Faculty Bibliography

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Merkel cell carcinoma (MCC) is an aggressive and rare cutaneous cancer of the mechanoreceptor unit of the skin with a neuroendocrine origin. MCC incidence has been on the rise over the past two decades. Risk factors include old age, chronic UV exposure, and immunosuppression. Although MCC is a cutaneous malignancy that is often misdiagnosed as a benign nodule at the time of diagnosis, it has an aggressive disease course due to its high recurrence and metastatic potential. The PD-1/PD-L1 checkpoint blockade has recently shown promising results in the management of advanced MCC. Avelumab and pembrolizumab are considered the new standard of care for metastatic MCC. Despite advances in the field, studies are needed to elucidate the role of immunotherapy for patients who are resistant to treatment. Most ongoing clinical trials aim to assess the efficacy of checkpoint inhibitor combination therapies. This article reviews the most current literature on the surgical and medical management of MCC.

INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients. METHODS:We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported. RESULTS:Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response. CONCLUSIONS:Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

Background: Cemiplimab, a PD-1 inhibitor, is indicated for treatment of cutaneous squamous cell carcinoma (CSCC) in patients (pts) with metastatic (mCSCC) or locally advanced (laCSCC) disease not eligible for curative surgery/radiation. Cemiplimab resulted in RECIST objective response rate (tumour response; complete+partial) of 44.0%, with median times to tumour response of 2.0 months and progression-free survival (PFS) of 18.4 months; the safety profile was consistent with other anti-PD-1 inhibitors. Cemiplimab-treated pts achieved clinically meaningful (CM) reductions in pain measured using the patient-reported EORTC QLQ-C30 pain domain. Interpretation of change in pain was further characterised by the relationship between time to a CM change in pain and tumour response.
Method(s): Adults (N=193) with confirmed diagnosis of invasive CSCC received IV cemiplimab 3 mg/kg Q2W (mCSCC n=59; laCSCC n=78) or 350 mg Q3W (mCSCC n=56). The QLQ-C30 was administered at baseline (BL) and day 1 of each treatment cycle. Kaplan-Meier (KM) survival analysis (with censoring at drop-out) was used to estimate time to 1^st CM (>=10-point) reduction (improvement) or increase (worsening) in QLQ-C30 pain scores. Pain medication use was captured over the treatment period.
Result(s): Compared to non-responders, pts with tumour response reported a CM reduction in pain from BL at 1^st tumour response (cycle 2) (P<0.0001) (Table); pain reduction was maintained at least through cycle 5 and was independent of opioid pain medication use. KM analysis showed median time to 1^st CM pain improvement and 1^st CM pain worsening (Table) approximated median times to tumour response and PFS, respectively.
Conclusion(s): In cemiplimab-treated CSCC pts, early pain reduction tracked with 1^st tumour response, and pain worsening with PFS. These results suggest that changes in pain may correlate with tumour response. [Formula presented] Clinical trial identification: NCT02760498. Editorial acknowledgement: Editorial writing support was provided by Jay Bienen, PhD, funded by Regeneron Pharmaceuticals, Inc., and Sanofi. Legal entity responsible for the study: Regeneron Pharmaceuticals, Inc. and Sanofi.
Funding(s): Regeneron Pharmaceuticals, Inc. and Sanofi. Disclosure: M.R. Migden: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Regeneron Pharmaceuticals, Inc.; Honoraria (self), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: Sunpharma. D. Rischin: Research grant/Funding (institution), Non-remunerated activity/ies: Regeneron Pharmaceuticals, Inc.; Research grant/Funding (institution): Roche; Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme; Research grant/Funding (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies: GlaxoSmithKline; Non-remunerated activity/ies: Sanofi. S. Hudgens: Advisory/Consultancy: Regeneron Pharmaceuticals, Inc. C-I. Chen, Z. Chen, V. Mastey, M.G. Fury, S. Li: Shareholder/Stockholder/Stock options, Full/Part-time employment: Regeneron Pharmaceuticals, Inc. C.D. Schmults: Advisory/Consultancy, Research grant/Funding (self): Castle Biosciences; Advisory/Consultancy, Research grant/Funding (self): Regeneron Pharmaceuticals, Inc.; Advisory/Consultancy: Sanofi; Research grant/Funding (self): Novartis; Research grant/Funding (self): Genentech; Research grant/Funding (self): Merck; Leadership role, Chair for NCCN: National Comprehensive Cancer Network. A.C. Pavlick: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Regeneron Pharmaceuticals, Inc.; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Array; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Amgen; Research grant/Funding (self): Celldex; Research grant/Funding (self): Forance. A. Guminski: Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses, Non-remunerated activity/ies: Sun Pharma; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: Eisai; Advisory/Consultancy: Pfizer; Non-remunerated activity/ies: Astellas; Research grant/Funding (institution), Clinical trial unit support: PPD Australia. A. Hauschild: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck Sharp & Dohme /Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Provectus; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/Funding (institution): Philogen; Advisory/Consultancy, Research grant/Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory/Consultancy: OncoSec. D. Bury, M. Sasane: Shareholder/Stockholder/Stock options, Full/Part-time employment: Sanofi. A.L.S. Chang: Advisory/Consultancy, Research grant/Funding (self): Regeneron Pharmaceuticals, Inc.; Advisory/Consultancy, Research grant/Funding (self): Merck; Research grant/Funding (self): Novartis; Research grant/Funding (self): Galderma. G. Rabinowits: Advisory/Consultancy: EMD Serono Pfizer; Advisory/Consultancy: Sanofi; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Regeneron Pharmaceuticals Inc.; Advisory/Consultancy: Merck; Advisory/Consultancy: Castle; Shareholder/Stockholder/Stock options: Syros Pharmaceuticals. S.F. Ibrahim: Research grant/Funding (self), Travel/Accommodation/Expenses: Regeneron Pharmaceuticals, Inc.; Research grant/Funding (self): Castle; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Genentech.
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OBJECTIVES/OBJECTIVE:Melanoma is one of the most common malignancies diagnosed during pregnancy. This study examined the impact of pregnancy on management decisions of melanoma patients treated at NYU Langone Health (NYULH). METHODS:We analyzed data for patients who were pregnant at initial or recurrent melanoma diagnosis at NYULH from 2012 to 2019 with prospective protocol-driven follow-up. RESULTS:Of the 900 female patients accrued during this period, 11 women in the childbearing range were pregnant at melanoma diagnosis. Six patients presented with early (stage 0 or I) disease and five with advanced (stage III or IV) melanoma. Women with early stage disease had normal deliveries and minimal changes to their treatment timeline and regimen. However, patients with more advanced stage disease opted for either termination of the pregnancy or early delivery and altered treatment timelines because of pregnancy. CONCLUSION/CONCLUSIONS:Both melanoma stage and gestational age at diagnosis contribute to the differences in the therapeutic management of melanoma in pregnant women. Given the complexity and variety of each case of melanoma during pregnancy, informed discussion between patients and physicians allows for individualized treatment plans that address each patient's unique situation.

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

Background Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. Methods C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/ fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. Results 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1 Conclusions Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2