bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting response to pembrolizumab in non-small cell lung cancer, by analyzing the spatial arrangement of tumor infiltrating lymphocytes using deep learning.
Authors: Ofek Efrat , Bar Jair , Zer Alona , Urban Damien , Mayer Chen , Sade Chen , Zelichov Ori , Groisman Alon , Laniado Avi , Gabay Yuval , Polychenko Willy , Gluskin Roman , Achtenberg Albert , Feinmesser Meora , Barshack Iris
Published: June 2021

9045

Background: Immune checkpoint inhibitors (ICI) have become the standard treatment for metastatic NSCLC, although only a small proportion of patients derive durable benefit. PDL1 expression is the only approved biomarker to select NSCLC patients for treatment with single-agent pembrolizumab, however its predictive value is limited and better predictive biomarkers are needed. The spatial arrangement of immune cells in the tumor microenvironment (TME), namely tumor infiltrating lymphocytes (TILs), emerges as a potential biomarker for ICI efficacy. In this work, we utilized deep-learning (DL) models to extract TME features from digitized H&E slides and evaluated their predictive and prognostic role in patients with mNSCLC treated with Pembrolizumab. Methods: NSCLC patients (n=90) treated with single-agent 1st line pembrolizumab in two centers were identified. 47 patients from one center were used to train the model, and 43 patients from another center were used for validating the model. Pre-treatment H&E whole slide images (WSI) were analyzed using a deep-learning model to identify and classify tumor cells, TILs, tumor and stromal areas, and spatial features were calculated. Spatial features were correlated with clinical outcome data to train a binary classifier that identifies patients with a favorable clinical outcome. The resulting classifier combined three spatial features and three clinical features. The classifier was then applied to the validation set and differences in duration of treatment (DOT), and overall survival (OS) between patients with positive and negative scores were assessed. Results: The classifier identified patients in the validation set to have either positive (n=18) or negative (n=25) scores. Baseline patient characteristics and PDL1 score were similar between the positive and negative groups. In a Kaplan-Meier (KM) analysis, OS was significantly higher in patients with a positive score compared to patients with a negative score (HR=0.35, 95% CI 0.13-0.98; p<0.05). Positive patients had a significantly higher median OS (NR vs.17.8m, p<0.05) and 2-year OS (70.8% vs. 33%, p=0.02) than negative patients. Median DOT was also higher in positive patients compared to negative patients (10.1m vs. 6.5m). Conclusions: Deep-learning models that analyze the TME from H&E whole-slide images can identify NSCLC patients with durable benefit on Pembrolizumab. Identifying NSCLC patients who are exceptionally sensitive to anti-PD-1 therapy as monotherapy may improve clinical decision making and spare patients the unnecessary adverse effects associated with the addition chemotherapy or another IO agent.
Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic non-small cell lung carcinoma.
Authors: Clay Timothy Dudley , Majem Margarita , Felip Enriqueta , Doger Bernard , Carcereny Costa Enric , Forster Martin , Krebs Matthew , Peguero Julio Antonio , Mueller Christian , Triebel Frederic
Published: June 2021

9046

Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 1st line non-small cell lung carcinoma (NSCLC) part of the phase II trial (NCT03625323). Methods: Patients (pts) with untreated, immunotherapy naïve, advanced NSCLC unselected for PD-L1 expression were recruited into part A. The study used a Simon's 2-stage design (17 pts planned for stage 1 and 19 pts for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), PK, PD and immunogenicity. Efti is administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks locally and with blinded independent central review (BICR) retrospectively. The study was approved by ethic committees and institutional review boards. Results: In total 36 pts were enrolled. At data cut-off (Jan 2021; median FU of 14 months), the median age was 69 yrs (range 53-84) and 69 % were male. The ECOG PS 0 and 1 was 42% and 58% respectively. Patients had squamous (42%) and non-squamous (58%) NSCLC and 95% presented with metastatic disease. All PD-L1 subgroups (TPS < 1 %, ≥ 1 % to ≤49 %; ≥50 %) were represented with 36% pts having ≥50% TPS. Pts received a median of 7.0 (range 1 – 31) pembrolizumab and 11.5 (range 1-22) efti administrations. Responses as per BICR and local read are shown in the table. ORR (local, iRECIST) by different PD-L1 subgroups was 27% for pts with TPS<1%, 39 % for TPS ≥1 %and 54% for ≥50 % TPS. Median PFS (n=36) was 8.2 months while median OS was not yet reached. The most common (> 20 %) treatment emergent adverse events (AEs) were asthenia (47 %), cough (36 %), decreased appetite (36 %), dyspnea (32 %), pruritus (31 %), fatigue (28 %), diarrhea (25 %), anemia (25 %), constipation (25 %) and back pain (22%). Two patients discontinued treatment due to adverse reactions (Grade 4 immune-mediated hepatitis, Grade 3 AST+ALT increase). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in 1st line advanced NSCLC patients across all PD-L1 (TPS) levels. Clinical trial information: NCT03625323. [Table: see text]
A phase II trial of chemotherapy plus pembrolizumab in patients with advanced NSCLC previously treated with a PD-1 or PD-L1 inhibitor: Big Ten Cancer Research Consortium BTCRC-LUN15-029.
Authors: Shukla Nikhil , Althouse Sandra K. , Perkins Susan , Furqan Muhammad , Leal Ticiana , Hanna Nasser H. , Durm Greg Andrew
Published: June 2021

