bluuebunny/crossref_metadata_2025 huggingface dataset:
Durable clinical outcomes in patients (pts) with advanced melanoma and progression-free survival (PFS) ≥3y on nivolumab (NIVO) ± ipilimumab (IPI) or IPI in checkmate 067.
Authors: Hodi F. Stephen , Chiarion-Sileni Vanna , Gonzalez Rene , Grob Jean-Jacques , Rutkowski Piotr , Lao Christopher D. , Cowey Charles Lance , Schadendorf Dirk , Wagstaff John , Dummer Reinhard , Queirolo Paola , Smylie Michael , Butler Marcus O. , Hill Andrew Graham , Marquez-Rodas Ivan , Ritchings Corey , Sakkal Leon A. , Wang Peter , Wolchok Jedd D. , Larkin James
Published: June 2023

9542

Background: NIVO + IPI has demonstrated durable clinical benefit at 7.5 y in pts with advanced melanoma in the phase 3 CheckMate 067 study. PFS curves plateaued at ~3 y in this study, suggesting that being alive and progression-free for ≥ 3 y (PFS ≥ 3y) may be a good surrogate for long-term clinical benefit. We conducted analyses to quantify this association. Methods: Pts with treatment (tx)-naive, unresectable stage III/IV melanoma (stratified by PD-L1 expression, BRAF mutation status, and metastasis stage) received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W, followed by NIVO 3 mg/kg Q2W (n = 314); NIVO 3 mg/kg Q2W + placebo (n = 316); or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Exploratory post hoc analysis was performed in pts with PFS ≥ 3y. Results: In the NIVO + IPI, NIVO, and IPI arms, respectively, 99 (32%), 78 (25%), and 21 (7%) pts had PFS ≥ 3y. Objective response rates (ORRs) in these pts were ≥ 95% (table). The majority of responses were complete responses (CRs; table); in almost all pts with partial responses (PRs) on NIVO + IPI or NIVO, target-lesion size decreased by ≥ 50%. At 7.5 y of follow-up among pts alive and progression-free at 3 y, PFS rates were ≥ 68%, overall survival (OS) rates were ≥ 85%, and melanoma-specific survival (MSS) rates were ≥ 95% in the 3 tx groups (table). Among pts in this group who died after 3 y on study, the majority of deaths were unrelated to disease (table). The majority of pts with PFS ≥ 3y who were alive and in follow-up were tx-free at the 7.5-y data cutoff (77/84, 57/64, and 13/16). Pts who received NIVO + IPI were off tx (median) for 75.5 mo (NIVO, 55.7 mo; IPI, 59.2 mo). Among pts with PFS ≥ 3y in the 3 tx groups, 4%, 5%, and 19% received subsequent systemic tx (table). No new safety signals were observed in pts with PFS ≥ 3y. Conclusions: This exploratory post hoc analysis suggested that PFS ≥ 3y may be a good surrogate for long-term MSS with NIVO + IPI or NIVO, with very few occurrences of progression or death due to melanoma in this population through 7.5 y. Most pts were tx-free without having received subsequent systemic tx after demonstrating PFS ≥ 3y. Further study of pts with PFS ≥ 3y may allow the burden of imaging and follow-up visits to be reduced in this group. Clinical trial information: NCT01844505 . [Table: see text]
The effect of LNS8801 alone and in combination with pembrolizumab in patients with metastatic uveal melanoma.
Authors: Shoushtari Alexander Noor , Chaney Marya F. , Cohen Justine Vanessa , Garyantes Tina , Lin Jessica Jiyeong , Ishizuka Jeffrey Joseph , Mita Alain C. , Mita Monica M. , Muller Carolyn , Natale Christopher , Orloff Marlana M. , Papadopoulos Kyriakos P. , Patel Sapna Pradyuman , Rodon Ahnert Jordi
Published: June 2023

9543

Background: LNS8801 is an oral, selective, small molecule agonist of the G-protein coupled estrogen receptor (GPER). LNS8801 treatment results in increased melanocytic differentiation, reduced c-Myc protein levels in cancer cells, inhibition of proliferation, suppression of invasion, and enhancement of immune recognition. In preclinical models, LNS8801 has demonstrated increased activity in combination with immune checkpoint inhibitors (ICIs). In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with advanced solid tumors (NCT04130516). Methods: Patients with measurable metastatic uveal melanoma (mUM) received LNS8801 (125 mg, QD, PO) alone or with pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective was safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics, objective response rate (ORR) and disease control rate (DCR, CR+PR+SD) per RECIST v1.1. Presence of a consensus, fully-functional, germline GPER coding sequence was assessed via Sanger sequencing on DNA extracted from blood as a potential predictive biomarker. Results: As of 1/25/23, 15 patients with mUM were treated with LNS8801 alone (n = 8) or a combination of LNS8801 and pembrolizumab (n = 7). Patients were previously treated with a median of 2 prior lines of systemic therapy. 4 of 8 monotherapy patients had AEs potentially related to study drug (all grade 1), with no AEs occurring in more than one patient. 6 of 7 combination patients had AEs potentially related to study drugs (grades 1-2), with fatigue occurring in more than one patient. Of the 14 patients evaluable for efficacy (7 mono, 7 combo), 7 had disease control (4 mono, 3 combo) resulting in a disease control rate of 50%. 1 patient treated with combination achieved a confirmed partial response. Consensus germline GPER was present in 2 of 12 sequenced patients (1 mono, 1 combo), and both of these patients have ongoing disease control lasting longer than 24 weeks. Conclusions: LNS8801 alone and in combination with pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients with mUM. The hypofunctional germline GPER variant appears over-represented in this cohort compared to the normal population, suggesting a potential significant role for GPER in the development of mUM. These data support further development of LNS8801 alone and in combination with pembrolizumab as a therapeutic approach to treat mUM patients, especially for patients with consensus germline GPER. Clinical trial information: NCT04130516 .
Real-world comparison between 6 weeks versus 3 weeks adjuvant pembrolizumab in high-risk stage IIB-IIID cutaneous malignant melanoma: Experience from an academic cancer center.
Authors: Shah Manan , Shafi Saba , Kendra Kari Lynn , Verschraegen Claire F. , Wu Richard Cheng Han
Published: June 2023

