Faculty Bibliography

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.

OBJECTIVE:Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006. PATIENTS AND METHODS/METHODS:Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147. RESULTS:Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both. CONCLUSIONS:These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use. CLINICAL TRIAL REGISTRY/UNASSIGNED:NCT01295827, NCT01704287, NCT01866319.

Declaration de liens d'interets: W. Samlowski a recu une subvention de la part de Novartis, Regeneron, Sanofi-Genzyme, BMS, Merck, Pfizer, Novartis, est consultant pour Novartis, Regeneron, Sanofi-Genzyme, BMS, Merck, Pfizer, Novartis, N.J. Robert a un conflit d'interet avec McKesson Life Sciences, E. D. Nwokeji a un conflit d'interet avec BMS, B. Baidoo a un conflit d'interet avec BMS, B. Schenkel est actionnaire de BMS, est employe de BMS, A. Moshyk est actionnaire de BMS, est employe de BMS, S. Kotapati est employe de BMS, T. Poretta est consultant pour BMS, N. Ameur est employe de BMS, J. S. Weber est actionnaire de CytoMx, Biond et Altor, a recu une subvention de la part de Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Pfizer et EMD Serono, BMS, est consultant pour Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Pfizer and EMD Serono, BMS, Celldex, CytoMx, Incyte, Biond, Protean, CV6 et Sellas. Supplement en ligne Materiel complementaire: Le materiel complementaire accompagnant la version en ligne de cet article est disponible sur. Supplement en ligne Materiel complementaire: [Formula presented]
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Introduction: Le NIVO a demontre une amelioration de la survie sans recidive (SSR) vs l'IPI chez les patients (pts) atteints d'un melanome de stade III/IV operes dans l'etude de phase 3, CheckMate 238. Les donnees mises a jour de SSR, de survie sans metastases a distance (SSMD) et de SG a 48 mois sont presentees. Materiel et methodes: Des pts ages de >= 15 ans avec un melanome de stade IIIB/C ou IV entierement reseque ont ete stratifies selon le stade et le statut PDL-1, et randomises selon un rapport 1 : 1 pour recevoir NIVO (3 mg/kg toutes les 2 semaines [sem]; n = 453) ou IPI (10 mg/kg toutes les 3 sem pour 4 doses, puis toutes les 12 sem; n = 453) pendant une duree maximale d'1 an ou jusqu'a recidive de la maladie/toxicite inacceptable. Le critere d'evaluation principal etait la SSR. Les criteres d'evaluation secondaires comprenaient la SG et la tolerance; la SSMD pour le stade III de la maladie etait exploratoire. Resultats: A 4 ans de suivi, NIVO a continue de demontrer une SSR superieure a l'IPI (HR : 0,71; IC95 % : 0,60-0,86; p = 0,0003). La SSMD chez les pts atteints d'une maladie de stade III etait en faveur du NIVO (HR : 0,79; IC95 % : 0,63-0,99). A 48 mois, le nombre d'evenements en SG (n = 211) etait plus faible que prevu (n = 302) et les taux de SG etaient comparables : 78 % (IC95 % : 73,7-81,5) avec NIVO et 77 % (IC95 % : 72,2-80,3) avec IPI (HR : 0,87; IC95 % : 0,66-1,14; p = 0,3148). Un traitement systemique ulterieur etait recu par 150 (33 %) pts traites par NIVO et 189 (42 %) pts traites par IPI; plus de pts traites par IPI (34 % vs 23 %) ont recu une immunotherapie systemique ulterieure. Des evenements indesirables lies au traitement (EILT) d'apparition retardee (rapportes plus de 100 jours apres la derniere dose) et de tous grades confondus ont ete observes chez 18 (4 %) pts traites par NIVO et 25 (6 %) pts traites par IPI, avec un grade 3/4 dans 3 (1 %) et 7 (2 %) des cas, respectivement.
Discussion(s): Le NIVO a continue de demontrer une amelioration de la SSR et de la SSMD par rapport a l'IPI a 48 mois chez les pts avec un melanome de stade III/IV a haut risque de recidive. Les evenements de SG (n = 211) etaient inferieurs aux previsions (n = 302). Les taux de SG etaient similaires pour NIVO et IPI, bien que l'utilisation d'un traitement ulterieur par immunotherapie systemique ait ete plus elevee dans le bras IPI. Les EILT d'apparition tardive etaient conformes au profil de tolerance etabli pour NIVO et IPI, avec plus d'evenements rapportes avec IPI.
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Introduction/UNASSIGNED:Most diseases involve a complex interplay between multiple biological processes at the cellular, tissue, organ, and systemic levels. Clinical tests and biomarkers based on the measurement of a single or few analytes may not be able to capture the complexity of a patient's disease. Novel approaches for comprehensively assessing biological processes from easily obtained samples could help in the monitoring, treatment, and understanding of many conditions. Objectives/UNASSIGNED:We propose a method of creating scores associated with specific biological processes from mass spectral analysis of serum samples. Methods/UNASSIGNED:A score for a process of interest is created by: (i) identifying mass spectral features associated with the process using set enrichment analysis methods, and (ii) combining these features into a score using a principal component analysis-based approach. We investigate the creation of scores using cohorts of patients with non-small cell lung cancer, melanoma, and ovarian cancer. Since the circulating proteome is amenable to the study of immune responses, which play a critical role in cancer development and progression, we focus on functions related to the host response to disease. Results/UNASSIGNED:We demonstrate the feasibility of generating scores, their reproducibility, and their associations with clinical outcomes. Once the scores are constructed, only 3 µL of serum is required for the assessment of multiple biological functions from the circulating proteome. Conclusion/UNASSIGNED:These mass spectrometry-based scores could be useful for future multivariate biomarker or test development studies for informing treatment, disease monitoring and improving understanding of the roles of various biological functions in multiple disease settings.