9073

Background: Chemoimmunotherapy with a platinum doublet plus a checkpoint inhibitor (CPI) is a standard of care for pts with advanced NSCLC. While some pts experience prolonged responses to initial CPI therapy, the majority of pts will eventually experience PD. It is unknown if continuing CPI treatment beyond progression has any advantages in this setting. We report the results of a phase 2 trial of chemotherapy plus pembrolizumab in pts with advanced NSCLC previously treated with a PD-1 or PD-L1 inhibitor. Methods: Pts experiencing PD after clinical benefit to CPI (PFS > 3 months) were enrolled. Pts received pembrolizumab 200 mg q3wks plus next-line chemotherapy (gemcitabine 1000 mg/m2 IV D1 and D8 q3wks, or docetaxel 60-75 mg/m2 IV D1 q3wks, or pemetrexed 500 mg/m2 IV D1 q3wks [non-squamous histology only]). The primary endpoint was PFS by RECIST 1.1. Key secondary endpoints included ORR, OS, and toxicity. The null hypothesis was median 3-month PFS with pembrolizumab plus next-line chemotherapy and the alternative hypothesis was median 6-month PFS with pembrolizumab plus chemotherapy. Results: 35 pts were enrolled. Median follow-up was 18.1 months and median age 63 (44-80). 51.4% male and 48.6% female. 82.9% were current or former smokers. Histology included 74.3% with adenocarcinoma, 20% with squamous cell carcinoma, 5.7% with NSCLC NOS. Treatment regimens included pembrolizumab/docetaxel (40%), pembrolizumab/gemcitabine (45.7%), or pembrolizumab/pemetrexed (14.3%). Median number of cycles of pembrolizumab was 6 (1-31). Median PFS using RECIST 1.1 and irRECIST was 5.2 months (95% CI 3.6-11.2, p < 0.05) and 6.9 months (95% CI 3.8-12), respectively. Median OS was 26.8 months (95% CI 13.4-30.9). Best response using RECIST 1.1 was PR (23.5%) and SD (53%). 45.7% of pts experienced G3 or higher treatment-related AEs (TRAEs). Most common TRAEs were fatigue (60%), anemia (51.4%), and nausea (42.9%). There were no treatment related deaths. Conclusions: Pembrolizumab plus next-line chemotherapy in pts with advanced NSCLC who experienced PD after clinical benefit to CPI was associated with prolonged PFS compared with historical controls of single agent chemotherapy. Further investigations into which pts would benefit from continued CPI treatment after progression is warranted. Clinical trial information: NCT03083808.
Association of concomitant NSAID and immunotherapy on outcomes in patients with non-small cell lung cancer: Analysis of the National Veterans Health Administration Database.
Authors: Moghanaki Drew , Stokes William A. , Behera Madhusmita , Jiang Renjian , Gutman David , Giuste Felipe , Burns Abigail , Sebastian Nikhil , Ramalingam Selvi , Sukhatme Vidula , Lowe Michael C. , Ramalingam Suresh S. , Sukhatme Vikas
Published: June 2021

