Carboplatin Paclitaxel Research Articles

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

Discussion on the Efficacy and Safety of Epirubicin Injection Combined with Paclitaxel Liposome Injection and Carboplatin Injection in the Treatment of Cervical Cancer

Discussion on the Efficacy and Safety of Epirubicin Injection Combined with Paclitaxel Liposome Injection and Carboplatin Injection in the Treatment of Cervical Cancer

Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune‐regulatory pathways in vitro, while RAD51‐High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51‐High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

A randomized phase III trial of adjuvant chemotherapy versus concurrent chemoradiotherapy for postoperative cervical cancer: Japanese Gynecologic Oncology Group study (JGOG1082)

BackgroundThe standard treatment for stage IB–IIB cervical cancer is radiotherapy or radical hysterectomy; after radical hysterectomy, adjuvant concurrent chemoradiotherapy is recommended for patients with high risk factors. However, adjuvant concurrent...

New Approved First-line Combining Therapy of NSCLC in 2020

In the past decades, lung cancer is considered one of the lethal cancers all across the world due to its evidenced greatest mortality and morbidity. Currently, the main clinical treatment methods for lung cancer involve surgery, chemotherapy, radiotherapy, anti-angiogenesis inhibitors and tyrosine kinase inhibitors. In the field of anticancer drugs, a variety of new anticancer drugs have been emerging in recent years. They include chemotherapy drugs with new delivery modes, targeted drugs for tyrosine kinase inhibitors, angiogenesis inhibitors, and immunotherapy drugs that have remained hot. But because cancer cells have complex escape mechanisms, the effectiveness of these single-drug treatments has been disappointing. In this case, a number of new combination therapies have emerged and achieved relatively good results. According to the 2020 third edition of the NCCN guidelines, four multi-therapy regiments (Erlotinib plus ramucirumab, Erlotinib plus bevacizumab, Carboplatin plus albumin-bound paclitaxel plus atezolizumab and Nivolumab plus ipilimumab) have passed clinical trials, adding first-line treatments. In this review, the research provided an overview of these four new approved combining treatment strategies in addition to predicting future drug development directions.

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

There is a paucity of robust clinical evidence for the role of neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer. The primary aim of the study was to identify the available data on the feasibility, safety and efficacy of neoadjuvant immunotherapy. A systematic review was conducted using electronic databases. Relevant studies were identified according to predefined selection criteria. Five relevant publications on 4 completed trials were identified. In most studies, >90% of patients were able to undergo surgery within the planned timeframe after neoadjuvant immunotherapy. There was a high incidence of open thoracotomy procedures, either planned or converted from a planned minimally invasive approach. Mortality ranged from 0 to 5%, but none of the reported deaths were considered directly treatment-related. Morbidities were reported according to adverse events related to neoadjuvant systemic therapy, and postoperative surgical complications. Survival outcomes were limited due to short follow-up periods. Major pathologic response ranged from 40.5 to 56.7%, whilst complete pathologic response of the primary tumor ranged from 15 to 33%. Radiological responses were reported according to RECIST criteria and fluorodeoxyglucose-avidity. This systematic review reported safe perioperative outcomes of patients who underwent resection following neoadjuvant immunotherapy. However, there was a relatively high incidence of open thoracotomy procedures, partly due to the technical challenges associated with increased fibrosis and inflammation of tissue, as well as the more advanced stages of disease in patients enrolled in the studies. Future studies should focus on identifying predictors of pathological response.