9545

Background: The KEYNOTE-555 trial demonstrated similar efficacy and safety profile of 6-week (q6w) pembrolizumab (400 mg/m2) vs 3-week (q3w) in unresectable and metastatic melanoma leading to FDA’s approval of this dosing schedule for adults in 2020. Limited real-world data is available on the use of 3 weeks vs 6 weeks pembrolizumab in the adjuvant setting in cutaneous melanomas. Q6w is hypothesized to cause more adverse effects due to higher drug concentration. Methods: We conducted a retrospective study of surgically resected Stage IIB-IIID cutaneous melanomas receiving adjuvant pembrolizumab from 2019-2022 at The James Comprehensive Cancer Center with a follow-up of ~1 year. Fifty patients [n=35 (q6w) and n=15 (q3w)] were included. The primary objectives were to compare disease free survival (DFS) and safety profile based on the NCI-CTCAE (v 5.0) criteria. Kaplan-Meier curves were generated for DFS comparisons between the two groups. Fisher’s exact test was used to compare the safety profile between the two groups. Accuracy of the sample size for final analysis was planned based on log rank test. With 15 patients (q3w) and 35 patients (q6w), our study had 80% power to detect differences in clinical outcomes. A p-value of less < 0.05 was considered statistically significant. The secondary objective was to compare overall survival (OS) which will be reported later with a longer follow-up. Results: The mean age in the q6w and q3w groups was 59 years and 69 years, respectively. The median follow up was ~ 9 months with males predominating in both groups (54% and 18%). In the q6w group, 68% had ECOG status 0 (vs.30% in q3w) and most of our patients (32%) were stage IIIB (vs. 6% in q3w) and 28% were stage IIIC (vs 12% in q3wk). BRAF mutation was present in 32% in q6w vs. 2% in q3w. Toxicity profile was noted to be similar in both groups with no significant statistical difference ( p-value=0.4), though there were more Grade-3 immune-related toxicities in 7 patients in the q6w group (vs 3 in q3wk). The most common grade 3 toxicity noted was colitis (n=4, q6w; n=1, q3w). Notably, no significant difference was noted in the DFS between the two groups ( p-value=0.6). At the time of analysis, 3/15 (20%) patients in q3w and 7/35 (20%) in the q6w group had disease progression with the most common site being the regional lymph-nodes. At the time of the last follow up, 96% of the patients were alive with only 2 deaths occurring due to non-cancer related causes. Conclusions: We demonstrate comparable efficacy of q6w and q3w adjuvant pembrolizumab for advanced stage melanoma, with a trend towards increased immune-mediated colitis events in q6w. [Table: see text]
Neoadjuvant T-VEC + nivolumab combination therapy for resectable early metastatic (stage IIIB/C/D-IV M1a) melanoma with injectable disease: NIVEC trial.
Authors: Zijlker Lisanne P. , van Houdt Winan J. , Stahlie Emma H.A. , Franke Viola , Rohaan Maartje W. , Delatzakis Antonios , Zuur Charlotte , Klop Willem M.C. , van de Wiel Bart A. , Kuijpers Anke , de Boer Elianne , van Thienen Johannes V. , Haanen John B. A. G. , Van Akkooi Alexander Christopher Jonathan
Published: June 2023

