Platinum-based Chemotherapy Regimens Research Articles

Abstract PD10-11: Efficacy of Platinum-based first-line chemotherapy among metastatic breast cancer (MBC) patients according to the germline BRCA1/2 mutational status: An analysis of the French ESME MBC database

Abstract Background: Platinum-based chemotherapy regimens (PtCT) have been shown to increase treatment efficacy when combined to neoadjuvant standard of care treatment of triple negative breast cancers (TNBC). In the metastatic breast cancer (MBC) setting, preclinical and clinical data suggest that PtCT could be more efficient than non-platinum based ones (non-PtCT) among patients (pts) with germline BRCA1/2 mutations (gBRCAm). However, published data remain controversial on this topic, particularly for MBC. We evaluated the progression-free (PFS) and overall survival (OS) under first-line PtCT and non-PtCT among gBRCAm carriers in ESME, a nationwide real-life MBC database. Methods: ESME MBC database (NCT03275311), is a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. Women with HER2- MBC and known hormone receptors (HR) and gBRCA1/2 (before or in the 6 first months of metastatic disease, gBRCAm / wild type / not tested) status, who received a first-line MBC CT were selected. Patients with other germinal mutations were considered as wild type. Primary objectives were OS and PFS under first-line CT (PtCT vs. non-PtCT) in the TNBC gBRCA1/2m population.Secondary objectives were OS and PFS during first-line CT (PtCT vs. non-PtCT) in the TNBC wild-type and “not tested” population, as well as among the HR+/HER2- pts.To avoid guarantee time bias related to oncogenetic testing, analyses were performed at baseline (CT initiation) and different landmark time points (3-month or 6-month after CT initiation). Thus, BRCA status was defined according to oncogenetic testings performed before the landmark time, and patients who progressed or censored before the landmark time were excluded. Results: 10,164 pts (2,794 TNBC; 7,370 HR+/HER2-) were included in this analysis. Pts who received PtCT were significantly younger, affected by a gBRCA1/2m, had a high histological grade and/or TNBC tumor, with more frequent visceral and central nervous system spreading than non PtCT ones. Median follow-up was 51.1 months [95%CI 49.6; 52.6]. All reported results were based on the gBRCA status defined at CT initiation and on multivariable analysis adjusted on age at MBC diagnosis, de novo MBC status, type and number of metastases. In the gBRCA1/2m TNBC population (N=132), PtCT was independently associated with a better PFS compared to non-PtCT (HR=0.56, 95%CI 0.38-0.84, p=0.005), without significant difference in OS (HR=0.79, 95%CI 0.51-1.23, p=0.29).No difference was seen in wild-type BRCA1/2 TNBC pts (N=269) according to the CT regimen, while, in the larger population of untested TNBC (N=2,393), PtCT was associated with worse OS (HR=1.18, 95%CI 1.03-1.34, p=0.016) compared to non-PtCT regimens, without significant difference in PFS (HR=1.07, 95%CI 0.95-1.22, p=0.26). No significant difference was seen regarding PFS nor OS in gBRCA1/2m HR+/HER2- pts (N=124) and in the wild-type BRCA1/2 HR+/HER2- population.However, in the larger population of untested HR+/HER2- pts (N=6,836), PtCT was independently associated with worse OS (HR=2.15, 95%CI 1.79-2.59, p<0.001) and PFS (HR=1.57, 95%CI 1.33-1.86, p<0.001) compared to non-PtCT regimens. Results were similar in landmark analyses at 3-month or 6-month after CT initiation. Conclusions: This large-scale real-life analysis suggests higher efficacy of PtCT in term of PFS in gBRCA1/2m TNBC pts. The small sample size and post-1st line treatments may preclude observing a significant OS difference. PtCT appeared however associated with worse outcomes in untested TNBC and HR+/HER2- pts. These results emphasize the need for BRCA1/2 characterization before considering these regimens in the MBC setting. Citation Format: William Jacot, Amélie Lusque, Audrey Mailliez, Thibault De la Motte Rouge, Luc Cabel, Christelle Levy, Anne Patsouris, Isabelle Desmoulins, Lionel Uwer, Marianne Leheurteur, Mathieu Robain, Olivier Caron, Thomas Bachelot, Thomas Filleron, Jean-Sébastien Frenel, Suzette Delaloge. Efficacy of Platinum-based first-line chemotherapy among metastatic breast cancer (MBC) patients according to the germline BRCA1/2 mutational status: An analysis of the French ESME MBC database [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-11.

