Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Neoadjuvant nivolumab + T-VEC combination therapy for resectable early stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: study protocol of the NIVEC trial.

BACKGROUND: Trials investigating neoadjuvant treatment with immune checkpoint inhibitors (ICI) in patients with melanoma have shown high clinical and pathologic response rates. Treatment with talimogene laherparepvec (T-VEC), a modified herpes simplex virus type-1 (HSV-1), is approved for patients with unresectable stage IIIB-IVM1a melanoma and has the potential to make tumors more susceptible for ICI. Combination ICI and intralesional T-VEC has already been investigated in patients with unresectable stage IIIB-IV disease, however, no data is available yet on the potential benefit of this combination therapy in neoadjuvant setting. METHODS: This single center, single arm, phase II study aims to show an improved major pathologic complete response (pCR) rate, either pCR or near-pCR, up to 45% in 24 patients with resectable stage IIIB-IVM1a melanoma upon neoadjuvant combination treatment with intralesional T-VEC and systemic nivolumab (anti-PD-1 antibody). Patients will receive four courses of T-VEC up to 4 mL (first dose as seroconversion dose) and three doses of nivolumab (240 mg flatdose) every 2 weeks, followed by surgical resection in week nine. The primary endpoint of this trial is pathologic response rate. Secondary endpoints are safety, the rate of delay of surgery and event-free survival. Additionally, prognostic and predictive biomarker research and health-related quality of life evaluation will be performed. DISCUSSION: Intralesional T-VEC has the capacity to heighten the immune response and to elicit an abscopal effect in melanoma in combination with ICI. However, the potential clinical benefit of T-VEC plus ICI in the neoadjuvant setting remains unknown. This is the first trial investigating the efficacy and safety of neoadjuvant treatment of T-VEC and nivolumab followed by surgical resection in patients with stage IIIB-IVM1a melanoma, with the potential of high pathologic response rates and acceptable toxicity. TRIAL REGISTRATION: This trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT- number: 2019-001911-22 ) and the Central Committee on Research Involving Human Subjects (NL71866.000.19) on 4th June 2020. Secondary identifying number: NCT04330430 .

Exploring supportive care and information needs through a proposed eHealth application among melanoma patients undergoing systemic therapy: a qualitative study.

BACKGROUND: During and after systemic therapy, patients with high risk and advanced melanoma experience challenges regarding cancer-related symptoms, treatment-related adverse events, and an impact of these symptoms on their physical and psychosocial well-being. Few studies have investigated the specific needs of these patients and the potential role of eHealth applications in meeting those needs. OBJECTIVE: To explore the supportive care and information needs of high risk and advanced melanoma patients, and how these needs can be supported by eHealth applications. METHODS: In this qualitative study, semi-structured interviews with high risk and advanced melanoma patients during or after systemic treatment were conducted to understand their needs and requirements as possible end-users of mobile eHealth applications. Interview transcripts were independently coded and thematically analyzed. RESULTS: Thirteen participants consented to be interviewed, aged 31 to 71 years. Nearly all patients (n = 12, 92%) experienced unmet information and supportive care needs during and after active treatment. Patients expected to value eHealth applications that facilitate information gathering, wellbeing interventions, and symptom management. The majority of patients (n = 10, 77%) anticipated various advantages from using an eHealth application, including increased autonomy, higher quality of life, and improved disease self-management. DISCUSSION: High risk and advanced melanoma patients have unmet supportive care and information needs during and after systemic treatment. The use of eHealth applications might be an effective way to meet these unmet needs. Patients anticipate a variety of advantages from using these applications, including deriving various benefits from the use of these applications, such as enhanced autonomy.

Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial.

OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

Vorinostat in patients with resistant BRAFV600E mutated advanced melanoma: a proof of concept study.

