bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of teclistamab, a humanized B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in relapsed/refractory multiple myeloma (R/R MM).
Authors: Usmani Saad Zafar , Mateos Maria-Victoria , Nahi Hareth , Krishnan Amrita Y. , van de Donk Niels W.C.J. , San Miguel Jesus , Oriol Albert , Rosiñol Laura , Chari Ajai , Adams Homer , Girgis Suzette , Wang Lin Shun Xin , Stephenson Tara , Kemmerer Kristy , Smit Jennifer , Elsayed Yusri A. , Infante Jeffrey R. , Goldberg Jenna D. , Banerjee Arnob , Garfall Alfred L.
Published: May 2020

100

Background: Teclistamab (JNJ-64007957) is a bispecific BCMA x CD3 antibody that induces T cell-mediated cytotoxicity against BCMA-expressing myeloma cells. Initial results from an ongoing study of teclistamab in RRMM (NCT03145181) are presented. Methods: Pts have MM and are RR to standard therapies. Primary objective for part 1 is to identify a recommended phase 2 dose(s). Multiple intravenous (iv) doses ± priming doses were explored. Adverse events (AEs) were graded per CTCAE v4.03 and cytokine release syndrome (CRS) per Lee et al 2014. Response was investigator-assessed using IMWG criteria; minimal residual disease (MRD) in bone marrow was assessed by next generation sequencing. Results: As of 31 Jan 2020, 66 pts had received iv teclistamab (0.3–270 µg/kg). Median age was 64 y (24–82), median prior therapies was 6 (2–14), 97% triple-class exposed, 83% triple-class refractory, and 38% penta-drug refractory. Most common treatment-related AEs (all grade) were CRS (56%), neutropenia (26%), and anemia (23%). CRS events were all grade 1–2 and generally confined to initial doses. 8% of pts had treatment-related neurotoxicity (3% grade ≥3), and 9% had infusion related reaction. Infection-related AEs were reported in 61% of pts (21% grade ≥3). 2 dose-limiting toxicities were reported: grade 4 delirium (resolved after 16 days) and grade 4 thrombocytopenia (resolved after 1 day). 36% of pts had treatment-related grade ≥3 AEs; neutropenia (20%) and anemia (14%) were most frequent. Only 1 grade 5 AE was reported (respiratory failure in the setting of pneumonia deemed unrelated by the investigator). PK results indicate that the half-life of teclistamab supports weekly dosing. On-target pharmacodynamic activity (T cell redistribution and activation along with transient release of cytokines) was observed at doses ≥9.6 µg/kg. Cytokine production was modulated with step-up dosing while T cell activation was maintained. 65 pts were evaluable for response. Activity was observed starting at treatment doses ≥38.4 µg/kg, with 20/52 (38%) pts achieving a response. At the highest dose, 7/9 (78%) pts responded (1 response pending confirmation). Of MRD-evaluable pts who had complete response, 2/2 were MRD negative at 10−6 with treatment ongoing > 12 mo. Conclusions: Teclistamab has manageable safety across all doses explored. A 78% overall response rate was observed at the highest weekly treatment dose in pts with advanced RRMM, supporting further evaluation of teclistamab in expansion cohorts. Clinical trial information: NCT03145181.
Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma: Five-year analysis of COMBI-AD.
Authors: Hauschild Axel , Dummer Reinhard , Santinami Mario , Atkinson Victoria , Mandalà Mario , Kirkwood John M. , Chiarion Sileni Vanna , Larkin James M. G. , Nyakas Marta , Dutriaux Caroline , Haydon Andrew Mark , Robert Caroline , Mortier Laurent , Schachter Jacob , Dasgupta Kohinoor , Gasal Eduard , Tan Monique , Long Georgina V. , Schadendorf Dirk
Published: May 2020

10001

Background: Previous results of the COMBI-AD trial (NCT01682083) showed a significant relapse-free survival (RFS) benefit with 12 mo of adjuvant D+T vs placebo (PBO) in pts with high-risk resected stage III BRAF V600E/K–mutant melanoma. In the primary analysis, 3-year RFS rates with D+T vs PBO were 58% vs 39% (hazard ratio [HR], 0.47 [95% CI, 0.39-0.58]; P < .001). An interim analysis of overall survival (OS) yielded 3-year OS rates of 86% with D+T vs 77% with PBO (HR, 0.57 [95% CI, 0.42-0.79]). Here we report data from 5-year analyses including long-term RFS and an updated cure rate model. Methods: COMBI-AD is a randomized, Phase III trial evaluating 12 mo of adjuvant D 150 mg twice daily + T 2 mg once daily vs 2 matched PBOs in pts with resected stage III BRAF V600E/K–mutant melanoma. Pts were stratified by BRAF status and disease stage (per AJCC 7 criteria). The primary endpoint is RFS; secondary endpoints include OS and distant metastasis–free survival (DMFS). A Weibull mixture cure rate model was applied to estimate the fraction of pts who will remain relapse free in the long term. As all patients had completed treatment by the time of the primary analysis, updated safety analyses were not performed. Results: This analysis represents a median follow-up of 60 mo for the D+T arm and 59 mo for the PBO arm. As of the data cutoff (Nov 8, 2019), 190 of 438 pts in the D+T arm and 262 of 432 pts in the PBO arm had an RFS event. Median RFS was not reached (NR; 95% CI, 47.9 mo-NR) with D+T vs 16.6 mo (95% CI, 12.7-22.1 mo) with PBO (HR, 0.51 [95% CI, 0.42-0.61]). The 4- and 5-year RFS rates were 55% (95% CI, 50%-60%) and 52% (95% CI, 48%-58%) with D+T vs 38% (95% CI, 34%-43%) and 36% (95% CI, 32%-41%) with PBO. These findings match those estimated by the cure rate model. The RFS benefit with D+T was evident across all AJCC 7 substages (HR [95% CI]: IIIA, 0.61 [0.35-1.07]; IIIB, 0.50 [0.37-0.67]; IIIC, 0.48 [0.36-0.64]). Median DMFS was NR in either arm but favored D+T (HR, 0.55 [95% CI, 0.44-0.70]). OS was not updated at this data cutoff as the prespecified number of events for the final OS analysis had not yet occurred. Conclusions: This 5-year analysis confirms the long-term benefit of adjuvant D+T in pts with resected stage III BRAF V600E/K–mutant melanoma. Clinical trial information: NCT01682083.
CheckMate 067: Long-term outcomes in patients with mucosal melanoma.
Authors: Shoushtari Alexander Noor , Wagstaff John , Ascierto Paolo Antonio , Butler Marcus O. , Lao Christopher D. , Marquez-Rodas Ivan , Chiarion-Sileni Vanna , Dummer Reinhard , Ferrucci Pier F. , Lorigan Paul , Smylie Michael , van Dijck Wim , Rizzo Jasmine I. , Hodi F. Stephen , Larkin James M. G.
Published: May 2020

