Faculty Bibliography

BACKGROUND:Nivolumab at a dose of 480 mg every 4 weeks (Q4W) is approved for the adjuvant treatment of melanoma. However, real-world data on this regimen are limited in this setting. METHODS:This retrospective observational study utilized data from the US Oncology Network iKnowMed electronic health record database and patient medical charts. Eligible patients were diagnosed with melanoma and received adjuvant nivolumab monotherapy from March to August 2018. Patients were grouped by dosing regimen: cohort 1 (C1), de novo nivolumab 480 mg Q4W; cohort 2 (C2), switched to nivolumab 480 mg Q4W after nivolumab 240 mg or 3 mg/kg every 2 weeks (Q2W); cohort 3 (C3), de novo nivolumab 3 mg/kg Q2W; or cohort 4 (C4), de novo nivolumab 240 mg Q2W. Patients were followed for up to 12 months. Duration of therapy and safety/tolerability were assessed. RESULTS:One hundred ninety-one patients were included (C1, n = 40; C2, n = 74; C3, n = 22; C4, n = 55). Duration of therapy was relatively consistent across cohorts (median, 10.3 months; range, 8.3-10.7). Likewise, proportions of patients experiencing treatment-related adverse events (TRAEs) were similar (range, 54.5%-60.1%), as were the most common events (fatigue, rash, diarrhea, hypothyroidism, nausea, and pruritus). However, proportions experiencing 'significant' TRAEs varied between cohorts. Proportions discontinuing treatment were relatively consistent across cohorts. Propensity score matching and sensitivity analyses generally supported the unadjusted findings. CONCLUSIONS:Real-world safety profiles of nivolumab 240 mg Q2W and 480 mg Q4W were similar, and both were comparable to the well-documented safety of weight-based dosing (3 mg/kg Q2W), further supporting their approval and use in the adjuvant setting for melanoma.

Background: There is an unmet medical need for patients (pts) with advanced melanoma who progress on immunotherapy/targeted therapy. Spartalizumab is an anti-PD-1 humanised monoclonal antibody (mAb) that may combine effectively with novel compounds to restore antitumour responses in PD-1 refractory disease. This is an analysis of a Phase 2, randomised, two-part, multicentre, open-PLATforM (NCT03484923) study in pts with unresectable/metastatic melanoma progressing after prior anti-PD-1/L1 therapy.
Method(s): The primary endpoint was overall response rate (ORR) per RECIST v1.1; secondary endpoints included duration of response and biomarker assessments. The selection phase comprised four arms combining spartalizumab with ieramilimab (anti-LAG3 mAb; Arm 1), capmatinib (2), canakinumab (3) or ribociclib (4). An adaptive design during the selection phase allowed dropping arms for futility, adding new arms and selecting arm(s) for expansion. Bayesian methodology was used for futility and efficacy assessments at each interim analysis (IA).
Result(s): As of February 1, 2021, 175 pts were randomized; 45, 43, 43 and 44 pts in each arm, respectively. Median age was 59 yrs, 57 percent received >2 prior therapies. Overall, 166/175 pts discontinued treatment, primarily due to progressive disease (65%). ORRs in Arms 1-4 were n = 3/45 (7%), 2/43 (5%), 2/43 (5%) and 3/44 (7%), respectively. All arms crossed the specific futility probability threshold and were declared futile at previous IAs. In Arm 1, 6 pts had LAG-3+ melanoma at baseline (>5% + tumour cells by IHC), of which two pts had a partial response, both ongoing for 23 months. Overall, grade >3 adverse events occurred in 59 percent of pts (53%, 5 1 % , 36%, 93% in Arms 1-4, respectively). There were 14 on-treatment deaths; 5/45 in Arm 1, primarily due to melanoma progression (4/45).
Conclusion(s): Although all tested combinations have been declared futile, pts with LAG-3+ melanoma may be more likely to respond to spartalizumab + ieramilimab treatment. Consequently, Arm 1A (spartalizumab +ieramilimab) was opened to recruit pts with previously treated unresectable/metastatic LAG- 3+melanoma. Arm 1A has fully recruited 21 pts. The data cut-off (DCO) for the interim analysis for Arm1A was 28-Oct-2021 based on the 21 pts and the analysis is currently ongoing