Abstract PS13-49: Effectiveness of platinum-based chemotherapy for hormone receptor-positive HER2-negative metastatic breast cancer

Abstract Background: Platinum-based chemotherapy (CT) regimens have activity in triple-negative breast cancer (TNBC), with overall response rates around 50%. The evidence for activity of these regimens for hormone receptor (HR)-positive breast cancer is scarce. We aimed to evaluate the effectiveness of platinum-based CT for HR-positive HER2-negative metastatic breast cancer. Methods: We evaluated, retrospectively, electronic medical records of patients with HR-positive HER2-negative metastatic breast cancer who have received, at least, 1 dose of platinum-based CT in the metastatic setting from Jan/2015 to May/2020 in a single cancer center. Data on clinical and demographic features, treatment, and outcomes were collected. The primary study endpoint was the clinical benefit rate at 3 months. Secondary endpoints were overall response rate, progression-free survival (PFS), overall survival (OS), and prognostic factors. Results: 244 patients were included. All patients were female, with a median age of 51.5 years, 59% were premenopause, 32.8% were metastatic at diagnosis, and 63.5% had ECOG-PS 0-1 by the time of platinum-based CT initiation. Although tests for hereditary breast and ovarian cancer were not available, 41% of patients met criteria for hereditary cancer testing. Most patients had invasive ductal carcinoma (90.2%), estrogen receptor >10% positive (92.2%), and progesterone receptor >10% positive (69.7%). Main sites of metastatic disease were bone (76.2%), lymph nodes (59.4%), lung (52.9%), and liver (62.7%). The majority of patients had received previous palliative systemic therapy before platinum-based CT; 36.5% had not received previous palliative endocrine therapy (ET), and 30.7% had not received previous palliative chemotherapy. The preferred platinum-based CT regimen was cisplatin plus gemcitabine (68.8%), and a small proportion received single-agent platinum-based CT (14.3%). Forty-three patients (17.7%) started platinum-based CT during hospitalization. Grade 3-4 treatment-related toxicities occurred in 40.9% of the patients. The clinical benefit rate at 3 months was 41.2% in the overall population, 46.7% when platinum-based CT was used as first-line CT, and 38.6% when used as subsequent CT line. Overall response rate was 26.7% in first-line platinum-based CT and 18.1% in subsequent CT line. Median PFS and OS were 3.2 months (95% CI 2.8 - 3.8) and 8.6 months (95% CI 6.8 - 9.9), respectively. One-year OS rate was 37.1% (95% CI 30.5 - 43.7%). Factors associated with worse OS were ECOG-PS 3-4 (HR 1.85, 95% CI 1.21-2.82, P=0.004), presence of liver metastases (HR 1.61, 95% CI 1.16-2.23, P=0.004), and platinum-based CT initiation during hospitalization (HR 1.74, 95% CI 1.18-2.56, P=0.005). Conclusion: Despite some activity of platinum-based CT for HR-positive HER2-negative metastatic breast cancer, especially as first-line CT, response rates were lower than historically observed in TNBC. Platinum-based CT was associated with poor PFS and OS outcomes. Negative prognostic factors for OS were ECOG-PS 3-4, presence of liver metastases, and initiation of the platinum-based CT during hospitalization. Citation Format: Lucas Fernando Uratani, Francesco Sansone Bermejo, Pedro HenriqueShimiti Hashizume, Renata Colombo Bonadio, Laura Testa. Effectiveness of platinum-based chemotherapy for hormone receptor-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-49.

Preliminary Cost-Effectiveness and Cost-Utility Analysis of Cemiplimab in Patients with Advanced Cutaneous Squamous Cell Carcinoma in Italy.

