Background: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary... Show moreBackground: Uveal melanoma (UM) is a rare intraocular tumor with a dismal prognosis once metastasized. This study provides a nationwide overview and time trends of patients diagnosed with primary UM in the Netherlands between 1989 and 2019. Methods: A retrospective population-based cohort study based on patients with primary UM from the database of the Netherlands Cancer Registry (NCR), linked with the national population registry Statistics Netherlands on inhabitants' cause of death. Two time periods (1989-2004, 2005-2019) were compared with descriptive statistics. Kaplan-Meier and (multivariate) Cox proportional hazard models were used to assess changes over time for overall survival (OS) and cancer-specific survival (CSS). Results: In total, 5036 patients were analyzed with a median age of 64.0 years at the time of diagnosis. The number of patients increased over time. In the first (1989-2004) and second (2005-2019) period, 32% versus 54% of the patients received radiotherapy (p < 0.001). The median FU time was 13.4 years. The median OS of the first and second periods was 9.5 (95% CI 8.7-10.3) versus 11.3 years (95% CI 10.3-12.3; p < 0.001). The median CSS was 30.0 years (95% CI NA) in the first period and not reached in the second period (p = 0.008). In multivariate analysis (MVA), female gender (HR 0.85; 95% CI 0.79-0.92, p < 0.001) and radiotherapy treatment (HR 0.73; 95% CI 0.64-0.83, p < 0.001) were associated with better OS. Radiotherapy treatment (HR 0.74; 95% CI 0.61-0.90, p = 0.002) was also associated with better CSS. The period of diagnosis was not associated with OS or CSS. Conclusions: In this study of patients with primary UM, there was a shift to the diagnosis of smaller tumors, possibly due to stage migration. There was also an increase in eye-preserving treatments over time. OS and CSS were modestly improved in the second time period; however, the time period was not associated with OS or CSS in multivariate analyses. Show less
Miao, B.P.; Hu, Z.Q.; Mezzadra, R.; Hoeijmakers, L.; Fauster, A.; S.C. du; ... ; Sun, C. 2023
The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. 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
BackgroundCheckpoint inhibitors have been shown to substantially improve the survival of patients with advanced melanoma. With this growing group of survivors treated with immunotherapies,... Show moreBackgroundCheckpoint 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.MethodsHealth-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.ResultsHealth-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 (beta = - .82, p = .022) and fatigue burden (beta = - .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).DiscussionOur results show that long-term advanced melanoma survivors treated with ipilimumab monotherapy experience relatively stable and high health-state utility scores. Show less
Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit... Show moreNeoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies. Show less
Simple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the... Show moreSimple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the introduction of immune and targeted therapy. In contrast, little is known about the effect of their introduction on the survival of MM. This study presents the incidence, clinical characteristics, treatment characteristics, and survival of MM over 30 years (1990-2019) in the Netherlands. We conclude that the incidence of MM remained stable, and survival has slightly improved when comparing the timeframe 2014-2019 with previous years. However, the prognosis of MM remains poor as compared to CM. Future studies addressing the effect of immune and targeted therapy in MM are needed to improve outcomes for patients with MM. Background: Mucosal melanoma (MM) is a rare tumour with a poor prognosis. Over the years, immune and targeted therapy have become available and have improved overall survival (OS) for patients with advanced cutaneous melanoma (CM). This study aimed to assess trends in the incidence and survival of MM in the Netherlands against the background of new effective treatments that became available for advanced melanoma. Methods: We obtained information on patients diagnosed with MM during 1990-2019 from the Netherlands Cancer Registry. The age-standardized incidence rate and estimated annual percentage change (EAPC) were calculated over the total study period. OS was calculated using the Kaplan-Meier method. Independent predictors for OS were assessed by applying multivariable Cox proportional hazards