First-line Platinum-based Therapy Research Articles

562TiP A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer

Ovarian, peritoneal, and fallopian tube cancer are deadly diseases with similar pathological and clinical features. Despite initial therapy with cytoreductive surgery and platinum-based therapy, many patients experience disease relapse either during (refractory) or within 6 months after (resistant) first-line platinum-based therapy. In these patients, various chemotherapies offer clinical activity but none is universally preferred. WEE1 tyrosine kinase is a critical component of G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of cyclin-dependent kinase 1 (CDK1). Inhibition of WEE1 leads to premature mitotic entry, DNA damage and apoptosis induction, and cell death. ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in nonclinical in vitro and in vivo models. A first-in-human study identified the maximum tolerated dose (MTD) of ZN-c3 when given as monotherapy. Combining ZN-c3 with chemotherapy may inhibit repair of chemotherapy-induced DNA damage and provide therapeutic benefit in this population. This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of ZN-c3 in combination with pegylated liposomal doxorubicin, carboplatin, paclitaxel, or gemcitabine. The primary objectives are to determine MTDs and recommended phase 2 doses for each combination by a modified Bayesian continual reassessment method. Subjects are adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1 or 2 prior chemotherapy regimens including platinum-based therapy and are refractory or resistant to platinum-based therapy. Study drug therapy is given in repeated 21- or 28-day cycles until disease progression or unacceptable toxicity. ZN-c3 is taken orally once daily. Chemotherapy is administered per protocol. Pharmacodynamic effects of therapy in tumor tissue and hair follicle samples will be explored. Subject recruitment is ongoing. NCT04516447 Zentalis Pharmaceuticals.

Prognostic Significance of Disease Control at 12 Weeks in Patients With Advanced Pancreatic Cancer Receiving FOLFIRINOX as First-line Chemotherapy.

The POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated improvement in progression-free survival (PFS) with olaparib maintenance in advanced pancreatic cancer (APC) patients with germline BRCA1/2 mutations who had disease control after 16 weeks of platinum-based first-line therapy. However, in the real-world, the first assessment is usually performed at 12 weeks. Therefore, this study aimed to identify the proportion of real-world patients with APC that have disease control at 12 weeks (DC12) after FOLFIRINOX, assess any associations of baseline variables with DC12, and to determine the effect of DC12 on PFS and overall survival (OS). APC patients treated with first-line FOLFIRINOX from 2011 to 2018 in Alberta, Canada, were identified. We conducted an analysis of baseline characteristics to identify factors associated with DC12 and to compare the PFS and OS of patients with DC12 to those with earlier disease progression. We identified 165 APC patients treated with FOLFIRINOX with unknown BRCA1/2 status, of which 56% were men, and the median age at diagnosis was 59 years (interquartile range, 38 to 75 y). Of these, 72 (44%) had DC12. Lower serum carbohydrate antigen 19.9 and normal serum albumin were associated with a higher likelihood of DC12. The PFS and OS of patients with DC12 was significantly higher than those with earlier progression (9.3 vs. 2.5 mo; hazard ratio, 0.22; 95% confidence interval, 0.15-0.32; P<0.001; 21.6 vs. 8.9 mo; hazard ratio, 0.35; 95% confidence interval, 0.25-0.49; P<0.0001). Less than half of real-world patients treated with first-line FOLFIRINOX have DC12. Patients with APC who have higher carbohydrate antigen 19.9 and low albumin are less likely to have DC12. DC12 is significantly associated with longer PFS and OS.

Irinotecan-based chemotherapy in extrapulmonary neuroendocrine carcinomas: survival and safety data from a multicentric Italian experience

Neuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs. Patients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. Thirty-four patients, 16 males, and 18 females, median age of 59 years (range 32-77), with metastatic NEC were included. Twenty-seven patients had Ki-67 ≥ 55% and four patients Ki-67 of <55% (for three patients data were not available). The median number of treatment cycles of the IRI-based regimen was 7.5 (range 1-16). Six partial responses (17.6%) and 9 stable diseases (26.5%) were observed, with a disease control rate of 44.1%. Median PFS and OS were 4.4 and 5.9 months, respectively. Neutropenia, anemia, and nausea were the only G3-G4 toxicities reported. Despite the relatively small sample size, IRI-based therapy demonstrated to be a valid option for patients with pretreated extrapulmonary NEC.