PurposeCutaneous squamous cell carcinoma (CSCC) is a common cancer that in most cases is curable with surgery. About 3–5% of patients develop advanced CSCC (aCSCC) and are no longer responsive to surgery or radiation therapy. The aim of this study was to assess the cost-effectiveness and cost-utility of cemiplimab, the first systemic therapy approved in Italy for patients with aCSCC, vs platinum-based chemotherapy from the Italian National Health Service (SSN) perspective.MethodsA partitioned survival model, which included three mutually exclusive health states, was developed to estimate costs and outcomes for patients with aCSCC, over a 30-year time horizon (lifetime). No direct evidence of the comparative efficacy and safety of cemiplimab versus other therapies currently exists. Therefore, a simulated treatment comparison (STC) was conducted to estimate the comparative efficacy of cemiplimab versus chemotherapy. Individual patient data for cemiplimab were collected from the EMPOWER-CSCC 1 trial whereas chemotherapy data were derived from a retrospective study. In the STC a regression model was used to predict outcomes for cemiplimab in the population observed in the comparator study. Costs of drug acquisition/administration and management of adverse events were included. Costs and outcomes were discounted at 3% per year. Incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were calculated; sensitivity and scenario analyses were performed to assess the robustness of results.ResultsIn the base-case, treatment with cemiplimab was associated with a gain of 4.89 LYs and 3.99 QALYs, compared with a platinum-based chemotherapy regimen, resulting in an estimated ICER of 27,821 €/LY gained and an ICUR of 34,110 €/QALY gained. Both ICER and ICUR were below the commonly used Italian SSN willingness to pay thresholds.ConclusionThe use of cemiplimab, compared with a platinum-based chemotherapy regimen, can be considered a cost-effective option for the treatment of aCSCC patients in Italy.

Driving Immune Responses in the Ovarian Tumor Microenvironment.

Ovarian cancer is the leading cause of death among gynecological neoplasms, with an estimated 14,000 deaths in 2019. First-line treatment options center around a taxane and platinum-based chemotherapy regimen. However, many patients often have recurrence due to late stage diagnoses and acquired chemo-resistance. Recent approvals for bevacizumab and poly (ADP-ribose) polymerase inhibitors have improved treatment options but effective treatments are still limited in the recurrent setting. Immunotherapy has seen significant success in hematological and solid malignancies. However, effectiveness has been limited in ovarian cancer. This may be due to a highly immunosuppressive tumor microenvironment and a lack of tumor-specific antigens. Certain immune cell subsets, such as regulatory T cells and tumor-associated macrophages, have been implicated in ovarian cancer. Consequently, therapies augmenting the immune response, such as immune checkpoint inhibitors and dendritic cell vaccines, may be unable to properly enact their effector functions. A better understanding of the various interactions among immune cell subsets in the peritoneal microenvironment is necessary to develop efficacious therapies. This review will discuss various cell subsets in the ovarian tumor microenvironment, current immunotherapy modalities to target or augment these immune subsets, and treatment challenges.

Utilization of systemic therapy for treatment of advanced urothelial carcinoma: Lessons from real world experience

Metastatic bladder cancer has poor overall survival. Though systemic therapies have shown to improve overall survival, real-world studies have shown that more than half of the patients do not receive any systemic therapy, while only around 15–20% receive second-line therapy. Even in patients receiving systemic therapies a disproportionately higher use of carboplatin is observed in the first line despite proven superior effectiveness of cisplatin. Reasons for these observations include moderate effectiveness and relatively toxicity of platinum-based chemotherapy regimens, concerns with performance status and co-morbidities in this predominantly older patient population, communications barriers, lack of social support, and access to affordable healthcare. Herein we discuss potential ways to overcome these challenges which include (1) preventing/delaying metastatic disease by maximizing the receipt of neoadjuvant cisplatin-based therapy, and development of better tolerated and more effective neoadjuvant and adjuvant therapies, (2) use of avelumab maintenance therapy after 4–6 cycles of platinum-based chemotherapy to overcome attrition of patients from first to second-line therapy, (3) advancing effective and well-tolerated systemic therapies such as enfortumab vedotin, and erdafitinib to the first-line metastatic setting or even to the localized setting, (4) further development of effective and well-tolerated therapies like sacituzumab govitecan, a novel antibody-drug conjugate and (5) improving affordability and accessibility to systemic therapy agents.

Management of Cervical Cancer in Pregnant Women: A Multi-Center Retrospective Study in China.