10019

Background: Mucosal melanoma is a rare but aggressive malignancy with a poor prognosis. Here we report 5-y outcomes in a subgroup of patients with mucosal melanoma treated in CheckMate 067 with nivolumab plus ipilimumab (NIVO+IPI), NIVO alone, or IPI alone. Methods: Patients with previously untreated stage III or IV melanoma were randomized 1:1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo until progression or unacceptable toxicity. Mucosal histology was not a stratification factor, and patients with mucosal melanoma were identified by local investigators in the study. Descriptive subgroup analyses were performed to evaluate efficacy (objective response rate [ORR], progression-free survival [PFS], overall survival [OS]), and safety. Results: A total of 79 patients with mucosal melanoma were treated. With a minimum follow-up of 60 mo, NIVO+IPI treatment was associated with the highest 5-y ORR (43% [vs 30% with NIVO and 7% with IPI]), PFS (29% [vs 14% and 0%, respectively]), and OS (36% [vs 17% and 7%, respectively]; Table), consistent with trends in the intent-to-treat (ITT) population; however, efficacy outcomes were generally less favorable overall relative to the ITT population. Complete response rates were higher with NIVO+IPI (14%) relative to monotherapy (NIVO, 4%; IPI, 0%) in patients with mucosal melanoma. Safety outcomes, including the grade 3/4 treatment-related adverse event rates of 54%, 26%, and 25%, respectively, were similar to the ITT population. Conclusions: This 5-y analysis showed that patients with mucosal melanoma in CheckMate 067 had similar safety outcomes but poorer long-term efficacy vs the ITT population. Patients with mucosal melanoma treated with NIVO+IPI appeared to have more favorable survival outcomes than those treated with NIVO or IPI alone. Novel therapies are needed to further improve long-term benefit in patients with mucosal melanoma. Clinical trial information: NCT01844505. [Table: see text]
Heterogeneous response and irAE patterns in advanced melanoma patients treated with anti-PD-1 monotherapy from different ethnic groups: Subtype distribution discrepancy and beyond.
Authors: Bai Xue , Quach Henry , Cann Christopher G , Zhang Michael , Kim Michelle S. , Kasumova Gyulnara G. , Si Lu , Tang Bixia , Cui Chuanliang , Yang Xiaoling , Wei Xiaoting , Cohen Justine Vanessa , Lawrence Donald P. , Sharova Tatyana , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Boland Genevieve Marie , Johnson Douglas Buckner , Guo Jun ,   MGH Nurse Practitioner Group
Published: May 2020

10020

Background: Programmed cell death receptor-1 (PD-1) monotherapy is the standard first line therapy for advanced cutaneous melanoma, with efficacy, toxicity, and their correlations well established. Yet these remain poorly characterized for non-Caucasians and for certain rarer melanoma subtypes. Methods: Clinical data from melanoma patients treated with anti-PD-1 monotherapy between 2009 and 2018 was collected retrospectively from three independent institutions from the US and China. Tumor response, survival outcome, and organ/system-specific immune-related adverse effects (irAEs) were directly compared between different subgroups. Results: Among 626 patients, 411 were Caucasian, 214 non-Caucasian; 369 had cutaneous melanoma, and 257 other subtypes. Both ethnicity and melanoma subtype were independently associated with benefit and irAEs. In multivariate analyses, Caucasians had significantly higher objective response rate (ORR) (OR 2.0, 95% CI 1.1-3.5), but this did not translate into a survival advantage (PFS, HR 0.8, 95% CI 0.6-1.1; OS, HR 1.0, 95% CI 0.7-1.4); melanoma of unknown primary shared similar response and survival profile with cutaneous, while acral (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.6, 95% CI 1.1-2.2; OS, HR 1.3, 95% CI 0.8-1.9), mucosal (ORR, OR 0.4, 95% CI 0.2-0.9; PFS, HR 1.4, 95% CI 1.0-2.0; OS, HR 1.7, 95% CI 1.1-2.6) and ocular (ORR, OR 0.1, 95% CI 0-0.6; PFS, HR 2.3, 95% CI 1.4-3.6; OS, HR 2.2, 95% CI 1.3-3.6) melanomas had inferior outcomes. Non-Caucasian cutaneous patients had a significantly worse ORR than Caucasians with cutaneous melanoma (P < .01). Distinct irAE patterns were observed, exemplified by lower incidence of most irAEs (although more frequent pneumonitis) in Caucasians, and higher and lower liver irAE incidence in ocular and mucosal melanomas, respectively. Endocrine, musculoskeletal and skin irAEs were associated with improved PFS and OS across ethnicities and nearly all melanoma subtypes, whereas heterogeneity existed for other irAE types. Conclusions: Ethnicity and melanoma subtype are associated with distinct response patterns, survival outcomes, and irAE profiles in the setting of anti-PD-1 monotherapy. More research is needed to elucidate the molecular and immunologic determinants of these variable outcomes.
Phase I trial of autologous cMET-directed CAR-t cells administered intravenously in patients with melanoma & breast carcinoma.
Authors: Shah Payal D , Huang Alexander Chan Chi , Xu Xiaowei , Zhang Paul J. , Orlowski Robert , Matlawski Tina , Shea Joanne , Cervini Amanda , Amaravadi Ravi K. , Tchou Julia C. , Schuchter Lynn Mara , Wherry E. John , Linette Gerald P. , Mick Rosemarie , Kulikovskaya Irina , Lacey Simon F. , Plesa Gabriela , June Carl H. , Vonderheide Robert H. , Mitchell Tara C.
Published: May 2020