regression models. Results: In total, 1496 patients were diagnosed with MM during 1990-2019, mostly in the female genital tract (43%) and the head and neck region (34%). The majority presented with local or locally advanced disease (66%). The incidence remained stable over time (EAPC 3.0%, p = 0.4). The 5-year OS was 24% (95%CI: 21.6-26.0%) with a median OS of 1.7 years (95%CI: 1.6-1.8). Age >= 70 years at diagnosis, higher stage at diagnosis, and respiratory tract location were independent predictors for worse OS. Diagnosis in the period 2014-2019, MM located in the female genital tract, and treatment with immune or targeted therapy were independent predictors for better OS. Conclusion: Since the introduction of immune and targeted therapies, OS has improved for patients with MM. However, the prognosis of MM patients is still lower compared to CM, and the median OS of patients treated with immune and targeted therapies remains fairly short. Further studies are needed to improve outcomes for patients with MM. 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
Purpose To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma ... Show morePurpose To define a safe treatment dose of ipilimumab (IPI) and nivolumab (NIVO) when applied in combination with percutaneous hepatic perfusion with melphalan (M-PHP) in metastatic uveal melanoma (mUM) patients (NCT04283890), primary objective was defining a safe treatment dose of IPI/NIVO plus M-PHP. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03). Secondary objective was response rate, PFS and OS.Materials and Methods Patients between 18-75 years with confirmed measurable hepatic mUM according to RECIST 1.1 and WHO performance score 0-1 were included. Intravenous IPI was applied at 1 mg/kg while NIVO dose was increased from 1 mg/kg in cohort 1 to 3 mg/kg in cohort 2. Transarterial melphalan dose for M-PHP was 3 mg/kg (maximum of 220 mg) in both cohorts. Treatment duration was 12 weeks, consisting of four 3-weekly courses IPI/NIVO and two 6-weekly M-PHPs.Results Seven patients were included with a median age of 63.6 years (range 50-74). Both dose levels were well tolerated without dose-limiting toxicities or deaths. Grade III/IV adverse events (AE) were observed in 2/3 patients in cohort 1 and in 3/4 patients in cohort 2, including Systemic Inflammatory Response Syndrome (SIRS), febrile neutropenia and cholecystitis. Grade I/II immune-related AEs occurred in all patients, including myositis, hypothyroidism, hepatitis and dermatitis. There were no dose-limiting toxicities. The safe IPI/NIVO dose was defined as IPI 1 mg/kg and NIVO 3 mg/kg. There was 1 complete response, 5 partial responses and 1 stable disease (3 ongoing responses with a median FU of 29.1 months).Conclusion Combining M-PHP with IPI/NIVO was safe in this small cohort of patients with mUM at a dose of IPI 1 mg/kg and NIVO 3 mg/kg. Show less
Background: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune... Show moreBackground: The gut microbiome plays an important role in immune modulation. Specifically, presence or absence of certain gut bacterial taxa has been associated with better antitumor immune responses. Furthermore, in trials using fecal microbiota transplantation (FMT) to treat melanoma patients unresponsive to immune checkpoint inhibitors (ICI), complete responses (CR), partial responses (PR), and durable stable disease (SD) have been observed. However, the underlying mechanism determining which patients will or will not respond and what the optimal FMT composition is, has not been fully elucidated, and a discrepancy in microbial taxa associated with clinical response has been observed between studies. Furthermore, it is unknown whether a change in the microbiome itself, irrespective of its origin, or FMT from ICI responding donors, is required for reversion of ICI-unresponsiveness. To address this, we will transfer microbiota of either ICI responder or nonresponder metastatic melanoma patients via FMT. Methods: In this randomized, double-blinded phase Ib/IIa trial, 24 anti-PD1-refractory patients with advanced stage cutaneous melanoma will receive an FMT from either an ICI responding or nonresponding donor, while continuing anti-PD-1 treatment. Donors will be selected from patients with metastatic melanoma treated with anti-PD-1 therapy. Two patients with a good response (& GE; 30% decrease according to RECIST 1.1 within the past 24 months) and two patients with progression (& GE; 20% increase according to RECIST 1.1 within the past 3 months) will be selected as ICI responding or nonresponding donors, respectively. The primary endpoint is clinical benefit (SD, PR or CR) at 12 