Phase II trial of vaginal cuff brachytherapy followed by dose-dense chemotherapy in early stage endometrial cancer patients with enriched, high-intermediate risk factors for recurrence

ObjectiveTo determine the feasibility of vaginal cuff brachytherapy (VCB) followed by 3 cycles of dose dense paclitaxel and carboplatin chemotherapy (ddTC) in enriched, high-intermediate risk (H-IR) patients with early stage endometrial cancer following hysterectomy. MethodsA phase II trial of early stage endometrial cancer patients treated with VCB (2100 cGy) followed by three cycles of carboplatin (AUC 6) and dose dense paclitaxel (80 mg/m2) weekly within 12-weeks of surgery was conducted. The primary endpoint was the proportion of patients completing both VCB and ddTC. Secondary outcomes include short and long-term toxicities, recurrence rate and sites, and progression free survival. Toxicity assessments were patient reported as well as those resulting in delays or dose modifications. ResultsA total of 32 evaluable patients with median age of 64.5 years were included. Most patients were endometrioid histology (18/32, 56.3%) and fully staged (21/32, 65.6%) to stage Ib (18/32, 56.3%). In total, 27/32 (84.4%) patients completed treatment per protocol. Protocol non-completion included renal insufficiency, paclitaxel reaction, and treatment refusal. Median time to VCB completion was 11 days with all patients completing three fractions of VCB. Acute toxicities with VCB included grade 1 and 2 gastrointestinal, genitourinary and fatigue symptoms. Acute toxicities associated with ddTC included infusion reaction and neutropenia. Most reported long-term toxicities were grade 1 or 2 and resolved with time. ConclusionsTreatment with VCB followed by three cycles of ddTC is well-tolerated with promising utility for treatment in enriched high-intermediate risk endometrial cancer patients. Recurrence-free and overall survival outcomes are not yet mature.

Therapeutic targeting of hypoxia and hypoxia inducible factor 1 with acriflavine in experimental esophageal adenocarcinoma

Background: Hypoxia or insufficient tissue oxygenation contributes to cancer aggressiveness and poor clinical prognosis. Typically, cancer cell lines are used in two-dimensional (2D) cultures for screening of anticancer agents, and they do not represent the hypoxic tumor microenvironment. In this study, we established a novel three dimensional (3D) spheroid co-culture model of esophageal adenocarcinoma (EAC). We then observed treatment response of chemo and hypoxia-targeting therapies in 2D, 3D and in vivo models of experimental EAC. Methods: EAC 3D spheroids were generated from co-culturing human EAC and fibroblast cell lines. NanoCulture® plates and dishes were used for 3D spheroid cultures. Hypoxic status was detected by adding hypoxia probe LOX-1 and fluorescent microscopy. Paclitaxel (PT), carboplatin (CP) and nanoparticle albumin-bound paclitaxel (NPT) were used as chemotherapeutic agents, whereas acriflavine was used as hypoxia-targeting agent. In vitro cell growth was detected by WST-1 assay, in vivo tumor growth was detected by measuring subcutaneous xenografts, apoptosis was detected by cleaved caspase 3/PARP expressions, and hypoxia-targeting was detected by HIF-1α expression. Results: 3D culture was more resistant to antiproliferative effect of chemotherapeutic agents PT, CP, NPT over 2D monolayer culture. Contrary to that, hypoxia-targeting agent acriflavine showed stronger antiproliferative effects in 3D culture than in 2D culture. We observed strong expression of hypoxia inducible factor-1α (HIF-1α) in 3D culture with no expression of HIF-1α in 2D culture, and acriflavine treatment completely abolished the HIF-1α expression in 3D culture. We also observed hypoxia inside the 3D culture spheroids, but not in cells grown in 2D culture. In addition, acriflavine showed significant in vivo antitumor efficacy both as monotherapy and in combination with NPT. Conclusion: Thus 3D cultures may be better than 2D cultures in simulating the important in vivo tumor characteristic of hypoxia, and HIF-targeting therapy acriflavine could be a novel treatment strategy for EAC.