9546

Background: Neoadjuvant systemic treatment with checkpoint inhibitors (ICI) has shown high response rates in patients with resectable metastasized melanoma. In patients with unresectable stage IIIB-IVA melanoma, intralesional treatment with talimogene laherparepvec (T-VEC) has also shown high and durable response rates. In this trial we investigated the safety and efficacy of neoadjuvant treatment with a combination of nivolumab and T-VEC in regionally metastasized melanoma. Methods: In this single arm phase II open-label trial (NCT04330430), 24 patients with resectable stage IIIB-IVA melanoma were included. Inclusion criteria were a RECIST 1.1 measurable lesion of ≥10mm and no prior systemic therapy. Treatment consisted of four doses of intralesional T-VEC (dose in ml according to the size of the lesions) and three doses of nivolumab 240 mg flat dose every two weeks, followed by surgery. The primary endpoint was pathological response rate according to the International Neoadjuvant Melanoma Consortium (INMC) criteria, secondary endpoints were delay or failure to perform surgery, event free survival (EFS) from time of randomization and safety. Results: Baseline characteristics are presented in the table. The overall pathological response rate was 74%, with a major pathological response (MPR = pathologic complete response (pCR) + near-pCR (max 10% viable tumor cells) in 15 patients (65%), a partial response in two patients (9%), a non-response in 4 patients (17%) and progression of disease (PD) in two patients (9%). In one patient the response was not evaluable because surgery was delayed due to a vena cava thrombosis. The two patients with PD had evidence of distant metastasis on preoperative imaging and therefore did not proceed to surgery as planned. Grade 2 treatment related adverse events (trAE) occurred in 7 patients (29%) and grade 3 in 2 (8%). There were no grade 4-5 trAEs. The 1-year EFS was 75% (95%CI 0.55-1). Conclusions: Neoadjuvant combination therapy of nivolumab and T-VEC for patients with regionally metastasized melanoma (satellite/in-transit +/- lymph node metastases) has an acceptable toxicity profile and has shown a significant major pathological response rate of 65%. Clinical trial information: NCT04330430 . [Table: see text]
Retreatment and rechallenge with BRAF/MEK inhibitors in patients with metastatic melanoma: Results from the observational study GEM1801.
Authors: Ayala de Miguel Pablo , Berciano-Guerrero Miguel-Angel , Muñoz-Couselo Eva , Manzano Jose Luis , CEREZUELA Fuentes Pablo , SORIA RIVAS AINARA , García Castaño Almudena , Crespo Guillermo , Puértolas Teresa , Aguado De La Rosa Carlos , Gutiérrez Sanz Lourdes , López Castro Rafael , Espinosa Enrique , Lecumberri Maria Jose , Majem Margarita , Medina Martinez Javier , Bellido Lorena , Fernandez Luis Antonio , Martin-Algarra Salvador , Marquez-Rodas Ivan
Published: June 2023

9547

Background: Most patients with BRAF-mutant melanoma eventually develop resistance to therapy with BRAF/MEK inhibitors and immune-checkpoint blockade. Alternative treatment strategies are required in these patients since further therapy options lack survival benefit. Small series have shown promising activity from re-exposure to BRAF/MEK inhibitors after a treatment free interval of targeted therapy (TT), probably due to regression of resistant tumors and proliferation of clones that maintain sensitivity to BRAF/MEKi. However, prospective evidence for this approach is limited. Here we report the results of 30 patients who received a second course of TT at relapse after adjuvant therapy (retreatment) or after first progression on TT in the advanced setting (rechallenge). Methods: GEM1801 is a prospective observational study from the Spanish Melanoma Group (GEM) including 893 patients with melanoma treated in 37 centers. This is a descriptive analysis of basal characteristics, response rates (RR), progression free survival (PFS) and overall survival (OS) from 30 patients that received retreatment or rechallenge with BRAF/MEKi in GEM1801 study. Results: 4 patients received retreatment and 26 rechallenge. For retreatment, BRAF/MEKi median free interval from end of adjuvant TT to subsequent retreatment was 17.8 months (range: 12.4 - 57.7). RR with retreatment were 25%, with a median PFS and OS of 5.7 and 8.5 months. For rechallenge, RR was 38.5% and median PFS and OS 11.1 and 22.2 months respectively. Patients who were selected for rechallenge had higher complete response (CR) rates to first TT (26.9% vs 20.3%; p= 0.026). Patients who experimented deeper responses with 1st TT in the metastatic setting showed a correlation to longer PFS to 2nd TT with 12-m PFS rates of 66.7% versus 35.7% (HR 9.09 [95%CI: 1.42-58]; p= 0.02). OS showed a not statistically significant improvement in patients who reported CR to first TD (24-m OS rate of 75% versus 40.7% respectively). BRAF/MEKi free interval since first progression and retreatment or rechallenge was not associated with prognosis. Prognostic factors as LDH and number of metastatic sites did not correlate with the efficacy of retreatment. Conclusions: Retreatment or rechallenge with BRAF/MEKi in the metastatic setting achieved encouraging efficacy and may be a valid therapeutic strategy in a selected group of patients. Response to first treatment, retreatment and rechallenge with BRAF/MEKi. Clinical trial information: NCT03605771 . [Table: see text]
A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.
Authors: Shaheen Montaser F. , Segar Jennifer Margaret , Chmielowski Bartosz , Drabick Joseph J. , McKean Meredith , Reeves James A. , Karapetis Christos Stelios , Orloff Marlana M. , Tolcher Anthony W. , Beck J. Thaddeus Thaddeus , Gastman Brian , De Asit , Paudyal Ben , Winkler Robert E , Li Mingyu , Ahmad Mohammad , Yang Dajun , Zhai Yifan
Published: June 2023

