bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between complete response and survival in advanced melanoma treated with talimogene laherparepvec (T-VEC) plus ipilimumab (ipi).
Authors: Chesney Jason Alan , Puzanov Igor , Collichio Frances A. , Milhem Mohammed M. , Hauschild Axel , Yi Min , Bhatta Sumita , Ismail Rubina , Garbe Claus , Singh Parminder , Mehnert Janice M.
Published: May 2020

10029

Background: This is the first randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor for advanced melanoma. At the 3-year (yr) follow-up, the combination (combo) of T-VEC and ipi demonstrated durable and statistically superior objective response rate (ORR) over ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% Cl, 1.6–6.0; P = 0.002). Complete response (CR) rate was 21.4% with the combo and 6.0% with ipi. Median overall survival (OS) was not reached in either arm. In this post hoc analysis, we utilized the 3-yr landmark data to explore the relationship between CR and OS in the combo arm. Methods: Pts with unresectable, stage IIIB-IV melanoma were randomized 1:1 to receive combo or ipi alone. T-VEC was administered intratumorally on day 1 of week (wk) 1 at 106 plaque-forming units (PFU)/mL followed by subsequent doses at 108 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were OS, progression-free survival, and safety. Results: 198 pts were randomized (98 to combo; 100 to ipi). As of February 25, 2019, the median follow-up time was 40.0 mos (range: 0.2–63.7) for the combo arm. Among 98 pts who received combo, 21 (21.4%) had a best overall response of CR including 8 who converted from an initial partial response (PR), 15 (15.3%) had PR, 19 (19.4%) had stable disease, 30 (30.6%) had progressive disease, and 13 (13.2%) were unevaluable. Of 21 pts achieving CR, 17 (81%) had ECOG status of 0, 16 (76.2%) had stage IIIB-IVM1a disease, and 16 (76.2%) had no visceral metastases. Median duration of CR was not reached (range: 5.4[+]–58.2[+] mos); 19 of 21 CRs lasted more than 6 months. The baseline tumor burden was lower in pts with CR than in those with non-CR. Median OS was not reached in pts with CR (range: 25.1[+]–63.7[+] mos) and was 47.6 mos (range: 0.2[+]– 63.7[+] mos) in pts with non-CR (Log-rank P = 0.0005). The Kaplan–Meier estimated 3-year OS rate was 100.0% for patients with CR and 52.3% for those with non-CR. Conclusions: CR rate was higher with T-VEC plus ipi than with ipi alone in pts with advanced melanoma (21.4% vs. 6.0%). In the combo arm, CR was associated with prolonged OS, and pts with CR tended to have better ECOG performance status, earlier-stage disease, and lower baseline tumor burden, as compared with those with non-CR. Clinical trial information: NCT01740297.
Surrogate endpoints for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials of advanced melanoma.
Authors: Nie Run-Cong , Yuan Shu-Qiang , Li Yuanfang , Chen Yingbo , Zhou Zhiwei
Published: May 2020

10030

Background: The mechanisms of action of anti-PD-1/PD-L1 agents are markedly distinct from those of cytotoxic agents, thus a critical issue that is under investigation is what is the optimal endpoint and how should tumor response be evaluated in anti-PD-1/PD-L1 trials for metastatic melanoma. Here, we assessed surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). Methods: PubMed and EMBASE were searched for phase 2/3 RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. Results: We included 8 RCTs (4,110 patients; 11 comparisons). We did not identify strong correlations between ORR (coefficient of determination [ R2]: 0.09 to 0.25), DCR (0.41 to 0.57) and OS. However, we noted a strong correlation between PFS and OS, with R2 of 0.82 in sample size, 0.75 in fixed effect, and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover ( R2: 0.94-0.94), phase 3 trials ( R2: 0.94-0.95), large trials ( R2: 0.78-0.86) and first-line trials ( R2: 0.83-0.91) strengthened the correlation. The STE for PFS was 0.78. Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.
A proteomic biomarker discovery platform for predicting clinical benefit of immunotherapy in advanced melanoma.
Authors: Shaked Yuval , Harel Michal , Issler Eran , Fremder Ella , Jacob Eyal , Dahan Nili , Bar Haim , Halaban Ruth , Sznol Mario , Sharon Ofer
Published: May 2020