Cost-Effectiveness of the Addition of Bevacizumab to First-Line Chemotherapy With Carboplatin and Paclitaxel in Patients With Non–Small Cell Lung Cancer

ObjectivesTo evaluate the incremental cost-effectiveness ratio (ICER) of the addition of bevacizumab to first-line chemotherapy with carboplatin and paclitaxel in patients with non–small cell lung cancer (NSCLC) from the perspective of the Colombian health system. MethodsA Markov model was employed to evaluate the cost-effectiveness of bevacizumab + carboplatin + paclitaxel (BCP) compared with carboplatin + paclitaxel (CP) in the treatment of NSCLS during a 4-year period. The health outcome was the number of life-years gained (LYG) and quality-adjusted life-years (QALYs) obtained from the survival curves reported in a clinical study. Costs were estimated using national tariff and reported in US dollars at a date in 2019. Costs and effectiveness outcomes were discounted at a rate of 3.5% per year. A probabilistic sensitivity analysis was performed on important parameters with a Monte Carlo simulation. ResultsThe costs of BCP and CP were $30 341 and $11 735, respectively. The LYG for BCP and CP were 0.34 and 0.29, respectively. The QALY for BCP and CP were 0.27 and 0.23. The ICER of BCP versus CP was $ 465 150 QALY. The results of the Monte Carlo simulation showed that CP was cost-effective in 100% of the iterations compared with BCP. ConclusionThe addition of bevacizumab to the scheme carboplatin + paclitaxel compared to carboplatin + paclitaxel for NSCLC is not cost-effective from the point of view of the Colombian health system.

Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

SummaryPevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

Recurrent cervical cancer treated with palliative chemotherapy: real-world outcome.

IntroductionCervical cancer is the third most common cancer in India. There is limited data on the treatment of relapsed cervical cancer from India; therefore, we report the outcomes of patients with recurrent cervical cancer who were treated with palliative chemotherapy (CT).Materials and methodsThis was a retrospective study of patients with recurrent cervical cancer who received palliative CT from January 2012 to December 2016. The demographic details, clinical profile and survival outcomes were collected. Patients were treated with carboplatin or paclitaxel and carboplatin. Local radiation was given for symptomatic patients. Patients were assessed for responses clinically and/or radiologically after three and six cycles of CT. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method.ResultsForty-six patients with recurrent cervical cancer were included in this analysis, with a median follow-up of 9.4 months. The median age was 49.5 (25–65) years and the median disease-free interval was 31.3 (2–196) months. Biopsy confirmation of relapse was established in 63%. The median number of CT cycles was six. Twenty-four (52.2%) patients completed six cycles of CT. The overall response rate was 56.5%. Patients with a complete or a partial response were more likely to have PFS > 6 months (p < 0.0001). Median PFS and OS were, respectively, 8.4 (95% CI 6.1–10.7) months and 10.3 (95% CI 6.8–13.8) months. The completion of all cycles of CT and the site of metastasis (nodal vs. visceral or combined) were found to be associated with OS.ConclusionPalliative CT with paclitaxel carboplatin is a safe and effective option in Indian patients with recurrent cervical cancer, with more than half of the patients completing the prescribed CT. Further prospective trials may be required to place this treatment in the right context, in this era of immunotherapy and targeted therapy. However, knowing the outcomes in our population and prognostic factors will help in better prognostication of patients, thereby channelling our limited resources where necessary.

Safety and effectiveness of pirfenidone combined with carboplatin-based chemotherapy in patients with idiopathic pulmonary fibrosis and non-small cell lung cancer: A retrospective cohort study.

