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.

PURPOSE/OBJECTIVE:Several biomarkers of response to immune checkpoint inhibitors (ICI) show potential but are not yet scalable to the clinic. We developed a pipeline that integrates deep learning on histology specimens with clinical data to predict ICI response in advanced melanoma. EXPERIMENTAL DESIGN/METHODS:We used a training cohort from New York University (New York, NY) and a validation cohort from Vanderbilt University (Nashville, TN). We built a multivariable classifier that integrates neural network predictions with clinical data. A ROC curve was generated and the optimal threshold was used to stratify patients as high versus low risk for progression. Kaplan-Meier curves compared progression-free survival (PFS) between the groups. The classifier was validated on two slide scanners (Aperio AT2 and Leica SCN400). RESULTS:= 0.03 for the Leica SCN400). CONCLUSIONS:Histology slides and patients' clinicodemographic characteristics are readily available through standard of care and have the potential to predict ICI treatment outcomes. With prospective validation, we believe our approach has potential for integration into clinical practice.

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.

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.

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.

BACKGROUND:The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared to the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared to AJCC7. METHODS:We analyzed a cohort of 1,315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve (AUC) of 5-year survival to predict RFS/OS. All statistical tests were two-sided. RESULTS:Stage IIC continued to have worse outcomes than those for stage IIIA patients, with 5-year RFS of 26.5% (95%CI=12.8-55.1%) vs. 56.0% (95%CI=37.0-84.7%) by AJCC8 (P = 0.002). For stage I, removing mitotic index as T classification factor decreased its prognostic value, although not statistically significantly (RFS C-index=0.63 [95%CI=0.56-0.69] to 0.56 [95%CI=0.49-0.63], P = 0.07; OS C-index=0.48 [95%CI=0.38-0.58] to 0.48 [95%CI=0.41-0.56], P = 0.90). For stage II, prognostication remained constant (RFS C-index=0.65 [95%CI=0.57-0.72]; OS C-index=0.61 [95%CI=0.50-0.72]), and. For stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index=0.65 [95%CI=0.60-0.70] to 0.70 [95%CI=0.66-0.75], P = 0.01). CONCLUSIONS:Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS:Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS:Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS:Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.

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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Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAF^V600, NRAS^Q61, and TERT^-124C>T and TERT^-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%) and/or TERT (78%). Thirteen patients had TERT^mutant discordant tumors; seven of these had a single tumor with both TERT^-124C>T and TERT^-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one in different tumors and the other had a single tumor with both mutations. One patient with a BRAF^mutant primary lacked mutant BRAF in least one of their metastases. Overall, we identified mutational heterogeneity in 18/99 (18%) patients. These results suggest that some primary melanomas may be comprised of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

BACKGROUND:Cemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498). METHODS:The primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability. RESULTS:For Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan-Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%). CONCLUSION/CONCLUSIONS:In patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses. TRIAL REGISTRATION NUMBER/BACKGROUND:Clinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498.