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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.).
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PURPOSE: The 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 resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival 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 the 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 BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Histone Deacetylase Inhibitors , Melanoma , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf , Vorinostat , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Melanoma/mortality , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Vorinostat/administration & dosage , Vorinostat/pharmacology , Female , Male , Middle Aged , Aged , Adult , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Proof of Concept Study , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Aged, 80 and overABSTRACT
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.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Melanoma/surgery , Quality of Life , Skin Neoplasms/drug therapy , Skin Neoplasms/surgery , Adjuvants, Immunologic , Combined Modality TherapyABSTRACT
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.
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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.
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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.
Subject(s)
Melanoma , Proto-Oncogene Proteins B-raf , Melanoma/drug therapy , Melanoma/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Humans , Male , Female , Adult , Middle Aged , AgedABSTRACT
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.
Subject(s)
Antineoplastic Agents, Immunological , Melanoma , Humans , Immune Checkpoint Inhibitors/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy , Melanoma/drug therapy , SyndromeABSTRACT
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 .
Subject(s)
Biological Products , Melanoma , Nivolumab , Oncolytic Virotherapy , Skin Neoplasms , Biological Products/therapeutic use , Clinical Trials, Phase II as Topic , Herpesvirus 1, Human , Humans , Melanoma/drug therapy , Neoadjuvant Therapy , Nivolumab/therapeutic use , Oncolytic Virotherapy/methods , Quality of Life , Skin Neoplasms/drug therapyABSTRACT
As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.
Subject(s)
Melanoma , Skin Neoplasms , Antibodies/therapeutic use , Biomarkers, Tumor , Humans , L-Lactate Dehydrogenase , Melanoma/diagnosis , Melanoma/drug therapy , Prognosis , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Prospective Studies , Retrospective Studies , S100 Calcium Binding Protein beta Subunit , Skin Neoplasms/diagnosisABSTRACT
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.
Subject(s)
Melanoma , Self-Management , Telemedicine , Humans , Melanoma/therapy , Qualitative Research , Quality of Life , Self-Management/psychologyABSTRACT
Following CARMENA and SURTIME, patients with metastatic renal cell carcinoma (mRCC) and International Metastatic RCC Database Consortium (IMDC) intermediate and poor risk receive systemic therapy with the primary tumour (primary) in place, with the option of deferred cytoreductive nephrectomy (CN) in responding patients. We retrospectively analysed the safety and efficacy of first-line nivolumab/ipilimumab in 71 primary mRCC patients (42.3% IMDC poor risk; 43.6% with more than three metastatic sites). The baseline mean primary diameter was 9.3 cm and median follow-up was 11.5 mo. Of 69 patients with at least one follow-up computed tomography scan, 23 (33.3 %) had a partial response (PR) of the primary after a median of 4.8 mo, which was associated with a 91.3% overall response rate at metastatic sites (MSs) and absence of progressive disease, irrespective of the IMDC risk. The complete response (CR) rate at MSs (n = 7 [10.1%]) is similar to the CR rate in CheckMate 214. Thirteen deferred CNs were performed (18.8%) after a median of 13 mo, rendering four patients disease free. Only 4.3% of primaries progressed; grade 3-4 immune-related adverse events occurred in 31.9%. Irrespective of the IMDC risk, patients with a PR in the primary had a 1-yr overall survival rate of 89% versus 67% in those without (p = 0.012). PATIENT SUMMARY: Patients with metastatic kidney cancer receiving immunotherapy with nivolumab and ipilimumab had superior response at metastatic sites and better survival irrespective of International Metastatic RCC Database Consortium (IMDC) risk.
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Immunotherapy is increasingly gaining applicability for several malignancies. While the survival of several malignancies has dramatically improved, immune-related adverse events (irAEs) can occur and can cause severe damage to patients. Side effects such as colitis are well known nowadays; however, with increased use of immunotherapy, less common side effects should also be addressed. In this article, 2 patients that received nivolumab developed exocrine dysfunction of the pancreas. Endocrine dysfunction has been well known, but exocrine dysfunction is less often described. It is important to be aware of this side effect because it is possibly underdiagnosed. Symptoms often mimic symptoms of malignancy, chemotherapy side effects, or immune-related colitis. Although the exact mechanism is yet to be elaborated, dormant CD8+ T cells are likely to be involved. No known therapy is yet been proven to be effective. More knowledge and research about irAEs will lead to possible therapies that will be effective. Currently, high-dose prednisone is recommended based on expert opinion.
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Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013-July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3-4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients ≥60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference.