BackgroundPirfenidone is an antifibrotic agent that is potentially effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, no study has reported on its prophylactic value against chemotherapy‐associated acute IPF exacerbations when combined with chemotherapy for non‐small cell lung cancer (NSCLC). The present study assessed the safety and effectiveness of pirfenidone combined with carboplatin‐based chemotherapy or immune checkpoint inhibitors (ICIs) in patients with IPF and NSCLC.MethodsA total of 14 patients with IPF and NSCLC who received treatment from 2013 to 2019 were included. Patients were treated with pirfenidone combined with carboplatin and nanoparticle albumin‐bound paclitaxel or S‐1 as first‐line chemotherapy. After confirming disease progression, patients received cytotoxic agents or ICIs, including nivolumab and pembrolizumab. Pirfenidone was continued regardless of chemotherapy changes. Overall survival (OS) and progression‐free survival (PFS) for lung cancer and IPF were calculated. Moreover, the cumulative incidence of acute exacerbation of IPF (AE‐IPF) within one year was evaluated.ResultsMedian PFS for lung cancer was 110 days (95% confidence interval [CI]: 57–199 days), while the median OS was 362 days (95% CI: 220–526 days). Moreover, PFS for IPF was 447 days (95% CI: 286–indeterminate days), and the cumulative incidence of AE‐IPF within one year was 18%. Notably, none of the patients developed AE‐IPF associated with first‐line chemotherapy. Among the included patients, four received ICIs, none of whom developed ICI‐associated AE‐IPF.ConclusionsThe present study found that pirfenidone combined with carboplatin‐based regimens or ICIs might be safe first‐line chemotherapy for patients with IPF and NSCLC.Key pointsSignificant findings of the study No patients with IPF and NSCLC who received pirfenidone in combination with first‐line carboplatin‐based chemotherapy or late‐line ICIs developed acute IPF exacerbations. What this study adds Pirfenidone might have a prophylactic effect against chemotherapy‐associated AE‐IPF.

818P Veliparib with carboplatin and paclitaxel in frontline high-grade serous ovarian cancer (HGSOC): Efficacy and safety of paclitaxel weekly and every 3 weeks in the VELIA study

The phase III randomised VELIA study (NCT02470585) demonstrated significantly improved progression-free survival (PFS) with carboplatin/paclitaxel (CP) and veliparib (VEL) induction therapy followed by VEL maintenance vs CP alone (HR 0.44; 95% CI 0.28–0.68; Coleman et al., N Engl J Med 2019). Investigators chose between IV P 175 mg/m2 every 3 weeks (Q3W), or 80 mg/m2 dose-dense (DD) weekly. This exploratory analysis evaluated PFS and safety by P regimen.

1798P Carboplatin-paclitaxel (CP) chemotheraphy as salvage treatment for small cell lung cancer (SCLC): A real-world evidence analysis

1798P Carboplatin-paclitaxel (CP) chemotheraphy as salvage treatment for small cell lung cancer (SCLC): A real-world evidence analysis

Abstract 975: Single cell RNA sequencing of esophageal adenocarcinoma before and after chemotherapy alone and with pembrolizumab identifies novel tumor immune microenvironment alterations