Nonplatinum‐based therapy with Paclitaxel and Capecitabine for advanced squamous cell carcinomas of the anal canal: A population‐based Danish anal cancer group study

BackgroundFirst‐line platinum‐based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second‐line treatment options are limited. Paclitaxel and Capecitabine are a well‐known regimen with a moderate toxicity profile, but its efficacy has not been evaluated.MethodsWe conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018.ResultsA total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42–83). Efficacy was observed, with an overall response rate in patients receiving first‐line (N = 28) and second‐line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression‐free survival (PFS) was 4.5 months (95% CI 3.3–5.9) and 3.8 months (95% CI 2.4–5.5) with OS of 6.7 months (95% CI 5.9–8.5) and 5.9 months (95% CI 3.9–14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS.ConclusionThis study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first‐line therapy is not feasible or as a potential second‐line treatment after failure of platinum‐based chemotherapy.

Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40mg/kg, i.p. injection weekly); G5: PTX (20mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2weeks. The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Second-line therapy improves overall survival in primary refractory non-small cell lung cancer (NSCLC) patients

BackgroundThe effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. Recently, immune checkpoint inhibitors have shown promising efficacy in NSCLC patients. However, little is known about the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We investigated the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC.Patients and methodsPatients with metastatic NSCLC diagnosed between 1990 and 2016 were assessed. Outcome parameters were collected and patients were characterized as either having primary progressive disease or clinical benefit [CB; defined as complete/partial remission (CR, PR) or stable disease (SD)]. Probabilities of survival were calculated using the Kaplan–Meier estimator. The log-rank test was used for comparing groups. Cox models were used to explore the prognostic value of covariables.ResultsThe analysis included 576 patients. Median overall survival (OS) was 9.5 months [95% confidence interval (CI) 8.47-10.47]; 62.7% of patients were treated with a platinum-based first-line therapy. Two hundred twenty-two patients (38.5%) were primary refractory to first-line therapy. Median OS was significantly shorter for those patients [7.4 versus 11.5 months, hazard ratio (HR) 1.61 (95% CI 1.34-1.93), P < 0.0001]. Poorer initial performance status was significantly associated with primary refractory disease (P = 0.015). Eighty-one (36.5%) primary refractory patients received a second-line therapy. Median OS was significantly longer for refractory patients receiving second-line therapy versus best supportive care [10.1 versus 5.0 months, HR 0.53 (95% CI 0.40-0.72), P < 0.0001].ConclusionsNearly 40% of patients are primary refractory to palliative first-line therapy and have a poor prognosis. Active second-line therapy can significantly improve the outcome. Therefore, patients with primary refractory NSCLC should be offered further active therapy. These real-life data for primary refractory patients form the basis for further research in sequencing of current palliative treatment options.

MO01.39 Liposomal Irinotecan in Adults with Small Cell Lung Cancer who Progressed on Platinum-Based Therapy: Subgroup Analyses by Platinum Sensitivity

Most patients with extensive small cell lung cancer (SCLC) develop drug resistance to platinum-based first-line therapy or discontinue for other reasons, and second-line therapies are limited. RESILIENT (ClinicalTrials.gov identifier NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of second-line liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based first-line therapy. Preliminary data from RESILIENT part 1 (cut off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al.

