Patients Experienced Disease Progression Research Articles

Combination Treatment With Paclitaxel, Carboplatin, and Cetuximab (PCE) as First-Line Treatment in Patients With Recurrent and/or Metastatic Nasopharyngeal Carcinoma.

Background: Platinum-containing doublet chemotherapy regimens are generally considered the standard first-line systemic therapy for recurrent or metastatic (R/M) nasopharyngeal cancer (NPC). Gemcitabine (GEM) plus cisplatin (CDDP) has become a standard therapy based on a phase 3 study in several countries, yet this regimen sometimes affects quality of life due to nausea or appetite loss. Here, we present the manageable toxicity and promising activity of paclitaxel + carboplatin + cetuximab (PCE) therapy for R/M NPC.Materials and Methods: We conducted a retrospective review of patients with R/M NPC who were treated with PCE from 2013 to 2019 at the National Cancer Center East, Kashiwa, Japan. PCE consisted of PTX 100 mg/m2 on days 1 and 8; CBDCA area under the blood concentration–time curve (AUC) 2.5 on days 1 and 8, repeated every 3 weeks; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly, as reported in the paper.Results: Fourteen patients were identified, consisting of 10 males and 4 females with a median age 59.6 years (range, 43–74). Among the 12 of 14 patients assessed for efficacy, overall response rate was 58.3%, with 2 complete responses and 5 partial responses. On median follow-up of 23.8 months, median overall survival was not reached with observed death events of 2. Median PFS was 4.1 months (95% CI, 2.6–5.6 months). Two patients experienced disease progression during cetuximab maintenance and restarted PCE treatment, then achieved partial response again. The most common grade 3 or 4 adverse events were neutropenia (21.4%) and skin reaction (14.3%). No treatment-related death was observed.Conclusion: Although the number of study population was small, our results suggest that PCE is feasible and potentially effective for R/M NPC, with a 58.3% response rate and 4.1-month PFS. Further prospective evaluation is warranted.

Long-term follow-up of abbreviated R-CHOP chemoimmunotherapy for completely resected limited-stage diffuse large B cell lymphoma (CISL 12-09).

The standard of treatment for completely resected limited-stage diffuse large B cell lymphoma (DLBCL) in patients without residual lesions has not yet been established. Previously, we designed a phase II trial to evaluate the safety and efficacy of three cycles of abbreviated R-CHOP in patients with completely resected limited-stage DLBCL and reported favorable survival outcomes. We present the long-term follow-up results to taking into account the importance of delayed relapse in patients with limited-stage DLBCL. With a median follow-up duration of 62.7months (range, 60.2-75.5months), the 5-year OS and DFS rates were both 95.0% (95% confidence interval, 85.59-104.11%). Only one patient experienced disease progression which was confirmed at 12.3months, and one patient with primary intestinal DLBCL developed non-small cell lung cancer 6years after treatment. The long-term results of our data support the use of three cycles of abbreviated R-CHOP for patients with completely resected limited-stage DLBCL. The study was reviewed and approved by the review boards of the participating institutes and registered at ClinicalTrials.gov , number NCT01279902, in August 3, 2010.

Abstract PO-004: A double-edged sword: Prolonged detection of SARS-COV-2 in patients receiving cancer-directed therapy