10037

Background: Immune checkpoint inhibitor-based immunotherapies that target CTLA-4 and the PD-1/PD-L1 axis have revolutionized the treatment of advanced melanoma due to their remarkable clinical benefit. However, only a limited number of patients respond to treatment. Therefore, biomarkers to identify appropriate candidates who will benefit from such therapy are needed. Our previous studies have identified therapy-induced, host-mediated mechanisms that drive resistance to a variety of cancer treatment modalities. Here, we explored whether assessing the systemic host-mediated response to immunotherapy can serve as a basis for predicting clinical outcome in melanoma patients. Methods: The cohort consisted of 34 advanced melanoma patients receiving anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. Clinical benefit was assessed. Plasma samples were obtained from patients at baseline and 2-4 weeks after a single treatment. Proteomic profiling of plasma samples was performed using ELISA-based protein arrays. A generalized linear model (GLM) was applied to a subset of the cohort (n = 13) to identify a proteomic signature that can predict clinical response to treatment. The predictive signature was then tested on the entire cohort (n = 33), excluding one patient with stable disease. Results: We identified a 10-protein signature that accurately distinguishes between responders and non-responders with an area under the curve (AUC) of 0.84 (confidence interval: 0.69-0.99, p-value 5.56E-04), and sensitivity and specificity of 0.94 and 0.79, respectively. These results are currently being validated in a larger cohort in an ongoing prospective study (PROPHETIC trial, NCT04056247). To explore the biological basis of resistance to immunotherapy, we performed a pathway enrichment analysis. Multiple mechanisms of resistance were identified in the non-responder group, including signaling pathways associated with immunosuppression and inflammation. Comparison between the two treatment modalities revealed pathways unique to each treatment, implying important differences between the two regimens. Conclusions: Our study provides insights into mechanisms of resistance to immunotherapy and paves the way towards the discovery of novel predictive biomarkers for patient stratification in melanoma.
FDG-PET metabolic tumor volume in advanced melanoma treated with ipilimumab and nivolumab (ipi/nivo).
Authors: Iravani Amir , Wallace Roslyn , Lo Serigne , Galligan Anna , Weppler Alison , Au-Yeung George , Kee Damien , Lau Peter Kar Han , Brady Benjamin M , Lee Belinda , McArthur Grant A. , Sandhu Shahneen Kaur , Hicks Rodney J.
Published: May 2020

10041

Background: Predictors of outcomes of immune checkpoint inhibitors (ICI) are desirable. We aim to investigate the prognostic value of 18F-fluorodeoxyglucose-PET/CT (FDG-PET) parameters at baseline and response monitoring of patients (pts) with advanced melanoma receiving ipi/nivo. Methods: From 2016-2019, melanoma pts who received ipi/nivo and had PET Response Criteria In Solid Tumors (PERCIST) measurable lesions on baseline FDG-PET were included. Baseline whole-body metabolic tumor volume (wbMTV), tumor stage, mutational status, ECOG performance score, lactate dehydrogenase (LDH) and treatment-line were correlated with overall survival (OS) in univariate and multivariate Cox-regression analysis. Response were assessed for a subset of pts with post-treatment FDG-PET based on PERCIST. Results: Of 162 pts receiving ipi/nivo, 122 pts (median age: 61; male: 73%; ECOG 0: 78%; raised LDH: 52%; M1c: 39%, M1d: 45% and BRAFV600E/Kmutation: 45%) met eligibility criteria. Forty percent received ipi/nivo as first-line treatment, 48% as second-line (25% post BRAF inhibitor(i)/MEKi and 23% post single-agent ICI) and 12% as third-line. At median follow-up of 21 months (mths), median OS was 20 mths (95% CI 11-not reached[NR]). Pts with above the median wbMTV had shorter OS than those with below the median wbMTV (NR vs 10 mths, 95% CI 8-NR; HR 2.0, 95% CI 1.2-3.4, p = 0.009). In multivariate analysis, wbMTV, ECOG and treatment-line were independently associated with OS. In 106 pts with post-treatment FDG-PET, 24 mths OS rate was higher for those with objective response (OR): 91% (95% CI 82-100%) vs stable disease:55% (27-100%) vs progressive disease:17% (8-35%) as best response, p < 0.001. OR was higher in first-line compared to second or third-line treatment, 75% vs 29-33% vs 23%, respectively, p = 0.0012. Conclusions: Increased baseline FDG-PET wbMTV is an independent prognostic biomarker in pts with advanced melanoma receiving ipi/nivo. FDG-PET response accurately predicts outcome. [Table: see text]
Estimating treatment-free survival (TFS) over extended follow-up in patients (pts) with advanced melanoma (MEL) treated with immune-checkpoint inhibitors (ICIs): Five-year follow-up of CheckMate 067.
Authors: Regan Meredith M. , Mantia Charlene , Werner Lillian , Tarhini Ahmad A. , Rao Sumati , Moshyk Andriy , Ritchings Corey , Rizzo Jasmine I. , Atkins Michael B. , McDermott David F.
Published: May 2020