412P Treatment patterns and selection criteria for advanced non-small cell lung cancer (NSCLC) patients unfit for platinum-based first-line therapy: Results of the MOON-OSS observational trial

412P Treatment patterns and selection criteria for advanced non-small cell lung cancer (NSCLC) patients unfit for platinum-based first-line therapy: Results of the MOON-OSS observational trial

1793P RESILIENT part 1: Pharmacokinetics of second-line (2L) liposomal irinotecan in patients with small cell lung cancer (SCLC)

RESILIENT (NCT03088813) is a two-part phase 2/3 study of the safety, tolerability and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Here we describe the pharmacokinetics (PK) of 2L liposomal irinotecan from RESILIENT part 1. Part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Patients aged ≥ 18 years, with an ECOG performance status of 0/1, received liposomal irinotecan 70 or 85 mg/m2 free base every 2 weeks. Seven PK samples per patient were scheduled. Plasma concentration data for total irinotecan (tIRI) and SN-38 (active metabolite) were analysed using a population PK model updated for SCLC. PK parameters were estimated with non-linear mixed effects modelling. Assessment of model adequacy was based on the uncertainty of parameter estimates and advanced evaluation methods (e.g. visual predictive check). Interindividual variability was examined using potential covariates including patient demographics and UGT1A1*28 genotype status. Derived PK parameters, Caverage and Cmax, were computed by dose from individually predicted PK profiles. As of 2 DEC 2019, 30 patients had received liposomal irinotecan (70 mg/m2, n = 25; 85 mg/m2, n = 5). tIRI PK is described by a two-compartment model with first-order elimination. SN-38 is formed directly by a first-order constant from the central compartment of liposomal irinotecan or following a transit compartment. UGT1A1*28 *7/*7 homozygous status (4/30 patients) was not associated with a significant impact on SN-38 clearance. Model evaluation was satisfactory for both tIRI and SN-38. After 70 and 85 mg/m2 respectively, median (coefficient of variation %) Caverage was 5.1 (48) and 5.5 (9) μg/mL for tIRI, and 1.6 (33) and 2.1 (16) ng/mL for SN-38, and Cmax was 36.1 (15) and 40.7 (14) μg/mL for tIRI and 3.7 (32) and 4.4 (10) ng/mL for SN-38. The PK of 2L liposomal irinotecan and SN-38 in patients with SCLC is well described by the population model. Findings suggest SN-38 clearance is not associated with UGT1A1*28 *7/*7 homozygous status. RESILIENT part 2 data will be added to the current dataset to enrich the PK characterization.

RESILIENT part II: an open-label, randomized, phase III study of liposomal irinotecan injection in patients with small-cell lung cancer who have progressed with platinum-based first-line therapy.

TPS9081 Background: Although small cell lung cancer (SCLC) is often sensitive to established first-line therapies, many patients relapse and develop drug resistance, and second-line therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Preliminary data from the dose-ranging part of the study (part 1) showed that liposomal irinotecan 70 mg/m2 administered every 2 weeks was well tolerated and had promising antitumor activity (Paz-Ares et al. ASCO 2019; poster 318). Here, we present the design of the second, larger part of the study, which will evaluate the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population. Methods: Part 2 of RESILIENT is a phase 3, open-label study with a planned sample size of 450. Patients are randomly allocated 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered every 2 weeks at 70 mg/m2 (free-base equivalent) and topotecan is administered for 5 consecutive days every 3 weeks at 1.5 mg/m2. As of January 2020, 80 patients have been enrolled in part 2 of the trial. Tumor assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions; symptom improvement is measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Safety assessments include monitoring for adverse events. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free survival (PFS), objective response rate, and proportion of patients reporting symptom improvement. Patients will continue study treatment until disease progression, unacceptable toxicity or study withdrawal and will then be followed for survival until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT03088813.

RESILIENT part I, an open-label, safety run-in of liposomal irinotecan in adults with small cell lung cancer (SCLC) who have progressed with platinum-based first-line (1L) therapy: Subgroup analyses by platinum sensitivity.

