Hiel, B. van der; Aalbersberg, E.A.; Eertwegh, A.J.M. van den; Veen, L.J.D.V. de van der; Stokkel, M.P.M.; Lopez-Yurda, M.; ... ; Haanen, J.B.A.G. 2024
Purpose: The aims of this study were to investigate whether (early) PERCIST response monitoring with F-18-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or... Show morePurpose: The aims of this study were to investigate whether (early) PERCIST response monitoring with F-18-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of F-18-FDG PET/CT during BRAF/MEKi.Patients and methods: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF-mutated melanoma who underwent contrast-enhanced CT and F-18-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns.Results: Using RECIST1.1, PFS was not significantly different between the response groups (P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR (P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR (P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, F-18-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When F-18-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new F-18-FDG-avid lesions.Conclusions: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early F-18-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new F-18-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease. Show less
Predicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to... Show morePredicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population-based cohort of 3525 patients with advanced cutaneous melanoma treated with anti-PD-1-based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal-external cross-validation. Included patients received anti-PD-1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence-all at start of ICI-, and location and type of primary melanoma, the presence of satellites and/or in-transit metastases at primary diagnosis and sex. The over-optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64-0.66). The range of predicted response probabilities was 7%-81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression-free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis. Show less
BackgroundEffectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking.MethodsData from all advanced melanoma patients treated... Show moreBackgroundEffectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking.MethodsData from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival.ResultsThe authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1-5.2), and median OS was 8.2 months (95% CI, 7.2-9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7-4.0) versus 5.2 months (95% CI, 4.5-5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival.ConclusionsThis study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge.This study confirms that patients with advanced melanoma derive benefit from rechallenge with BRAFi(/MEKi). Elevated lactate dehydrogenase levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit on rechallenge. Show less
Zwart, W.H.; Dijkstra, E.A.; Putter, H.; Marijnen, C.A.M.; Nilsson, P.J.; Velde, C.J.H. van de; ... ; Glimelius, B. 2023
Objective:To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years.Background:Multimodality treatment improves local control in rectal cancer. Total... Show moreObjective:To analyze risk and patterns of locoregional failure (LRF) in patients of the RAPIDO trial at 5 years.Background:Multimodality treatment improves local control in rectal cancer. Total neoadjuvant treatment (TNT) aims to improve systemic control while local control is maintained. At 3 years, LRF rate was comparable between TNT and chemoradiotherapy in the RAPIDO trial.Methods:A total of 920 patients were randomized between an experimental (EXP, short-course radiotherapy, chemotherapy, and surgery) and a standard-care group (STD, chemoradiotherapy, surgery, and optional postoperative chemotherapy). LRFs, including early LRF (no resection except for organ preservation/R2 resection) and locoregional recurrence (LRR) after an R0/R1 resection, were analyzed.Results:Totally, 460 EXP and 446 STD patients were eligible. At 5.6 years (median follow-up), LRF was detected in 54/460 (12%) and 36/446 (8%) patients in the EXP and STD groups, respectively (P=0.07), in which EXP patients were more often treated with 3-dimensional-conformed radiotherapy (P=0.029). In the EXP group, LRR was detected more often [44/431 (10%) vs. 26/428 (6%); P=0.027], with more often a breached mesorectum (9/44 (21%) vs. 1/26 (4); P=0.048). The EXP treatment, enlarged lateral lymph nodes, positive circumferential resection margin, tumor deposits, and node positivity at pathology were the significant predictors for developing LRR. Location of the LRRs was similar between groups. Overall survival after LRF was comparable [hazard ratio: 0.76 (95% CI, 0.46-1.26); P=0.29].Conclusions:The EXP treatment was associated with an increased risk of LRR, whereas the reduction in disease-related treatment failure and distant metastases remained after 5 years. Further refinement of the TNT in rectal cancer is mandated. Show less
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... Show moreDespite 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. Show less