9559

Background: Alrizomadlin is a novel, orally active small-molecule MDM2 inhibitor that activates p53-mediated apoptosis in tumor cells, also functions as a host immunomodulator, and may restore antitumor activity in patients with cancer that has progressed on PD-1/PD-L1 inhibitors. Alrizomadlin is currently being investigated for treatment of patients with unresectable or metastatic cutaneous melanoma that progressed on prior immunotherapy. Methods: This multicenter clinical trial was conducted in the United States and Australia in patients with unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Eligible patients had an ECOG performance status of 0-2. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary and interim results are reported for 31 patients with cutaneous melanoma, of whom 21 were male and 10 female, with a median (range) age of 65 (27-84) years. Treatment-related adverse events (TRAE) of any grade ( > 10%) for either alrizomadlin or pembrolizumab were reported in 30/31 (96.8%) patients. These AEs included nausea (71%), vomiting (38.7%), fatigue (35.5%), thrombocytopenia (32.3%), diarrhea (25.8%), neutropenia (19.4%), decreased appetite (16.1%), and decreased leukocyte count (12.9%). A total of 4/31 (12.9%) patients reported treatment-related serious AEs, including anemia, thrombocytopenia, deep vein thrombosis, joint effusion, pulmonary embolism, and vomiting. In 26 efficacy-evaluable patients, the confirmed overall response rate (ORR; partial response [PR] + complete response [CR]) was 23.1%, including 2 patients reporting CRs and 4 reporting PRs based on RECIST v.1.1. The initial analysis indicated that the ORR observed in patients whose disease had failed IO treatment was primarily due to alrizomadlin combined with pembrolizumab, not the delayed effect of prior immunotherapy. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates clinical efficacy in these patients with highly refractory unresectable or metastatic cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy. Internal study identifier: APG-115-US002. Clinical trial information: NCT03611868 .
Correlation of DNA methylation signatures with response to immune checkpoint inhibitors in metastatic melanoma.
Authors: Ressler Julia Maria , Tomasich Erwin , Hatziioannou Teresa , Ringl Helmut , Heller Gerwin , Silmbrod Rita , Zila Nina , Tschandl Philipp , Hoeller Christoph , Berghoff Anna Sophie , Preusser Matthias
Published: June 2023

9561

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic melanoma with objective response rates of 40-58%. However, reliable biomarkers to predict treatment response are lacking. Tumor tissue methylation profiles were recently proposed to have predictive value in various solid organ tumor entities. Methods: Patients with metastatic melanoma, American Joint Committee on Cancer (AJCC; 8th Edition) stage IV, receiving first-line ICI-based therapy, were retrospectively identified and formalin-fixed paraffin-embedded tumor tissue samples (FFPE) prior to ICI therapy were retrieved. We analyzed DNA methylation profiles of > 850.000 CpG sites in tumor specimens by Infinium MethylationEPIC microarrays. DNA methylation profiles were then correlated with radiological response (iRECIST). Results: 71 patients with metastatic melanoma (44 (62.0%) male, 27 (38.0%) female) were investigated; median progression free survival (PFS) was 8.5 months (range: 0 – 104.1 months) and median overall survival (OS) was 30.6 months (range: 0 – 104.1 months), respectively. 29 (40.8%) patients achieved an objective response to ICIs. Microarray analyses revealed a methylation signature including mainly hypomethylation, corresponding to the response to ICIs. Based on the 500 mostly differentially methylated genes, a total of 3 clusters were identified with the majority of responders being in cluster 2 (12/12) and 3 (12/22). The predictive performance of the methylation signature was high with 80% sensitivity, 81% specificity, and an AUC of 0.853. Conclusions: Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICIs in patients with metastatic melanoma.
Exploring the clinical significance of specific immune-related adverse events (irAE) in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy.
Authors: Asher Nethanel , Bar-Hai Neta , Ben-betzalel Guy , Stoff Ronen , Grynberg Shirly , Schachter Jacob , Shapira-Frommer Ronnie
Published: June 2023

9566

Background: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Methods: This is a real world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the effects of specific irAE on treatment efficacy. Results: Three hundred and ninety-five (395) patients were treated with either monotherapy anti PD-1 (65.4%), combination ICI (24.3%), or anti CTLA-4 (10.3%). Median age was 68 years (12-99y), and 57% were male. The median follow up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAE were dermatologic (n = 110, 27.8%), vitiligo (n = 48, 12.1%), rheumatologic (n = 68, 17.2%), gastro-intestinal (n = 66, 16.7%), and endocrine (n = 61, 15.4%). The development of irAE was associated with a significantly longer median PFS (19.3m vs 4.5m; HR 0.46, p < 0.001) and median OS (55m vs 16.9m; HR 0.44, p < 0.001). Specific irAE that were significantly associated with survival benefic were rheumatologic (HR 0.34 for PFS, p < 0.001; HR 0.38 for OS, p < 0.001), dermatologic (HR 0.58 for PFS, p < 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p < 0.001; HR 0.29 for OS, p < 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p < 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, dermatologic and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other dermatologic irAE during ICI treatment, is correlated with a noteworthy survival advantage. These irAE may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.
NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.
Authors: Ascierto Paolo Antonio , Bossi Paolo , Mandalà Mario , Queirolo Paola , Spagnolo Francesco , Bassetto Franco , Rampinelli Vittorio , Giovacchini Francesco , Pennacchioli Elisabetta , Caraco Corrado , Parrinello Gianpiero , Mallardo Domenico , Giannarelli Diana , Trojaniello Claudia , Massi Daniela , Chiarion-Sileni Vanna
Published: June 2023

9576

Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( < 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .
Prognostic significance of immune-related adverse events and immunosuppression in patients with melanoma receiving adjuvant anti-PD-1 therapy.
Authors: Knight Andrew David , Karapetyan Lilit , Bruno Sabrina , Abushukair Hassan Mohammed , Bo Na , Wang Hong , Sander Cindy , Kirkwood John M. M.
Published: June 2023