10043

Background: We previously defined a novel outcome, TFS, to characterize the time between ICI therapy cessation and subsequent therapy initiation/death. TFS is part of an integrated analysis to comprehensively describe how pts spend overall survival (OS) time, on and off treatment, with/without treatment-related toxicity. We reported survival states, including TFS, in ICI-treated pts with MEL in the phase 3 CheckMate 067 trial (NCT01844505) over the 36-mo period since randomization (Regan. J Clin Oncol. 2019); 60-mo results are presented here. Methods: Data were analyzed for 937 pts with MEL who started treatment with nivolumab (NIVO) plus ipilimumab (IPI), NIVO, or IPI in CheckMate 067. TFS was defined as the area between the Kaplan–Meier (KM) curves for 2 conventional time-to-event endpoints defined from randomization: time to protocol therapy cessation and time to subsequent therapy/death. TFS was also divided into TFS with/without grade ≥3 treatment-related adverse events (TRAEs), and OS was estimated. The area under each KM curve was estimated by the 60-mo restricted mean (r-mean) time to event and expressed as a percentage of the 60-mo period. Bootstrapped 95% CIs were calculated for differences. Results: Over the 60-mo period, pts spent an average of 33%, 17%, and 20% of time free of treatment after receiving NIVO+IPI, NIVO, and IPI, respectively (r-mean TFS, 19.7, 9.9, and 11.9 mo; Table). NIVO+IPI-treated pts had r-mean TFS that was 9.8 mo longer than NIVO-treated pts (95% CI, 6.7–12.8) and 7.8 mo longer than IPI-treated pts (95% CI, 4.6–11.0). Mean TFS with grade ≥3 TRAEs remained a small proportion of the 60-mo period at 3%, 2%, and < 1% with NIVO+IPI, NIVO, and IPI, respectively. Conclusions: With extended follow-up, average TFS with/without toxicity represented greater percentages of the 60-mo vs 36-mo period for NIVO+IPI and NIVO, but not for IPI. Pts treated with NIVO+IPI continued to have TFS twice as long as those treated with NIVO alone, due to earlier therapy cessation for toxicity without disease progression and subsequent resolution of many of those toxicities. The majority of TFS time was spent without grade ≥3 TRAEs across all arms. [Table: see text]
Integrated biomarker study of neoadjuvant pepinemab and nivolumab in patients with resectable metastatic melanoma.
Authors: Lowe Michael C. , Olson Brian , Martinez Anthony , Hammons Jacklyn , Delman Keith A. , Yushak Melinda Lynne , Allor Melanie , Reilly Christine A. , Mallow Crystal L. , Evans Elizabeth E. , Fisher Terrence Lee , Lesinski Gregory B. , Kudchadkar Ragini Reiney
Published: May 2020

10061

Background: SEMA4D has broad immunomodulatory effects in the tumor microenvironment (TME); blocking SEMA4D in combination with checkpoint inhibitors (CI) promotes immune infiltration, reduces recruitment of myeloid cells, enhances T cell activity, and promotes tumor regression. We hypothesized that adding pepinemab (VX15/2503), which targets SEMA4D, to CI would increase immunomodulatory effects and augment response in melanoma (NCT03769155). Methods: Patients with resectable stage IIIB/C/D melanoma were enrolled to control (no neoadjuvant therapy) or treatment cohorts (n = 8 in four cohorts of pepinemab plus nivolumab, ipilimumab, nivolumab/ipilimumab or alone). Here we report results from patients receiving two doses of nivolumab (360mg) and pepinemab (15mg/kg) every three weeks followed by surgery. Primary endpoint was T cell infiltration into the TME; secondary endpoints include pathologic response rates, peripheral immune profile, and safety. Results: Ten patients are reported: two were controls, eight received neoadjuvant therapy. Two patients had pathologic complete response, one had a near-complete pathologic response ( < 1% viable tumor), one had a partial response (41% viable tumor) and four had stable disease (73-90% viable tumor). All neoadjuvant patients underwent surgery without delay; one patient experienced grade 3 post-operative cellulitis. There were two treatment-related grade 3 adverse events (weakness and arthralgia). Pharmacodynamic studies confirmed saturation of PD-1 and SEMA4D in peripheral and tumor-infiltrating T cells. T/B cell (CD8+/CD20+) ratios, a surrogate for T cell infiltration, were higher in post-treatment tumors compared to pre-treatment and were higher in the tumor bed compared to normal adjacent tissue. Flow cytometric evaluation identified an increase in CD26hi CD4+ and CD8+ tumor-infiltrating effectors in treated patients compared to controls and an increase in peripheral frequencies of the PD-1-responsive effector HLA-DR+CD38+Ki67+ CD4+ and CD8+ T cells following treatment. Treatment increased infiltration of myeloid populations into the TME, increased expression of PD-L1 on TME myeloid populations, and increased expression of the SEMA4D receptor Plexin-B2 on the surface of TME CD45− and M2 macrophages and MDSC. Conclusions: Neoadjuvant nivolumab and pepinemab results in increased T cell infiltration with excellent major response rate (38%) and expected safety profile. We continue to enroll patients using other rational combinations of pepinemab and CI. Clinical trial information: NCT03769155.
Survival analysis between narrower surgical margins and guideline-recommended margins for excision of cutaneous squamous cell carcinoma: A multicenter, retrospective study of 1,204 Japanese cases.
Authors: Baba Natsuki , Nakamura Yasuhiro , Kato Hiroshi , Matsushita Shigeto , Fujimoto Noriki , Iino Shiro , Saito Shintaro , Asai Jun , Ishikawa Masashi , Yatsushiro Hiroshi , Kawahara Yu , Matsuya Taisuke , Araki Ryuichiro , Teramoto Yukiko , Sasaki Katsuhito , Asami Yuri , Hasegawa Minoru , Yamamoto Akifumi
Published: May 2020