Zeijl, M.C.T. van; Breeschoten, J. van; Wreede, L.C. de; Wouters, M.W.J.M.; Hilarius, D.L.; Blank, C.U.; ... ; Eertwegh, A.J.M. van den 2023
Background: In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grade 3-4 adverse events (AEs). Here, we... Show moreBackground: In phase III trials, ipilimumab plus nivolumab combination therapy is highly efficacious for advanced melanoma, despite many treatment-related grade 3-4 adverse events (AEs). Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma.Methods: Patients with advanced melanoma who received first-line ipilimumab plus nivolumab between 1-1-2015 and 30-6-2021 were selected from the Dutch Melanoma Treatment Registry. We evaluated response status at 3, 6, 12,18, and 24 months. OS and PFS were estimated with the Kaplan-Meier method. Separate analyses were performed for patients with or without brain metastases and for patients who met the inclusion criteria of the Checkmate-067 trial.Results: In total, 709 patients received first-line ipilimumab plus nivolumab. Three hundred sixty (50.7%) patients experienced grade 3-4 AEs with 211 of them (58.6%) patients requiring hospital admission. Median treatment duration was 42 days (IQR = 31-139). At 24-months, disease control was achieved in 37% of patients. Median PFS since the start of treatment was 6.6 months (95%CI: 5.3-8.7), and median OS was 28.7 months (95%CI: 20.7-42.2). CheckMate-067 trial-like patients had a 4-year OS of 50% (95%CI: 43-59). Among patients with no, asymptomatic or symptomatic brain metastases, the 4-year OS probabilities were 48% (95%CI: 41-55), 45% (95%CI: 35-57), and 36% (95%CI: 27-48).Conclusion: Ipilimumab plus nivolumab can achieve long-term survival in advanced melanoma patients in a real-world setting, including patients not represented in the CheckMate-067 trial. However, the proportion of patients with disease control in the real-world is lower compared to clinical trials. Show less
The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanomathat develop brain metastases (BM) remains unpredictable. In this study, we aimed to identifyprognostic factors... Show moreThe efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanomathat develop brain metastases (BM) remains unpredictable. In this study, we aimed to identifyprognostic factors in patients with melanoma BM who are treated with ICIs. Data from advancedmelanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained fromthe Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment ofBM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potentialclassifiers and overall survival (OS) as the response variable. In total, 1278 patients were included.Most patients were treated with ipilimumab–nivolumab combination therapy (45%). The survivaltree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. Thestrongest clinical parameter associated with survival in advanced melanoma patients with BM wasthe serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomaticBM had the worst prognosis. The clinicopathological classifiers identified in this study can contributeto optimizing clinical studies and can aid doctors in giving an indication of the patients’ survivalbased on their baseline and disease characteristics. Show less
BackgroundPatients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical...Show moreBackgroundPatients diagnosed with haematologic malignancies (HMs) have a higher risk of developing subsequent solid tumours, such as melanoma. Patients with HM were mostly excluded from clinical trials but potentially derive less benefit from immune checkpoint inhibitors (ICIs) due to disease- or treatment-related T- or B-cell dysfunction.MethodsAll advanced melanoma patients treated with anti-PD-1-based treatment or targeted therapy between 2015 and 2021 were included from the prospective nationwide Dutch Melanoma Treatment Registry. Progression-free survival (PFS) and melanoma-specific survival (MSS) were analysed for patients with HM (HM+) and without HM (HM−). A cox model was used to account for confounders associated with PFS and MSS.ResultsIn total, 4638 advanced melanoma patients received first-line anti-PD-1 monotherapy (n = 1763), ipilimumab-nivolumab (n = 800), or BRAF(/MEK) inhibitors (n = 2075). Concurrent HMs were present for 46 anti-PD1-treated patients, 11 ipilimumab-nivolumab-treated patients and 43 BRAF(/MEK)-inhibitor-treated patients. In anti-PD-1-treated patients, the median PFS was 2.8 months for HM+ and 9.9 months for HM− (p = 0.01). MSS was 41.2 months for HM+ and 58.1 months for HM− (p = 0.00086). In multivariable analysis, the presence of an HM was significantly associated with higher risk of melanoma progression (HRadj 1.62; 95% confidence interval [95% CI] 1.15–2.29; p = 0.006) and melanoma-related death (HRadj 1.74; 95% CI 1.09–2.78; p = 0.020). Median PFS and MSS for first-line BRAF(/MEK-) inhibitor-treated HM+ and HM− patients were not significantly different.ConclusionsPatients with HM and advanced melanoma show significantly worse melanoma-related outcomes when treated with ICI, but not targeted therapy, compared to patients without HM. Clinicians should be aware of potentially altered effectiveness of ICI in patients with active HM. Show less
