Real-world relapse-free survival data on adjuvant anti-PD-1 therapy for patients with newly diagnosed and recurrent stage III melanoma.

We aimed to compare the relapse-free survival (RFS) in patients treated with adjuvant anti-programmed cell death-1 (anti-PD-1) therapy for a first diagnosis of stage III melanoma to patients treated after resection of the recurrences. Patients treated with adjuvant anti-PD-1 therapy after complete resection of stage III melanoma between September 2018 and January 2021, were included. Depending on when adjuvant anti-PD-1 treatment was initiated, patients were divided over 2 cohorts: for the first diagnosis (cohort A) or for a second or subsequent diagnosis (cohort B) of stage III melanoma. Clinical data and RFS were compared between cohorts. 66 patients were included: 37 in cohort A, 29 in cohort B. Median follow-up time from the start of adjuvant therapy was 21 months and 17 months in cohorts A and B, respectively. Significant differences in ulceration of the primary tumor ( P  = 0.032), stage according to the 7th AJCC (American Joint Committee on Cancer , P  = 0.026) and type of metastatic involvement ( P  = 0.005) were found between cohorts. In cohorts A and B, 18 (49%) and 8 (28%) patients developed a recurrence and the 1-year RFS was 51% and 72%, respectively. In cohort B, RFS remained longer in the patients of which the interval between first diagnosis of stage III melanoma and start of adjuvant therapy was >48 months compared to ≤48 months (83% vs. 65%, P  = 0.253). This study demonstrates that patients with recurrent stage III disease, not previously treated with adjuvant systemic therapy, may derive similar benefit to a first diagnosis of stage III patients if access to adjuvant therapy changes.

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.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

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 .

Outcomes with adjuvant anti-PD-1 therapy in patients with sentinel lymph node-positive melanoma without completion lymph node dissection.

Until recently, most patients with sentinel lymph node-positive (SLN+) melanoma underwent a completion lymph node dissection (CLND), as mandated in published trials of adjuvant systemic therapies. Following multicenter selective lymphadenectomy trial-II, most patients with SLN+ melanoma no longer undergo a CLND prior to adjuvant systemic therapy. A retrospective analysis of clinical outcomes in SLN+ melanoma patients treated with adjuvant systemic therapy after July 2017 was performed in 21 international cancer centers. Of 462 patients who received systemic adjuvant therapy, 326 patients received adjuvant anti-PD-1 without prior immediate (IM) CLND, while 60 underwent IM CLND. With median follow-up of 21 months, 24-month relapse-free survival (RFS) was 67% (95% CI 62% to 73%) in the 326 patients. When the patient subgroups who would have been eligible for the two adjuvant anti-PD-1 clinical trials mandating IM CLND were analyzed separately, 24-month RFS rates were 64%, very similar to the RFS rates from those studies. Of these no-CLND patients, those with SLN tumor deposit >1 mm, stage IIIC/D and ulcerated primary had worse RFS. Of the patients who relapsed on adjuvant anti-PD-1, those without IM CLND had a higher rate of relapse in the regional nodal basin than those with IM CLND (46% vs 11%). Therefore, 55% of patients who relapsed without prior CLND underwent surgery including therapeutic lymph node dissection (TLND), with 30% relapsing a second time; there was no difference in subsequent relapse between patients who received observation vs secondary adjuvant therapy. Despite the increased frequency of nodal relapses, adjuvant anti-PD-1 therapy may be as effective in SLN+ pts who forego IM CLND and salvage surgery with TLND at relapse may be a viable option for these patients.

Predictors of Sentinel Lymph Node Metastasis in Patients with Thin Melanoma: An International Multi-institutional Collaboration.

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for patients with T1b melanomas and T1a melanomas with high-risk features; however, the proportion of patients with actionable results is low. We aimed to identify factors predicting SLNB positivity in T1 melanomas by examining a multi-institutional international population. METHODS: Data were extracted on patients with T1 cutaneous melanoma who underwent SLNB between 2005 and 2018 at five tertiary centers in Europe and Canada. Univariable and multivariable logistic regression analyses were performed to identify predictors of SLNB positivity. RESULTS: Overall, 676 patients were analyzed. Most patients had one or more high-risk features: Breslow thickness 0.8-1 mm in 78.1% of patients, ulceration in 8.3%, mitotic rate > 1/mm2 in 42.5%, Clark's level ≥ 4 in 34.3%, lymphovascular invasion in 1.4%, nodular histology in 2.9%, and absence of tumor-infiltrating lymphocytes in 14.4%. Fifty-three patients (7.8%) had a positive SLNB. Breslow thickness and mitotic rate independently predicted SLNB positivity. The odds of positive SLNB increased by 50% for each 0.1 mm increase in thickness past 0.7 mm (95% confidence interval [CI] 1.05-2.13) and by 22% for each mitosis per mm2 (95% CI 1.06-1.41). Patients who had one excised node (vs. two or more) were three times less likely to have a positive SLNB (3.6% vs. 9.6%; odds ratio 2.9 [1.3-7.7]). CONCLUSIONS: Our international multi-institutional data confirm that Breslow thickness and mitotic rate independently predict SLNB positivity in patients with T1 melanoma. Even within this highly selected population, the number needed to diagnose is 13:1 (7.8%), indicating that more work is required to identify additional predictors of sentinel node positivity.

Single agent Talimogene Laherparepvec for stage IIIB-IVM1c melanoma patients: A systematic review and meta-analysis.

Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete- and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41-100% of all patients and 0-11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities.

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.