The clinical benefit of treatment with BRAF- and MEK-inhibitors in melanoma is limited due to resistance associated with emerging secondary mutations. Preclinical and clinical studies have shown that short-term treatment with the HDAC inhibitor vorinostat can eliminate cells harboring these secondary mutations causing resistance. This proof of concept study is to determine the efficacy of sequential treatment with vorinostat and BRAFi/MEKi in resistant BRAFV600E mutant melanoma. The primary aim is demonstrating anti-tumor response of progressive lesions according to RECIST 1.1. Secondary end points are to determine that emerging resistant clones with a secondary mutation in the MAPK pathway can be detected in circulating tumor DNA and purged by short-term vorinostat treatment. Exploratory end points include pharmacokinetic, pharmacodynamic and pharmacogenetic analyses (NCT02836548).

A Phase II, single-arm trial of neoadjuvant axitinib plus avelumab in patients with localized renal cell carcinoma who are at high risk of relapse after nephrectomy (NEOAVAX).

Surgery is the standard treatment for nonmetastatic renal cell carcinoma. Despite curative intent, patients with a high risk of relapse have a 5-year metastasis-free survival rate of only 30% and prevention of recurrence is an unmet need. In a Phase III trial (JAVELIN Renal 101), progression-free survival of axitinib + avelumab was superior to sunitinib with a favorable objective response rate and no added toxicity profiles as known for axitinib or avelumab single agent. NEOAVAX is designed as open label, single arm, Phase II trial with a Simon's two-stage design evaluating neoadjuvant axitinib + avelumab followed by complete surgical resection in 40 patients with high-risk nonmetastatic clear-cell renal cell carcinoma. Primary end point is remission of the primary tumor (RECIST 1.1; Response Evaluation Criteria In Solid Tumors) following neoadjuvant therapy. Secondary end points include disease-free survival, overall survival, rate of metastasis and local recurrence, safety, and tolerability. Exploratory end points include investigation of effects on neoangiogenesis, immune infiltrates and myeloid-derived suppressor cell components to support a rationale for the combined use of axitinib and avelumab (NCT03341845).

Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors.

BACKGROUND: BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors. METHODS: Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib. RESULTS: 245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27). CONCLUSIONS: Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients.

BACKGROUND: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). RESULTS: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. CONCLUSION: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.

Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases.

PURPOSE: Melanoma patients with a high risk of recurrence may benefit from immunotherapy with mRNA-electroporated autologous monocyte-derived dendritic cells (DCs). Further benefit may be found in combining DC-therapy with interferon alfa-2b. PATIENTS AND METHODS: The long-term clinical outcome of AJCC stage III/IV melanoma patients who had no evidence of disease at the time of treatment with autologous mRNA-electroporated DCs in a single-center pilot clinical trial was analyzed. Antigen loading was accomplished by co-electroporation of mRNA encoding a fusion protein between MAGE-A1, -A3, -C2, Tyrosinase, MelanA/MART-1, or gp100, and an HLA class II-targeting sequence. DCs were administered by 4-6 bi-weekly intradermal injections. IFN-α-2b (5 MIU TIW) was initiated either at recurrence (cohort 1), concomitant with DCs (cohorts 2 and 3), or following the fourth DC administration (cohort 4). RESULTS: Thirty melanoma patients were recruited between April 2006 and June 2009. DC-related adverse events included grade 2 local injection site reactions in all patients, grade 2 fever and flu-like symptoms in one patient, and skin depigmentation in seven patients. After a median follow-up of over 6 years, the median relapse-free survival is 22 months (95% CI 12-32 months). Twelve patients have died. The median overall survival has not been reached; the 2-year and 4-year survival rates are 93 and 70%, respectively. CONCLUSIONS: Adjuvant therapy following the resection of melanoma metastases with autologous mRNA-electroporated DCs, combined with interferon alfa-2b, is tolerable and results in encouraging long-term overall survival rates justifying further evaluation in a randomized clinical trial.

Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula.

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature's adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543-555, 2007; Melief in Immunity 29:372-383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265-277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111-1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.

Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation.

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4(+) and CD8(+) T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8(+) T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM.

Real-world health-related quality of life outcomes for patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 therapy.