BACKGROUND:Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results. METHODS:This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906. FINDINGS/RESULTS:Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported. INTERPRETATION/CONCLUSIONS:At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. FUNDING/BACKGROUND:Bristol Myers Squibb and Ono Pharmaceutical.

Background Several studies suggest the gut microbiome may be a novel, modifiable biomarker for clinical efficacy of immune checkpoint inhibitors (ICIs). Microbiome profiling of pre-treatment samples demonstrated that high alpha-diversity and enrichment of specific bacterial species are associated with improved tumor responses in melanoma, renal cell cancer (RCC), and non-small cell lung cancer (NSCLC). Despite these reports, the specific bacteria or communities helpful or harmful have been inconsistent across study populations, and further correlation with immune and mutational biomarkers are limited or lacking. We hypothesize that, by use of a larger sample size and a consistent computational approach, we would derive a clearer microbial profile that correlated with immunotherapeutic outcomes. Methods We re-analyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n=303 unique patients) of responder (R) and nonresponse (NR) using a consistent computational approaches (Resphera Insight and MetaPhlAn2). Using novel microbiota signatures, we identified Re-analysis Indices for Rand NR-associated bacteria and validated the result in three addition cohorts with available raw sequencing data in patients with melanoma, hepatocellular cancer (HCC), and NSCLC (n=105). Results Our results confirm signals reported in each study, though some bacteria reported initially were not statistically significant after correction for false discovery rate. Likely, in part, because our analysis allows for comparison of individual species across cohorts, we were able to identify new bacterial signatures, such as Oxalobacter formigenes, Roseburia hominis and Veillonella parvula, Clostridium hathewayi, enriched in R and NR respectively. When our Re-analysis Index was compared to an index assembled from the literature, we noted improvement occurred in a sensitivity and specificity analysis, especially in NR-associated signals. Moreover, we found that alpha-diversity was not consistently predictive of response or nonresponse to ICIs. Our Re-analysis Index also validated in melanoma patients and HCC but did not perform as well in the NSCLC cohort, suggesting the need for further refinement based on tumor type. Conclusions In summary, this bioinformatics platform improves on existing pipelines by standardizing critical preprocessing and downstream analysis tools, enabling comprehensive evaluations of taxonomic and functional signals across sequencing datasets. Notably, the NR-associated Re-analysis Index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (p < 0.01). Our integrated analyses suggest an approach to identify patients who would benefit from microbiome-based interventions targeted to improve response rates by using a biomarker for nonresponse

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.