9107

Background: Preclinical data suggests the efficacy of immune checkpoint inhibitors (ICI) may be enhanced with concomitant nonsteroidal anti-inflammatory (NSAID) medications. Real-world evidence to support investigating this hypothesis in prospective randomized trials are needed. Methods: A retrospective cohort study queried the VA Corporate Data Warehouse (VA-CDW) to identify patients diagnosed with NSCLC who were treated with ICI between 2010-18. Exposure to concomitant NSAID was determined whenever NSAID prescriptions were released from the VA pharmacy within 90 days of the first ICI infusion. Chi-square and ANOVA tests were used to compare baseline characteristics. The outcome of overall survival (OS) was measured from the start of ICI. Cox proportional hazard regression was used to adjust for demographic, clinical, tumor, and treatment characteristics. Results: The study cohort consisted of 3,415 patients with NSCLC treated with ICI, and 2,336 (64%) were exposed to concomitant NSAID. The median age was 69, male 97%, race: white 73%, black 21%, and 66% lived in urban areas. Most patients were initially diagnosed with stage III or IV disease (68%); tumor histology: adenocarcinoma 48% and squamous cell 38%. Comorbidity counts were 0 in 40%, 1-3 in 30%, and 4+ in 30%. Chemotherapy was delivered before ICI in 54% and concurrently with ICI in 31%. The most commonly used NSAIDs were aspirin (35%), ketorolac (11%), and ibuprofen (7%); 44% were exposed to more than one NSAID. With a median follow-up of 8 months, exposure to concomitant NSAIDs was associated with a longer OS (HR = 0.90; 0.83-0.98, p = 0.01) after adjusting for all available potential confounders on multivariable analyses. Longer OS persisted following propensity score matching (HR = 0.89; 0.82-0.97 p = 0.007). Other factors significant for OS on multivariable testing included use of chemotherapy after ICI (HR = 0.53 [0.40-0.69], p < 0.001), concurrent chemotherapy during ICI (HR = 0.68 [0.62-0.74], p < 0.001), younger age, black race, female gender, and adenocarcinoma histology. Among the various NSAIDs analyzed on the multivariable analyses, only diclofenac approached statistical significance (HR = 0.78 [0.59-1.03], p = 0.08). Limiting the comparison to patients exposed to diclofenac (n = 101) versus no NSAIDs (n = 1,298), the comparison demonstrated a similar trend for OS (HR = 0.79 [0.60-1.04], p = 0.094), although the association was attenuated after propensity-score matching (HR = 0.90 [0.63-1.29], p = 0.57). Conclusions: This retrospective cohort study of Veterans with NSCLC who were treated with ICI identified that concomitant receipt of NSAIDs is associated with longer OS.
Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.
Authors: Graziano Stephen L. , Pavlick Dean C. , Sokol Ethan , Ramkissoon Shakti H. , Severson Eric Allan , Huang Richard S.P. , Mata Douglas A. , Decker Brennan , McGregor Kimberly , Danziger Natalie , Ross Jeffrey S.
Published: June 2021

9116

Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]
Five-year overall survival (OS) in COLUMBUS: A randomized phase 3 trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients (pts) with BRAF V600-mutant melanoma.
Authors: Dummer Reinhard , Flaherty Keith , Robert Caroline , Arance Ana Maria , de Groot Jan Willem , Garbe Claus , Gogas Helen , Gutzmer Ralf , Krajsová Ivana , Liszkay Gabriella , Loquai Carmen , Mandalà Mario , Schadendorf Dirk , Yamazaki Naoya , Pickard Michael D. , Zohren Fabian , Edwards Michelle L. , Ascierto Paolo Antonio
Published: June 2021

9507

Background: Combined BRAF/MEK inhibitor therapy has demonstrated benefits on progression-free survival (PFS) and OS and is standard of care for the treatment of advanced BRAF V600-mutant melanoma. Here we report a 5-year update from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 pts with advanced/metastatic BRAF V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to encorafenib 450 mg QD + binimetinib 45 mg BID (COMBO450), encorafenib 300 mg QD (ENCO300), or vemurafenib 960 mg BID (VEM). An updated analysis including PFS, OS, objective response rate (ORR; by blinded independent central review), and safety was conducted after minimum follow-up of 65.2 months (mo). Data are as is; study is ongoing. Results: At data cut-off (Sep 15, 2020), there were 131 (68%), 117 (60%), and 145 (76%) deaths in the COMBO450, ENCO300, and VEM treatment arms, respectively. The median OS (95% CI) and 5-year OS rate (95% CI) with COMBO450 were 33.6 (24.4–39.2) mo and 34.7% (28.0–41.5), respectively (median follow-up: 70.4 mo). The 5-year OS rate (95% CI) in COMBO450 pts who had normal lactate dehydrogenase (LDH) levels at baseline was 45.1% (36.5–53.2). Median OS and 5-year OS rates for ENCO300 and VEM, as well as for pts with normal and high LDH levels and > 3 organs involved at baseline, are shown in the table. For COMBO450, ENCO300, and VEM, the 5-year PFS rate was 22.9%, 19.3%, and 10.2%; ORR (95% CI) was 64.1% (56.8–70.8), 51.5% (44.3–58.8), and 40.8% (33.8–48.2); and the median duration of response (DOR) was 18.6, 15.5, and 12.3 mo, respectively. Safety results were consistent with the known tolerability profile of COMBO450. Additional efficacy and updated safety analyses will be presented. Following study drug discontinuation, the most common subsequent treatment in all arms was checkpoint inhibitors. Conclusions: Updated OS and DOR results with COMBO450 demonstrate continued long-term benefits in pts with BRAF V600-mutant melanoma. Clinical trial information: NCT01909453. [Table: see text]
Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).
Authors: Long Georgina V. , Atkinson Victoria , Lo Serigne , Guminski Alexander David , Sandhu Shahneen Kaur , Brown Michael Paul , Gonzalez Maria , Scolyer Richard A. , Emmett Louise , McArthur Grant A. , Menzies Alexander M.
Published: June 2021

9508

Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]
Discrepancies in response and immune-related adverse events (irAE) of anti-PD-1 monotherapy between races and primary sites in patients (pts) with advanced nonacral cutaneous melanoma (NACM).
Authors: Bai Xue , Shoushtari Alexander Noor , Betof Warner Allison , Quach Henry , Cann Christopher G , Zhang Michael , Pallan Lalit , Harvey Catriona , Si Lu , Tang Bixia , Cui Chuanliang , Kim Michelle S. , Sharova Tatyana , Flaherty Keith , Long Georgina V. , Menzies Alexander M. , Sullivan Ryan J. , Boland Genevieve Marie , Johnson Douglas Buckner , Guo Jun ,   MGH Melanoma Clinical Research Team
Published: June 2021