Background: This retrospective multi-center study aimed to describe the epidemiological characteristics, clinical features, and management of patients with cervical cancer in pregnancy (CCIP) and evaluate maternal and infant outcomes.Methods: The data of patients with CCIP were retrospectively collected from those diagnosed and treated in 17 hospitals in 12 provinces in China between January 2009 and November 2017. The information retrieved included patients' age, clinical features of the tumor, medical management (during pregnancy or postpartum), obstetrical indicators (i.e., gestational age at diagnosis, delivery mode, and birth weight), and maternal and neonatal outcomes. Survival analyses were performed using Kaplan–Meier survival curves and log-rank tests that estimated the overall survival of patients.Results: One-hundred and five women diagnosed with CCIP (median age = 35 years) were identified from ~45,600 cervical cancer patients (0.23%) and 525,000 pregnant women (0.020%). The median gestational age at cancer diagnosis was 20.0 weeks. The clinical-stage of 93.3% of the patients with CCIP was IB1, 81.9% visited the clinic because of vaginal bleeding during pregnancy, and 72.4% had not been screened for cervical cancer in more than 5 years. To analyze cancer treatments during pregnancy, patients were grouped into two groups, termination of pregnancy (TOP, n = 67) and continuation of pregnancy (COP, n = 38). Analyses suggested that the TOP group was more likely to be diagnosed at an earlier gestational stage than the COP group (14.8 vs. 30.8 weeks, p < 0.001). The unadjusted hazard ratio for the COP group's overall survival was 1.063 times that of the TOP group (95% confidence interval = 0.24, 4.71). There were no significant differences between the TOP and COP groups in maternal survival (p = 0.964). Thirty-three of the infants of patients with CCIP were healthy at the end of the follow-up period, with a median age of 18 ± 2.8 months.Conclusions: Most patients with CCIP had not been screened for cervical cancer in over 5 years. The oncologic outcomes of the TOP and COP groups were similar. A platinum-based neoadjuvant chemotherapy regimen could be a favorable choice for the management of CCIP during the second and third trimesters of pregnancy.

Small cell carcinoma of the prostate after low-dose-rate brachytherapy: a case report

BackgroundSmall cell carcinoma of the prostate is a rare condition with important differences from prostatic adenocarcinoma in terms of clinical and prognostic characteristics. A low prostate-specific antigen and a symptomatic patient, including paraneoplastic symptoms, characterize small cell carcinoma of the prostate. Diagnosis is made on the basis of prostate biopsy, and fluorodeoxyglucose positron emission tomography/computed tomography is often used for staging because up to 60% of patients present with de novo metastatic disease. Patients with metastatic disease are usually treated with platinum-based cytotoxic chemotherapy regimens similar to those used for small cell carcinoma of the lung. However, prognosis remains poor, with a median overall survival of 9 to 17 months despite therapy.Case presentationThis report describes a case of an 80-year-old Caucasian patient with lymph node and bone metastatic small cell carcinoma of the prostate following low-dose-rate brachytherapy for a low-risk prostate carcinoma and treated with chemotherapy and immunotherapy.ConclusionLow-dose-rate brachytherapy might be an etiology of small cell prostate cancer.

Folate Receptor α: A New Target for an Old Enemy?

Ovarian cancer remains one of the biggest challenges in daily gynaeco-oncologic practice due to its high morbidity and mortality. Platinum-based chemotherapy regimens have been the mainstay of advanced ovarian cancer treatment for several decades. However, up to 85% of the patients with advanced disease experience recurrence even after optimal treatment. There are few therapeutic options for platinum-resistant disease. The rise of immunotherapy in oncology is enormous and a great success, unfortunately, ovarian cancer lags behind other tumors. In this article, we present an overview of an interesting possible target both in the detection and therapy of ovarian cancer. Folate receptor α (FRα) seems to be a promising target given that it is mostly expressed in tumor cells rather than in non-malignant tissue and can be found in ovarian cancer. The latest research shows new possibilities in using FRα as a target in positron emission tomography (PET) as a diagnostic target for cancer cells. Currently, despite early failures, there are promising clinical trials ongoing with FRα-targeted antibody-drug conjugate and small molecules.

Phase I study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in patients with small cell lung cancer (SCLC).

TPS9080 Background: SCLC is an aggressive neuroendocrine tumor with poor prognosis and few treatment options. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed on the surface of most SCLC tumors but minimally expressed in normal tissues. As such, DLL3 may be a promising therapeutic target. AMG 757 is an HLE BiTE immune therapy designed to redirect cytotoxic T cells to cancer cells by binding to DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. In addition to its direct antitumor effect, BiTE immune therapy can inflame the tumor microenvironment. Combining AMG 757 with a PD-1 pathway inhibitor may lead to increased antitumor activity by enabling sustained T cell-dependent killing of tumor cells. Methods: NCT03319940 is an open-label, ascending, multiple-dose, phase 1 study evaluating AMG 757 as monotherapy; the protocol was recently amended to also evaluate AMG 757 in combination with pembrolizumab. The study will include a dose exploration (monotherapy and combination) followed by a dose expansion (monotherapy). Key eligibility criteria: adult patients with relapsed/refractory SCLC whose disease progressed or recurred after at least 1 platinum-based chemotherapy regimen, ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety/tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757 as monotherapy and in combination with pembrolizumab. Secondary objectives are to characterize pharmacokinetics and evaluate preliminary antitumor activity; exploratory objectives are to assess immunogenicity and changes in biomarkers in blood and tumor tissue. In the dose exploration phase, dose escalation/de-escalation decisions will be guided by a Bayesian logistic regression model; backfill enrollment at dose levels deemed safe and tolerable will be allowed. The study is open and recruiting patients. Clinical trial information: NCT03319940.