10035

Background: Advanced relapsed/refractory melanoma and metastatic triple-negative breast cancer are lethal diseases for which effective therapies are limited. We conducted a pilot phase I clinical trial (NCT03060356) to establish the safety and feasibility of intravenous autologous chimeric antigen receptor (CAR) T cell immunotherapy targeting cMET, a cell-surface antigen that is highly expressed in these cancers. Methods: Subjects had metastatic or unresectable melanoma (Mel) or triple-negative breast cancer (BC) with ≥30% expression of cMET on archival tissue or screening biopsy. Eligible subjects had measurable disease and progression on at least 1 prior therapy. Patients (pts) received up to 6 doses (1x108 total T-cells per dose) of RNA electroporated anti-cMET CAR T cells over a 2-week period without antecedent lymphodepleting chemotherapy. Subjects underwent pre- and post-infusion biopsies. The primary objective was to determine feasibility and safety of treatment. Results: 77 subjects (39 mel, 38 BC) were prescreened for tumor cMET expression and 37 (17 mel, 20 BC) met the eligibility threshold. Seven pts (4 BC, 3 Mel) received cMET-directed CAR T infusions on study. Mean age was 50 years (35-64); median (M) ECOG 0 (0-1); M prior lines of chemotherapy/immunotherapy were 4/0 for BC pts and 1/3 for Mel pts. 6 of 7 pts received all planned CAR T cell infusions, and 1 received 5 infusions. 5 pts experienced grade (G) 1 or G 2 toxicity that was possibly or definitely related to study. Toxicities occurring in ≥1 pt included: anemia (n = 3), fatigue (n = 2), and malaise (n = 2). No G ≥3 toxicities or cytokine release syndrome were observed. No pts discontinued therapy due to toxicity. Best response was stable disease in 4 pts (2 BC, 2 Mel) and PD in 3 pts (2 BC, 1 Mel). Messenger RNA signals corresponding to CAR T cells were detected by RT-PCR in the peripheral blood of all pts during the infusion period and in 2 pts after the infusion period. 6 pts underwent baseline biopsy and 4 pts underwent post-infusion biopsy. Immunohistochemical stains of CD3, CD4, CD8, CD163, L26, PD1, PDL1, Foxp3, Ki67, Granzyme B and Phospho-S6 were performed on pre- and post-treatment tissue biopsies and are being evaluated. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells was safe and feasible. Future directions include examination of this target using a lentiviral construct in combination with lymphodepleting chemotherapy. Clinical trial information: NCT03060356.
Spatial proximity of CD8 T cells to tumor cells as an independent biomarker for response to anti-PD-1 therapy.
Authors: Slagter Maarten , Rozeman Elisa A. , Ding Huiwen , Versluis Judith M. , Valenti Mesele , Peters Dennis , Broeks Annegien , Rooijen Charlotte van , Horlings Hugo , Haanen John B. A. G. , Hooijberg Erik , Wessels Lodewyk F. A. , Blank Christian U. , Schumacher Ton N.
Published: May 2020

10038

Background: Only a subset of advanced melanoma patients respond to anti-PD-1 (aPD1) monotherapy. Upfront identification of (non-)responsiveness would help guide first-line treatment decisions, prevent overtreatment and unnecessary risk for toxicities. T cell density and expression of T cell related genes have been associated with response to aPD1, but are imperfect predictors. We investigated whether spatial proximity of CD8 T cells to tumor cells improves upon the predictive value of T cell density alone. Methods: Pretreatment tumor specimens from melanoma patients treated with aPD1 in the Netherlands Cancer Institute were stained for DAPI, SOX10/Melan-A, CD4, CD8, FOXP3 and PD-1 by multiplex immunofluorescence. Sections were imaged on Vectra and analyzed using HALO to optimize marker thresholds and demarcate tumor and stroma. T cell proximity to tumor cells was evaluated as difference in area under the curve between i) a spatial G-function quantifying T cell density around tumor cells in tumor areas and ii) analogous null distributions obtained by random permutation of cell labels. This assessment of co-clustering is independent of cell density and heterogeneity therein and does not reflect repulsion of T cells to stromal/marginal areas. Clinical characteristics, RECIST response and survival were collected from patient records. Associations between T cell density, T cell proximity to Sox10/Melan-A+ tumor cells, other clinical biomarkers (LDH, M stage and WHO performance status) and response were examined in a Bayesian hierarchical logistic regression. Results: Tumor specimens of 98 patients were included, of whom 45 were treated with aPD1 as first-line therapy and 33 had an objective response. CD8 T cell proximity to tumor cells was associated with response in an independent, comparatively strong, and tissue dependent manner (cutaneous tissue: 2.78 [2.45, 3.17], visceral: 2.30 [1.95, 2.72], lymphoid: 2.12 [1.88, 2.40], format: maximal posteriori odds ratio [89% equal-tailed credibility interval]), in a multivariate model correcting for CD8 T cell density (1.74 [1.62, 1.88]), LDH (1.93 [1.72, 2.16]), M stage (0.92 [0.87, 0.98]) and WHO performance status (0.79 [0.72, 0.88]). Our model achieved an area under the ROC curve of 77.7%, whereas an analogous model omitting the proximity variable achieved 73.1%. Conclusions: Our analyses show that spatial proximity of CD8 T cells to tumor cells functions as an independent biomarker for response to aPD1 and suggests that preexisting CD8 T cell tumor reactivity is reflected by this spatial proximity.
Circulating tumor DNA (ctDNA) using Guardant360 to predict response in BRAF V600 WT metastatic melanoma (MM) patients (pts) receiving immune checkpoint inhibitors (ICI).
Authors: Lee Jenny HJ , Carlino Matteo S. , Menzies Alexander M. , Odegaard Justin Iver , Lefterova Martina , Scolyer Richard A. , Long Georgina V. , Rizos Helen
Published: May 2020