Abstract Introduction: SARS-CoV2 (S-2) infection duration (S-2-D) and its impact on patients with cancer and mild to moderate COVID-19 undergoing cancer-directed therapy (CDT), especially in the underserved population, is not well described. We conducted a retrospective study to analyze S-2 positive (+) patients on CDT to describe the S-2-D and its impact on CDT. Methods: 299 patients with cancer were tested with nasopharyngeal (NP) S-2 PCR assay at Columbia University Medical Irving Center (CUIMC), a Minority-NCI Community Oncology site, of whom 77(26%) tested positive. We retrospectively analyzed 25 S-2 (+) patients with mild to moderate COVID-19 receiving CDT. NP PCR were repeated every one to two weeks until two successive negative (-) PCRs were obtained prior to restarting CDT. Time to two (-) PCR and serology results were recorded. Cycling thresholds (Ct) were obtained for S-2 specific targets and represented an indirect measure of viral load. Results: Demographics of N=25 patients included Hispanic (N=17, 68%), Black (N=1, 4%), White (N=6, 24%), and undeclared (N=1, 4%). Among the tumor histologies represented, gastrointestinal (N = 9, 36%), breast (N = 4, 16%), sarcoma (N = 3, 12%), and myeloma (N=2, 8%) were most common. Median time in days (d) to two (-) PCR was 24 (6-69). Nine (36%) patients were persistently (+) for more than six weeks. 20 patients had CDT interruption with a median time of 55 days off CDT. Two (10%) patients experienced disease progression during CDT interruption. 13 patients had >1 sequential (+) PCR. The mean time between 1st and 2nd NP S-2 PCR was 16d. There was a non-statistically significant trend towards a higher S-2 specific Ct on the 2nd NP S-2 PCR as compared to the 1st (31.21 vs 22.31, p=0.10). One patient was noted to be PCR (+) despite having developed S-2-specific IgG. Conclusion: Patients with cancer receiving CDT appear to have prolonged detectable S-2 by PCR, which can lead to interruption of CDT and POD in patients. Patients from underserved communities may be at greater risk given health care disparities. Further data are needed to help select patients with mild to moderate COVID-19 who can safely continue CDT while balancing the risk of worsening infection and risk of spread. The increased Ct over time in our patients suggest a decrease in viral load and infectious probability. Our lack of statistical significance is likely due to small sample size. Ct along with serology can be tools to help guide when and which patients can restart CDT. However, these tests need further investigation for applicability and validity. Citation Format: Winston Wong, Claire Brevia, Michael May, Susan Whittier, Eldad Hod, Ilenia Pellicciotta, Gary K. Schwartz, Maura Abbott, Gulam A. Manji. A double-edged sword: Prolonged detection of SARS-COV-2 in patients receiving cancer-directed therapy [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-004.

Mantle Hücreli Lenfoma Hastalarımızın Klinik ve Laboratuvar Özellikleri: Kesitsel Bir Çalışma

Mantle cell lymphoma (MCL) comprises less than 10% of non-Hodgkin's lymphoma cases. Major independent risk factors are identified as the MCL International Prognostic Index (MIPI) and Ki-67 proliferation index of tumor. The aim of this study is retrospectively evaluate MCL patients treated and followed-up in our department. Materials and Methods: This study included 27 MCL patients medical records of whom could be reached. The data was reviewed to figure out MIPI score, bone marrow involvement, extranodal involvement, treatment protocols, treatment response, relapse status, and transplant history. Patients were followed-up for a mean duration of 64.4 (1-246) months. Subsequent to the first-line treatment, complete response was achieved in 17 (63%) and partial response was achieved in 3 (11%) patients, whereas 7 (26%) patients experienced disease progression. Median PFS following first-line treatment was 29 (3-120) months. Based on the classification by MIPI scoring, low-risk patients had significantly longer median survival than that of high-risk patients (194 months vs 126 months, p=0.04), and the patients at moderate-risk had significantly longer PFS compared to high-risk patients (41month vs 3 months, p=0.025). Median age, stage III-IV, and short duration of PFS in patients with high MIPI score were our findings in parallel with available literature. R-hyper-CVAD/MTX-AraC was mostly preferred first-line treatment at our center with a shorter median PFS compared to literature. Given the expanding use of target-driven therapies for MCL, we believe our results are noteworthy in comparing such therapies with pre-existing therapies.

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.

TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals.

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.

