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 .

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.

BACKGROUND: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy. METHODS: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR. RESULTS: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions. CONCLUSIONS: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Challenges in sentinel node pathology in the era of adjuvant treatment.

BACKGROUND: With the approval of adjuvant therapy for stage III melanoma, accurate staging is more important than ever. Sentinel node biopsy (SNB) is an accurate staging tool, yet the presence of capsular nevi (CN) can lead to a false-positive diagnosis. PATIENTS AND METHODS: Retrospective analysis of the American Joint Committee on Cancer 7th edition stage IIIA melanoma patients who were treated at our institute between 2000 and 2015. SNB slides were reviewed for this study by an expert melanoma pathologist. RESULTS: Of 159 eligible patients, 14 originally diagnosed with metastatic melanoma merely had CN (8.8%). Another two merely had melanophages (1.3%). Thus, 10.1% of SNs were considered false positive after revision. In 12 patients, the SN tumor burden was originally reported as larger than 1 mm but turned out to be less than 1 mm. Four patients originally reported as SN tumor burden less than 1 mm before revision turned out to have larger than 1 mm. These patients might have been over- or undertreated in the current era of adjuvant therapy for stage III melanoma. CONCLUSIONS: Distinguishing metastatic melanoma from benign CN and melanophages can be a diagnostic challenge. We plead for an expert pathologists' review, especially when using the SNB + results to determine treatment consequences.

The extent of surgery for stage III melanoma: how much is appropriate?

Since the first documented lymph node dissection in 1892, many trials have investigated the potential effect of this surgical procedure on survival in patients with melanoma. Two randomised controlled trials were unable to demonstrate improved survival with completion lymph node dissection versus nodal observation in patients with sentinel node-positive disease, although patients with larger sentinel node metastases (>1 mm) might benefit more from observation than from dissection, and could potentially be considered for adjuvant systemic therapy instead of complete dissection. Adjuvant immunotherapy with high-dose ipilimumab has led to improvements in overall survival, whereas therapy with nivolumab and pembrolizumab has improved relapse-free survival with greater safety. Furthermore, adjuvant-targeted therapy with dabrafenib and trametinib has improved survival outcomes in BRAFV600E and BRAFV600K-mutated melanomas. Three neoadjuvant trials have all shown high response rates, including complete responses, after short-term combination therapy with ipilimumab and nivolumab with no recurrences so far, although follow-up is still short. Despite the absence of a survival benefit with completion lymph node dissection in patients with sentinel node-positive or negative disease, the use of sentinel node staging will increase because of the introduction of effective adjuvant therapies. However, routine completion lymph node dissection for sentinel node-positive disease should be reconsidered. Accordingly, existing clinical guidelines are currently being revised. For palpable (macroscopic) nodal disease, the type and extent of surgery could be reduced if the index node can accurately predict the response and if studies show that lymph node dissection can be safely foregone in patients with a complete response. Overall, the appropriate type and extent of surgery for stage III melanoma is changing and becoming more personalised.

High response rates for T-VEC in early metastatic melanoma (stage IIIB/C-IVM1a).

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET-CT and histological biopsies for response evaluation. Median follow-up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1-2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T-VEC. Best ORR for T-VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T-VEC in early metastatic (stage IIIB/C-IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.

Validation of a Nomogram for Non-sentinel Node Positivity in Melanoma Patients, and Its Clinical Implications: A Brazilian-Dutch Study.

BACKGROUND: Non-sentinel node (NSN) positivity impacts the prognosis of melanoma patients; however, the benefits of completion lymph node dissection in patients with positive sentinel nodes (SNs) are limited. OBJECTIVE: We aimed to present a predictive nomogram for NSN positivity in melanoma patients with a positive SN biopsy. METHODS: This retrospective analysis from patients who underwent SN biopsy in a Brazilian institution from 2000 to 2015 was used for the construction and internal validation of the nomogram. This nomogram was then externally validated in a cohort of Dutch patients. RESULTS: The Brazilian cohort comprised 1213 patients, with a mean follow-up of 5.11 years. Breslow thickness (odds ratio [OR] 1.170, 95% confidence interval [CI] 1.043-1.314]; p = 0.008), number of positive SNs (OR 1.092, 95% CI 1.034-1.153; p = 0.001), and largest diameter of the metastatic deposit (OR 3.217, 95% CI 1.551-6.674; p = 0.002) were statistically significant for NSN positivity. Internal validation was performed using a bootstrapping technique. A good performance was observed (Brier score 0.097) and an excellent power of discrimination was achieved (area under the curve [AUC] 0.822). The nomogram was then applied to the Dutch cohort, and its overall performance (Brier score 0.085), calibration (Hosmer-Lemeshow goodness-of-fit test; p = 0.198), and discriminatory power (AUC 0.752, 95% CI 0.615-0.890) were all adequate. CONCLUSIONS: We presented a nomogram for assessing NSN probability that should not only be used for surgical considerations but also for risk stratification and clinical decisions. Internal validation has shown that this is an adequate model, while external validation increases the model's reliability and suggests that it can be globally incorporated.

Talimogene laherparepvec monotherapy for head and neck melanoma patients.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, intralesionally administered in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. Ten patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events (AEs), and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35-97) years with a median follow-up of 11.6months. Of these 10 patients, 5 had a complete response (CR), 3 had a partial response, 1 had stable disease and 1 showed progressive disease (PD) as their best response. Best overall response rate (ORR) was 80%. Median progression-free survival was 10.8 months (95% confidence interval, 2.2-19.4). Grade 1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 50% achieving a CR. This realworld data demonstrates promising results and suggests T-VEC can be an alternative to systemic therapy in this select, mostly elderly patient population.