BACKGROUND: While adjuvant therapy with anti-programmed cell death protein-1 (anti-PD1) for patients with resected stage III/IV melanoma has been shown to improve recurrence-free survival, the overall survival benefit remains uncertain. This study aims to evaluate the impact of adjuvant anti-PD1 therapy on the health-related quality of life (HRQOL) of patients with resected stage III/IV melanoma METHODS: Data was used from two melanoma registries in Australia and the Netherlands. Patients with resected stage III/IV melanoma treated with adjuvant anti-PD1 who completed a baseline and at least one post-baseline HRQOL assessment were included. HRQOL was assessed using the EORTC QLQ-C30 at baseline, 3, 6, and 12 months. Established thresholds were used for interpreting changes in QLQ-C30 scores. RESULTS: 92 patients were included. Mean symptom and functioning scores improved or remained stable at 12 months compared to baseline. However, a substantial proportion of patients experienced a clinically significant decline in role (39%, µ = -50.8), social (41%, µ = -32.7), or emotional (50%, µ = -25.1) functioning at 12 months compared to baseline. Younger patients were more likely to experience clinically significant deteriorations in role (OR=1.07, 95% CI: 1.02-1.13, p < 0.01) and social (OR=1.06, 95% CI: 1.01-1.11, p = 0.013) functioning. CONCLUSION: A significant proportion of patients with resected stage III/IV melanoma who received adjuvant anti-PD1 experienced clinically significant declines in role, social and emotional functioning at 12 months compared to baseline. This highlights the HRQOL issues that may arise during adjuvant anti-PD1 therapy which may require supportive care intervention.

A proof-of-concept study of sequential treatment with the HDAC inhibitor vorinostat following BRAF and MEK inhibitors in BRAFV600mutated melanoma.

PURPOSE: Development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600 mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of the resistant tumor cells. We aimed to assess the anti-tumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600 melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi resistant BRAFV600 melanoma were treated with vorinostat 360 mg QD for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics of vorinostat and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Twenty-six patients with progressive BRAFi/MEKi resistant BRAFV600 mutated melanoma received treatment with vorinostat. Twenty-two patients were evaluable for response. The ORR was 9% (one complete response for 31.2 months and one partial response for 14.9 months. Median PFS and OS were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. CONCLUSIONS: Intermittent treatment with vorinostat in patients with resistant BRAFV600mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable anti-tumor responses were observed in a minority of patients (9%).

Dendritic cells loaded with mRNA encoding full-length tumor antigens prime CD4+ and CD8+ T cells in melanoma patients.

It is generally thought that dendritic cells (DCs) loaded with full-length tumor antigen could improve immunotherapy by stimulating broad T-cell responses and by allowing treatment irrespective of the patient's human leukocyte antigen (HLA) type. To investigate this, we determined the specificity of T cells from melanoma patients treated with DCs loaded with mRNA encoding a full-length tumor antigen fused to a signal peptide and an HLA class II sorting signal, allowing presentation in HLA class I and II. In delayed-type hypersensitive (DTH)-biopsies and blood, we found functional CD8(+) and CD4(+) T cells recognizing novel treatment-antigen-derived epitopes, presented by several HLA types. Additionally, we identified a CD8(+) response specific for the signal peptide incorporated to elicit presentation by HLA class II and a CD4(+) response specific for the fusion region of the signal peptide and one of the antigens. This demonstrates that the fusion proteins contain newly created immunogenic sequences and provides evidence that ex vivo-generated mRNA-modified DCs can induce effector CD8(+) and CD4(+) T cells from the naive T-cell repertoire of melanoma patients. Thus, this work provides definitive proof that DCs presenting the full antigenic spectrum of tumor antigens can induce T cells specific for novel epitopes and can be administered to patients irrespective of their HLA type.

Common toxicities associated with immune checkpoint inhibitors and targeted therapy in the treatment of melanoma: A systematic scoping review.