Real-world treatment patterns of maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: Are some patients missing out?

e18042 Background: The clinical utility of maintenance therapy (MT) for patients with platinum-sensitive recurrent ovarian cancer (PSROC) has been validated in several clinical trials. We assessed real world treatment patterns using a US nationwide electronic health record database. Methods: A retrospective study of patients with PSROC between March 2017 and July 2019 was conducted using the Flatiron Health database. This longitudinal, demographically and geographically diverse de-identified database covers &gt; 2.2 million oncology patients in &gt; 280 cancer clinics. Patients were excluded if second or third line (2L or 3L) platinum-based chemotherapy (PBT) regimens included less than four or more than eight cycles of platinum. Information regarding somatic or germline BRCA mutations and homologous recombination deficiency (HRD) were obtained. Results: 2292 patients with PSROC were identified (had 2L or 3L treatment); 1214 of these received PBT at recurrence; 610 completed the PBT for recurrence on or after March 2017; 351 received 4–8 cycles of PBT; 225 patients had ≥2 months of active surveillance or were receiving MT of PARPi or bevacizumab (B) and were included in this analysis. 183 patients (80%) had BRCA testing and 14 patients (6%) had HRD testing. 46 (20%) had a germline or somatic BRCA mutations (t BRCA), 134 (59%) had a wildtype wt BRCA gene, and 48 (21%) were unknown. Of patients with tBRCA, 63% received a PARP inhibitor (PARPi), 17% received B, 20% received active surveillance. Of patients with wt BRCA, 40% received a PARPi, 24% received B, and 37% received active surveillance. Olaparib was the most commonly used PARPi among tBRCA patients (26%), while niraparib was most commonly used among wt BRCA patients (21%). MT was more common in younger patients, those with a better performance status and with a BRCA mutation. MT use trend increased by 21% during the study period. As PARPi use increased, the use of active surveillance as a post-platinum regimen decreased during the later time periods (Table). Conclusions: In this real world population, the majority of patients with PSROC are receiving maintenance therapy. While genetic testing is improving, universal testing of all patients with ovarian cancer remains the goal. The results provide insight into the shifting treatment patterns for patients with ovarian cancer. [Table: see text]

A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma.

6009 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by TP53 mutations ( &gt; 90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. As such, USC may therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This two-stage single arm Phase 2 study was conducted to assess the activity of the Wee1 inhibitor adavosertib as monotherapy in recurrent USC. Methods: Women with recurrent USC (defined as non-carcinosarcoma uterine cancers with any serous component) were eligible. Patients (pts) were required to have had at least one prior platinum-based chemotherapy regimen; those with known MSI-H/MMRd disease were required to have received prior PD1/PDL1 therapy or to be ineligible for such therapy. There was no upper limit on the number of prior lines pts could have received. All pts were required to have RECIST measurable disease. Pts received adavosertib 300mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Coprimary endpoints were objective response and progression-free survival at 6 months (PFS6). Results: Between OCT-11-2018 and SEP-30-2019, 35 pts enrolled on study. Median follow-up is 4.6 months. The median number of prior lines was 3 (range 1-8). 34 pts were considered evaluable for response. In these pts, 9 confirmed and 1 unconfirmed responses were observed, for an ORR of 29.4% (95% CI 15.1-47.5%). The PFS at 6 months was 58.7% (95% CI: 39.5-73.7%). The median PFS is 6.1 months and the median duration of response is 9.0 months. Frequently observed Grade 3 or higher related adverse events included neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%). Immunohistochemistry and targeted next-generation sequencing were performed to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in women with USC. The observed monotherapy activity is higher than in other diseases, and additional exploration of the biology of Wee1 inhibition in USC is needed. Further studies of adavosertib in this patient population are planned. Clinical trial information: NCT03668340.

Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial

In ARIEL3, rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology.

JUND-dependent up-regulation of HMOX1 is associated with cisplatin resistance in muscle-invasive bladder cancer.