9530

Background: Ultraviolet (UV)-induced high tumor mutation burden (TMB) of NACM is associated with response to anti-PD-1 monotherapy (aPD-1). Anatomic location of the primary lesion (reflecting UV exposure) and race (reflecting eumelanin level) may serve as surrogates for TMB and be associated with varying response and irAE patterns. Methods: Pts with advanced NACM receiving aPD-1 between 2009-2019 were retrospectively analyzed from 5 institutions in the US, Australia and China. Best response, survival (PFS and OS), and organ/system-specific irAEs were compared by race (Caucasian [C] vs non-Caucasian [NC]) and primary anatomic site. Results: Among 697 patients, 616 were C, 81 were NC. Complete response rate (CRR) was 24.8% (95%CI, 21.4-28.4) and 2.6% (95%CI, 0.3-9.1) and ORR was 54.9% (95%CI, 50.9-58.9) and 15.6% (95%CI, 8.3-25.6) in C and NC, respectively (both P<.001). Median PFS was 16.5 (95%CI, 12.0-23.1) and 5.2 (95%CI, 3.6-7.6) months, median OS was 60.5 (95%CI, 49.9-not reached [NR]) and 29.2 (95%CI, 17.9-NR) months, in C and NC, respectively (P<.001 and =.04). In multivariate analyses, C had significantly higher CRR (OR 13.4, 95%CI 3.1-57.4), ORR (OR 10.6, 95%CI 4.6-24.5), and longer PFS (HR 0.5, 95%CI 0.4-0.7) than NC. Compared to a head primary site, NACM from less UV-exposed regions had significantly lower CRR (upper trunk, OR 0.6, 95%CI 0.4-0.96; lower limb, OR 0.5, 95%CI 0.2-0.9), ORR (lower limb, OR 0.6, 95%CI 0.3-0.9) and poorer PFS (perineum/buttock, HR 2.1, 95%CI 1.2-3.5; lower limb, HR 1.6, 95%CI 1.2-2.2) and OS (perineum/buttock, HR 3.8, 95%CI 2.2-6.8; lower limb, HR 1.7, 95%CI 1.2-2.4). Overall irAE incidence was similar between C and NC but irAE subtypes varied. C had significantly higher incidence of GI (12.2%, 95%CI 9.5-15.3% vs 1.2%, 95%CI, 0.03-6.7%, P=.001), respiratory (10.3%, 95%CI 7.8-13.2% vs 0, P<.001) and grade 3/4 (15.4%, 95%CI 12.4-18.8% vs 6.2%, 95%CI 2.0-13.8%, P=.03) irAEs; and lower incidence of endocrine (13.8%, 95%CI 10.9-17.0% vs 32.1%, 95%CI 22.2-43.4%, P<.001) and liver (4.8%, 95%CI 3.2-7.1% vs 13.6%, 95%CI, 7.0-23.0%, P=.005) irAEs. IrAEs did not vary by primary NACM site. Conclusions: Race and primary site are independently correlated with distinct response and survival outcomes in pts with advanced NACM receiving aPD-1. IrAE subtypes vary by race although overall irAE incidence does not.
Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.
Authors: Ma Vincent T , Sun Yilun , Sitto Merna , Waninger Jessica , Fecher Leslie Anne , Green Michael , Lao Christopher D.
Published: June 2021

9549

Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p<0.001) and OS (HR: 0.19, 95% CI 0.10-0.38; p<0.001) compared to progressive disease (PD) [Table]. Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.17, 95% CI 0.11-0.26; p<0.001) and OS (HR: 0.13, 95% CI 0.07-0.23; p<0.001) [Table]. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 (95% CI 0.45-1.53; p=0.540) for PFS and HR 0.56 (95% CI 0.24-1.30; p=0.175) for OS. Conclusions: Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.[Table: see text]
Treatment outcomes in patients (pts) with melanoma brain metastases (MBM) treated with systemic therapy: A systematic literature review (SLR) and meta-analysis.
Authors: Tawbi Hussein Abdul-Hassan , Long Georgina V. , Meyer Nicolas , Breznen Boris , Vyas Charmy , Leung Lisa , Moshyk Andriy , Pushkarna Divya , Thakkar Pratik K. , Fazeli Mir Sohail , KOTAPATI SRIVIDYA , Schadendorf Dirk
Published: June 2021