10050

Background: ctDNA detected by ddPCR predicts ICI response in MM, although its utility is limited to pts with known recurring mutations eg. BRAF, NRAS, KIT. We sought to overcome this limitation by using a next generation sequencing approach in BRAF V600 wild type (WT) MM pts. Methods: Plasma was collected at baseline and Week (wk) 6 in 35 BRAF V600 WT MM pts treated with ICI. Cell free (cf)DNA was analyzed using Guardant360 and only somatic non-synonymous and promoter variants were considered. Pts who failed cfDNA extraction at baseline were excluded (n = 3). Favorable ctDNA was defined as undetectable ctDNA at wk 6 and unfavorable ctDNA defined as detectable ctDNA at wk6. Response was according to RECIST at first restaging. Results: Of the evaluable 32 pts (64 plasma samples), median baseline cfDNA quantity was 33ng (range 4-657ng) and ctDNA was detected in 29/32 pts (91%). All 3 pts with undetectable baseline ctDNA had less than 10ng cfDNA compared to only 1/29 pts with detectable baseline ctDNA. Number of mutations identified in the 29 ctDNA-positive pts was 4 per pt (range 1-22). Response assessment was performed on 30 evaluable pts. Candidate driver mutation(s) in BRAF, NF1, or N/K/HRAS were identified in 26/30 pts. These mutations were often detected with other established mutations involved in tumorigenesis (eg. TERT promoter), or passenger mutations (eg. clonal hematopoiesis). Analysis of driver mutations revealed a sensitivity and specificity in predicting treatment failure of 92% and 93%, respectively (table). When all mutations identified were evaluated for treatment response, 9/18 responding pts retained some ctDNA at wk 6, although this never included TERT variants. The resulting sensitivity and specificity in predicting treatment failure changed to 100% and 50%, respectively, when all cfDNA variants were included. Conclusions: The extensive coverage of Guardant360 improves ctDNA detection in BRAF V600 WT MM pts, allowing non-invasive, rapid, and longitudinal assessment of response in a broader population. The expanded coverage also identifies passenger variants of potential non-MM origin, eg. clonal hematopoiesis, and with significant overlap with ctDNA, it is not possible to distinguish between the two in the circulation. We therefore recommend identification and monitoring of known cancer driver mutations only. [Table: see text]
The use of plasma proteomic markers to understand the biology of immunotherapy response.
Authors: Mehta Arnav , Rucevic Marijana , Sprecher Emmett , Hultin Rosenberg Lina , Lieb David , Kasumova Gyulnara G. , Kim Michelle S. , Bai Xue , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Hacohen Nir , Boland Genevieve Marie
Published: May 2020

10062

Background: Despite recent successes with immune checkpoint blockade (ICB) in melanoma, the prognosis for most patients remains dire. Whereas small fraction of patients are able to achieve disease control, most do not respond or are limited by immune-related toxicities. Robust non-invasive predictors of ICB response have the potential to guide clinical decision and alter management of patients, however, no such predictors currently exist. Methods: We applied a highly-multiplex Proximity Extension Assay to simultaneously detect > 1000 proteins in the plasma of anti-PD-1 treated melanoma patients. Our cohort comprised 116 patients, 66 responders (R) and 50 non-responders (NR). Additional 65 patients comprised a validation cohort with 30 R and 35 NR, and included 50 patients who developed treatment-related toxicities. Plasma samples were collected at baseline, 6-weeks and 6-months after starting the treatment. A subset of patients had single-cell RNA-seq performed on tumor tissue. Group differences and treatment effects were evaluated by linear model with maximum likelihood estimation for model parameters and Benjamini and Hochberg multiple hypothesis correction. Results: At baseline, 6 significantly differentially expressed (DE) proteins were identified between R and NR. Elevated expression of ST2 and IL-6, two key immunoregulatory proteins were found in NR. At 6-weeks, more dynamic changes occurred and 79 significantly DE proteins were identified between R and NR, including proteins implicated in primary or acquired resistance as IL-8, MIA, TNFR1 and potential novel targets as MCP-4/CCL13, ICOSLG and VEGF. Proteomic changes identified at baseline and 6-weeks were more profound at 6-months, and moreover 238 proteins were confirmed significant between R and NR. Importantly, we were able to leverage these differences to build classifiers of R and NR subsets. We compared mRNA expression of DE proteins within the tumor microenvironment by leveraging scRNAseq data from a subset of these patients. Enriched expression of these genes was uncovered in certain myeloid and exhausted T cell subsets, thus shedding insight into the potential role of these cell subsets in ICB response. Conclusions: Plasma proteomic profiling of anti-PD1 treated patients identified important tumor and immune changes associated with response. Non-invasive means discovery of circulatory protein biomarkers may predict sensitivity to immunotherapy and uncover biological insights underlying primary resistance.
Using digital-image analysis of tumor-infiltrating lymphocytes to predict survival outcomes in primary melanoma.
Authors: Chou Margaret , Illa-Bochaca Irineu , Minxi Ben , Giles Keith M. , Darvishian Farbod , Jour George , Moran Una , Shapiro Richard L. , Berman Russell S. , Osman Iman , Zhong Hua
Published: May 2020