The standard-of-care for metastatic muscle-invasive bladder cancer (MIBC) is platinum-based chemotherapy regimens. Acquired resistance that occurs frequently through unidentified mechanisms, however, remains the major obstacle for implementing therapeutic effectiveness. Here, using data mining and analysis on clinical samples, we show that expression of JUND, a core component of activator protein-1 family, was significantly induced in cisplatin (CDDP)-resistant MIBC. Accumulation of nuclear JUND was associated with low post-chemotherapy survival in MIBC patients. In both genetically engineered cell models and murine xenograft models, we provided evidence that bladder cancer (BC) cells with excessive JUND expression were less responsive to CDDP treatment. This CDDP resistance was further demonstrated to be mediated, at least in part, by transactivation of HMOX1 [the gene encoding heme oxygenase-1 (HO-1)], one of the most important antioxidant signalling pathways of cell adaptation to stress. One mutation within the HMOX1 promoter successfully abolished oxidative stress-enhanced and JUND-driven HMOX1 promoter activation, suggesting that this unique site synergized for maximal HO-1 induction in CDDP-challenged BC cells. Overall, our data highlight an indispensible role of JUND, both as a target as a modifier of the oxidative stress signalling, in conferring an adaptive response during the pathogenesis of CDDP resistance in MIBC.

A phase II study of the combination chemotherapy of bevacizumab and gemcitabine in women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer

IntroductionBevacizumab and gemcitabine are key drugs for treating recurrent epithelial ovarian cancer. However, information about the combination of bevacizumab and gemcitabine is insufficient. We conducted a phase II study to assess the feasibility, clinical activity, and toxicity of this combination chemotherapy.MethodsThis study included women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer who received one to three regimens of platinum-based chemotherapy between April 1, 2015 and December 31, 2018. The patients received bevacizumab 15 mg/kg intravenously on day 1 and gemcitabine 1000 mg/m2 intravenously on days 1 and 8 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of three cycles of chemotherapy. This study was registered in the University Medical Information Network (UMIN) Clinical Trials Registry (UMIN000016619).ResultsAmong the 19 patients, 18 (95%) received ≥3 and 9 (47%) received ≥6 cycles of the study therapy. The objective response rate was 42% (complete response of 16% and partial response of 26%), and the clinical control rate was 84%. Hematological toxicity included neutropenia grade 3/4 in 9 patients (47%), anemia grade 3/4 in 2 (11%), and thrombocytopenia grade 3/4 in 1 (5%). One patient (5%) had grade 3 hypertension, and 1 (5%) had grade 3 protein urea. Possibly related grade 3 pulmonary toxicity was observed in 1 patient. Three patients needed dose reduction of gemcitabine to 800 mg/m2 due to treatment delay by 15 to 21 days on day1. There was no treatment delay more than 14 days on day 8. The median progression-free survival duration was 5.1 months and median overall survival duration was 21.3 months.ConclusionThe combination chemotherapy with gemcitabine and bevacizumab was feasible, effective and safe. This combination chemotherapy may be explored in a further randomized trial.

Factors associated with compliance to chemotherapy amongst cancer patients in a radiotherapy facility

Objectives: To study compliance with chemotherapy schedules in cancer patients and associated factors.Study Background: This study was conducted in Radiotherapy/Oncology Department, Ahmadu Bello University Teaching Hospital (ABUTH) Zaria which has a 10-bed capacity chemotherapy room, within 11 weeks from 1st March 2018 to 18th May 2018. Almost all the patients were on 3- weekly cyclical chemotherapy with very few patients on 2-weekly or 4- weekly courses. The hospital serves as a centre of excellence for oncology in the Northern region of Nigeria. The bulk of the patients are from a low socio-economic class.Methodology: The study is a prospective cross-sectional study involving a total of 140 patients. Data collection from patients' record (age, diagnosis, stage at diagnosis, comorbidities, chemotherapy regimen, previous treatments received etc.), the record of the date of chemotherapy course and assessment ECOG performance for each patient during each chemotherapy course were recorded in a designed booklet. This was conducted for over 11 weeks. Ethical clearance was obtained. Patients' consent was obtained, and care was taken to maintain the confidentiality of patients. Data collected were inputted and analyzed using Statistical Program for Social Sciences (SPSS) version 21.0.Results: There was a statistically significant correlation between compliance with chemotherapy schedule and patients' performance status, prior radiotherapy, combination chemotherapy and use of platinum-based chemotherapy regimen. However, there were no correlations with patients' age, sex, chemotherapy course, stage of the disease, previous oncologyrelated surgery (excluding biopsies), comorbidities and blood transfusion during chemotherapy.Conclusion: This study suggests that patients' performance status, prior radiotherapy, use of platinum-based chemotherapy and combination chemotherapy schedule are significant to compliance with chemotherapy

Salvage treatment for children with relapsed/refractory germ cell tumors: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience.