Abstract The PD-1 inhibitor, pembrolizumab, was recently approved for PD-L1+ esophageal squamous cell cancer (ESCC) with a response rate (RR) of 14.3-16.7% (KEYNOTE -180, 181). Pembrolizumab is minimally active in esophageal adenocarcinoma (EAC) (RR 5.2%-7.7%, KEYNOTE-180,-181). Biomarkers, such as PD-L1 expression and mutation burden are poor predictors for response to pembrolizumab in EAC. We examined the tumor immune microenvironment (TIME) by single cell RNA sequencing (scRNAseq) in EAC to improve our understanding of local immunity in EAC and how it changes with treatment. Patients with locally advanced EAC (pT2N+ or pT3-4N-/+, M0) underwent endoscopic biopsies of the tumor and adjacent non-tumor tissue (NTA) at baseline and following induction treatment with either paclitaxel/carboplatin (PC) alone or PC + pembrolizumab (NCT02998268 clinicaltrials.gov). These biopsies were subjected to scRNAseq analysis using the 10X genomics platform. scRNAseq data from 65,538 individual cells isolated from 17 baseline endoscopic EAC tumor biopsies revealed dozens of cell populations that largely grouped into 9 different clusters. Across all the baseline tumor samples assessed, epithelial (47.8%), keratinocytes (9.9%), and endothelial cells (9.8%) were the most abundant cell populations, consistent with tumor architecture in vivo. Among the immune cells (20% of the total), B cells (7.1%), T cells (6.9%) and Monocytes (2.2%) were the most abundant tumor-associated cell populations. We further assessed matched baseline and on-treatment biopsies (n=10) from six patients that received PC and four patients that received PC + pembrolizumab. We saw a significant reduction in tumor epithelial cells upon treatment in both arms suggesting effectiveness of treatment (P&amp;lt;0.001). PC alone significantly induced tumor-associated B cells (P≤0.0007) and T cells (P≤0.002) with treatment. In contrast, treatment with pembrolizumab + PC specifically was associated with significant increase in tumor-associated neutrophils (P&amp;lt;0.001) and dendritic cells (P≤0.007). Interestingly, comparing across PC only vs PC + Pembrolizumab, we see an increase in number of B cells (P≤0.020), neutrophils (P&amp;lt;0.001) and NK cells (P&amp;lt;0.001) with addition of Pembrolizumab. Furthermore, specific immune cell subsets including CD4+ Th17, Th2, Treg and CD8+ stimulated cells show significant associations with treatment regimens. Our study demonstrates that scRNAseq provides a rich description of the TIME with significant value for clinical trials. The TIME of EAC is complex, largely immunosuppressive, and chemotherapy with, or without, pembrolizumab is associated with significant unique alterations in TIME. We are currently investigating differences in TIME composition between tumor and NTAs to better understand the components that contribute to tumor growth. Citation Format: Prashant V. Thakkar, Sandipto Sarkar, Chao Zhang, Dina Elmonshed, Emma Futamura, Doron Betel, Manish A. Shah. Single cell RNA sequencing of esophageal adenocarcinoma before and after chemotherapy alone and with pembrolizumab identifies novel tumor immune microenvironment alterations [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 975.

Primary results from CECILIA, a global single-arm phase II study evaluating bevacizumab, carboplatin and paclitaxel for advanced cervical cancer

ObjectiveAdding bevacizumab to cisplatin–paclitaxel for advanced cervical cancer significantly improves overall and progression-free survival. We evaluated bevacizumab with a widely used carboplatin–paclitaxel backbone. MethodsPatients with metastatic/recurrent/persistent cervical cancer not amenable to curative surgery and/or radiotherapy received 3-weekly bevacizumab 15 mg/kg, paclitaxel 175 mg/m2, and carboplatin AUC 5 until progression or unacceptable toxicity. Maintenance bevacizumab was allowed. Patients with ongoing bladder/rectal involvement, prior cobalt radiotherapy, a history of fistula/gastrointestinal perforation, or recent bowel resection/chemoradiation were excluded. The primary objective was to determine incidences of gastrointestinal perforation/fistula, gastrointestinal-vaginal fistula, and genitourinary fistula. ResultsAmong 150 treated patients, disease at study entry was persistent in 21%, recurrent in 56%, and newly diagnosed metastatic in 23%. After 27.8 months' median follow-up, median bevacizumab duration was 6.7 months; 57% received maintenance bevacizumab. Seventeen patients (11.3%; 95% CI: 6.7–17.5%) experienced ≥1 perforation/fistula event: gastrointestinal perforation/fistula in 4.7% (1.9–9.4%), gastrointestinal-vaginal fistula in 4.0% (1.5–8.5%), and genitourinary fistula in 4.7% (1.9–9.4%). Of these, 16 were previously irradiated, several with ongoing radiation effects. The most common grade 3/4 adverse events were neutropenia (25%), anemia (19%), and hypertension (14%). Five patients (3%) had fatal adverse events. Objective response rate was 61% (95% CI: 52–69%), median progression-free survival was 10.9 (10.1–13.7) months, and median overall survival was 25.0 (20.9–30.4) months. ConclusionsBevacizumab can be combined with carboplatin–paclitaxel in the CECILIA study population. The fistula/gastrointestinal perforation incidence is in line with GOG-0240; efficacy results are encouraging.Trial registration number.NCT02467907 (ClinicalTrials.gov).