10066

Background: Inclusion of tumor-infiltrating lymphocytes (TIL) into AJCC staging criteria has been proposed due to evidence suggesting its prognostic significance. However, subjective inter-observer discordance prevents adoption of semi-quantitative TIL grading (e.g. absent, non-brisk, brisk) into clinical practice. We hypothesize that digital-image analysis (DIA) of TIL can provide a standardized, quantitative scoring system that more accurately predicts survival compared to currently used semi-quantitative grading methods. Methods: Clinical data and tumor specimens were analyzed from prospectively enrolled primary melanoma patients in the New York University Interdisciplinary Melanoma Cooperative Group with median follow-up of 5 years. H&E-stained slides were digitized using an Aperio ScanScope at 20X magnification. QuPath software was used for automated TIL quantification. Cox regression analysis was used to assess the improved prognostic value of TIL on recurrence-free (RFS) and overall survival (OS). Patients were separated into high- and low-TIL groups using a score threshold determined by the Youden Index. Results: 453 patients (18% stage I, 42% stage II, 40% stage III) were scored using automated TIL assessment and scores were significantly correlated with better RFS and OS per 10% increase in TIL (stage adjusted hazard ratio [aHR] = 0.92 [0.84-1.00] for RFS and aHR = 0.90 [0.83-0.99] for OS). A model combining TIL score with stage increased prognostic ability for both RFS (0.68 to 0.70, P = 0.02) and OS (0.62 to 0.64, P = 0.01), as assessed by concordance indices (C-index). Kaplan-Meier curves of high- ( > 16.6%) versus low-TIL (≤16.6%) patients showed clear separation in RFS and OS (median RFS = 155 vs 48 months, P < 0.001; median OS = 155 vs 89 months, P = 0.002). For comparison, a subset of the cohort (n = 250) was semi-quantitatively graded (absent, non-brisk, brisk) by an attending melanoma pathologist; however, this did not significantly differentiate RFS between groups (P > 0.05). Conclusions: A standardized, quantitative TIL scoring system significantly improved prediction of RFS and OS in primary melanoma patients compared with semi-quantitative TIL grading. Incorporation of quantitative TIL scoring into prognostic algorithms, such as AJCC criteria, should be considered.
Using a clinicopathologic and gene expression model to identify melanoma patients at high risk for disease relapse.
Authors: Eggermont Alexander M. , Bellomo Domenico , Tjien-Fooh Félicia , Wever Renske , Quattrocchi Enrica , Sominidi Damodaran Sindhuja , Van Vliet Martin , Dwarkasing Jvalini , Meves Alexander
Published: May 2020

10068

Background: The identification of early stage melanoma patients at high risk for relapse is still difficult. Roughly 50% of melanoma deaths occur in patients who were initially diagnosed with nonmetastatic melanoma. Therefore, a strong clinical need has emerged for diagnostic tools that can identify melanoma patients at high risk for relapse. Here, we assessed the performance of a recently developed model (Bellomo et al., JCO Precis Oncol. 2020: in press), combining clinicopathologic and gene expression variables (CP-GEP), in identifying melanoma patients that have a high risk for disease relapse. Methods: We assessed the prognostic performance of the CP-GEP model in a cohort of 837 consecutive melanoma patients from Mayo Clinic who had a sentinel lymph node biopsy (SLNb) performed within 90 days of their diagnosis. The CP-GEP model combines Breslow thickness and patient age, with the expression of 8 genes in the primary tumor, to stratify patients according to their risk of relapse: CP-GEP High Risk or CP-GEP Low Risk. The main clinical endpoint of this study was five-year relapse free survival (RFS). Results: Patients were stratified based on SLNb status and CP-GEP classification. 76% of the patients were SLNb negative and had an RFS of 79% versus 52% for SLNb positive patients; HR, 3.21; P < 0.0001. 60% of the patients were identified as CP-GEP High Risk and had an RFS of 62% versus 87% for CP-GEP Low Risk patients; HR, 4.12; P < 0.0001. Within the SLNb negative group (637 patients of which 65% stage I), 51% of patients were classified as CP-GEP High Risk. Here, RFS was 70% for CP-GEP High Risk patients versus 89% for CP-GEP Low Risk patients; HR, 3.61; P < 0.0001. The prognosis of these CP-GEP High Risk patients is similar to stage IIC/IIIA patients with reported RFS ranging from 63% to 77%. This confirms the heterogeneity in prognosis among patients with stage I/II melanoma disease. Conclusions: The CP-GEP model can be successfully used to stratify patients based on their risk for relapse. In particular, it can be used to identify SLNb negative patients with a high risk for disease relapse who may benefit from therapeutic interventions. Independent validation studies are ongoing to validate the CP-GEP model in various patient populations. [Table: see text]
KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy.
Authors: Wong Michael K.K. , Kelly Ciara Marie , Burgess Melissa Amber , Lewis Karl , Grewal Jaspreet Singh , Olszanski Anthony J. , McGreivy Jesse , Rothbaum Wayne , Qamoos Hope , DeCaprio James A.
Published: May 2020