Malignant germ cell tumors (GCTs) are a heterogeneous group of rare neoplasms in children. Optimal outcome is achieved with multimodal therapies for patients with both localized and advanced disease, especially after the introduction of platinum-based chemotherapy regimens. In this respect, data on salvage treatment for children with relapsed or platinum-refractory disease are still limited. Retrospective analysis of data regarding patients affected by malignant GCTs with platinum-refractory or relapsed disease after first-line treatment according to AIEOP TCGM 2004 protocol was conducted. Twenty-one patients, 15 females and 6 males, were considered for the analysis. All 21 patients received second-line conventional chemotherapy (SLCT), two of these immediately after surgery for local relapse removal. Two patients showed a progression of disease during SLCT and died of disease shortly thereafter, whereas 19 patients were in partial remission (PR) or complete remission (CR) after SLCT. Treatment after SLCT consisted in surgery on residual tumor mass (9/19) followed by high dose of chemotherapy (HDCT) with autologous hematopoietic stem cell support (16/19). The overall survival (OS) and event-free survival of the whole populations are 71% and 66.6%, respectively. Platinum-refractory patients OS is 54.5% compared with 91.5% of the relapsed group. There were no treatment-related deaths. SLCT followed or not by HDCT is an effective salvage treatment for children with relapsed/refractory GCTs. However, the role of HDCT following SLCT needs to be further investigated, especially regarding the identification of specific patient subgroups, which can benefit from this more intensive treatment.

Use of First-Line PARP Inhibitors in Ovarian Cancer

Platinum-based chemotherapy regimens are the mainstay of advanced ovarian cancer treatment. However, up to 85% of the patients experience recurrence under these settings. To fill this gap, novel front-line treatment strategies have been established, leading to unprecedented clinical benefits. For example, first-line bevacizumab, an anti-angiogenic agent, plus chemotherapy followed by bevacizumab maintenance, has emerged as a new standard of care for newly diagnosed high risk ovarian cancer patients. This was based on the results of the phase III GOG 0218 and ICON-7 trials. More recently, poly(ADP)-ribose polymerase (PARP) inhibitors, including niraparib, olaparib and veliparib, have offered a new treatment option as part of the front-line treatment in ovarian cancer. Here we provide an overview of three recent studies that may lead to a paradigm shift in the first-line treatment for advanced ovarian cancer.

1000P - Efficacy and safety of oral poly (ADP-ribose) polymerase inhibitor fluzoparib in patients with BRCA1/2 mutations and platinum sensitive recurrent ovarian cancer

BackgroundFluzoparib is a potent orally administered poly(ADP-ribose) polymerase (PARP) inhibitor. The safety and tolerability of fluzoparib has been evaluated in a phase 1 trial (NCT02575651). In this study, we aim to characterize the efficacy and safety of fluzoparib in patients (pts) with germline BRCA1/2 mutations and platinum sensitive recurrent ovarian cancer who had received ≥2 prior lines of chemotherapy. MethodsThis was an open-label, multi-centre, phase 2 study of oral fluzoparib in pts with recurrent ovarian cancer. Adult pts (≥18 years) with germline BRCA1 or BRCA2 mutations and platinum-sensitive recurrent high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with two or more previous platinum-based chemotherapy regimens were enrolled. Patients were treated with fluzoparib capsule at 150mg orally twice daily up to disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. ResultsFrom April 4 2018 to March 21 2019, 113 pts at Chinese national-wide 26 sites were received the fluzoparib. At the data cutoff date (April 15, 2019), 103 pts were efficacy evaluable (follow-up ≥8 weeks). The ORR and disease control rate (DCR) were 64.1% (66/103) and 95.1% (98/103), respectively. Complete response (CR) was observed in 9 pts (8.7%). Median duration of response (DOR) and progression free survival (PFS) have not yet been reached. Any grade treatment-related AEs (TRAEs) occurred in 108 patients (95.6%). The most common (≥20%) TRAE were nausea (55.8%), fatigue (47.8%), white blood cell count decreased (44.2%), anemia or decreased hemoglobin (42.5%), neutrophil count decreased (31.9%), decreased appetite (30.1%), thrombocytopenia (29.1%), and vomiting (23.9%). The most common grade ≥3 TRAE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption and dose reduction in 31.0% and 21.1% of patients, respectively. ConclusionsFluzoparib demonstrated promising antitumor activity and acceptable safety in patients with advanced BRCA1/2-mutated ovarian cancer. And this is the first report of a PARP inhibitor in Chinese patients with BRCA1/2 mutations and recurrent ovarian cancer. Clinical trial identificationNCT03509636. Legal entity responsible for the studyJiangsu Hengrui Medicine Co. LTD, China. FundingJiangsu Hengrui Medicine Co. LTD. DisclosureJ. Zou: Shareholder / Stockholder / Stock options: Jiangsu Hengrui Medicine Co. LTD. Q. wang: Shareholder / Stockholder / Stock options: Jiangsu Hengrui Medicine Co. LTD. All other authors have declared no conflicts of interest.