10063

Background: Controversy exists regarding the optimal surgical margin for cutaneous squamous cell carcinoma (cSCC). Current NCCN Guidelines recommend excision with a 4–6-mm clinical margin for low-risk cSCC and wider ( > 6-mm) clinical margin for high-risk cSCC tumors. However, adherence to this guideline is often difficult, as high-risk cSCCs frequently occur on the faces of elderly patients. Thus, we aim to investigate the correlation between different surgical margins and prognosis in patients with cSCC. Methods: Patients with cSCC who had undergone surgical excision of the primary site between 2011 and 2019 at 11 Japanese institutions were included in this study. Patients were divided into two groups: the standard margin group (SMG) with excisions adhering to the guideline-recommended margins, and narrower margin group (NMG) with excisions with narrower margins than are guideline-recommended. Local recurrence-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS) were estimated using Kaplan–Meier analysis and compared between the two groups. Results: A total of 1204 patients with cSCC (SMG, 637; NMG, 567) were included in this study. RFS was significantly lower in SMG than in NMG (5-year RFS 72% vs 79%; P = 0.03); however, no statistically significant differences were observed between the two groups in LRFS (5-year LRFS 80% vs 82%; P = 0.41) or OS (5-year OS 84% vs 83%; P = 0.90). Due to striking statistical significance in several characteristics of patients between the two groups, subgroup analyses, focusing on the cohort of head and neck cSCCs, were also performed. The patient characteristics were similar between SMG and NMG in both the T1-sized tumor ( < 2 cm, SMG, 182; NMG, 250) and T2-sized tumor (2 cm ≤ tumor < 4 cm, SMG, 130; NMG, 136) cohorts, based on AJCC-TNM staging (8th edition). There were also no significant differences between the SMG and NMG in LRFS (5-year LRFS, T1: 80% vs 86%; P = 0.59; T2: 85% vs 84%; P = 0.84), RFS (5-year RFS, T1: 80% vs 81%; P = 0.84; T2: 77% vs 76%; P = 0.99), or OS (5-year OS, T1: 82% vs 87%; P = 0.42; T2: 88% vs 85%; P = 0.68). Furthermore, when the NMG was divided into the two margin groups (margins reduced by < 3 mm or ≥3 mm from the standard margin), no significant difference was observed in LRFS, RFS, and OS. Conclusions: This study did not reveal a significant impact of the size of clinical excision margins on survival in patients with cSCCs. Strikingly, the narrower margins may be more appropriate for < 4 cm-sized head and neck cSCCs.
Cemiplimab as first intervention for patients with locally advanced cutaneous squamous cell carcinoma.
Authors: Atlas Jennifer Lynn , Kanos Marina , Symanowski James Thomas , Brickman Daniel , Forster Meghan , Frenkel Catherine , Milas Zvonimir , Sarantou Terry , White Richard L. , Amin Asim
Published: May 2020

10065

Cemiplimab as First Intervention for Patients with Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) Background: Cutaneous squamous cell carcinoma is the second most common non-melanoma skin cancer. Early stage disease is managed with local intervention in the form of surgery or radiation and translates into cure for greater than 95% of the patients. Patients with high risk disease who have large primary lesions, neural, or nodal involvement are usually not amenable to cure with local intervention and may experience significant morbidity, disfigurement, or functional deficits. These patients had no effective systemic treatment options until recent approval of cemiplimab. We report the outcomes for upfront treatment with cemiplimab in locally advanced cSCC. Methods: This is a single institution retrospective study of patients with locally advanced cSCC defined as those requiring more than simple excision and/or complex repair or regional disease with nodal involvement who received at least two doses of cemiplimab between January 1, 2018 through January 17, 2020. Patients with radiologically measurable disease had response evaluated per RECIST criteria. Patients who had no measurable disease had their clinical response (complete resolution or healing of primary lesion) assessed per treating physician and need or lack of local intervention documented. Adverse events were assessed and graded per CTCAE criteria. The primary end point was to ascertain the need for local intervention. Results: Thirty six patients were eligible. Twenty-two (61%) patients treated with upfront cemiplimab were able to avoid local intervention with surgery and/or radiation; four patients progressed or died on treatment. Three (8%) patients received local intervention. Eleven (31%) patients are still receiving cemiplimab and local intervention decision is pending. The overall response rate was 69% and the clinical benefit rate was 92%. The median treatment duration was six months and the median number of doses received was six. Adverse events occurred in 31% of patients; the most common adverse event was dermatitis. Conclusions: Upfront treatment with cemiplimab in patients with locally advanced cSCC obviated need for disfiguring/complex surgery or radiation in majority of patients. Cemiplimab was tolerated well; no new safety signals were observed. Neo-adjuvant phase II study is in development.
Radiomic signatures to predict response to targeted therapy and immune checkpoint blockade in melanoma patients (pts) on neoadjuvant therapy.
Authors: Colen Rivka R. , Ologun Gabriel O. , Zinn Pascal , AK Murat , Arora Reetakshi , Burton Elizabeth M. , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Patel Sapna Pradyuman , Diab Adi , Wong Michael K. , McQuade Jennifer Leigh , Ross Merrick I. , Ahmed Sara , Elshafeey Nabil , Gershenwald Jeffrey E. , Davies Michael A. , Tetzlaff Michael T. , Amaria Rodabe Navroze , Wargo Jennifer Ann
Published: May 2020