10072

Background: MCC is an aggressive neuroendocrine skin cancer with very poor prognosis. Immune checkpoint inhibition was recently shown to benefit some patients (pts). There are few effective treatments (tx) and no standard of care for those who relapse on or are refractory to anti-PD-1/L1 agents (R/R). In p53WT MCC, oncoproteins from the Merkel cell polyomavirus can inhibit p53 tumor suppressor functions via L-MYC/EP400-dependent activation of MDM2. KRT-232, a potent, selective, orally available MDM2i, is being evaluated in pts with p53WTMCC who are R/R to anti-PD-1/L1 tx. Methods: In stage 1 of this open-label, multicenter, phase 2 study (NCT03787602) pts initially received KRT-232 240mg QD days 1-7 of a 21 day (d) cycle (cy). This cohort was closed due to Grade (Gr) 3/4 cytopenias and pts were moved to 240mg QD days 1-5 of a 28d cy to allow for hematologic recovery. Two new arms were opened: 240mg and 180mg QD days 1-5 of a 28d cy. The primary endpoint is objective response rate (ORR) by RECIST 1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety and tolerability of KRT-232. Results: At the time of this analysis, 11 pts were treated with KRT-232: 6 on the 240mg 7/21d, 3 on the 240mg 5/28d and 2 on the 180mg 5/28d schedules. Median age was 66; 46% of pts had ECOG 1 (range 0-1), the median prior lines of systemic therapy was 3 (range 1-4) and 82% had prior radiation tx. Treatment-emergent adverse events (AEs), regardless of grade or causality, were reported in all pts: 55% had Gr 3-4 AEs and 36% had serious AEs (SAEs). The most common AEs included neutropenia (55%), anemia, leukopenia and thrombocytopenia (each 45%), diarrhea, nausea and fatigue (each 36%), and lymphopenia, hypomagnesaemia, lipase increase and sinus tachycardia (each 27%). SAEs were mainly due to cytopenias. One Gr 5 AE of respiratory failure/ascites was attributed to progression. Median time on study was 11.3 wks (range 1.3-20.9). Two of 11 pts on active tx have not yet reached the first response assessment (wk 6). Of the 9 pts who have reached wk 6, 2 PRs and 1 SD (converted to PR at wk 12) were reported. At the second response assessment (wk 12), 2 PRs were reported; one of the PRs at wk 6 has not yet reached wk 12. The ORR was 33% (3/9 pts) . Conclusions: KRT-232 demonstrates promising monotherapy activity in MCC p53WT pts who failed anti-PD-1/L1 tx. This is the first clinical proof-of-concept for inhibiting the MDM2 pathway in MCC. Safety and efficacy continue to inform KRT-232 dose and schedule optimization. Clinical trial information: NCT03787602.
Efficacy of imiquimod in the management of lentigo maligna.
Authors: Dréno Brigitte , Dinulescu Monica , NGuyen Jean-Michel , Maillard Hevé , Le Duff Florence , Machet Laurent , Beylot-Barry Marie , Legoupil Delphine , Wierzbicka-Hainaut Ewa , Bedane Christophe , Leccia Marie Thérèse , Debarbieux Sébastien , Meyer Nicolas , Monestier Sandrine , Bens Guido , Denis Marc G. , Bossard Celine , Vergier Beatrice , Khammari Amir
Published: May 2020

10074

Background: Lentigo maligna (LM), a melanocytic proliferation occurring on photoexposed skin, might progress to LM melanoma. Surgery is recommended as first-line treatment. However, the main challenge is the size of the excision inducing often-aesthetic injuries on the face and thus often refused by patients. The excision margins of 5 to 10 mm remain without international consensus. Several studies have shown that imiquimod induced LM regression, acting by enhancing IFN-γ production and effector function of T cells. The main goal of this study is to investigate the effect of imiquimod versus placebo in neoadjuvant setting to decrease the excision size as from the first surgical procedure. Methods: We performed a prospective, randomized, open, multicenter, phase III clinical study (NCT01720407). The health authority and ethics committee approvals were obtained and all subjects signed an informed consent. The primary endpoint was to demonstrate that in neoadjuvant situation, imiquimod could reduce the surgical excision size of LM with a healthy tissue margin of 5 mm. The main inclusion criteria were: Patients > 18 years fit for surgery. LM of the head histologically confirmed and not previously treated. Surface lesion ≥ to 1cm² and ≤ to 20cm². The two treatment arms were imiquimod or placebo followed by LM excision. Imiquimod or placebo were applied once daily, 5 days/week for 4 weeks followed by 5 mm margin surgery performed four weeks after the last treatment application. For sample size, 268 patients were expected to demonstrate a difference of 15% between the two arms in a bilateral situation with an alpha risk of 5% and a beta risk of 20%. Results: The trial involved 273 patients, 238 (105 men (44%) and 133 women (56%), mean age of 71 ± 10.2 years, were analyzed in modified ITT. Statistical analysis was performed on 122 patients in the imiquimod arm and 116 patients in the placebo arm. For the primary endpoint, the first extralesionnal excision has been achieved for 112 (91.8%) patients in the imiquimod arm and for 98 (84.5%) placebo patients group. There was no significant difference (p value = 0.1067) between the two arms. However, regarding the surface of LM, imiquimod allowed a highly significant reduction (4.2 cm² ± 4.6 to 2.3 cm² ± 3.3) compared to LM treated by placebo (4.0 cm² ± 3.5 to 4.0 cm² ±3.3; p < 0.0001). Conclusions: This randomized prospective study shows that imiquimod reduces the LM area (-50%) after one month of treatment. Reducing the surface of LM with imiquimod is not associated with a higher risk of intralesional excision (marge 5mm), with a significant esthetic result (less excised surface). Clinical trial information: NCT01720407.
Exploring the clinical efficacy of the total body skin exam.
Authors: Harding Tanner , Seyffert Jennifer , Maner Brittany , Kunadia Anuj , Camner Shawn , Yungmann Martin , Cotter Murray , Solomon James A.
Published: May 2020

10078

Background: The clinical efficacy of the total body skin exam has long been the subject of debate. A 2016 report by the United States Preventative Services Task Force (USPSTF) found the current body of evidence was “insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in [asymptomatic] adults.’’ However, the USPSTF based its recommendations on studies evaluating mainly the ability of primary care physicians to diagnose melanoma through total body skin exams (TBSE). This study seeks to address this insufficiency in the current literature by exploring the clinical efficacy of the dermatology provider performed TBSEs as a screening tool with respect to the detection of malignant melanoma (MM), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Methods: A search was performed within the electronic medical record of a large multi-state dermatology group practice for all instances of new and established patient office visits occurring from 1 January 2018 to 31 December 2019. Per practice policy, it is denoted whether each office visit includes a TBSE or partial skin exam (PSE). The number of MM, SCC, and BCC diagnoses made within the context of each class of skin exam was analyzed. Results: Of the 930,706 office visits analyzed, 438,027 TBSEs and 492,679 PSEs were performed. For each of the three types of skin cancer surveyed, the number of cancers diagnosed in the context of a TBSE was significantly greater than the number diagnosed in the context of a PSE. One MM was diagnosed per 161.0 TBSEs and 371.3 PSEs ( Χ2 ( df = 1, N = 930706) = 662, p < 0.001). One SCC was diagnosed per 56.7 TBSEs and 108.4 PSEs ( Χ2 ( df = 1, N = 930706) = 1258.5, p < 0.001). One BCC was diagnosed per 10.2 TBSEs and 17.8 PSEs ( Χ2 ( df = 1, N = 930706) = 5884, p < 0.001). Conclusions: Skin cancer is detected at significantly higher rates in TBSEs than PSEs. The finding that one MM is detected in 161 TBSEs may be compared to one cervical cancer is detected in 3,776 Pap smears. Thus, a TBSE is 23.5 times more likely to identify a MM than a Pap smear is to identify a cervical cancer. This trend holds even when adjusted for prevalence. Further analysis will allow for the comparison of exam types with respect to patient age, staging, lesion size, and Breslow depth at time of cancer diagnosis. This continued analysis will allow for a more detailed risk benefit-analysis and insight into the clinical efficacy of the TBSE.
A multiparameter classifier to predict response to lapatinib plus trastuzumab (LT) without chemotherapy in HER2+ breast cancer (BC).
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Wang Tao , Pascual Tomás , Weigelt Britta , Galvan Patricia , Rexer Brent Neil , Forero-Torres Andres , Wolff Antonio C. , Nanda Rita , Storniolo Anna Maria , Krop Ian E. , Goetz Matthew P. , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F.
Published: May 2020