IBCL-176: Single-Centre Experience with Stem-Cell Transplantation in Patients with Transformed Lymphoma: A Potential Curative Option

Context: Outcomes of patients with transformed lymphoma have historically been poor, prompting many centres to include stem-cell transplant (SCT) as part of the treatment strategy. However, several studies in the rituximab era suggest that survival may be more favourable than previously recognized, questioning the need for such intensive therapies. Objective: We analyzed the efficacy of SCT in transformed lymphomas at a single reference Transplant Unit. Design: We collected data from 51 patients; the indication was a diagnosis of diffuse large B-cell lymphoma (DLBCL) transformed from an indolent lymphoma, from 1995 to 2018. Of them, 36 received an auto-SCT and 15 an allo-SCT. Results: Median age was 60 (range, 40-69) and 52 (range, 35-65) years for patients receiving auto-SCT and allo-SCT, respectively. Patients in the allo-SCT group had been more intensively pretreated, as 13 (87%) patients received >3 lines of treatment before SCT and 13 (87%) underwent a previous auto-SCT, whereas patients in the auto-SCT group were pretreated with a median of 2 (range, 1 to 4) lines of treatment. Regarding disease status at transplant, most patients (78% and 73% in the auto and allo-SCT groups, respectively) were transplanted in complete remission (CR). All auto-SCT patients received BEAM as conditioning regimen, whereas patients in the allo-SCT group received several fludarabine-based combinations. Transplant-related mortality (TRM) was 3.2% and 27% in the auto and allo-SCT groups, respectively. With a median follow-up of 61 and 50 months,4-year overall survival (OS) and progression-free-survival (PFS) were 87% and 76%, for the auto-SCT patients, and 52% and 56%, respectively, for the allo-SCT patients. In the auto-SCT group, 12 (33%) patients experienced disease progression and 7 (19.5%) died (5 [13.9%] from lymphoma), whereas in the allo-SCT group, only 2 (13%) patients had disease progression but 4 (27%) died due to transplant-related causes. Conclusions: SCT is a potentially curative option for patients with transformed lymphoma, since more than a half of patients are long-term survivors. Progression is the major cause of failure in auto-SCT whereas allo-SCT patients died because of toxicity. Efforts need to be made to identify patients who do not benefit from auto-SCT to avoid toxicity.

IBCL-057: Liquid Biopsy-Based Monitoring of Ezh2 Mutations in Follicular Lymphoma: Implications for Non-Invasive Disease Monitoring and Targeted Therapy

Context: Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphomas, with an average overall survival rate of 15 years. The majority of FL patients experience disease progression or high-grade transformation to a more aggressive lymphoma, raising the need for effective treatment response monitoring, which, however, is hampered by the limited specificity and sensitivity of the most widely used, imaging-based PET-CT method. Molecular analysis of tumor-derived circulating DNA (ctDNA), frequently referred as liquid biopsy, is a promising, minimally invasive, radiation-free disease monitoring tool for patients suffering from a wide range of different tumor types. Recent studies interrogating the genomic background of FL have revealed activating mutations in the epigenetic regulator EZH2 gene in 25% of patients at diagnosis. Objective: In this feasibility study, we tested the power of detection and time-resolved monitoring of EZH2 mutations in ctDNA of FL patients receiving immunochemotherapy (ICT). Methods: Thirty-five blood plasma samples have been collected from 19 EZH2 mutant FL patients treated with ICT. After ctDNA isolation, EZH2 mutations were screened in each sample using digital droplet PCR (Bio-Rad Laboratories, USA). The acquired genetic results were compared with PET-CT-based imaging data where available. Results: EZH2 mutations were detected in plasma samples of four patients suffering from active or transformed FL. All patients with EZH2 wild type plasma samples were in complete or partial remission. In patients with EZH2 mutation-positive ctDNA, allele frequencies of the mutations correlated with the amount of metabolically active tumor sites observed on PET-CT scan images. Variant allele frequencies of EZH2 mutations rapidly declined or dropped below the detection limit upon successful treatment, while in one patient, treatment failure was associated with high EZH2 variant allele frequency. We also demonstrated spatial heterogeneity of EZH2 mutations in another case where different EZH2 mutations deriving from distinct anatomical sites could simultaneously be detected in the plasma. Conclusions: Our results suggest that liquid biopsy-based EZH2 mutation analysis with sensitive digital droplet PCR method offers a real-time, radiation-free, sensitive treatment response monitoring tool for patients with active EZH2 mutant FL.