10067

Background: Metastatic melanoma pt outcomes have been revolutionized by targeted therapy (TT) and immune checkpoint blockade (ICB), which are now being evaluated in the neoadjuvant (neoadj) setting. While tumor-based biomarkers may help predict response, predictors of response obtained by less invasive strategies could greatly benefit pt care and allow real-time treatment response monitoring. Radiomic signatures derived from computerized tomography (CT) images have recently been shown to predict response to ICB in stage IV pts. However, the association of radiomic features with pathological response following neoadj therapy has not been assessed. We sought to determine if radiomic assessment predicts pCR in pts receiving neoadj TT and ICB. Methods: We collected data for a cohort of melanoma pts with locoregional metastases who were treated with neoadj TT (n = 33) or ICB (n = 30). Pts received systemic therapy for 8-10 weeks prior to planned surgical resection. Responses were evaluated radiographically (RECIST 1.1) and via pathological assessment (evaluating for pathologic complete response; (pCR) versus < pCR). Thirty two pts (19 ICB; 13 TT) were included in the radiomics analysis based on the availability of appropriate CT imaging. A total of 310 unique radiomic features (10 histogram-based and 300 second-order texture features) were calculated from each extracted volume of interest (VOI). Feature extraction was performed on baseline and initial on-treatment pre-operative CT scans. Features associated with pCR were assessed using a feature selection approach based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of pCR to ICB or TT. Leave-One-Out Cross-Validation was performed to evaluate the robustness of the estimates. Results: Out of 310 radiomic features, three features measured at baseline were able to predict a pCR to neoadj ICB or TT with sensitivity, specificity and accuracy of 100%, though these signatures were non-overlapping. In the on-treatment pre-operative scans, 3 distinct features (also non-overlapping and distinct from the predictive pre-treatment signatures) also predicted pCR to ICB and TT with 100% sensitivity, specificity and accuracy. Conclusions: Radiomic signatures in baseline and on-treatment CT scans accurately predict pCR in melanoma pts with locoregional metastases treated with neoadj TT or ICB. These provocative findings warrant further investigation in larger, independent cohorts.
Effect of automated TIL quantification in early-stage melanoma on accuracy of standard T staging using AJCC guidelines.
Authors: Moore Michael , Friesner Isabel D , Rizk Emanuelle M. , Trager Megan , Celebi Julide T. , Rich Jeani , Chikeka Ijeuru , Kurc Tahsin , Wang Jing , Rohr Bethany , Robinson Eric , Geskin Larisa J. , Horst Basil , Gardner Kevin , Niedt George , Messina Jane , Ferringer Tammy , Saltz Joel H. , Vanguri Rami , Saenger Yvonne M.
Published: May 2020

10076

Background: Patients diagnosed with early stage melanoma are at risk of recurrence and death. Adjuvant therapy decreases risk but incurs toxicity and expense. While tumor-infiltrating lymphocytes (TILs) improve prognosis, studies have shown conflicting results due, at least in part, to inter-observer variability. Thus, TILs are not included in standard American Joint Committee on Cancer (AJCC) staging. Here, we quantitatively analyze TILs in hematoxylin and eosin (H&E) melanoma images using two machine learning algorithms. Methods: H&E images were evaluated by two methods for patients with resectable stage I-III melanoma from Columbia (N = 81) and validated using samples from Geisinger and Moffitt (N = 128). For both methods, H&E images were manually annotated using open source software, QuPath, to specify tumor regions. For Method A, images were divided into patches and, for each patch, a probability was generated to detect lymphocytes. Patches above a set threshold were considered to be “TIL positive”. Ratio of TIL positive patches to total patches was assessed for every image. For Method B, a classifier was manually trained in QuPath and then applied on each image to determine the ratio of the areas of all immune cells to all tumor cells as previously published. Cutoff values to define high and low risk groups were established based on a test set and then validated in an independent cohort. Results: Both methods distinguished patients with visceral recurrence from those without for the Columbia training set (Method A p = .0015, Method B p = .043). Using Method A, Kaplan-Meier curve at the selected cutoff also correlated significantly with disease specific survival (DSS) for Columbia (p = .022) and was validated in the Geisinger/Moffitt (p = .046) cohort. Cox analysis using Method A showed that TIL status predicted DSS in the validation set (p = .047) and added significantly to depth and ulceration (HR = 3.43, CI: 1.047-11.257, p = .042). Conclusions: Both open source machine learning algorithms find significantly higher TILs in patients who do not develop metastasis. Notably, Method A may add to standard predictors, such as depth and ulceration. These results demonstrate the promise of computational algorithms to enhance visual grading, and suggest that digital TIL evaluation may add to current AJCC staging. [Table: see text]
Pooled ctDNA analysis of the MONALEESA (ML) phase III advanced breast cancer (ABC) trials.
Authors: Andre Fabrice , Su Fei , Solovieff Nadia , Arteaga Carlos L. , Hortobagyi Gabriel N. , Chia Stephen K. L. , Neven Patrick , Bardia Aditya , Tripathy Debu , Lu Yen-Shen , Wang Yingbo , Rodriguez-Lorenc Karen , Taran Tetiana , Babbar Naveen , Slamon Dennis J.
Published: May 2020

