funding from Bristol Myers Squibb, TigaTx and Philips. TL has received research funding from Philips. All remaining authors have declared no conflicts of interest. ### Funding StatementThis research was funded by The Netherlands Organization for Health Research and Development (ZonMW, project number 848101007) and Philips.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Medical Ethics Committee of the University Medical Center Utrecht waived ethical approval for this workI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesN/A

To account for the impact of treatment on health-related quality of life (HRQoL), health economic models require insights into changes in HRQoL during the disease course. We estimated health state utilities of advanced (unresectable stage IIIc/IV) melanoma patients treated with systemic treatment in clinical practice in the era of novel immuno- and targeted therapies. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry of patients who received systemic treatment in clinical practice (data cut-off May 2020). Patients either completed the EQ-5D-3L (included 2014 to mid-2016) or the EQ-5D-5L (included from mid-2016). EQ-5D-5L utilities were estimated using the Dutch value set. EQ-5D-3L scores were mapped to EQ-5D-5L utilities using the eq5dmap command in STATA. Using a random-effects model to account for panel data, we estimated utilities for seven health states including three progression-free (PF1-PF3) and three progressive disease (PD1-PD3) health states and one health state after the third progression (HS7) to assess HRQoL in subsequent treatment lines. A total of 182 and 356 patients completed 528 and 1263 EQ-5D-3L and EQ-5D-5L questionnaires, respectively. Patients were on average 61 years and 59% was male. Of all patients, 54% had a good prognosis, 20% an intermediate prognosis and 27% a poor prognosis. Quality of life was higher in progression-free periods (good prognosis PF1: 0.843 [95%CI:0.823-0.863]; PF2: 0.823 [95%CI:0.799-0.846]; PF3: 0.812 [95%CI:0.778-0.845]) compared to progressive disease periods (good prognosis PD1: 0.785 [95%CI:0.753-0.818]; PD2:0.780 [95%CI:0.737-0.823]; PD3: 0.784 [95%CI:0.718-0.851]; HS7: 0.774 [95%CI:0.720-0.828]). Compared to patients with a good prognosis, patients with an intermediate (-0.021 [95%CI:-0.057-0.016]) and poor (-0.073 [95%CI:-0.106- -0.039]) prognosis had lower health state utilities. Health state utilities of patients with advanced melanoma treated with systemic treatment in clinical practice are better in patients with a good prognosis. Irrespective of prognosis, quality of life is higher during progression-free periods compared to progressive disease periods.

Ambulatory monitoring using wearable devices combined with online symptom monitoring in a home-based setting could improve quality of care for patients during imunotherapy. The aim of this study was to evaluate the feasibility of the online CAMP-IT platform and explore the first results of the Fitbit and patient-reported outcome (PRO) data generated by the platform. Consenting patients with advanced melanoma, scheduled to receive treatment with immune checkpoint inhibitors (ICIs) were connected to the platform consisting of Fitbit, smart thermometer, and smartphone app for 12 weeks after start of ICIs. Participants were asked to complete a weekly PRO-CTCAE survey (15 items) in the app, take daily temperature measurements and wear the Fitbit continuously. Weekly averages of Fitbit-measured daily steps were calculated and changes over time were analyzed using linear mixed effect models. Feasibility was determined in terms of compliance rates with questionnaires and temperature measurements (> 75%) and for Fitbit use recording at least 100 steps for at least 75% of assigned days. At follow-up, satisfaction was scored on a 0-10 scale. A total of 41 out of 44 eligible patients were included. Median age was 59 (range 30-74) years and 51% was female. Metastatic disease was present in 44% of patients and 32% received combination ICI therapy. Mean compliance with temperature measurements, PRO-CTCAE surveys and Fitbit was 76%, 86%, and 96%, resp. Mean daily steps in week 1 was 6997 (SD 3306) and did not decrease significantly over time (p =0.72). Grade 3 AEs occurred in 43% of patients and the most commonly reported grade 3 AEs were fatigue (30%), headache (20%), and shortness of breath (15%). Presence of grade 3 AEs was accompanied with significant lower activity levels in matching weeks compared with absence (median steps: 5269 vs 7911, resp., p <0.001). Overall satisfaction rating was 7.5. The use af a comprehensive ambulatory monitoring platform is feasible and acceptable in patients receiving ICIs for advanced melanoma. Combining objective data from wearable devices with PROs offers new possibilities in ambulatory monitoring of AEs. Future studies should examine their value in early detection of AEs.