9561

Background: The introduction of immunotherapy and targeted therapy has revolutionized the treatment landscape for metastatic melanoma. However, clinical trial data in pts with MBM are scarce; here we summarize the available clinical evidence. Methods: An SLR was conducted by searching EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases through November 13, 2020. When available, Kaplan-Meier (K-M) curves for overall survival (OS) were digitized and converted to pseudo-individual pt data using the Guyot algorithm. A meta-analysis of the pooled K-M curves was performed for selected interventions, including immunotherapies and targeted therapies. Median OS was calculated either through the meta-analysis of K-M curves or as a weighted average of median OS (table). When interventions were reported in only 1 study, the value reported was used instead of the weighted average and compared qualitatively with the other results. Results for treatment modalities other than systemic agents will also be presented. Results: The SLR included 70 publications that evaluated systemic therapies in pts with MBM for qualitative evidence synthesis: 12 pertaining to 7 randomized controlled trials, 55 pertaining to 46 single-arm studies, and 3 involving nonrandomized comparative studies. The pt population was highly heterogeneous with respect to prior therapies, pt characteristics, and neurological symptoms. For the meta-analysis, a total of 25 K-M curves from 12 studies representing 6 interventions and 1043 pts were digitized. Based on the pooled K-M curves, median OS was numerically longer with nivolumab plus ipilimumab (NIVO + IPI; 28.3 mo; 95% CI, 19.7-31.9) than with the other interventions (range 5.7-11.8 mo; table). Similar OS benefit was also observed with NIVO + IPI when the weighted average of the median was used (in a long-term study, median OS was 29.2 mo) compared with the other interventions. Conclusions: Given the lack of comparative clinical trial data in pts with MBM, there remains an unmet need to determine the best approach to treat these pts. This analysis suggested a clinical advantage with NIVO + IPI compared with other systemic agents analyzed. The heterogeneity of the available data added uncertainty to our treatment assessments. Therefore, these findings warrant further research into the best approach to improve outcomes in pts with MBM.[Table: see text]
Health-related quality of life (HRQoL) in patients (pts) with locally advanced basal cell carcinoma (laBCC) treated with cemiplimab: Analysis of a phase II, open-label clinical trial.
Authors: Stratigos Alexander J. , Chen Chieh-I , Ivanescu Cristina , Lewis Karl D. , Peris Ketty , Bechter Oliver Edgar , Harnett James , Mastey Vera , Reaney Matthew , Daskalopoulou Christina , LaFontaine Patrick R. , Konidaris Gerasimos , Bury Denise , Yoo Suk Young , Mohan Kosalai Kal , Coates Ebony , Bowler Timothy Geoffrey , Fury Matthew G. , Sekulic Aleksandar
Published: June 2021

9566

Background: Cemiplimab-rwlc is the first immunotherapy to receive approval in the US, fully for pts with laBCC and accelerated for metastatic BCC, post hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. Cemiplimab resulted in clinically meaningful anti-tumor activity in pts with laBCC who progressed on or were intolerant to hedgehog inhibitor therapy (NCT03132636). This analysis evaluated HRQoL in these pts. Methods: Adults with laBCC and ECOG performance status ≤1 (n=84) received IV cemiplimab 350 mg Q3W for up to 9 treatment cycles. At baseline (BL) and day 1 of each cycle (C), pts completed EORTC QLQ-C30 and SKINDEX-16 questionnaires that assess Global Health Status (GHS)/QoL, functioning, and BCC-related symptoms. Mixed-effects repeated measures (MMRM) models were used to estimate least squares (LS) mean (standard error [SE]) change from BL during treatment (i.e., across C2 to C9); changes ≥|10| points were considered clinically meaningful. Responder analyses were conducted in pts with non-missing data from BL to determine the proportions with clinically meaningful improvement or deterioration, or stability on QLQ-C30 and SKINDEX-16 at C2 and C9; a 10-point threshold was considered meaningful for both instruments. Results: BL scores showed moderate to high levels of functioning and low symptom burden. In MMRM models, overall changes from BL on QLQ-C30 indicated stability for GHS/QoL and all scales except for clinically meaningful worsening of fatigue (LS mean [SE] change 12.5 [3.9]; P<.05). In responder analysis, the majority of pts reported clinically meaningful improvement or stability at C2 and C9 on all QLQ-C30 functioning scales and the key symptom of pain but not fatigue (Table). On SKINDEX-16, MMRM models showed clinically meaningful improvement on the emotional subscale (LS mean [SE] change –13.2 [3.9]; P<.05) and stability on the symptom and functional subscales. Responder analysis showed clinically meaningful improvements or stability across the SKINDEX-16 subscales in approximately 80% of pts at C2, and 70–80% of pts at C9. Conclusions: In laBCC pts treated with cemiplimab, the majority reported clinically meaningful improvement or stability in GHS/QoL and functional status while maintaining a low symptom burden except for fatigue. Clinical trial information: NCT03132636. [Table: see text]
Isolated same-basin lymph node recurrence after precision lymph node excision for clinically evident melanoma metastasis.
Authors: Lynch Kevin , Hu Yinin , Farrow Norma , Song Yun , Meneveau Max , Kwak Minyoung , Lowe Michael C. , Bartlett Edmund , Beasley Georgia , Karakousis Giorgos , Slingluff Craig L.
Published: June 2021