Abstract 799: CDKN2A mutation predicts immunotherapy resistance in stage III/IV NSCLC

Abstract Purpose: Immune checkpoint blockade (ICB) has improved outcomes for patients with non-small cell lung cancer (NSCLC). However, most patients experience disease progression. There is limited data regarding molecular predictors of progression, particularly in those patients predicted to respond most favorably. We used a next-generation sequencing (NGS) platform to identify genomic aberrations associated with clinical outcomes following ICB in NSCLC. Methods: We retrospectively reviewed stage III/IV NSCLC patients who received radiotherapy (RT) in our department and underwent NGS with OncoPlus, a 1212-gene hybrid capture genomic sequencing assay. We characterized tumor mutations and insertions/deletions for patients who received ICB as well as other systemic therapies and investigated their associations with clinical outcome. Results: 149 patients with stage III/IV NSCLC received RT from 2011-2019 and underwent OncoPlus. Median age was 65, median ECOG was 1, and 125 had a smoking history. 87% had adenocarcinoma. AJCC 8th edition staging: IIIA (n=24), IIIB (n=14), IIIC (n=3), IVA (n=16), and IVB (n=92). 79% had PD-L1 staining: 0% in 45 patients (38%), 1-49% in 34 (29%), and ≥50% in 38 (32%). All received RT to a median of 2 lesions (range 1-15); 48% received palliative RT and 52% received ≥1 course of definitive RT (conventional or ablative). The majority received systemic therapy: 68% (n=102) received chemotherapy, 55% (n=82) received ICB, and 30% (n=44) received targeted therapies. Median follow-up was 18 months (range 1-95); most experienced isolated distant failure (n=64, 43%) or regional/distant failure (n=35, 23%) following their first RT course. The most frequent pathogenic mutations/indels were TP53 (68%, n=101), KRAS (31%, n=45), CDKN2A (27%, n=40), STK11 (26%, n=39), EGFR (19%, n=28), and TP53/KRAS co-mutation (17%, n=26). We found CDKN2A mutation (25%)/deletion (75%) was associated with inferior median recurrence-free survival (RFS; 3 vs. 6 mo., p=0.013) and more markedly median OS (13 vs. 38 mo., p=0.015) compared to wild-type tumors. On multivariate Cox proportional hazards analysis including stage, ECOG, PD-L1 %, TMB, type of RT, and # of RT sites, CDKN2A loss was independently associated with 2.5-fold risk of progression (p=0.018) and 3.3-fold risk of death (p=0.05). In high TMB (top 25th%; n=21) or high PD-L1 (>50%; n=30) NSCLCs, CDKN2A loss was negatively associated with RFS (TMB p=0.005; PD-L1 p=0.034) and in the high PD-L1 cohort with a trend towards inferior OS (p=0.08). Conclusions: In a large cohort of stage III/IV NSCLC patients treated with systemic therapy and RT, NGS identified CDKN2A mutation/deletion as a predictor of ICB resistance and poor outcome. In the context of recent evidence for sensitivity to CDK4/6 inhibition of CDKN2A-deficient tumors, our findings raise the possibility of utilizing currently available targeted agents in the treatment of CDKN2A-deficient NSCLC patients progressing on ICB. Citation Format: Stanley I. Gutiontov, Sean Pitroda. CDKN2A mutation predicts immunotherapy resistance in stage III/IV NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 799.

Elevated tumor-to-liver standardized uptake value ratio (TLR) from preoperative 18F-FDG PET/CT predicts poor prognosis of patients with clear cell renal cell carcinoma after nephrectomy