9580

Background: Treatment with anti-Programmed Death-1 (PD-1) therapy reduces the risk of recurrence for patients (PT) with resectable Stage IIB-IV melanoma (MEL). This treatment is associated with the development of immune-related adverse events (irAEs), which may necessitate use of immunosuppressive therapy and treatment discontinuation. This project investigates the impact of irAE and immunosuppressive therapy in survival outcomes of PTs with MEL. Methods: PTs with stage IIB-IV resectable MEL who received adjuvant or neoadjuvant treatment with anti-PD-1 therapy were enrolled from the University of Pittsburgh Melanoma Center biospecimen repository. The association between irAEs/immunosuppressive therapy and recurrence-free survival (RFS) and overall survival (OS) were evaluated by univariate and multivariate Cox proportional hazards regression models. Results: A total of 6059 PT were consented to the repository: stage III = 1,328, stage IIB = 403, and stage IIC = 269 PT. Of these PT, 180 men and 93 women received adjuvant anti-PD-1 therapy. Average age at diagnosis was 61. BRAF mutation present in 94 PTs: V600E = 71 PT, V600K = 11 PT. Documented irAEs occurred in 50.9% of PTs. Cutaneous irAEs were most common (65/139, 46.8%), followed by endocrine (45/139 32.4%), and visceral organ (37/139, 26.6%). Of the 32 visceral organ irAEs, 15 were gastrointestinal, 10 pulmonary, 5 hepatic, and 1 renal. Systemic corticosteroids > 10mg of prednisone equivalent were administered during adjuvant therapy for 24.9% of PT. In the univariate model, development of irAEs was associated with improved OS (HR = 0.38; CI 0.18-0.83, p = 0.015). In a multivariate analysis after adjusting for age and sex, irAE development continued to be associated with improved OS (HR = 0.38; CI 0.17-0.82, p = 0.014). RFS did not differ for patients that developed irAEs (HR = 0.9; CI 0.59-1.4, p = 0.67). Steroid treatment was not associated with a change in OS (HR = 1.04; CI 0.46-2.4, p = 0.93) or RFS (HR = 0.96; CI 0.59-1.56, p = 0.87). Conclusions: Half of stage IIB-IV resectable MEL PT receiving adjuvant anti-PD1 therapy developed irAEs, of which 24% required steroid therapy. Development of irAE was associated with improved OS and corticosteroid use for irAE did not mitigate adjuvant therapy outcome benefits.
Early ctDNA reduction may identify patients with stable disease and long OS on tebentafusp.
Authors: Feng Dan , Collins Laura , Callahan Margaret K. , Sullivan Ryan J. , Piperno-Neumann Sophie , Nathan Paul D. , Hassel Jessica Cecile , Goodall Howard , Holland Chris , Ranade Koustubh , Shoushtari Alexander Noor
Published: June 2023

9589

Background: Tebentafusp, a bispecific (gp100 × CD3) ImmTAC showed significant overall survival (OS) benefit (HR 0.51) versus investigator’s choice in a Phase (Ph) 3 trial in first line (1L) HLA-A*02:01+ adult patients (pts) with metastatic uveal melanoma (mUM) [Nathan NEJM 2021]. In Ph2 and Ph3 trials of tebentafusp, OS was improved regardless of RECIST best response and the degree of early reduction in ctDNA was a better predictor of OS [Carvajal Nat Med 2022; Sullivan AACR 2023]. Here we explored whether early on-treatment reduction in ctDNA could distinguish pts with stable disease (SD) and long OS vs those with SD and short OS in a Ph3 trial of tebentafusp in 1L mUM pts. Methods: 1L HLA-A*02:01+ pts with mUM received 68 mcg tebentafusp weekly intravenously after intra-patient dose escalation (NCT03070392). Response was assessed by investigators per RECISTv1.1. Sera collected at baseline (BL) and week 9 on tebentafusp were analyzed for ctDNA using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Landmark OS from week 9 was analyzed in subsets with ≥0-3 log reductions in mean tumor molecules (MTM) per ml of serum on treatment. Data cutoff 11-Nov-2022. Results: 76/245 (36%) tebentafusp-treated pts had best response of SD, with a median OS of 29 months and were evaluable for ctDNA. Baseline tumor burden as assessed by sum of longest lesion diameters and percentage of pts with elevated BL serum LDH were greater in the subset with < 1 year (yr) OS (median 70 mm and 64%, respectively) than in subsets with OS ≥ 1 yr (median 42 mm, 11%) or OS ≥ 2 yrs (median 31 mm, 9%). Almost half (36/76; 47%) of all SD pts had detectable ctDNA mutations in one or more UM genes at baseline. Baseline ctDNA levels were similar across survival groups. By week 9 on-treatment, ctDNA reduction was observed in 34/36 (94%) evaluable SD pts, including 29/36 (81%) with ≥ 0.5 log reduction, 18/36 (50%) with ≥ 2 log reduction and 16/36 (44%) with undetectable ctDNA (clearance). Deeper reductions in ctDNA were associated with better OS (Table). Conclusions: In this Ph3 trial, ctDNA reduction by week 9 on tebentafusp was strongly associated with improved OS in pts with best RECIST SD. Early ctDNA reduction may predict SD patients with long OS on tebentafusp. [Table: see text]
Evolution of breast cancer management in the Dominican Republic in the 21st century.
Authors: Molaire Robens , Monanci Miguel , Hidalgo Dayanara
Published: June 2023