1009

Background: Biomarker analyses have been presented separately for each Phase III ML trial, which tested efficacy and safety of ribociclib (RIB) with different endocrine therapy (ET) combination partners as first- or second-line treatment for hormone receptor–positive, HER2-negative (HR+/HER2−) ABC. Here, using the largest pooled biomarker dataset of a CDK4/6 inhibitor in ABC to date, we identify potential biomarkers of response or resistance to RIB across ML trials. Methods: Baseline ctDNA from 1503 patients (pts) enrolled in ML-2, 3, and 7 was assessed using next-generation sequencing with a targeted panel of 557 genes. Genes with an alteration frequency ≥2% and in ≥15 pts per treatment arm were included (83 genes). Genetic alteration was defined as presence of a mutation, short insertion/deletion, or copy number alteration. Cox proportional hazard model of progression-free survival (PFS) was fit with gene-by-treatment interaction. Genes with interaction P< 0.10 and genes of interest were investigated. Results: Pts with alterations in FRS2 and PRKCA (treatment interaction P< 0.05) as well as MDM2, ERBB2, AKT1, and BRCA1/2 ( P> 0.05 but considered actionable) had a trend for increased PFS benefit of RIB vs PBO (Table). Pts with alterations in CHD4, BCL11B, ATM, or CDKN2A/2B/2C derived little to no added PFS benefit with RIB vs PBO ( P interaction < 0.10; hazard ratio [HR] > 0.80). Data on genes implicated in the literature as potential mechanisms of resistance to ET and/or CDK4/6 inhibition ( ESR1, PTEN, FAT1, RB1, and NF1) will be presented. Conclusions: Results of this pooled analysis of the ML-2, 3, and 7 trials, the largest biomarker analysis of any CDK4/6 inhibitor in ABC, revealed several potential biomarkers of response ( FRS2, MDM2, PRKCA, ERBB2, AKT1, and BRCA1/2) or resistance ( CHD4, BCL11B, ATM, or CDKN2A/2B/2C) to RIB. Clinical trial information: NCT01958021; NCT02422615; NCT02278120 . [Table: see text]
A phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1).
Authors: Tolaney Sara M. , Kalinsky Kevin , Kaklamani Virginia G. , D'Adamo David R. , Aktan Gursel , Tsai Michaela L. , O'Regan Ruth , Kaufman Peter A. , Wilks Sharon , Andreopoulou Eleni , Patt Debra A. , Yuan Yuan , Wang Grace , Xing Dongyuan , Kleynerman Ella , Karantza Vassiliki , Diab Sami
Published: May 2020

1015

Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]
Comparison of StemPrintER, a novel biology-based genomic predictor of distant recurrence in breast cancer, with Oncotype DX in the TransATAC cohort.
Authors: Pece Salvatore , Sestak Ivana , Montani Francesca , Tillhon Micol , Freddi Stefano , Maisonneuve Patrick , Colleoni Marco , Veronesi Paolo , Disalvatore Davide , Viale Giuseppe , Buus Richard , Cuzick Jack M. , Dowsett Mitchell , Di Fiore Pier Paolo
Published: May 2020

1020

Background: Accurate prediction of distant metastasis (DM) in early stage ER+/HER2- breast cancer (BC) patients is vital to avoid over/under-treatment with adjuvant chemotherapy (CT). The OncotypeDX Recurrence Score (RS) is a widely used tool to assist clinical decision-making for CT. The StemPrintER Risk Score (SPRS) is an alternative genomic predictor based on the biology of cancer stem cells that predicts recurrence risk in ER+/HER2- BCs (Pece S. et al., EBioMedicine 2019). Here, we analyze the prognostic value of SPRS in the TransATAC cohort of post-menopausal ER+/HER2- BC patients, and compare the prognostic information provided by SPRS and RS for 10-year risk of DM. Methods: The likelihood χ2 (LRχ2) and Kaplan-Meier survival analyses were used to assess prognostic information provided by SPRS, RS and the clinical treatment score (CTS) in 818 TransATAC patients treated with anastrozole or tamoxifen for 5 years. Comparative analyses were made for DM risk over the 10-year follow-up, as well as in the early (0-5 years) or late (5-10 years) interval, according to nodal status. Results: Used as a continuous variable, SPRS was an independent predictor of DM in years 0-10 among all patients when adjusted for clinical parameters as expressed by the CTS [HR=1.43 (1.18-1.73), P<0.0001], as well as in node-negative [HR=1.51 (1.17-1.94), P=0.001] but not node-positive (N1-3) patients [HR=1.29 (0.95-1.75), P=0.11]. A predefined SPRS cut-off was used to stratify patients into low vs. high risk groups [LOW: N=454, 10-year DM rate=5.8%; HIGH: N=364, 10-year DM rate=21.9%; HRHIGH vs. LOW=2.96 (1.85-4.73); P<0.0001]. SPRS outperformed RS in providing prognostic information for 10-year DM risk (SPRS: HR=1.79, P<0.0001, LRχ2=33.4; RS: HR=1.52, P<0.0001, LRχ2=22.1), with even greater differences in late DM prediction in N0 patients. SPRS also provided more prognostic information than RS to CTS (ΔLRχ2: SPRS+CTS vs. CTS= 14.9; RS+CTS vs. CTS= 9.7). Conclusions: In ER+/HER2- TransATAC BC patients, SPRS was highly prognostic for DM and was superior to RS in providing additional prognostic information to conventional clinicopathological parameters.
The contribution of clinical subtype to survival differences among patients with de novo and recurrent metastatic breast cancer (dMBC).
Authors: File Danielle Marie , Pascual Tomas , Deal Allison Mary , Wheless Amy , Dees Elizabeth Claire , Carey Lisa A.
Published: May 2020