1011

Background: Several trials have shown 25-30% pathologic complete response (pCR) rates in patients with HER2+ BC treated with LT therapy (+ endocrine therapy if ER+), but no chemotherapy (CTX). We hypothesize that a multiparameter classifier, comprised of HER2 gene and protein levels, intratumor heterogeneity (ITH), HER2-enriched (E) subtype, and PIK3CA mutation status can identify patients whose tumors are “addicted” to HER2 signaling and are likely to achieve pCR from a CTX-sparing de-escalation strategy. Methods: Baseline specimens from 2 trials (TBCRC023 [NCT00999804] and PAMELA [NCT01973660]) of neoadjuvant CTX-sparing LT (+ endocrine therapy if ER+) in HER2+ BC were used. HER2 protein and ITH (scored for % 3+ by IHC), and gene amplification (HER2:CEP17 ratio and copy number (CN) by CISH) were measured on the same slide by the dual gene protein assay (GPA). HER2-E and PIK3CA mutation status were assessed by research-based PAM50 and MSK-IMPACT platforms, respectively. A decision tree algorithm was used to determine the GPA cutoffs and to construct the classifier of response (by pCR) in TBCRC023, which was then validated in PAMELA. Results: Of the evaluable patients from TBCRC023 (N = 130) and PAMELA (N = 151), GPA data were available for 121 and 94 cases, respectively. Both cohorts exhibited similar distributions for HER2 ratio, CN, and % 3+, and a strong correlation between HER2 ratio and CN (R > 0.92). In TBCRC023, 73 cases had data from GPA, PAM50, and IMPACT, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio > 4.6 and % 3+ > 97.5% in both the GPA data cohort (N = 121) and complete data cohort (N = 73). With PAM50 and IMPACT data, the model added HER2-E and PIK3CA wild-type (wt). For practical reasons, the classifier was locked as HER2 ratio ≥ 4.5 AND % 3+ ≥ 90% AND PIK3CA-wt AND HER2-E, which yielded a PPV of 55% and NPV of 94%. Validation in PAMELA using 45 cases with data for all 3 assays yielded PPV of 44% and NPV of 82%. 29 TBCRC023 cases without IMPACT data could be predicted to be non-pCR, of which 26 were correct (NPV = 89%). In PAMELA, 66 additional cases could be predicted to be non-pCR, of which 54 were correct (NPV = 81%). Conclusions: We have constructed a multiparameter classifier that can predict pCR with targeted therapy alone that compare to pCR rates of CTX + dual anti-HER2 in unselected patients. Prospective validation in a clinical trial is warranted. [Table: see text]
Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer.
Authors: Gucalp Ayca , Boyle Leigh Ann , Alano Tina , Arumov Artavazd , Gounder Mrinal M. , Patil Sujata , Feigin Kimberly , Edelweiss Marcia , D'Andrea Gabriella , Bromberg Jacqueline , Goldfarb Shari Beth , Ligresti Louise , Wong Serena Tsan-Lai , Traina Tiffany A.
Published: May 2020

1017

Background: Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR) +, estrogen receptor (ER)/progesterone receptor (PR)- breast cancer (BC). The functional role of AR was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy. TBCRC011 established the safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with AR+/ER/PR- metastatic BC (MBC) with a median progression free survival (PFS) of 12 weeks (wks) (95% CI, 11–22 wks). In preclinical data, palbociclib (P) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 BC cells. It has been shown that AR+ triple negative BC (TNBC) expresses a luminal profile and has intact Rb protein, the target of P activity. We conducted this Phase I/II trial of the AR inhibitor B in combination with the CDK4/6 inhibitor P in pts with AR+/ER/PR/HER2- BC (NCT02605486) to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in pts with androgen-dependent BC. Methods: Postmenopausal pts with AR+ TN MBC defined as IHC ≥ 1% nuclear staining (DAKO, Clone AR441 (5/2016-11/2016) then Ventana AR SP107 (11/2016-6/2018), ECOG ≤2, measurable/non-measurable disease were eligible for enrollment. Any number of prior regimens was permitted. Pts received B 150 mg daily and P 125 mg daily 3 wks on 1 wk off. Pts were evaluated for toxicity every 2-4 wks and for response every 8-12 wks. Primary endpoint: 6 month (mo) PFS. Secondary endpoints: clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC. A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If ≥ 11/33 pts were PF at 6 mo then B+P would warrant further study. Results: As of 1.1.20 33 pts were enrolled on study with median (med) age 67 (42-79), performance status 0 (0-1). Number of pts with visceral metastases: 20, measurable disease: 22. AR% 1-9: 3, 10-50: 6; 51-100: 24. Med prior lines for MBC: 3 (0-9). Best response: (31 evaluable pts): 11 pts PF at 6mo: 10 SD > 6mo, 1 PR. Med wks on study: 14 (2-101). Toxicity > 10% grade >3 related: Number of pts with leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3. One pt with febrile neutropenia. One death due to disease progression within 30 days off study. Conclusions: In this selected subset of pts with AR+ TN MBC, this study met its prespecified endpoint with 11 pts PF at 6 mo on B 150 mg + P 125 mg. B+P has been well tolerated with no unexpected toxicity observed. Clinical trial information: NCT02605486 .
Clinical efficacy and molecular effects of lenvatinib (Len) and letrozole (Let) in hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Lim Joline Si Jing , Wong Andrea , Ow Samuel Guan Wei , Ngoi Natalie , Ang Yvonne Li'en , Chan Gloria , Eng Lim Siew , Chong Wan Qin , Choo Joan , Lee Matilda , Tan Hon Lyn , Jan Yi-hua , Tan Kien Thiam , Sundar Raghav , Tan David Shao Peng , Soo Ross A. , Chee Cheng Ean , Yong Wei-Peng , Goh Boon C. , Lee Soo-Chin
Published: May 2020