e12500

Background: Breast cancer is a major public health problem. Despite knowing the management, clinicians are forced to provide less than optimal care when diagnostic and/or treatment are lacking. For that, we decided to do a review about breast cancer treatment during the 21 st century in Dr. Heriberto Pieter Oncology Institute. Methods: A retrospective study was done to describe and evaluate the management of patients with breast cancer. A random sample of 100.00 patients was selected, which was reduced to 64.00 after the inclusion-exclusion criteria application like lacking immunohistochemistry, partial treatment. and less than 5 years with the diagnosis. Results: Molecular subtypes included luminal A: estrogen receptor+ and/or progesterone receptor+, Her2Neu3- (44%); luminal B: estrogen receptor + and/or progesterone receptor +, Her2Neu 3+(9%); Her2Neu 3: estrogen receptor-, progesterone receptor -, Her2Neu 3+ (19%); basal-like: estrogen receptor-, progesterone receptor-, Her2Neu3- (28%). Chemotherapy history: 63% with neoadjuvant chemotherapy; 78% with adjuvant chemotherapy, 18.75% as primary and 59.37% as secondary; 17% with palliative chemotherapy, 3% as primary and 14% as secondary. Surgical history: 31% with primary modified radical mastectomy (MRM), 63% with secondary MRM, and 2% with quadrantectomy. Radiotherapy: 11% with primary radiation therapy (RT), 36% with secondary RT, and 3% with palliative RT. Hormonal therapy of patients: 33% with tamoxifen, 11% with aromatase inhibitors, 8% with combination of hormonal therapy, and 22% with extended adjuvant hormone therapy of more than 5 years. Primary endpoints were disease-free survival at 5 years (67%), objective response rate to neoadjuvant chemotherapy (100% according to RECIST criteria), and overall survival at 5 years (87.5%). Currently in Dominican Republic there is availability of more target therapy for Her2Neu3 like pertuzumab, lapatinib, other drugs for positive hormone receptor named CDK4/6 inhibitors (palbociclib, ribociclib), olaparib for germline BRCA mutation and pembrolizumab for basal like or triple negative breast cancer (TNBC). Finally, according to the latest World Health Organization (WHO) data published in 2020, breast cancer deaths in Dominican Republic reached 1,460 or 2.14% of total deaths. The age adjusted death rate is 28.28 per 100,100 and the number of new cases in 2020 for breast cancer was 3,412 (17.2%). Conclusions: This review allows us to track the evolution of breast cancer management in Dominican Republic during the 21st century. It highlights the efforts made to apply guidelines on breast cancer management in general and global objective response to neoadjuvant regimen. It also highlights the need to implement more primary prevention and early detection since 52% of patients belong to the locally advanced category. [Table: see text]
Management of adjuvant endocrine therapy (AET) side effects in patients with breast cancer: A single cancer center experience.
Authors: Kuhn Elaine Patricia , Pirruccello Jonathan P. , Stone Simon , Tosteson Tor D , Schwartz Gary N. , Chamberlin Mary D.
Published: June 2023

e12503

Background: Up to 50% of breast cancer survivors are unable to complete the recommended 5-year course of adjuvant endocrine therapy (AET), usually due to side effects. Patients who develop side effects may change to a different medication (‘switch’) or may treat side effects with additional medications or non-pharmacologic strategies. While there are numerous evidence-based treatments available for side effects of AET, the benefit of switching AET is less well known. We have previously reported on the association between switching and early discontinuation of AET. Here, we provide further insight into the use of switching vs side effect management at our cancer center. Methods: We conducted a retrospective chart review of patients diagnosed between 2011-2014 with early stage, ER+/HER2- breast cancer. Clinical data extracted by chart review included side effects and treatment history. Patients were grouped based on whether they received a switch vs side effect management and compared for variables of interest using Chi-squared tests and confidence intervals. Multiple logistic regression was used to assess long-term adherence, adjusting for side effect type and severity. Results: A total of 228 patients with early-stage ER+/HER2- breast cancer were evaluated. Among them, 162 patients (71.0%) received treatment for side effects. A medication switch was offered in 98/162 (60.5%) cases, with side effect management (SEM) alone offered in the remaining (39.5%). Patients who switched were more likely to have reported severe side effects compared to patients who received SEM alone (OR 4.56, 95% CI (2.1, 9.8), p < 0.001). Hot flashes were more frequent in patients who received SEM compared with those switching (89% vs 59%, respectively, p < 0.001), while arthralgias were more frequent in the patients who were offered a switch (70% vs 47%, p = 0.002). ‘Other’ side effects were also more frequent in patients who switched (58% vs 30%, p < 0.001). Among patients who discontinued therapy early, the majority did so within the first 12 months (18/43, 42%). The long-term adherence rate was 73% overall, and it was significantly lower in the subset of patients who received a switch compared to those who received SEM – 62% vs 91% respectively, p < 0.001. Significance was maintained after adjusting for side effect type and severity with multiple logistic regression, p = 0.013. Conclusions: Despite limited evidence, rates of switching are high in clinical practice. Switching is more common in patients with severe symptoms, and those who report arthralgias and uncommon side effects. Switching was associated with poor long-term adherence. Due to the potential for selection bias, conclusions are limited as to whether switching itself is ineffective. A prospective randomized trial is under development at our cancer center to address this question.
Re-referral for post-op radiation in elderly breast cancer patients who initially omit RT but are unable to tolerate endocrine therapy.
Authors: Kaleem Tasneem , Brampton Shelley
Published: June 2023