INTRODUCTION: This systematic scoping review compares the toxicities experienced by patients receiving immune checkpoint inhibitors (ICIs) or targeted therapy (TT) for stage III (resected and unresectable) and stage IV melanoma. METHODS: OVID Medline, Embase, and PsycInfo were searched to identify Phase III trials reporting toxicities of FDA-approved ICIs and TT for advanced melanoma. AEs that were reported by ≥ 10% of patients in the evaluated trials were included. RESULTS: Toxicity profiles of 11208 patients from 24 studies were reviewed. The rate of AEs was lower with ICIs compared to TT. However, ICIs were associated with higher rates of long-term or permanent AEs compared to TT, where toxicities generally were shortterm and reversible with treatment discontinuation. CONCLUSION: The toxicity profiles of ICIs and TT vary substantially. Whilst the rate of AEs was lower with ICIs than during TT, it was also associated with higher rates of potentially chronic AEs.

Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease?

Background: Upfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. Objective: To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design setting and participants: This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysis: We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitations: At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. Conclusions: CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summary: In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.

An eHealth App (CAPABLE) Providing Symptom Monitoring, Well-Being Interventions, and Educational Material for Patients With Melanoma Treated With Immune Checkpoint Inhibitors: Protocol for an Exploratory Intervention Trial.

BACKGROUND: Since treatment with immune checkpoint inhibitors (ICIs) is becoming standard therapy for patients with high-risk and advanced melanoma, an increasing number of patients experience treatment-related adverse events such as fatigue. Until now, studies have demonstrated the benefits of using eHealth tools to provide either symptom monitoring or interventions to reduce treatment-related symptoms such as fatigue. However, an eHealth tool that facilitates the combination of both symptom monitoring and symptom management in patients with melanoma treated with ICIs is still needed. OBJECTIVE: In this pilot study, we will explore the use of the CAPABLE (Cancer Patients Better Life Experience) app in providing symptom monitoring, education, and well-being interventions on health-related quality of life (HRQoL) outcomes such as fatigue and physical functioning, as well as patients' acceptance and usability of using CAPABLE. METHODS: This prospective, exploratory pilot study will examine changes in fatigue over time in 36 patients with stage III or IV melanoma during treatment with ICI using CAPABLE (a smartphone app and multisensory smartwatch). This cohort will be compared to a prospectively collected cohort of patients with melanoma treated with standard ICI therapy. CAPABLE will be used for a minimum of 3 and a maximum of 6 months. The primary endpoint in this study is the change in fatigue between baseline and 3 and 6 months after the start of treatment. Secondary end points include HRQoL outcomes, usability, and feasibility parameters. RESULTS: Study inclusion started in April 2023 and is currently ongoing. CONCLUSIONS: This pilot study will explore the effect, usability, and feasibility of CAPABLE in patients with melanoma during treatment with ICI. Adding the CAPABLE system to active treatment is hypothesized to decrease fatigue in patients with high-risk and advanced melanoma during treatment with ICIs compared to a control group receiving standard care. The Medical Ethics Committee NedMec (Amsterdam, The Netherlands) granted ethical approval for this study (reference number 22-981/NL81970.000.22). TRIAL REGISTRATION: ClinicalTrials.gov NCT05827289; https://clinicaltrials.gov/study/NCT05827289. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49252.

IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation.

BACKGROUND: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.

Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient.

Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8(+) T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4(+) T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8(+) T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in (18)F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.

Patterns of response in patients with pretreated metastatic melanoma who received ipilimumab 3 mg/kg in a European expanded access program: five illustrative case reports.

Ipilimumab 3 mg/kg was the first agent to improve survival of pretreated advanced melanoma patients. Nonconventional response patterns to ipilimumab have been reported widely, but most of these data were from studies with ipilimumab 10 mg/kg. Here, case reports from five patients treated within an expanded access program (EAP) with ipilimumab at its licensed dose of 3 mg/kg illustrate the efficacy of ipilimumab in an expanded access setting and the range of different tumor response patterns encountered. The durable clinical benefit seen in these patients despite the observed atypical response patterns highlights the necessity for comprehensive clinical decision making.