IntroductionAlthough optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant...Show moreIntroductionAlthough optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastasesin patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial.Material and methodsPatients were randomly assigned to short-course radiotherapy followed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course chemoradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre- and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated.ResultsIn total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19–27] and 30% [95% CI 26–35] (HR 0.72 [95% CI 0.56–0.93]; P = 0.011) in the EXP and SC-G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0–3.1] in the EXP and 3.2 years [95% CI 2.3–4.1] in the SC-G groups (HR 1.39 [95% CI 1.01–1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM.ConclusionsCompared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of metastases, particularly liver metastases. Show less
Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to... Show moreSince the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy. Show less
BackgroundPre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients... Show moreBackgroundPre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial.Patients and methodsPatients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT− group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT−/− group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression.ResultsIn total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT− and pCT−/− groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT−), and 0.5 and 0.8 (pCT ≥75% versus pCT−/−). However, all 95% confidence intervals included 1.ConclusionsThese data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant. Show less
Breeschoten, J. van; Eertwegh, A.J.M. van den; Hilarius, D.L.; Haanen, J.B.; Blank, C.U.; Aarts, M.J.B.; ... ; Wreede, L.C. de 2023
IntroductionWhen analysing patient survival, one is often interested in cause of death. Little is known about the presence of population mortality in advanced melanoma patients. The aim of this... Show moreIntroductionWhen analysing patient survival, one is often interested in cause of death. Little is known about the presence of population mortality in advanced melanoma patients. The aim of this study was to assess population mortality after different response states in advanced melanoma patients in the Netherlands, and analyse the contribution of disease and population mortality for different age groups.MethodsWe selected patients diagnosed between 2013 and 2019 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. A multi-state model with response states integrating population mortality was fitted. One-year landmark analyses were performed to assess outcomes after each response state.ResultsOverall, 5119 patients were selected. Five-year probabilities of melanoma-related mortality in patients alive in complete response at one year after diagnosis increased with age, and was 17.2% (95% confidence interval: 13.0–21.4) for patients aged <65 years and 28.7% (95% confidence interval: 24.3–33.1) in patients aged ≥80 years. Population mortality only played a large role for older patients (75 years and above) alive at 1 year after diagnosis with a partial or complete response.ConclusionEven though survival outcomes of advanced melanoma patients have improved over the last decade, the vast majority of patients still die due to melanoma-related mortality. Show less
Simple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is... Show moreSimple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is known about how these therapies compare to each other in everyday practice. The aim of our study was to describe the toxicity and survival of patients treated with BRAF/MEK therapy and anti-PD-1 therapy in daily practice. We demonstrated that grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early treatment discontinuation (71.1%). We also show that at 12 months, patients treated with BRAF/MEK therapy have less progression than those treated with anti-PD-1 therapy. However, this is no longer the case at 18 months. Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade >= 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness. Show less
Kooij, M.K. van der; Joosse, A.; Suijkerbuijk, K.P.M.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Blank, C.U.; ... ; Kapiteijn, E. 2022
Treatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either... Show moreTreatment with targeted therapy and immune checkpoint inhibitors has significantly improved survival of patients with advanced melanoma. Unfortunately, a large proportion of patients are either primary non-responders or will eventually develop secondary resistance. In 2017, Nosrati and colleagues published a prediction scale in the British Journal of Cancer, which included five clinical parameters that were associated with lower response to anti-PD-1 treatment; female sex (1 point), age <65 years (1 point), history of ipilimumab (anti-CTLA-4) treatment (2 points), elevated lactate dehydrogenase (LDH) (1 point), and the presence of liver metastasis (2 points) [1]. This study used a derivation cohort of 228 patients treated in California, and a validation cohort of 87 patients treated in Switzerland. The primary outcome measure was best tumour response to treatment evaluated using computed tomography at 12 and 16 weeks after the first administration of anti-PD-1 monotherapy, and every 12 weeks thereafter. The aim of this correspondence is to validate the prediction scale, published by Nosrati and colleagues. Show less
BACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable... Show moreBACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5x10(9) TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P < 0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. Show less
Ismail, R.K.; Suijkerbuijk, K.P.M.; Boer, A. de; Dartel, M. van; Hilarius, D.L.; Pasmooij, A.M.G.; ... ; Wouters, M.W.J.M. 2022
Recent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS)... Show moreRecent results of patients with advanced melanoma treated with first-line BRAF-MEK inhibitors in clinical trials showed 5-year survival in one-third of patients with a median overall survival (OS) of more than 2 years. This study aimed to investigate these patients' real-world survival and identify the characteristics of long-term survivors. The study population consisted of patients with advanced cutaneous melanoma with a BRAF-V600 mutated tumor who were treated with first-line BRAF-MEK inhibitors between 2013 and 2017. Long-term survival was defined as a minimum OS of 2 years from start therapy. The median progression-free survival (mPFS) and median OS (mOS) of real-world patients (n = 435) were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival and 19% reached 4-year survival. Real-world patients often had brain metastases (41%), stage IV M1c disease (87%), ECOG PS >= 2 (21%), >= 3 organ sites (62%) and elevated LDH of >= 250 U/I (49%). Trial-eligible real-world patients had an mOS of 17.9 months. Patients surviving more than 2 years (n = 116) more often had an ECOG PS <= 1 (83%), normal LDH (60%), no brain metastases (60%), no liver metastases (63%) and <3 organ sites (60%). Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice. Long-term survivors generally had more favorable characteristics with regard to age, LDH level and metastatic sites, compared to patients not reaching long-term survival. Show less
Blankenstein, S.A.; Bonenkamp, J.J.; Aarts, M.J.B.; Berkmortel, F.W.P.J. van den; Blank, C.U.; Blokx, W.A.M.; ... ; Akkooi, A.C.J. van 2022
Simple Summary Nodular melanoma is associated with a higher locoregional recurrence rate and worse overall survival outcomes. Whether this histologic subtype affects the efficacy of immunotherapy... Show moreSimple Summary Nodular melanoma is associated with a higher locoregional recurrence rate and worse overall survival outcomes. Whether this histologic subtype affects the efficacy of immunotherapy or targeted therapy is unclear. The aim of our multi-center nationwide study is to identify the efficacy of immunotherapy and BRAF/MEKi therapy in metastatic nodular melanoma compared with the efficacy in metastatic superficial spreading melanoma. Our study results demonstrate no difference between the effectiveness of immunotherapy and BRAF/MEKi in metastatic nodular versus superficial melanoma patients. A shorter distant metastasis-free survival and reduced overall survival (measured as the time between primary melanoma up to death or last follow-up) was observed in the nodular melanoma patient group, suggesting worse overal survival of nodular melanoma is mainly driven by propensity of metastatic outgrowth of nodular melanoma after primary diagnosis. Nodular melanoma (NM) is associated with a higher locoregional and distant recurrence rate compared with superficial spreading melanoma (SSM); it is unknown whether the efficacy of systemic therapy is limited. Here, we compare the efficacy of immunotherapy and BRAF/MEK inhibitors (BRAF/MEKi) in advanced NM to SSM. Patients with advanced stage IIIc and stage IV NM and SSM treated with anti-CTLA-4 and/or anti-PD-1, or BRAF/MEKi in the first line, were included from the prospective Dutch Melanoma Treatment Registry. The primary objectives were distant metastasis-free survival (DMFS) and overall survival (OS). In total, 1086 NM and 2246 SSM patients were included. DMFS was significantly shorter for advanced NM patients at 1.9 years (CI 95% 0.7-4.2) compared with SSM patients at 3.1 years (CI 95% 1.3-6.2) (p < 0.01). Multivariate survival analysis for immunotherapy and BRAF/MEKi demonstrated a hazard ratio for immunotherapy of 1.0 (CI 95% 0.85-1.17) and BRAF/MEKi of 0.95 (CI 95% 0.81-1.11). A shorter DMFS for NM patients developing advanced disease compared with SSM patients was observed, while no difference was observed in the efficacy of systemic immunotherapy or BRAF/MEKi between NM and SSM patients. Our results suggests that the worse overall survival of NM is mainly driven by propensity of metastatic outgrowth of NM after primary diagnosis. Show less