Re-introduction of T-VEC Monotherapy in Recurrent Melanoma is Effective.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus type 1, which can be administered intralesionally in patients with stage IIIB/C-IVM1a (American Joint Committee of Cancer; AJCC 7th edition) unresectable melanoma. In the case of disease recurrence, T-VEC can be re-introduced for the same category of patients. Five patients with recurrent disease after a prior achieved complete response (CR) recommenced treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events and baseline characteristics. All 5 patients that were re-treated with T-VEC presented with in-transit metastases on the lower limb. Median age at baseline was 72.1 years with a median follow-up time of 30.4 months. Histologically proven CR was achieved after a median of 8 T-VEC courses on the initial exposure. Duration of response (time between first CR and recurrence) varied between 3.8 and 14.2 months. All 5 patients achieved a histologically and/or positron emission tomography/computed tomography proven CR again after re-introduction of T-VEC with a median of 5 courses. One patient (20%) developed a second recurrence and is currently still on treatment with T-VEC. No patients developed distant metastases. Grade 1 adverse events occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site pain. Response to re-introduction of T-VEC monotherapy in this select patient population is promising. This real world data on re-introduction of T-VEC monotherapy in stage IIIB/C-IVM1a melanoma suggests T-VEC could be a treatment option for chronic disease control.

A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB-IVM1a Melanoma in Four European Countries.

INTRODUCTION: Talimogene laherparepvec (T-VEC; IMLYGIC®, Amgen Inc.) is an oncolytic immunotherapy approved in Europe for the treatment of unresectable metastatic melanoma (stage IIIB-IVM1a). This study characterised real-world use of T-VEC in four European countries. METHODS: Data on demographics, treatment pattern, safety, and clinical effectiveness were examined in a retrospective chart review of patients with stage IIIB-IVM1a unresectable melanoma treated with T-VEC in surgical (the Netherlands) and medical (Austria, Germany, UK) oncology settings. RESULTS: Overall, 66 patients were included (the Netherlands: n = 31; Austria, Germany, UK: n = 35). The median age was 69 years and 59.1% were female. At the time of T-VEC initiation, 47 patients (71.2%) had stage IIIB/C disease; of these, 30 were from the Netherlands. Although 72.7% patients overall received T-VEC as first-line therapy, this was higher in the Netherlands than the other countries (93.5% vs 54.3%). Of the 47 patients who discontinued T-VEC, 26 (55.3%) had no remaining injectable lesions (potentially indicating complete response); 20/26 of these patients were from the Netherlands. One patient discontinued T-VEC due to toxicity. CONCLUSION: This study is the first comprehensive multinational evaluation of the use of T-VEC to treat unresectable stage IIIB/C-IVM1a melanoma in real-world clinical practice in Europe. The differences between European countries were apparent, with physicians in the Netherlands using T-VEC in patients with earlier advanced disease stage and in the first-line setting compared with other countries.

Complete response to talimogene laherparepvec in a primary acral lentiginous melanoma.

Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.

External validation of the American Joint Committee on Cancer 8th edition melanoma staging system: who needs adjuvant treatment?

Now effective adjuvant therapy has arrived in melanoma, accurate staging and patient selection to optimize its risk/benefit ratio is crucial. The American Joint Committee on Cancer staging system is the most widely used and validated melanoma staging system, which recently released its 8th edition. We aimed to externally validate the prognostic and discriminatory ability for survival of the 8th edition compared to the 7th edition and evaluate prognostic factors. Prospective database of stage III melanoma (2000-2016). Prognostic factors for melanoma-specific survival and distant metastasis-free survival were analyzed. Survival differentiation of the 7th and 8th edition was assessed with log-rank tests and Cox proportional hazards models. Discriminatory ability was compared using the receiver operating characteristic and Akaike's Information Criterion. Six hundred forty patients were included (median follow-up 59 months). Median melanoma-specific survival was 138 months, distant metastasis-free survival 96 months. Age, Breslow thickness, ulceration of the primary tumor and number of positive lymph nodes (N) were independent prognostic parameters for distant metastasis-free survival and melanoma-specific survival. The 8th edition performed slightly better than the 7th edition in terms of survival discrimination but showed slightly worse distant metastasis-free survival and melanoma-specific survival differentiation between stage IIIA and IIIB. Sentinel node (SN) metastasis size cutoff of 1 mm differentiated survival in both 7th and 8th edition stage IIIA, showing excellent distant metastasis-free survival and melanoma-specific survival for patients with a SN metastasis size <1 mm. The 8th edition performed at least comparably, if not better than the 7th in terms of survival discrimination. However, survival in both 7th and 8th edition stage IIIA melanoma remains heterogeneous. EORTC SN tumor burden criteria can further stratify survival and help patient selection for adjuvant therapy.

Exogenous Cushing's syndrome due to a Chinese herbalist's prescription of ointment containing dexamethasone.

Eczema in children is a chronic disabling condition. The impact of this condition on the lives of families is often underestimated by conventional physicians. As a consequence parents may investigate complementary treatment options. Close monitoring by a paediatrician is essential, considering that a variety of adverse effects can occur during the use of complementary treatment. We present a 5-year-old girl with eczema. She visited a Chinese herbalist who prescribed an ointment. The parents noticed that the eczema resolved fast, itching decreased and she was finally sleeping well. However, her behaviour changed and appetite increased. Undetectable levels of serum cortisol were found, which was indicative of exogenous Cushing's syndrome. Analysis of the ointment revealed the presence of dexamethasone. Hydrocortisone substitution and subsequently a reduction schedule were implemented, after which endogenous cortisol production recovered after 4 months. Physicians should be aware that unregistered herbal medicine can contain potent drugs such as glucocorticoids.