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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 8âweeks 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 50âmonths (interquartile range 37.7-57.1âmonths), median recurrence-free survival was 9.9âmonths (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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytoreduction Surgical Procedures , Melanoma/drug therapy , Melanoma/surgery , Adult , Aged , Female , Humans , Imidazoles/administration & dosage , Magnetic Resonance Imaging , Male , Melanoma/genetics , Melanoma/pathology , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Netherlands , Oximes/administration & dosage , Positron Emission Tomography Computed Tomography , Prospective Studies , Proto-Oncogene Proteins B-raf , Pyridones/administration & dosage , Pyrimidinones/administration & dosageABSTRACT
PURPOSE: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors. PATIENTS AND METHODS: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W. RESULTS: Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12-27 months) in colorectal cancer (n = 2), non-small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3-positive staining, including one patient with NSCLC who received prior PD-1 therapy. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Immune Checkpoint Inhibitors , Neoplasms , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Drug Combinations , Hepatitis A Virus Cellular Receptor 2/immunology , Immune Checkpoint Inhibitors/administration & dosage , Neoplasm Staging , Neoplasms/drug therapy , Neoplasms/pathology , Programmed Cell Death 1 Receptor/immunologyABSTRACT
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).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Melanoma/drug therapy , Proto-Oncogene Proteins B-raf/genetics , Vorinostat/therapeutic use , Drug Administration Schedule , Drug Resistance, Neoplasm/genetics , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Melanoma/genetics , Melanoma/pathology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mutation , Proof of Concept Study , Proto-Oncogene Proteins B-raf/antagonists & inhibitorsABSTRACT
BACKGROUND: We previously reported that dendritic cell-based mRNA vaccination plus ipilimumab (TriMixDC-MEL IPI) results in an encouraging rate of tumor responses in patients with pretreated advanced melanoma. Here, we report the TriMixDC-MEL IPI-induced T-cell responses detected in the peripheral blood. METHODS: Monocyte-derived dendritic cells electroporated with mRNA encoding CD70, CD40 ligand, and constitutively active TLR4 (TriMix) as well as the tumor-associated antigens tyrosinase, gp100, MAGE-A3, or MAGE-C2 were administered together with IPI for four cycles. For 18/39 patients, an additional vaccine was administered before the first IPI administration. We evaluated tumor-associated antigen specific T-cell responses in previously collected peripheral blood mononuclear cells, available from 15 patients. RESULTS: Vaccine-induced enzyme-linked immunospot assay responses detected after in vitro T-cell stimulation were shown in 12/15 patients. Immune responses detected in patients with a complete or partial response were significantly stronger and broader, and exhibited a higher degree of multifunctionality compared with responses in patients with stable or progressive disease. CD8+ T-cell responses from patients with an ongoing clinical response, either elicited by TriMixDC-MEL IPI or on subsequent pembrolizumab treatment, exhibited the highest degree of multifunctionality. CONCLUSIONS: TriMixDC-MEL IPI treatment results in robust CD8+ T-cell responses in a meaningful portion of stage III or IV melanoma patients, and obviously in patients with a clinical response. The levels of polyfunctional and multiantigen T-cell responses measured in patients with a complete response, particularly in patients evidently cured after 5+ years of follow-up, may provide a benchmark for the level of immune stimulation needed to achieve a durable clinical remission. TRIAL REGISTRATION NUMBER: NCT01302496.
Subject(s)
Cancer Vaccines/administration & dosage , Dendritic Cells/transplantation , Ipilimumab/administration & dosage , Melanoma/therapy , Skin Neoplasms/therapy , Adult , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , CD8-Positive T-Lymphocytes/immunology , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Dendritic Cells/immunology , Electroporation , Female , Follow-Up Studies , Humans , Immunization, Secondary , Lymphocyte Activation , Male , Melanoma/diagnosis , Melanoma/immunology , Melanoma/mortality , Middle Aged , Neoplasm Staging , Progression-Free Survival , RNA, Messenger/genetics , RNA, Messenger/immunology , Remission Induction/methods , Skin Neoplasms/diagnosis , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Transplantation, Autologous , Vaccination/methodsABSTRACT
BRAF + MEK inhibition is preferentially applied as first-line therapy in BRAF V600-mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short-term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p = .790). Median was PFS 2.5 months versus 1.2 months (p = .145), and median OS was 30.6 versus 14.1 months (p = .007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p = .956) and 0.48 for OS (p = .055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only.
Subject(s)
Disease Progression , Immune Checkpoint Inhibitors/therapeutic use , Melanoma/drug therapy , Melanoma/genetics , Molecular Targeted Therapy , Mutation/genetics , Proto-Oncogene Proteins B-raf/genetics , Adult , Female , Humans , Kaplan-Meier Estimate , Male , Melanoma/pathology , Middle Aged , Retrospective Studies , Treatment OutcomeABSTRACT
In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB". It should have read "TNF-α signaling via NF-κB". The error has been corrected in the HTML and PDF versions of this article.