9576

Background: While management of the nodal basin for melanoma has largely moved to observation for microscopic sentinel lymph node (SLN) metastasis, complete lymph node dissection (CLND) remains the current standard of care for melanoma patients with macroscopic, clinically detectable lymph node metastases (cLN). As CLND is associated with high surgical morbidity, we sought to study whether cLN may be safely managed by excision of only clinically abnormal nodes (precision lymph node dissection, PLND). Currently, a small subset of patients with cLN do not undergo CLND because of frailty or patient preference. We hypothesized that in these selected patients, PLND would provide acceptable regional control rates. Methods: Retrospective chart review was conducted at four academic tertiary care hospitals to identify melanoma patients who underwent PLND for cLN. cLN were defined as palpable or radiographically abnormal nodes. Recurrences were categorized as local/in-transit, same-basin lymph node, or distal lymph node/visceral. The primary outcome was isolated same-basin recurrence after PLND. Results: Twenty-one patients underwent PLND for cLN without synchronous distant metastases (characteristics of primary lesions summarized in Table). Reasons for forgoing CLND included patient preference (n=8), imaging indeterminate for distant metastases (n=2), comorbidities (n=4), loss to follow up (n=1), partial response to checkpoint blockade (n=1), or not reported (n=5). The inguinal node basin was the most common site (n=10), followed by the axillary (n=8) and cervical basins (n=3). A median of 2 nodes were resected at PLND, and 68% of resected nodes were positive for melanoma (median: 1, range: 1-3 nodes). Median follow-up was 23 months from PLND, and recurrence was observed in 28.6% of patients overall. Only 1 patient (4.8%) developed an isolated same-basin recurrence. The 3-year cumulative incidence of isolated same-basin recurrence was 5.3%, while risk of isolated local/in-transit recurrence or distant basin/visceral metastasis were 19.8% and 33.3%, respectively. Complications from PLND were reported in 1 patient (4.8%) and were limited to post-operative seroma and lymphedema. Conclusions: These pilot data suggest that PLND may offer acceptable regional disease control for cLN. Post-operative morbidity from PLND was also low, raising the possibility that PLND may provide adequate regional disease control without the morbidity associated with CLND. These data justify additional, prospective evaluation of PLND in selected patients.[Table: see text]
Genome-wide association study to reveal novel germline markers of melanoma survival.
Authors: Chat Vylyny , Ferguson Robert , Morales Leah , Moran Una , Kim Min Jae , Snuderl Matija , Osman Iman , Weber Jeffrey S. , Kirchhoff Tomas
Published: June 2021

9581

Background: Cutaneous melanoma (CM) is the most invasive form of skin cancer accounting for ̃80% of all skin cancer related deaths. While tumor staging (based on recent AJCC classification) is routinely used in prognostic assessment, a large fraction of the outcomes is not explained by AJCC staging system. This urges for the discovery of a more personalized prognostic surrogates. Growing evidence highlights the role of germline genetics in CM progression; yet, to date no systematic prognostic germline study has been conducted in melanoma. We performed the first genome-wide association analysis (GWAS) to identify germline variants associated with melanoma survival. Methods: A cases/case GWAS was performed using the Infinium global screening array (GSA v3.0) to genotype 1,117 stage 0-III melanoma patients with no history of immunotherapy treatments ascertained at New York University Langone Health (NYULH). We randomly divided the study cohort into a discovery (N=630) and a validation (N=487) sets and tested the association of > 5 million imputed germline variants with melanoma overall survival (OS) by fitting Cox-proportional hazard ratio (HR) regression in an additive genetic model adjusting for sex, age at diagnosis, AJCC 8th staging, tumor anatomic sites, and top 3 principal components. Results: We found 151 independent variants associated with melanoma OS (p< 5×10−5) in the discovery cohort. Two of these associations validated in the independent replication set ( Bonferroni threshold for 151 tests: p < 0.003) with enhanced clinical and statistical significance in the pooled meta-analysis: rs4128212 [HR =2.47(1.75-3.48); p=2.2× 10−7], and rs13212644 [HR =2.59 (1.72-3.88); p=4.2× 10−6]. We further tested the combined effect of these two variants and found the presence of at least one risk allele of the variants associated with a substantially increased risk of death, surpassing GWAS level of significance (HR=3.74 (2.43-5.74); p=1.5×10−9). Conclusions: We present the results of first GWAS testing an association of germline variation with melanoma OS. Stemming from a unique patient population with extensive clinical follow-up data, we identified two prognostic germline loci with large HR effect size >2.5 that were independently validated. The observed association is independent of established histopathologic markers. While rs4128212 was mapped to a putative cancer prognostic gene locus (PLPP4: phospholipid phosphatase 4), rs13212644 was an eQTL (expression quantitative trait loci) for GCLC (Glutamate-Cysteine Ligase Catalytic Subunit), a key regulator in glutathione synthesis previously linked with favorable melanoma survival. The significantly enhanced combined effect of these two loci (HR >3.5; p<5×10−9) indicates a great promise for their clinical utility as independent personalized predictive markers of melanoma progression.
Application of RSClin to guide treatment recommendations for premenopausal patients with early-stage hormone-positive breast cancer and intermediate risk oncotype recurrence scores.
Authors: Zimmerman Brittney Shulman , Berwick Shana , Kessler Alaina J , Seidman Danielle , Hovstadius Sara Malin , Moshier Erin , Blanter Julia , Berkalieva Asem , Jaffer Shabnam , Berger Natalie F , Cascetta Krystal Pauline , Tiersten Amy
Published: June 2021