Immune checkpoint inhibitors (ICIs) have improved survival outcomes for patients with melanoma. Unfortunately, only a minority of patients experiences durable responses, while ICI treatment is accompanied with high toxicity rates and treatment costs. In an effort to predict ICI response, we have previously shown the predictive value of blood-based kinase profiling (Hurkmans et al. JITC 2020). The aim of this prospective study is to identify whether tyrosine kinase activity profiling can predict ICI response in patients with advanced melanoma. Patients with irresectable stage III or IV melanoma were included in this multicenter study. Peripheral blood mononuclear cells (PBMCs) were isolated before start of anti-PD-1 treatment. Tyrosine kinase activity profiles of PBMCs were measured using a micro-array comprising 144 different peptide-substrates for tyrosine kinases (Pepscan). Durable response was set as a partial or complete response (RECIST v1.1) ≤1 year after treatment initiation and lasting for ≥6 months. The classification model was established based on the tyrosine kinase activity profiles determined in a calibration cohort (N = 71) and applied to an independent validation cohort (N = 75). The validated model had an predictive accuracy (correct classification rate) of 64% (CI95 = 52-75%). This accuracy strongly improved (up to 76%; CI95 = 60-89%) when only treatment-naive patients or patients without brain metastases at baseline were included in the validated model (38 out of 75 patients). In addition, for the subgroup of treatment-naive patients, the kinome analysis showed a significant difference in the progression-free survival between patients predicted as being a responder versus non-responders. Tyrosine kinase activity profiling predicts a durable response to ICIs for patients with advanced melanoma. In clinical practice, the model can be further improved when applied in a particular sub-population of patients with melanoma and when used in combination with existing (bio)markers. Finally, after validation of our findings in an ongoing extension study, the final aim is to implement the kinome analysis clinically.

In the randomized, 2-part, multicenter, open-label, phase 3 COLUMBUS study, encorafenib (enco) + binimetinib (bini)—approved in the US, EU, and other countries—and enco alone improved 5-year PFS and OS vs vemurafenib (vemu) in patients (pts) with BRAF V600E/K–mutant metastatic melanoma. We retrospectively investigated genetic and transcriptional correlates of response and intrinsic resistance to enco + bini in an exploratory biomarker (BM) analysis of COLUMBUS Part 1. Baseline (BL) tumor samples were analyzed using the ACE ImmunoID NeXT whole exome and whole transcriptome sequencing assays (Personalis). PFS and OS were analyzed (data cutoff: 15 Sep 2020) based on treatment (tx) type and presence of specific genetic or transcriptomic alterations at BL. High tumor mutation burden (TMB) was defined as above median TMB [8.6 mutations (muts)/megabase]. 366 tissue samples were successfully analyzed. We present results from the comparison of enco + bini (116 pts) vs vemu arms (130 pts). Median (m) PFS in the enco + bini and vemu arms was 14.9 and 5.7 mo, respectively (HR [95% CI], 0.55 [0.40–0.76]), and mOS was 34.8 and 18.6 mo, respectively (HR, 0.67 [0.50–0.90], similar to that observed in the safety cohort. PFS and OS by tx arm and BM status are shown in the table. High TMB, PD-L1 expression (exp), and IFNg signature were associated with longer PFS and OS in the enco + bini arm vs vemu arm. High ErbB2 exp and PI3KCA pathway muts were associated with shorter survival outcomes in the enco + bini arm vs the vemu arm. Pts with high immune-related signatures derived greater clinical benefit from enco + bini vs vemu. High ErbB2 exp and PI3KCA pathway muts are potential resistance mechanisms to enco + bini. Addition of checkpoint inhibitors or PI3KCA pathway–targeted therapies to enco + bini in selected pts may further improve clinical benefit for pts with BRAF V600E/K–mutant metastatic melanoma.Table: 786OEnco + bini vs vemumPFS, moHR;95% CImOS, moHR;95% CITMB, median≤9.2 vs 7.30.60;0.39–0.9426.0 vs 18.60.84;0.56–1.27>24.0 vs 5.70.49;0.30–0.7947.5 vs 16.90.53;0.34–0.82PD-L1 exp, median≤14.5 vs 5.70.56;0.34–0.9222.3 vs 19.40.86;0.54–1.36>33.2 vs 5.60.35;0.20–0.6167.3 vs 15.10.39;0.23–0.65IFNγ signature-14.5 vs 5.60.44;0.27–0.7226.0 vs 16.10.76;0.48–1.19+33.2 vs 7.30.41;0.23–0.7267.3 vs 16.90.41;0.24–0.70PI3K, PTEN, Akt, or mTORwt18.7 vs 5.70.45;0.30–0.6641.8 vs 18.80.56;0.39–0.79mut7.5 vs 7.31.04;0.56–1.9312.5 vs 16.11.23;0.71–2.13ErbB2 exp, median≤34.9 vs 5.60.29;0.17–0.5067.3 vs 15.80.44;0.26–0.72>12.9 vs 7.30.63;0.38–1.0723.4 vs 18.60.74;0.46–1.19 Open table in a new tab