AimTo assess the potential of using preoperative 18F-FDG PET/CT to predict the prognosis of patients with clear cell renal cell carcinoma (ccRCC) after nephrectomy. MethodsSixty-nine patients with newly diagnosed ccRCC who underwent 18F-FDG PET/CT prior to surgery were retrospectively reviewed. The metabolic parameters of maximum standardized uptake value (SUVmax) and tumor-to-liver ratio (TLR) from 18F-FDG PET/CT were obtained. Clinicopathological characteristics, including the World Health Organization/the International Society of Urological Pathology (WHO/ISUP) grade, pathological tumor node metastasis (pTNM) stage, venous tumor thrombus, and so on, were acquired. Univariate and multivariate Cox proportional hazards analyses were performed to identify the prognostic factors for disease-free survival (DFS). ResultsOf the 69 patients, 25 patients (36.2%) experienced disease progression during the follow-up period. In univariate analysis, the primary tumor size (>4.85 cm), pTNM stage (Ⅲ/Ⅳ), WHO/ISUP grade (G3/4), venous tumor thrombus, adjuvant therapy, SUVmax (>3.55), and TLR (>1.66) were found to correlate with the incidence of decreased DFS (P < 0.05). In multivariate analysis, TLR (P = 0.007, HR: 5.489, 95%CI: 1.605-18.774) and pTNM stage (P = 0.024, HR: 10.385, 95%CI: 1.361-79.238) were revealed to serve as independent prognostic predictors for DFS after adjustment for other variables. Only 3 cases (8.3%) with normal TLR showed disease progression, while 22 cases (66.7%) with elevated TLR experienced disease progression. ConclusionccRCC patients with preoperatively elevated TLR (>1.66) and high pTNM stages (Ⅲ/Ⅳ) had significantly unfavorable survival outcomes. These patients should be carefully monitored to detect the possibility of disease progression after nephrectomy as early as possible.

DS-7080a, a Selective Anti-ROBO4 Antibody, Shows Anti-Angiogenic Efficacy with Distinctly Different Profiles from Anti-VEGF Agents.

PurposeNeovascular age-related macular degeneration (nAMD) results from choroidal neovascularization (CNV) and causes severe vision loss. Intravitreal anti-vascular endothelial growth factor (VEGF) therapies have significantly improved therapeutic outcomes; however, a substantial number of patients experience disease progression. Roundabout 4 (ROBO4) has been reported to be a vascular-specific protein that stabilizes vasculature in ocular pathological angiogenesis. To explore ROBO4 targeting as a novel treatment against neovascularization, we generated a humanized anti-human ROBO4 antibody, DS-7080a, and evaluated its efficacy.Methods ROBO4 mRNA in human whole eye cross-sections was examined by in situ hybridization. Human umbilical vein endothelial cell (HUVEC) migration was measured in the presence of VEGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), or conditioned medium of primary human retinal pigment epithelial (HRPE) cells. CNV was induced in cynomolgus monkeys by laser irradiation. Vascular leakage was measured by fluorescein angiography, and pathological changes were determined by histology.Results ROBO4 mRNA was detected in choroidal vessels of nAMD patients. DS-7080a suppressed HGF- or bFGF-induced HUVEC migration in addition to that induced by VEGF. Further, HUVEC migration induced by HRPE-conditioned medium was inhibited by either DS-7080a or ranibizumab in a similar manner, and the combination of these showed further inhibition. In a laser-induced CNV monkey model, single intravitreous administration of 1.1 mg/eye of DS-7080a reduced the incidence of grade 4 leakage from 44.45% in control eyes to 1.85% (P < 0.05 by Dunnett's test).ConclusionsAnti-ROBO4 antibody DS-7080a suppressed HUVEC migration in a distinctly different fashion from anti-VEGF agents and improved laser-induced CNV in non-human primates.Translational RelevanceDS-7080a may be a novel treatment option for nAMD.

A Multivariable Regression Model-based Nomogram for Estimating the Overall Survival of Patients Previously Treated With Nivolumab for Advanced Non-small-cell Lung Cancer.

Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms. Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS. The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab. The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.

Multicenter Single-Arm, Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial

PurposeTo assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC). Patients and MethodsEligible patients had pretreated RAS (renin–angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity. ResultsOverall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash. ConclusionAccording to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.

Real-world treatment patterns and clinical outcomes of advanced melanoma patients following disease progression on anti-PD-1-based therapy.