OBJECTIVES/OBJECTIVE:To evaluate the safety of immune checkpoint inhibitor use in patients with pre-existing neurological autoimmune diseases. METHODS:In this retrospective case-series, we examined exacerbations of underlying disease and the occurrence of immune-related adverse events in 5 patients who had been diagnosed with a neurological autoimmune disease prior to receiving immune checkpoint inhibitor therapy for advanced malignancy. RESULTS:Two patients had a prior diagnosis of myasthenia gravis, two had Guillain-Barré syndrome, and one had chronic idiopathic demyelinating polyneuropathy. Only one patient experienced a flare of neurological autoimmune disease. Four of the five patients experienced immune-related adverse events unrelated to their neurological disease. CONCLUSIONS:In this case-series, exacerbations of neurological autoimmune disease were less common and less severe than expected. Further research is needed to determine which individuals are at greatest risk of neurological autoimmune disease complication while receiving immune checkpoint inhibitor therapy.

PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.

PURPOSE/OBJECTIVE:Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics. METHODS:A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions. RESULTS:A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively. CONCLUSION/CONCLUSIONS:Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

OBJECTIVE:The aim of this case-based clinical review is to provide a practical approach for clinicians regarding the management of patients with immune checkpoint inhibitor (ICI)-mediated endocrinopathies. METHODS:A literature search was conducted using PubMed, Embase and Scopus, and appropriate keywords. The discussions and strategies for diagnosis and management of ICI-mediated endocrinopathies are based on evidence available from prospective randomized clinical studies, cohort studies, cross-sectional studies, case-based studies, and expert consensus. RESULTS:Immunotherapy with ICIs has transformed the treatment landscape of diverse cancer types, but frequently results in immune-mediated endocrinopathies that can cause acute and persistent morbidity, and rarely, death. The patterns of endocrinopathies differ between inhibitors of the CTLA-4 and PD-1/PD-L1 pathways, but most often involve the thyroid and pituitary glands. Less common but important presentations include insulin-deficient diabetes mellitus, primary adrenal insufficiency, primary hypoparathyroidism, central diabetes insipidus, primary hypogonadism, and pancreatitis with or without subsequent progression to diabetes or exocrine insufficiency. CONCLUSION/CONCLUSIONS:In recent years, with increasing numbers of cancer patients being treated with ICIs, more clinicians in a variety of specialties are called upon to diagnose and treat ICI-mediated endocrinopathies. Herein, we review case scenarios of various clinical manifestations, and emphasize the need for a high index of clinical suspicion by all clinicians caring for these patients including endocrinologists, oncologists, primary care providers, and emergency department physicians. We also provide diagnostic and therapeutic approaches for ICI-induced endocrinopathies, and we propose that patients on ICI-therapy be evaluated and treated in a multidisciplinary team in collaboration with endocrinologists.

Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.

Image-based analysis as a method for mutation detection can be advantageous in settings when tumor tissue is limited or unavailable for direct testing. Here, we utilize two distinct and complementary machine learning methods of analyzing whole slide images (WSI) for predicting mutated BRAF. In the first method, WSI of melanomas from 256 patients were used to train a deep convolutional neural network (CNN) in order to develop a fully automated model that first selects for tumor-rich areas (Area Under the Curve AUC=0.96) then predicts for mutated BRAF (AUC=0.71). Saliency mapping was performed and revealed that pixels corresponding to nuclei were the most relevant to network learning. In the second method, WSI were analyzed using a pathomics pipeline that first annotates nuclei and then quantifies nuclear features, demonstrating that mutated BRAF nuclei were significantly larger and rounder nuclei compared to BRAF WT nuclei. Lastly, we developed a model that combines clinical information, deep learning, and pathomics that improves the predictive performance for mutated BRAF to AUC=0.89. Not only does this provide additional insights on how BRAF mutations affect tumor structural characteristics, machine learning-based analysis of WSI has the potential to be integrated into higher order models for understanding tumor biology.