1030

Background: Patients with de novo metastatic breast cancer (dMBC) have superior median overall survival (mOS) compared to recurrent metastatic breast cancer (rMBC). Whether patient characteristics, prior treatment, tumor stage and innate biological differences contribute to this observation is unknown. Methods: Clinical and pathological data from patients diagnosed with MBC from 2011 to 2017 at the University of North Carolina (UNC) was obtained from the prospective UNC Metastatic Breast Cancer Clinical Database (223 dMBC, 607 rMBC). Only patients with known survival status were included. Subtype was determined by hormone receptor (HR) and HER2 staining of the primary tumor. Pathologic staging results were used when available, otherwise clinical staging was used. Patient and tumor characteristics were compared using chi-square testing, and survival outcomes by Cox proportional hazards modeling. Results: 26.9% of patients with MBC presented with dMBC, with significant variation in the ratio of dMBC to rMBC across subtypes. In particular, there were more cases of HER2+ dMBC than rMBC (26.9% vs 14.0%) and fewer cases of triple negative dMBC (20.6% vs 35.3%)(p-value < 0.001). Nearly half of all cases of HR-/HER2+ MBC were de novo (48.2%). dMBC was significantly associated with older age (p = 0.002), lower grade (p = 0.027), higher T and N stage (p < 0.001) and African American race (30% vs 22%, p = 0.022). There was no significant difference in proportion of patients with visceral metastatic disease or in number of metastatic sites at diagnosis. Median follow up was 39 months in both cohorts. mOS was 12 months greater in dMBC than rMBC (34m vs 22m, p < 0.001). These differences were significant across all subtypes except HR+/HER2+. The difference in mOS between dMBC and rMBC was greatest in the HR-/HER2+ subgroup (45m vs 15m, p = 0.006). In multivariable analysis, dMBC remained associated with improved survival (adjusted hazard ratio 0.59, p < 0.001) independent of variables including age, race, subtype, grade and number of metastatic sites at diagnosis. Conclusions: Patients with dMBC have significantly better prognosis than those with rMBC. This improved outcome is in part due to subtype variation, with more triple negative and fewer HER2+ tumors in rMBC, however these differences largely remained when stratified by subtype. In multivariable analysis, de novo presentation of MBC remained an independently significant contributor to longer survival. Further investigation should focus on biologic differences between dMBC and rMBC.
Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2+/HR+ metastatic breast cancer.
Authors: Loft Matthew , Lok Sheau Wen , De Boer Richard H. , Malik Laeeq , Greenberg Sally , Yeo Belinda , Anton Angelyn , Nott Louise M. , Richardson Gary Edward , Collins Ian M. , Torres Javier , Barnett Frances Sarah , Devitt Bianca Alix , Gibbs Peter , Gately Lucy
Published: May 2020

1038

Background: The combination of dual anti-HER2 targeted therapy and chemotherapy is the current first line standard of care for HER2+ metastatic breast cancer. Endocrine therapy (ET) is the backbone of treatment in hormone receptor positive (HR+) disease, but the role of the addition of endocrine therapy following chemotherapy in HER2+/HR+ disease remains unclear as pivotal first line clinical trials excluded endocrine therapy use. Methods: Data from a multi-site community cohort of consecutive HER2+ metastatic breast cancer patients diagnosed between 1 January 2012 and 31 August 2019 was examined. Patients were treated at clinician discretion. The subset of patients eligible for this analysis were those that were HR+ and had received first line dual anti-HER2 targeted therapy. Results: Of 132 eligible patients included in the analysis, 78 (59.1%) received endocrine therapy and 54 (40.9%) did not. Median follow up was 25.9 months. There were no significant differences between the two groups based on age, performance status, previous therapy or de novo disease (Table), however, patients with bone metastases were more likely to receive ET in conjunction with first line dual anti-HER2 therapy (71% vs 52%, p= .043). The addition of ET was associated with improved progression free (HR 2.1, 95% CI 1.2-3.5, p = 0.007) and overall survival (HR 2.7, 95% CI 1.2-5.5, p = 0.007) in multivariate analysis. No increase in serious adverse events was noted although endocrine therapy related toxicities were not specifically collected. Conclusions: In this real-world series, the addition of ET to first line dual anti-HER2 therapy in HER2+/HR+ metastatic breast cancer was associated with improved progression free and overall survival. Further research is required to validate these findings and examine the role of CDK4/6 inhibitors in this disease, but may provide reassurance to clinicians considering ET in this clinical context. [Table: see text]
Preliminary safety, efficacy and pharmacokinetics (PK) results of KN026, a HER2 bispecific antibody in patients (pts) with HER2-positive metastatic breast cancer.
Authors: Ji Dongmei , Zhang Jian , Shen Weina , Du Yiqun , Xu June , Yang Jing , Luo Xin , Kong Paul , Yang Fei , Hu Xi-Chun
Published: May 2020