1019

Background: Preclinical studies show cross talk between RET and estrogen receptor, with at least additive treatment (Tx) effect of Len, a RET inhibitor, with Let. Our previous work concluded a recommended phase 2 dose (RP2D) of Len 14mg daily and Let 2.5mg daily (Lim, ASCO 2019). We present efficacy data from dose escalation and expansion cohorts. Methods: Safety, tolerability and efficacy data of MBC patients in both dose escalation (Len dose level 1 [DL]:20mg, DL -1:16mg and DL -2:14mg) and expansion (Len 14mg) cohort of this phase Ib/II study of combination Len+Let study was analysed. Patients were treated with single-agent Len for 2 weeks, followed by Len+Let until disease progression (PD). Serial tumor biopsies at baseline, after Len alone, 4 weeks post Len+Let, and upon PD, were sequenced for 440 genes with the ACTOnco+ platform. Results: A total of 33 pts (DL1 6pts, DL-1 6pts, DL-2 + expansion 21pts) with median 5 lines of prior Tx (range 0-11) were enrolled; 87.9%, 75.8%, and 75.8% had prior endocrine therapy (ET), ET+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. Objective response rate (ORR), disease control rate (DCR) ≥6 months (m), median duration of response (DOR), and percentage progression-free (PPF) at 12m were 33.3%, 45.5%, 11.5m (range 6.3-22.4), and 27.2% respectively. Among patients who previously progressed on CDK4/6i (n = 25), ORR, DCR ≥6m, median DOR, and PPF at 12m were 24.0%, 40.0%, 13.7m (range 6.3-18.2), and 12.0% respectively. Of note, 3/25 (12%) patients had durable response to Len+Let lasting ≥12m, despite having only modest PFS on ET+CDK4/6i (3, 7, and 12 months respectively). Most frequent all-grade toxicities (tox) were HTN (n = 15, G3:15), hypothyroidism (n = 20, G3:0) and fatigue (n = 13, G3:2), with no G4/5 tox. No new toxicity signals were observed compared to dose escalation phase. Pre-treatment tumor molecular profiling showed responders to be more likely to harbor NEFH, USH2A and PTCH1 mutations, while non-responders were more likely to carry PIK3R1, APC and PALB2 mutations. Sequencing of serial biopsies showed downregulation of BRD4, PTCH1, KIT, NTRK1 and CREBBP after Len treatment. Conclusions: Len+Let showed significant anti-tumor activity with meaningful duration of response, even in pts who failed prior CT or ET+CDK4/6i. The results support further investigation in randomized studies. Tumor profiling identified mutations associated with response and insights on molecular effects of lenvatinib. Clinical trial information: NCT02562118 .
Prognostic and predictive value of ESR1 mutations in postmenopausal metastatic breast cancer (MBC) patients (pts) resistant to aromatase inhibitors (AI), treated with palbociclib (PAL) in combination with endocrine therapy (ET) or capecitabine (CAP) in the PEARL study.
Authors: Martin Miguel , Zielinski Christoph , Ruiz-Borrego Manuel , Carrasco Eva Maria , Ciruelos Eva , Muñoz Montserrat , Bermejo Begoña , Vila Mireia Margeli , Turner Nicholas C. , Casas Maribel , Anton Antonio , Murillo Jaso Laura , Lang Istvan , Bartlett Cynthia Huang , Koehler Maria , Martin Nuria , Corsaro Massimo , Swift Claire , Nisenbaum Bella , Gil Gil Miguel J.
Published: May 2020

1022

Background: Prior retrospective data has shown ESR1 mutation is an acquired resistant mechanism to AI. However, little is known about ist prognostic and predictive value to endocrine-based therapy and chemotherapy. PEARL study compared PAL+ET vs CAP in AI resistant patients. Here we wxplored prospectively the ESR1 mutational status based on updated PFS and OS. Methods: PEARL is a phase 3 study with 2 subsequent cohorts: cohort 1 with 296 pts randomized to PAL+Exemestane (EXE) vs CAP and cohort 2 with 305 pts randomized to PAL+ Fulvestran (FUL) vs CAP. ESR1 hotspot mutations were analyzed in circulating free DNA at baseline by digital PCR. Cox regresion analysis for PFS and OS were performed. Adjusted hazard ratios (aHR) and interaction test between treatment and ESR1 status were calculated. Results: ESR1 mutational status was assessed in 557 pts, 91% and 94% treated with CAP and PAL+ET, respectively; 164 (29%) had ESR1 mutations. Characteristics between ESR1 wild-type (WT) and mutated pts were balanced except for ECOG, prior sensitivity to ET, treatment line, prior AI for metastatic disease and time from first metastatic diagnosis to randomization. Median follow-up was 22.5 months (m). Median PFS was 9.6 vs. 7.5 m (HR: 1.06 [0.88 - 1.28], p = 0.522) and median OS was 30.2 vs 30.3 (HR: 0.99 [0.78 - 1.26] p = 0.934), for CAP vs. PAL+ET, respectively. No interaction was seen between treatment arm and ESR1 status either for PFS (p = 0.538) or OS (p = 0.957). Conclusions: In luminal MBC, ESR1-mutated pts had poorer OS than ESR1-WT pts regardless of treatment received. Clinical trial information: NCT02028507 . [Table: see text]