weeks, confirmed on a CT scan at 16 weeks. The secondary endpoint is safety, defined as the occurrence of grade & GE; 3 toxicity. Exploratory endpoints are progression-free survival and changes in the gut microbiome, metabolome, and immune cells. Discussion: Transplanting fecal microbiota to restore the patients' perturbed microbiome has proven successful in several indications. However, less is known about the potential role of FMT to improve antitumor immune response. In this trial, we aim to investigate whether administration of FMT can reverse resistance to anti-PD-1 treatment in patients with advanced stage melanoma, and whether the ICI-responsiveness of the feces donor is associated with its 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
Rauwerdink, D.J.W.; Doorn, R. van; Hage, J. van der; Eertwegh, A.J.M. van den; Haanen, J.B.A.G.; Aarts, M.; ... ; Kapiteijn, E. 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
Oratie uitgesproken door Prof. C.U. Blank MD bij de aanvaarding van het ambt van Bijzonder hoogleraarInterne Geneeskunde aan de Universiteit Leiden op vrijdag 14 oktober 2022
Breeschoten, J. van; Ismail, R.K.; Wouters, M.W.J.M.; Hilarius, D.L.; Wreede, L.C. de; Haanen, J.B.; ... ; Eertwegh, A.J.M. van den 2022
Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free... Show moreNeoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial (NCT02977052) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg(-1) and nivolumab 3 mg kg(-1). In patients achieving major pathologic response (MPR, <= 10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to <= 50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy +/- synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab. Show less
Neoadjuvant immunotherapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) + anti-programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological... Show moreNeoadjuvant immunotherapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) + anti-programmed cell death protein 1 (PD1) monoclonal antibodies has demonstrated remarkable pathological responses and relapse-free survival in -80% of patients with clinically detectable stage III melanoma. However, about 20% of the treated patients do not respond. In pretreatment biopsies of patients with melanoma, we found that resistance to neoadjuvant CTLA4 + PD1 blockade was associated with a low CD4/interleukin-2 (IL-2) gene signature. Ex vivo, addition of IL-2 to CTLA4 + PD1 blockade induced T cell activation and deep immunological responses in anti-CTLA4 + anti-PD1-resistant human tumor specimens. In the 4T1.2 breast cancer mouse model of neoadjuvant immunotherapy, triple combination of anti-CTLA4 + anti-PD1 + IL-2 cured almost twice as many mice as compared with dual checkpoint inhibitor therapy. This improved efficacy was due to the expansion of tumor-specific CD8(+) T cells and improved proinflammatory cytokine polyfunctionality of both CD4(+) and CD8(+) T effector cells and regulatory T cells. Depletion studies suggested that CD4(+) T cells were critical for priming of CD8(+) T cell immunity against 4T1.2 and helped in the expansion of tumor-specific CD8(+) T cells early after neoadjuvant triple immunotherapy. Our results suggest that the addition of IL-2 can overcome resistance to neoadjuvant anti-CTLA4 +anti-PD1, providing the rationale for testing this combination as a neoadjuvant therapy in patients with early-stage cancer. Show less
Background: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal... Show moreBackground: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease.Methods: Open-label, single-center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first-line treatment, with or without the limited extrahepatic disease. The primary objective is to determine the safety, toxicity, and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at 1 year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, chi-square test). To study the association between risk factors and toxicity, a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.Discussion: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. Show less
IMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a... Show moreIMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen.OBJECTIVE To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population.DESIGN, SETTING, AND PARTICIPANTS Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021.MAIN OUTCOMES AND MEASURES Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen.RESULTS A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted.CONCLUSIONS AND RELEVANCE The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial. Show less