e12511

Background: The RSClin model, which incorporates the Oncotype Recurrence Score (RS) and clinicopathologic features, was recently developed to further tailor prognosis and prediction of chemotherapy benefit for patients with early-stage hormone positive (HR+) breast cancer (BC) (Sparano et al, 2020). The RSClin calculator is available online to assist treatment planning for situations where chemotherapy benefit is uncertain. Covariates include Oncotype RS, tumor grade, tumor size and patient age. The risk calculator generates a 10-year distant recurrence risk and absolute chemotherapy benefit. This tool may be especially helpful to determine treatment management for premenopausal patients with early-stage HR+ BC with intermediate risk (IR) Oncotype RS (16-25). We retrospectively applied RSClin to this patient population to determine if it would have changed treatment recommendations. Methods: We identified premenopausal women with node-negative early-stage BC with IR RS (16-25) within our large Oncotype database. Using the RSClin model, we selected >5% absolute chemotherapy benefit as a reasonable cutoff to recommend chemotherapy. We compared the treatment recommendation based on RSClin with the treatment previously recommended by breast oncologists at our large academic medical center in New York City. Results: There were 86 patients who met criteria with a median age of 46 years. Of these, 26 patients (30%) were recommended chemotherapy plus endocrine therapy (ET) and 60 (70%) were recommended ET alone. After applying the RSClin model (data available for 83/86 patients), 19 (23%) would have resulted in a change in treatment recommendation and 64 (77%) would have remained unchanged. Overall, 8 (10%) would have withheld chemotherapy when it was previously offered and 11 (13%) would have recommended chemotherapy when it was previously excluded. There were 8 (9%) secondary invasive breast events in this population, with 2 (2%) being ipsilateral, 3 (3%) being contralateral and 3 (3%) metastatic at a median follow up of 46.9 months. Conclusions: The RSClin model would have changed management of premenopausal patients with IR RS in 23% of patients. This model, although not yet prospectively validated, may help individualize therapy for patients with less definitive treatment plans. Using RSClin, we can aim to minimize recurrence rates and avoid unnecessary chemotherapy in selected patients. This model is easy to apply and will have important clinical utility moving forward.
Study on the extract of Huangqi and Ezhu for the crosstalk of exosomes mediating tamoxifen resistance on LCC9 cells.
Authors: Cui Shasha , Zhang Dongni , Lu Wenping
Published: June 2021

e12517

Background: Estrogen receptor (ER)-positive breast cancer is the most frequent subtype accounting for about 70% of all cases. Tamoxifen (TAM) is still the most effective drug for treating ER+/PR+ breast cancer. However, recurrence and metastasis still occur in 30-50% of patients due to TAM resistance. Furthermore, studies have shown that breast cancer stem cells (BCSCs) play an important role in TAM resistance, and exosomes regulate dynamic changes of BCSCs in tumor microenvironment. Additionally, the extract of Huangqi and Ezhu (EHE) has been shown to inhibit multiple TAM-associated resistance signaling pathways. In the current study, we investigated the effect of EHE to reverse TAM-resistance in LCC9 cells via crosstalk of distinct types of exosomes. Methods: Exosomes were extracted from LCC9 cells by ultracentrifugation and characterized by particle size detection, transmission electron microscopy and western blot analysis. Subsequently, isolated LCC9 exosomes were used to treat bone marrow stem cells (BMSCs) with EHE only, TAM only, EHE and TAM (EHETAM), and no treatment (negative control, NC). After treatment, exosomes of BMSCs were isolated and incubated further with LCC9 cells. CCK-8 assay and flow cytometry analysis were performed, and protein expression in treated LCC9 cells was tested by western blot analysis. Results: Data from CCK-8 assay showed that compared with the NC group, proliferation of LCC9 cells was significantly reduced in the presence of exosomes of BMSCs treated with TAM (82.9%, 77.1% , 75.4%), EHE (73.2 %, 69.5% , 68.2 %) and EHETAM (68.9 %, 52.3%，54.1% ) after 24h, 48h, and 72 h, respectively (p < 0.001). EHE and EHETAM groups have more effective inhibition on cell proliferation than TAM only group on the different time separately(p < 0.001).Flow cytometry analysis demonstrated that compared with the NC group(6.1%), increased apoptosis was observed for groups of TAM (8.1%), EHE (12.5%) and EHETAM (12.2%) (p < 0.001). Compared with TAM only group, EHE and EHETAM groups also have significantly higher cell death rate (p < 0.001). Lower CD44 and HER2 expression and higher ERα expression were observed in EHE, TAM, and EHETAM than those of NC group by western blot analysis of treated LCC9 cells. Conclusions: EHE treatment can reverse TAM-resistance by interfering with the crosstalk between BMSCs and breast cancer cells exosomes to induce more active apoptosis and reduce TAM-resistant CD44+ cancer stem cells.
Prediction of long-term prognosis over ten years in ER-positive HER2-negative early-stage breast cancer using 18F-FDG PET/CT before treatment.
Authors: Tsukada Hiroko , Tsukada Jitsuro , Noguchi Eiichiro , Okamoto Takahiro
Published: June 2021