Abstract LB-297: Metabolic alterations in plasma associated with survival in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is an aggressive histological subset of lung cancer accounting for ~15% of diagnosed lung cancers (more than 230,000 patients in the US in 2018). Five-year survival rates for advanced SCLC are below 10% with a 2% 5-year survival rate for distant metastatic disease. The dismal survival rates are governed by a lack of targetable oncogenic mutations, a lack of therapeutic avenues, diagnosis at advanced (metastatic) stage, and expected therapeutic resistance to standard-of-care therapies. There is an unmet clinical need to identify new therapeutic avenues for SCLC and develop factors that would impact prognosis and predict therapeutic response. Circulating metabolites are functional surrogates for cellular phenotypes, making them ideal to study in cellular transformation and tumor progression. We hypothesize that alterations in cellular metabolism will correlate with patient prognosis and therapeutic response/resistance in SCLC. The clinical cohort was comprised of 27 SCLC patients treated at Samsung Medical Center, Seoul, South Korea. Of these, 15 patients were diagnosed with extensive disease, while 10 patients were detected with limited and 2 patients with intermediate disease. All of the patients were treated with platinum-based cytotoxic chemotherapy regimens. The plasma samples were collected at three stages, before treatment (baseline), six-weeks post treatment, and at clinical relapse. We employed targeted, quantitative metabolomics to query the plasma metabolome of the SCLC patients. The results describe comparisons of baseline and six-week post treatment samples with clinical outcomes. In this SCLC cohort the mutational profile (prevalent mutations in RB1 and TP53) was consistent with other SCLC datasets, although this set tended to have higher incidence of BRCA1/2 mutations. At the baseline measurement, plasma concentrations of 5 acylcarnitines including C14:2, C10:1, C12, C12:1, C14:1-OH and a lysoglycerophosphocholine (lysoPC a C16:1) were significantly associated with progression-free survival (PFS); while proline and acyl carnitine C10:1 were significantly associated with overall survival (OS) across the cohort. When comparing those patients who progressed rapidly on platinum-based therapy (&amp;lt; 93 days) to those that progressed more slowly (&amp;gt; 236 days), two sphingolipids (SM C24:1, SM C20:2) and asymmetric dimethylarginine (ADMA) were significantly increased in those patients progressing more rapidly. In looking at the metabolic alterations across 6-weeks of therapeutic exposure, we saw 5 glycerophospholipids were significantly lower (FDR adjusted p &amp;lt; 0.05). In exploratory analyses (unadjusted p &amp;lt; 0.05), plasma levels of 43 lipids including 31 glycerophospholipids, 7 sphingolipids, 5 acylcarnitines were increased. Overall, exposure to chemotherapy was associated with altered plasma lipid levels. The higher circulating acylcarnitines may indicate modulation of carnitine palmitoyltransferase and suppression of the beta-oxidation process. Thus, changes in the plasma metabolome may be associated with OS and PFS in SCLC, and indicative of rapid recurrence on standard therapies. A larger investigation of the plasma metabolome in SCLC may identify biomarkers of patient prognosis and/or therapeutic response/resistance, necessary advancements towards abating the dismal patient survival rates in this disease. Citation Format: Khyatiben V. Pathak, Se-Hoon Lee, Marissa McGilvrey, Krystine Mansfield, Derek Cridebring, Denise J. Roe, Timothy G. Whitsett, Keunchil Park, Patrick Pirrotte. Metabolic alterations in plasma associated with survival in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-297.

Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).

TPS8577 Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.