Abstract A13: Therapeutic AXL inhibition with AVB-S6-500 improves response to chemotherapy and induces a homologous recombination deficiency in ovarian cancer

Abstract Background: Over 80% of patients with advanced ovarian cancer will develop chemoresistance and die within 5 years. Biomarkers to predict chemoresponse and novel therapies to target chemoresistance would be practice changing. We aim to establish serum and tissue GAS6 as predictive biomarkers of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Further, we desired to understand the affect AVB has on DNA damage response (DDR). Methods: AVB was supplied by Aravive Biologics. High-grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor cells (OVCAR8, OVCAR5, COV62, and POV71-hTERT) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent (IF) assays targeting γH2AX were used to evaluate DNA damage and additional assays targeting 53BP1, RAD51, BRCA1, and BRCA2 were used to evaluate DNA damage response in cells treated with AVB, carboplatin, and/or AVB+carboplatin. Flow cytometry was used to evaluate RPA binding and cell cycle. Results: Patients with high pretreatment tumor GAS6 expression (&amp;gt;85%, n=7) or serum GAS6 concentrations (&amp;gt;25ng/mL, n=13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression (&amp;lt;45%, n=4) (P=0.010) or low serum GAS6 concentrations (&amp;lt;15ng/mL, n=5) (P=0.002). Carboplatin plus AVB (2μM, 5μM) and paclitaxel plus AVB (1μM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p&amp;lt;0.05) in all tumor cell lines. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (P&amp;lt;0.001). Increased DNA damage occurred in tumor cells treated with AVB than controls and in tumor cells treated with carboplatin+AVB than carboplatin alone (OVCAR8, COV362, CAOV3, OVCAR3-TPMES P&amp;lt;0.001). Cells treated with AVB either alone or in combination with carboplatin demonstrated decreased binding of protein involved in homologous recombination including RPA, RAD51, BRCA1, and BRCA2 (P&amp;lt;0.05). Conversely, these same cells demonstrated increased binding of the nonhomologous end joining protein 53BP1 (P&amp;lt;0.05). There were no differences in cell cycle among the treatment groups. Conclusions: High GAS6 is associated with poor neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability and tumor growth. AVB imparts a homologous recombination deficiency through downregulation of homology-directed DNA repair with an associated upregulation of nonhomologous end joining. Citation Format: Mary Margaret Mullen, Elena Lomonosova, Hollie Noia, Daniel Wilke, Alyssa Oplt, Lei Guo, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. Therapeutic AXL inhibition with AVB-S6-500 improves response to chemotherapy and induces a homologous recombination deficiency in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A13.

Paclitaxel as a possible continuation maintenance therapy in advanced non-small-cell lung cancer

Background: Understanding the molecular basis of lung cancer has led to the development of targeted agents with a significant clinical benefit. This benefit is confined to patients with specific molecular tumor characteristics. However, chemotherapy represents the backbone of treatment in fit patients and is associated with a significant overall survival prolongation and quality of life improvement. Aim: To evaluate the effect of a continuation maintenance therapy with paclitaxel in advanced NSCLC patients with weekly paclitaxel. Patients and Methods: The current study included patients with advanced non-small-cell lung cancer (NSCLC) (stage IIIB or IV) with performance status ≤ 2 who experienced good initial good response, or stable disease after receiving 4 cycles of paclitaxel carboplatin. Patients were randomized into 2 arms, the first arm received weekly paclitaxel (70 mg/m2) as continuation maintenance therapy for 3 weeks of 4 weeks cycle. The treatment was continued until disease progression or unacceptable toxicity (maintenance arm). The second arm was kept under observation (observation arm). Results: There was a better lung cancer symptoms scale in the maintenance arm. Both times to progression and overall survival for the maintenance arm was higher (P value 0.16 and 0.047, respectively). Treatment-related toxicities were significantly higher in the maintenance arm as compared to the observation arm (P value <0.001). Conclusion: Maintenance with paclitaxel can be a reasonable option in patients with NSCLC who experienced a complete or partial response after initial paclitaxel carboplatin combination.