e12507

Background: Omission of Radiation in the setting of Elderly patients 70 yo and above with ER+, cN0, pT1 tumors who receive adjuvant endocrine therapy (HT) is standard of care per NCCN. However, the average adherence rate of HT ranges from 41% to 72%, which is not optimal for patient outcomes. In our institution, we evaluated the treatments of all patients who qualified for omission of radiation upfront and the number of re-referrals for adjuvant radiation in Elderly Breast cancer patients who were unable to tolerate HT past 6 months. Methods: Data was obtained through the National Cancer Registry at our institution for 2021 and reviewed mid 2022. Inclusion criteria included patients diagnosed with Pathologically Invasive Breast Cancer AJCC Stage I-IIB age 70 and above. A total of 176 patients were eligible for review. 86 patients did not qualify for inclusion into study due to 7 receiving surgical treatment outside our system. Furthermore, 81 patients did not qualify due to the following reasons or combination: Mastectomy (19), Triple Negative, Greater than 2 cm, N+, AI only. A total of 90 patients qualified for omission and review. Six month HT therapy cut off was extrapolated by Barbieri et al who determined a 6 month delay of RT after surgery was not associated with an increased risk of relapse. Results: From the 90 patients who qualified for omission of radiation, 67 % (n = 60) of patients chose radiation omission, 30% (n = 27) of patients chose upfront radiation, and 3% (n = 3) of patients declined all therapy. Of the 60 patients who chose omission, 87% of patients had continued HT, however 2 patients passed away within 1 year of surgery. A total of 13% of patients (n = 8) who omitted radiation did not go past 6 months of HT, and only 2 out of 8 patients (25%) were referred back to radiation oncology and moved forward with treatment. For the 27 patients who chose radiation upfront even though they qualified for omission, the most common reason per records was the patient was unsure after initial multidisciplinary clinic that they would be able to tolerate HT. Interestingly, 27% of these patients ended up stopping HT within 9 months due to side effects. Conclusions: Omission of radiation is an option for Elderly Early stage breast cancer patients in the setting of HT. However, HT compliance is variable due to side effects. In our one year single institution study, only 25% of patients who omitted RT and did not get past 6 months of HT were sent back for radiation. We encourage an increased awareness and communication between Radiation Oncology and Medical Oncology regarding the option of radiation for patients who do not pass 6 months of HT. Our institution has implemented an Epic message system and Breast Navigation to aid in re-referral. It is also imperative at the time of Radiation Oncology consultation to discuss the possibility of intolerance to HT in the setting of omission may indicate radiation therapy at a later date.
Amelioration of acute radiation dermatitis in patients with breast cancer by a bioadhesive barrier-forming oral gel (Episil): A single-center, open, parallel, randomized controlled trial.
Authors: Li Qian , Ning Fangling , Liu Changmin
Published: June 2023

e12519

Background: Episil is a bioadhesive barrier-forming oral liquid gel that can relieve mucositis caused by radiotherapy (RT) and hence relieves pain effectively.The purpose of this trial is to compare the efficacy and safety of Episil in improving acute radiation dermatitis in breast cancer patients. Methods: Key eligibility criteria were as follows: Pathologically confirmed breast cancer; female ≥18 years of age; planning to receive postoperative radiation therapy; surgery with modified radical or breast-conserving surgery; fully healed surgical incision; intact skin in the irradiated area; KPS score ≥80; no severe endocrine or metabolic disease; voluntary participation and signed informed consent; ability to read and understand and good compliance. The primary endpoint was the grading of radiation dermatitis during treatment. Results: A total of 102 patients were included from January 2022 to December 2022. The patients were grouped in a 2:1 ratio by randomized number table method, 67 patients received Episil combined with conventional skin care and 35 patients served as the control group receiving conventional skin care only. Two patients in the Episil group dropped out halfway. According to the RTOG grading, the skin reaction rate and the degree were significantly better in the Episil group than control group (24.62%, 72.31%, 3.08, 0, 0 VS 0, 85.71%, 14.29%, 0, 0, 0) in the 0, 1, 2, 3 and 4 grades respectively (P<0.001). And the pruritus score was significantly lower in the Episil group than in the control group (P<0.05). The results of the EORTC QLQ-C30 Quality of Life Questionnaire showed that the overall health (P<0.05) and overall quality of life (P<0.05) were better in the Episil group than control group after radiotherapy. Relative to the control group, the Episil group produced significantly lower rates of stress, anxiety, and depression (P<0.05) and had less impact on family life and social activities (P<0.05). Most importantly, the Episil group produced fewer pain reactions after the end of radiotherapy. Conclusions: In breast cancer patients receiving radiotherapy, Episil may significantly reduce the grading of acute radiation dermatitis, reduce patient symptoms, and improve patient quality of life. Clinical trial information: ChiCTR2200059646 .
Therapy decision-making after pre-operative endocrine therapy in HR+ HER2- early breast cancer.
Authors: Sorokina Irina , Ignatieva Maria , Kolyadina Irina Vladimirovna , Kvetenadze Gurami , Ivanyuk Maria , Gorbunova Maria , Zhukova Lyudmila
Published: June 2023