e12542

Background: Although ER-positive, HER2-negative early-stage breast cancer is considered to have a relatively good prognosis, it is known to occur long-term recurrence for more than 10 years. 18F-FDG PET/CT has been reported to be useful in predicting short-term recurrence of breast cancer (2-5 years), but its correlation with long-term prognosis over ten years in ER-positive HER2-negative breast cancer is not clear. In the present study, we examined whether tumor FDG accumulation of pre-treatment PET/CT can be a predictor of long-term overall survival (OS) in ER-positive, HER2-negative early-stage breast cancer patients. Methods: Of 639 primary breast cancer patients treated at our institution between January 2007 and May 2010, 332 patients with stage 2 or less and ER-positive HER2-negative tumors who were able to confirm whether or not they had recurred at ten years postoperatively were included in the study. The impact of patients' characteristics, tumor background, and tumor FDG accumulation of pretreatment PET/CT image on OS was investigated using Cox regression analysis. P < 0.05 was considered to be a statistically significant difference. Results: There were 33 (9.9%) recurrences and 13 (3.9%) deaths during a median observation period of 121 months. Univariate analysis showed that tumor SUVmax / FDG accumulation in lymph nodes / stage / N category / diameter of invasion / nuclear grade were candidate predictors of OS. Multivariate analysis revealed that SUVmax (Hazzard ratio 1.36 [95% CI 1.13-1.63], P < 0.001) was the only predictor of OS. Conclusions: In patients with ER-positive HER2-negative early-stage breast cancer, tumor SUVmax on pretreatment PET/CT was the only independent predictor of OS.
Assessment of the treatment results in patients with breast cancer coexisting with pregnancy: A single-center observational study.
Authors: Skrzypczyk-Ostaszewicz Anna , Jagiello-Gruszfeld Agnieszka I. , Giermek Jerzy , Nowecki Zbigniew
Published: June 2021

e12566

Background: This study discusses the analysis of the prospectively collected material on pregnant patients treated for breast cancer at the Department of Breast Cancer and Reconstructive Surgery of the Maria Skłodowska-Curie National Oncology Institute - National Research Institute (until 2020: Oncology Center - Institute) in Warsaw, in the years 1995 - 2020. 84 patients were included into the final analysis and 72 children were assessed simultaneously. Methods: The paper summarizes information on the diagnosis and treatment of breast cancer during pregnancy, the course of pregnancy and childbirth and the birth parameters of children i.e. weight, length and Apgar score, as well as the dependencies between them, mainly the impact of some breast cancer, diagnosis and treatment process features on the newborns. The patietnt’s survavial - DFS ( disease free survival) and OS ( overall survival) - was also analyzed. The course of breast cancer diagnosis and treatment data were obtained from the patients’ medical documentation (medical records) and from information provided by the mothers during follow-up visits and read in the children's health books. In order to answer the research questions, statistical analyzes were conducted using the IBM SPSS Statistics 26 package. Results: In the analyzed period, the disease recurrence was recognized in 34 (40.5%) patients, and 24 (28.6%) patients died. The median disease-free survival (DFS) was 12.3 years (147.5 months), and the median overall survival (OS) was not reached during the follow-up period. The estimated 5-year survival rates for DFS and OS were 57.9% and 74.5% respectively, and for 10-year survival - 51.4% and 64.5%. The study showed a statistically significant relationship between the baseline clinical advancement and DFS. It has been also analyzed how the diagnosis, treatment and method of pregnancy termination changed in two time periods (1995-2012 and 2013-2020). There were no statistically significant differences in survival - both DFS and OS - between the group of patients treated before and after 2012. In the assessment of the impact of some factors on the birth children parameters (weight and length), statistically significant results were obtained for: pregnancy advancement at diagnosis, breast cancer stage at diagnosis, pregnancy advancement at the start of chemotherapy, the chemotherapy regimen (classic or dose-dense), the number of cycles of chemotherapy given during pregnancy, and the number of drugs used in supportive treatment. Conclusions: The entire analysis has become not only an insightful characteristic of the studied group, but also these results may be important in everyday clinical practice and may help to optimize the management of an extremely complex and difficult situation, which is the coexistence of pregnancy with a malignant disease that threatens the mother’s life.