PARP Inhibitors in the Treatment of Early Breast Cancer: The Step Beyond?

Exquisitely exploiting defects in homologous recombination process, poly(ADP-ribose) polymerase (PARP) inhibitors have recently emerged as a promising class of therapeutics in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with germline breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) mutations (gBRCA1/2m). In this setting, PARP inhibitors, either as single agent or in combination with platinum-based chemotherapy, significantly increased progression-free survival, as compared to conventional chemotherapy. Accordingly, further therapeutic advances are expected at an earlier stage of the disease. In the neoadjuvant setting, veliparib failed to increase the pathological complete response rate when added to a carboplatin-based regimen, in unselected triple-negative breast cancer patients. Similarly, when administered before anthracycline-cyclophosphamide, the neoadjuvant olaparib-paclitaxel combination was not superior to carboplatin–paclitaxel, in patients with HER2-negative breast cancer and BRCA1/2 mutation, or homologous recombination defect. Yet, neoadjuvant talazoparib, administered as a single-agent in patients with HER2-negative breast cancer and germline BRCA1/2 mutation, achieved an impressive pathological complete response rate of nearly 50%. In the adjuvant setting, the results from the OlympiA phase III study, evaluating adjuvant olaparib in HER2-negative early breast cancer and germline BRCA1/2 mutations, are eagerly awaited. Ongoing trials should clarify whether PARP inhibitors might improve outcome when administered in the adjuvant or neoadjuvant setting in early breast cancer patients with BRCA1/2 mutation or homologous recombination defect.

PET-directed chemoradiation (CRT) with induction FOLFOX compared to induction carboplatin/paclitaxel (CP) in patients with locally advanced esophageal adenocarcinoma (EA).

4554 Background: Induction chemotherapy with PET-directed CRT and surgery is the standard treatment for locally advanced EA at our institution. Following results of the CALGB 80803 trial, FOLFOX has recently replaced CP as the preferred induction regimen. Methods: We retrospectively evaluated patients with locally advanced EA treated with induction CP vs FOLFOX, followed by trimodality therapy between January 2010 and June 2019. Patients treated with CP with RT followed by surgery without induction chemo were also included. We compared pathological complete response (pCR) and near pCR (ypN0 with ≥90% response) rates in the induction FOLFOX group to the induction CP and no-induction groups. Univariable and multivariable analyses were used to adjust for confounding factors. Disease-free survival (DFS) was estimated by the Kaplan-Meier method and compared between groups using max-combo weighted log rank test. Results: 445 patients were included. Patients in the induction FOLFOX group had significantly higher pCR and near pCR rates vs induction CP patients. Notably, pCR rate was 38% among FOLFOX PET responders vs 19% in non-responders. In multivariable analysis, compared to induction CP, induction FOLFOX administration was an independent predictor of near pCR (OR: 2.22, 95%CI: 1.20-4.20, p = 0.012). Compared to 24% pCR rate among no-induction patients, induction FOLFOX pCR rate was slightly higher at 32%. DFS by 2-years was higher in induction FOLFOX compared to no-induction-treated patients (62% vs. 42%, p = 0.05). Postoperative complication rates were similar among the three groups. Conclusions: PET-directed CRT with FOLFOX instead of CP improves pCR and near pCR rates. Improved DFS was observed in the FOLFOX vs no-induction patients. Longer follow-up is needed to confirm any survival benefits. [Table: see text]