1041

Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It blocks ligand-dependent and independent tumor growth and enhances HER2 receptor internalization. In preclinical studies, KN026 showed activity in trastuzumab plus pertuzumab resistant tumor cell lines. This first-in-human study evaluated the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy of KN026 monotherapy. Methods: This dose-escalation and expansion study enrolled Chinese patients (pts) with metastatic breast cancer who have failed prior anti-HER2 therapy. All pts intravenously received KN026 monotherapy at ascending dose of 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose limiting toxicity (DLT) evaluation period was 28 days for QW and Q2W, and 21 days for Q3W. Efficacy evaluation was performed by RECIST 1.1 every 6 weeks and safety assessment according to CTCAE v 4.03. Results: As of the Jan, 22, 2020, 63 pts [median age: 54 years (31~69)] enrolled and 62 pts were included in the efficacy analysis. 41 pts remained on treatment and 22 pts discontinued treatment due to disease progression (n = 21) and adverse events (n = 1). The median treatment duration was 12 weeks (range: 4~62 weeks). Median prior lines of therapies are 3 (range: 1~15), and median prior lines of HER2 target therapies are 2 (range: 1~12). No DLTs were observed. Treatment-related AEs (TRAEs) occurred in 49 pts and 4 pts experienced 4 grade 3 TRAE (hypertension, infusion related reaction, transaminases increased and ventricular arrhythmia). The common (≥ 10%) TRAE were pyrexia (23.8%), diarrhea (19.0%), aspartate aminotransferase increased (15.9%), neutrophil count decreased (11.1%) and white blood cell count decreased (11.1%). The objective response rate at recommended Phase 2 dose levels (n = 56) was 32.1% (95% CI 20.3, 46.0) and disease control rate 76.8% (95% CI 63.6, 87.0). Pharmacokinetic analysis showed exposure (Cmax and AUC0-t) of KN026 increased by dose. The recommended Phase 2 dose (RP2D) were 20 mg/kg Q2W and 30 mg/kg Q3W. Conclusions: KN026 is well tolerated and has demonstrated encouraging anti-tumor activity in HER2-positive breast cancer patients who have failed standard anti-HER2 therapies. The recommended Phase 2 dose (RP2D) of KN026 were 20 mg/kg Q2W and 30 mg/kg Q3W. Phase II trials in various HER2-positive and HER2-low/intermediate solid tumors are currently ongoing. Clinical trial information: NCT03619681 .
Final analysis of phase I study of ceritinib in pediatric patients with malignancies harboring activated anaplastic lymphoma kinase (ALK).
Authors: Schulte Johannes H , Moreno Lucas , Ziegler David Simon , Marshall Lynley V. , Zwaan C. Michel , Irwin Meredith , Casanova Michela , Sabado Constantino , Wulff Beate , Stegert Mario , Wang Luojun , Hurtado Felipe K. , Branle Fabrice , Fischer Matthias , Geoerger Birgit
Published: May 2020

10505

Background: Activation of anaplastic lymphoma kinase has been detected in several pediatric malignancies, including anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), neuroblastoma and others. Preliminary findings from this phase 1, multicenter, dose-escalation study (NCT01742286) indicated a Maximum Tolerated Dose (MTD)/Recommended Dose for Expansion (RDE) of the potent oral ALK inhibitor ceritinib to be 510 mg/m2 (fasted) and 500 mg/m2 (fed) in pediatric patients (pts). Here, we report final safety, pharmacokinetics (PK) and efficacy results. Methods: Children aged ≥1 to <18 years with advanced, mostly pretreated, ALK-aberrant malignancies were enrolled in this study. Dose escalation was conducted to determine the MTD/RDE of ceritinib (primary objective), in both fasted and fed states, following which pts entered an expansion phase to evaluate safety, tolerability, and efficacy at the MTD/RDE. Secondary objectives were evaluation of safety, PK, and efficacy (overall response rate [ORR], duration of response [DOR] and progression-free survival [PFS]). Results: A total of 83 pts (median age, 8 years) with ALK-aberrant malignancies were enrolled into dose-escalation (n = 40) and expansion (n = 43) study periods. Of these, 55 pts (neuroblastoma, n = 30; IMT, n = 10; ALCL, n = 8; others, n = 7) were treated with ceritinib at MTD/RDE (510 mg/m2 [fasted], n = 13; 500 mg/m2 [fed], n = 42). Systemic exposure of ceritinib between the two doses was comparable, so data were pooled for efficacy assessment. The ORRs (95% CI) were 75% (34.9-96.8) for pts with ALCL, 70% (34.8-93.3) for IMT and 20% (7.7-38.6) for neuroblastoma. The median DOR was 15 months (95% CI: 5.8, 22.2) for the 6/30 pts with neuroblastoma who had confirmed CR or PR treated at fasted/fed MTD/RDE. Median DOR was not reached for those with ALCL and IMT. Most common adverse events (AEs) (N = 83; all-grades, all-causality, ≥50% of pts): vomiting (86.7%), diarrhea (78.3%), increased ALT (65.1%), increased AST (59.0%), nausea (56.6%), and abdominal pain (50.6%). Grade 3/4 AEs were observed in 80.7% of pts (mostly transaminase elevations) and were manageable. Six pts (7.2%) were discontinued from ceritinib due to a grade 3/4 AE (mostly transaminase elevation). Conclusions: Substantial activity was observed with ceritinib at the RDE in pts with IMT, ALCL and heavily pretreated neuroblastoma. The toxicity profile of ceritinib in children was manageable and similar to that previously reported in adults. Clinical trial information: NCT01742286.