e22036 Background: Despite the success of anti-programmed cell death-1 (PD-1) based therapies that prolong survival in advanced melanoma, some patients experience disease progression. Real-world treatment patterns and outcomes after progression on anti-PD-1 based regimens are unknown. Methods: Adults with advanced melanoma and a record of disease progression on anti-PD-1 treatment (alone or in combination) between 1 Sept 2014–31 Jan 2019 were selected from the Flatiron Health Oncology electronic medical record (EMR) database for this retrospective study. Index progression date was defined as an event where the treating clinician concluded in the patient record that there had been disease progression. The first subsequent therapy received was identified. Kaplan-Meier methods estimated overall survival (OS) with 95% confidence interval (CI) after the progression date. Analyses were run separately for BRAF mutant (mt) and wild type (wt). Results: Among 2,169 patients with advanced melanoma treated with an anti-PD-1, 213 BRAFmt and 302 BRAFwt had a record of progression following anti-PD-1 initiation and were included; an additional 82 BRAFmt and 138 BRAFwt were excluded due to death without a record of progression. Median age was 64 and 71 years, respectively; 27.7% and 9.9% had &gt;1 line of therapy prior to the anti-PD-1. Among the BRAFmt patients who progressed on anti-PD-1, 94 (44.1%) received no subsequent therapy, 80 (37.6%) BRAF±MEK (± IO), and 16 (7.5%) anti-CTLA4 alone or with anti-PD-1 after progression on the initial anti-PD-1; 11% received other treatments with no clear pattern of care. Median (95% CI) OS from the index progression date for BRAFmt was 11.9 (8.2–16.9) months. In a subgroup of these BRAFmt patients with BRAF treatment prior to or during the first anti-PD-1 line (N = 65), 52.3% had no subsequent therapy and a median OS of 4.0 (2.7–7.5) months. Among the BRAFwt patients who progressed on anti-PD-1, 186 (61.6%) received no subsequent therapy, 46 (15.2%) received anti-CTLA4 alone or with anti-PD-1, 26 (8.6%) switched anti-PD-1s, and 15% received other treatments. Median (95% CI) OS for BRAFwt was 10.1 (8.8–12.5) months. Conclusions: In this real-world retrospective study, &gt; 40% of BRAFmt and &gt; 60% of BRAFwt patients did not initiate a new regimen after progression on anti-PD-1 therapy. Median OS after progression was &lt; 1 year. This may be overestimated, as it excluded patients who died before progression was recorded in the EMR. These findings highlight a need for more effective treatments for advanced melanoma.

Updated results of the ASPEN trial from a cohort of patients with MYD88 wild-type (MYD88WT) Waldenström macroglobulinemia (WM).

e20056 Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with WM harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations ( N Engl J Med. 2015;372:1430). The ASPEN trial evaluated zanubrutinib (ZANU), a potent and selective BTK inhibitor, in WM patients. Methods: In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 ( MYD88 mutation) or cohort 2 ( MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression. The objective was to assess the safety and efficacy of ZANU in patients with MYD88WT WM. Results: In total, 28 patients with 26 MYD88WT WM were enrolled into cohort 2. The median age was 72 years; 5 patients were treatment-naïve (TN) and 23 patients were relapsed/refractory (R/R; ≥1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With the median follow-up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. The overall response rate was 80.8%, with a major response rate of 50.0%, including a very good partial response (VGPR) rate of 26.9% (Table). Progression-free survival event-free rate at 12 months was 72.4%. The most frequently reported adverse events (AEs) were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient. There were no fatal AEs. Conclusions: ZANU showed clinically meaningful antitumor activity, including achieving major responses and durability of responses, and was considered well-tolerated with a low discontinuation rate due to AEs, in patients with MYD88WT WM. ZANU demonstrated efficacy regardless of MYD88 mutational status in WM. Clinical trial information: NCT03053440 . [Table: see text]

First-line combination immunotherapy for metastatic non-small cell lung cancer.

Immunotherapy has recently become an important treatment modality, especially for non-small cell lung cancer (NSCLC) and melanoma patients. Several large-scale phase III trials of first-line treatments for metastatic NSCLC have documented prolonged patient survival, including progression-free survival and overall survival for immune checkpoint inhibitors (ICIs) used alone or in combination with chemotherapy. However, a significant proportion of patients experienced disease progression shortly after starting single-agent ICI treatment even after biomarker selection, such as programmed cell death-ligand 1 and tumor mutation burden. The present review was performed to identify ways to enhance ICI efficacy in the first-line treatment of metastatic NSCLC patients. At least four effective ways of combination treatment modalities are currently available, namely, immune therapy in combination with radiotherapy, chemotherapy, antiangiogenesis, or other immunotherapeutic agents.