e12520

Background: Nowadays, the right way for therapy decision-making in HR+ HER2- early breast cancer (BC) includes the complex of validated multigene assays (VMA) result with clinical and IHC evaluation. Given the inability to use VMA in routine clinical practice, the short-term pre-operative endocrine therapy (P-ET) allows to estimate more precisely plan the further adjuvant therapy (AT) in the patients (pts) with early HR+ HER2- BC. Our work is aimed to share of pts with P-ET benefit, or tumor phenotype reversion for proper treatment planning in pts with early HR+ HER2- BC. Methods: HR+ HER2- BC pts stages I-II any level of Ki67 and any grade (G) have received P-ET (letrozole (L)/anastrozole (A)/tamoxifen (TAM)) no less than 2 weeks until surgery in A.S. Loginov MCSC, Russia. Enrollment period was Jun’20 - Jan’23. The study was aimed to access P-ET efficiency in pts with baseline Ki67>10% downgrading to ≤10% (1), tumor ET sensitivity in the whole group (2) and/or phenotype transformation during P-ET followed by changing AT strategy (3). Results: At the data cut-off (Jan’23) 998 pts (5 pts were men) with HR+ HER2- BC were enrolled with median age 63,5 (range:26-85). The median time of P-ET was ≈19,5 days (range: 14-42). Pts flow according to tumor Ki67 level dynamic is show. 54% (434) pts with initially Ki67 level >10% decreased Ki67≤10% after P-ET in whom 36% (314) pts avoided adjuvant chemotherapy. In Ki67≤10% baseline group (n=187) tumor Ki67 level after P-ET increased >30% in every fifth case (n=35, 19%), that may reflect the initial ET resistance. Ki67 level dynamic change under P-ET was observed regardless of the TAM/IA use. 4% (38) pts has resulted the phenotype change to HER2+ BC (n=32) and TNBC (n=6) with subsequent AT decisions (anti-HER2-based or dose dense regimens, respectively). In this group there weren’t any Ki67 decrease after P-ET that additionally confirms the unmet need for treatment plan correction. Conclusions: In HR+ HER2- BC pts the results of P-ET with TAM or IA before surgery helps to estimate pts prognosis and further AT strategy: to identify the pts population of whom chemotherapy can be avoided while maintaining treatment efficacy with a better quality of life (1), to assess the initial ET tumor sensitivity (Ki67 baseline level independently) (2), to radically change the planned AT to achieve optimal treatment results (3). Mature data of long-term pts outcome are awaited. [Table: see text]
The use of minimal residual disease in patients with high-risk breast cancer.
Authors: Kameoka Alyssa , Fukui Jami Aya
Published: June 2023

e12521

Background: Breast cancer is the most frequently diagnosed cancer worldwide and the second leading cause of cancer death in women in the United States. Despite being disease-free after primary treatment, studies have shown that up to 30% of patients present with disease recurrence. Circulating tumor DNA (ctDNA) in blood is a minimally invasive technique to characterize individual cancer biology and monitor disease. Previous studies have demonstrated that ctDNA can be a sensitive and specific approach to breast cancer follow up and surveillance of disease recurrence for all subtypes. Methods: We evaluated 38 high risk breast cancer patients utilizing a personalized and tumor-informed ctDNA assay at 3-6 month intervals. We defined high risk as: any stage III disease, triple negative breast cancer (TNBC) or HR-/HER2+ breast cancer who received neoadjuvant chemotherapy treatment (NACT), pregnancy associated breast cancer, metastatic breast cancer without any evidence of disease, history of bilateral breast cancer, high risk genetics (i.e. BRCA1 or BRCA2 mutations), young age at diagnosis (<40 years old) and/or breast cancer recurrence of any subtype. Results: Patient ages ranged from 34 to 83 (average: 53.3 years old) and included a diverse race/ethnicity population: White (n=12, 31%), Japanese (n=9, 23.7%), Native Hawaiian (n=6, 15.8%), Chinese (n=4, 10.5%), Filipino (n=4, 10.5%), Black (n=1, 2.6%), Hispanic (n=1, 2.6%), and Korean (n=1, 2.6%). Of the 38 cases, there was one ctDNA positive finding seen in a high risk case (young age at diagnosis and BRCA2 mutation) of clinical stage IIA HR+/HER2- breast cancer. After NACT, bilateral mastectomies, and radiation, patient remained on tamoxifen (declined ovarian function suppression) and was initially ctDNA negative until a second test identified detectable ctDNA. Restaging scans however did not show any evidence of disease. A third ctDNA test three months later, continued to be positive without any evidence of disease. All other cases showed negative ctDNA testing with an average of 1.55 ctDNA tests done per patient over two years. However, one case of clinical stage IIB TNBC had contralateral recurrence despite negative testing. After receiving NACT, bilateral mastectomies, post-operative paclitaxel and radiation, two ctDNA tests done three months apart were negative. Conclusions: There is potential use for this ctDNA platform in high risk breast cancer patients but larger studies need to be done. [Table: see text]