Cut-Off Analysis of CTC Change under Systemic Therapy for Defining Early Therapy Response in Metastatic Breast Cancer.

Detection of circulating tumor cells (CTC) can distinguish between aggressive and indolent metastatic disease in breast cancer patients and is thus considered an independent, negative prognostic factor. A clear decline in CTCs is observed in patients who respond to systemic therapy. Nevertheless, CTCs can decrease in patients experiencing disease progression during systemic therapy, too. This study aims to determine the differences between CTC decline in patients responding to therapy and those in whom disease is progressing. Therefore, CTC values were compared at the start and after one cycle of a new line of systemic therapy. In all, 108 initially CTC-positive patients (with ≥5 intact CTCs in 7.5 mL blood) were enrolled in this study and intact and apoptotic CTCs were measured via the CellSearch® system. A cut-off analysis was performed using Youden’s J statistics to differentiate between CTC change in the two groups. Here, 64 (59.3%) patients showed stable disease or partial response vs. 44 (40.7%) presenting disease progression. Median overall survival was 23 (range: 4–92) vs. 7 (2–43) months (p < 0.001). Median intact CTC count at enrollment was 15.0 (5–2760) vs. 30.5 (5–200000) cells (p = 0.39) and 2.5 (0–420) vs. 8.5 (0–15000) cells after one cycle of systemic therapy (p = 0.001). Median apoptotic CTC count at enrollment was 10.5 (0–1500) vs. 9 (0–800) cells (p = 0.475) and 1 (0–200) vs. 3 (0–250) cells after one cycle of systemic therapy (p = 0.01). A 50% reduction in baseline apoptotic CTC count represents the optimal cut-off to differentiate between therapy response and disease progression. An apoptotic CTC reduction of ≤10% is 74% specific for early disease progression.

Pattern of disease progression following stereotactic radiosurgery in malignant glioma patients

IntroductionThe clinical benefit of stereotactic radiosurgery (SRS) in the treatment of malignant glioma remains controversial. We analyzed failure patterns of malignant gliomas following SRS to identify the clinical implications of SRS against these malignancies. Materials and methodsWe retrospectively reviewed 58 consecutive patients who received SRS with a gamma knife for their malignant glioma from January 2013 to December 2018. A total of 51 patients were available for analysis of failure patterns. Failure patterns were defined by the recurrent tumors’ spatial relation to SRS target as follows: in-field local recurrence, remote recurrence, and leptomeningeal seeding. If patients demonstrated several types of failure patterns simultaneously, we categorized them as a combined failure pattern. ResultsIn-field local recurrence was found in 47.1% of patients. Other types of failure patterns were as follows: remote recurrence (19.6%), leptomeningeal seeding (13.7%), and combined failure pattern (19.6%). The majority of patients (52.9%) experienced disease progression beyond the radiation field of SRS, which implies limited efficacy of local therapy against these invasive tumors. The prognosis of patients differed according to failure pattern and patients with local recurrence had better survival outcomes compared to other types of disease progression (p-value = 0.0015, log-rank test). ConclusionsThis study illustrated that SRS could not improve survival of malignant gliomas significantly even when it had some effect within radiation field. Our findings support utilizing a multidisciplinary treatment strategy to improve the prognosis of malignant gliomas and suggest that SRS is one element of that treatment strategy.

Mantle cell lymphoma relapsed after autologous stem cell transplantation: a single-center experience.

BackgroundAutologous stem cell transplantation (autoSCT) can extend remission of mantle cell lymphoma (MCL), but the management of subsequent relapse is challenging.MethodsWe examined consecutive patients with MCL who underwent autoSCT at Veterans Affairs Puget Sound Health Care System between 2009 and 2017 (N=37).ResultsTen patients experienced disease progression after autoSCT and were included in this analysis. Median progression free survival after autoSCT was 1.8 years (range, 0.3–7.1) and median overall survival after progression was only 0.7 years (range, 0.1 to not reached). The 3 patients who survived more than 1 year after progression were treated with ibrutinib.ConclusionOur findings suggest that ibrutinib can achieve relatively prolonged control of MCL progressing after autoSCT.

Abstract P3-11-03: Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer

Abstract Background: Niraparib is a selective poly(ADP-ribose) polymerase 1/2 inhibitor that has demonstrated antitumor activity in advanced triple-negative breast cancer (TNBC) in combination with a programmed cell death 1 inhibitor, with the greatest clinical activity seen in tumors with breast cancer susceptibility gene (BRCA) mutations. Pharmacologically, niraparib has demonstrated a wide volume of distribution and high cell membrane permeability. In breast and ovarian cancer xenograft mouse models, niraparib achieved tumor exposures that were 3.3 times greater than plasma exposure. The objective of this study is to evaluate the antitumor activity of single-agent niraparib in the neoadjuvant treatment of patients with localized, human epidermal growth factor receptor 2 (HER2)-negative, BRCA-mutated breast cancer. The relative concentration of niraparib in tumor versus plasma was also assessed. Methods: Eligible patients were ≥18 years old, with HER2-negative, BRCA-mutated (germline or somatic) resectable breast cancer with a tumor size of ≥1 cm who had not received prior treatment for the current malignancy. Patients received niraparib 200 mg once daily for 2 months. At the end of 2 months, at their treating physician’s discretion, patients proceeded directly to surgery, received additional cycles of niraparib (maximum of 6 months), or received neoadjuvant chemotherapy. The primary endpoint was tumor response rate measured by magnetic resonance imaging (MRI) after 2 months of treatment. Response was defined as a ≥30% reduction in tumor volume from baseline. Secondary endpoints included tumor response rate measured by ultrasound, quantified percent change in tumor volume measured by MRI or ultrasound, pathological complete response, and safety and tolerability. Additionally, niraparib concentrations were measured in tumor and plasma samples using qualified liquid chromatography-tandem mass spectrometry. Results: Twenty-one patients were enrolled. As of June 2019, 18 patients had both an MRI and ultrasound scan at the end of month 2 and were evaluable for response. Ten patients are currently on treatment. The median age of patients was 43 years (range, 21-73). Fourteen patients had a BRCA1 mutation, 6 patients had a BRCA2 mutation, and 1 patient had both. Fifteen patients had TNBC, and 6 patients had hormone receptor-positive disease. All 18 response-evaluable patients had a clinical response after 2 months of treatment by at least one imaging modality; no patient experienced disease progression. Tumor response rate measured by MRI after 2 months of treatment was 89% (n/N = 16/18). Results measured by ultrasound were similar, with a 94% response rate at cycle 2 (n/N = 17/18). The median percent decrease in tumor volume after 2 months of treatment was 88% (range, 26-100%) and 89% (range, 23-100%) as measured by MRI and ultrasound, respectively. In the 5 samples measured thus far, niraparib concentrations in tumor biopsies after 2 months of treatment ranged from approximately 4-131-fold higher than those in corresponding plasma samples. Efficacy and tumor concentration data for all patients will be presented at the meeting. The most common (≥10%) drug-related treatment-emergent adverse events (TEAEs) of any grade were nausea, fatigue, anemia, insomnia, and decreased appetite. The only drug-related grade ≥3 toxicity in ≥10% of patients was anemia (3 patients). Three patients had a dose reduction due to a TEAE; no patient discontinued treatment due to a TEAE. Conclusion: Niraparib was well tolerated and showed promising antitumor activity in the neoadjuvant treatment of patients with localized HER2-negative, BRCA-mutated breast cancer. Niraparib achieved 4-131-fold higher concentrations in tumor than in plasma. Clinical trial information: NCT03329937. Funding: TESARO: A GSK Company (Waltham, MA, USA) sponsored the study. Citation Format: Hyo Han, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, James Reeves, Andre Liem, Adrianna Milillo Naraine, Julie Nangia, David Page, Meghan Duncan, Ming Shan, Yongqiang Tang, Julie R Graham, Leif W Ellisen, Steven Isakoff, Laura Spring. Pilot neoadjuvant study of niraparib in HER2-negative, BRCA-mutated resectable breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-03.