9069 Background: Most patients with extensive SCLC develop drug resistance to platinum-based 1L therapy or discontinue for other reasons, and second-line (2L) therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of 2L liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based 1L therapy. Preliminary data from RESILIENT part 1 (cut-off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al. WCLC 2019 OA03.03). Objective response rate (ORR; secondary endpoint) was 44% (11/25). Here we report efficacy analyses in post hoc subgroups by platinum sensitivity. Methods: RESILIENT part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Eligible patients were aged ≥ 18 y, with an ECOG performance status score of 0/1 and adequate organ function; a single line of prior immunotherapy was allowed. Participants received liposomal irinotecan 70 mg/m2 or 85 mg/m2 free base every 2 weeks, with tumor assessments every 6 weeks (RECIST v1.1). Analyses were undertaken for the dose-finding phase recommended dose (RD) in subgroups of platinum-resistant/sensitive patients (with/without progression within 90 days from completion of 1L therapy). Results: During dose finding, 5 patients received liposomal irinotecan 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 received 70 mg/m2 (deemed tolerable; RD for dose-expansion phase in which 13 more patients were included). Analyses included all 25 patients receiving the RD (mean exposure, 13.95 weeks [median 14.86; SD 7.222]). In the platinum-sensitive subgroup (33.3% men; median age 62.0 y) ORR was 53.3% (8/15) and 12-week disease control rate (DCR12wks) was 60% (9/15); in the platinum-resistant subgroup (50% men, median age 58.0 y) both ORR and DCR12wks were 30% (3/10). Overall and progression-free survival (secondary endpoints) are not yet mature. Conclusions: ORR and DCR12wks were numerically higher in platinum-sensitive than in platinum-resistant patients with SCLC who had progressed with platinum-based 1L therapy before receiving 2L liposomal irinotecan 70 mg/m2 in this phase 2 study. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial vs topotecan, will provide further data. Clinical trial information: NCT03088813.

DiM: Prognostic Score for Second- or Further-line Immunotherapy in Advanced Non–Small-Cell Lung Cancer: An External Validation

BackgroundOther than the programmed cell death ligand 1 (PD-L1) value, oncologists have only the clinical characteristics of patients with advanced non–small-cell lung cancer (aNSCLC) to determine candidates for immunotherapy. A clinical prognostic score composed of the Eastern Cooperative Oncology Group performance status, sex, histologic type, stage, platinum-based first-line therapy, and response to first-line therapy has categorized 3 prognostic groups for patients undergoing second-line chemotherapy. We sought to validate the same score for patients with aNSCLC treated with second- or further-line immunotherapy. Materials and MethodsWe collected data from 2 Italian centers. A score was generated to divide patients into 3 prognostic groups: best, score < 5; intermediate, score 5 to 9; and worst, score > 9. Overall survival (OS) and progression-free survival (PFS) were the endpoints. ResultsA total of 347 patients were included for analysis. Their median age was 66 years (range, 30-88 years), most were aged < 70 years (67.5%), 70.7% were men, 79.5% were smokers, and 74.6% had had adenocarcinoma. The Eastern Cooperative Oncology Group performance status was 0 for 23%, 1 for 54.5%, and 2 for 22.5%. Of the 347 patients, 28% were in the best prognosis, 51% in the intermediate, and 21% in the worst prognosis group, respectively. The median OS was 18.0 months for the best, 8.5 months for the intermediate (hazard ratio [HR] vs. best, 1.83; 95% confidence interval [CI], 1.35-2.47; P < .001) and 2.6 months for worst (HR vs. best, 5.77; 95% CI, 3.99-8.33; P < .001) group. The median PFS was 3.4 months for the best, 3.7 months for the intermediate (HR vs. best, 1.35; 95% CI, 1.03-1.77; P = .032), and 1.9 months for the worst (HR vs. best, 2.51; 95% CI, 1.80-3.50; P < .001) group. ConclusionsThe prognostic score was able to predict the outcomes of patients with aNSCLC who had received immunotherapy. The worst category showed a dismal life expectancy and probably would not benefit from active systemic therapy. Thus, for these patients, best supportive care could be the best choice.

Real-world eligibility of advanced pancreatic (APC) patients for maintenance olaparib.

653 Background: The POLO trial demonstrated an improvement in progression free survival (PFS, 7.4 months vs. 3.8 months; hazard ratio, HR, 0.53; 95% confidence interval, 95% CI, 0.35 to 0.82; P=0.004) with olaparib compared to placebo, as maintenance therapy in APC patients with germline BRCA 1/2 mutations with disease control after 16 weeks (DC16) of platinum-based first-line therapy. This study aims to identify the proportion of real-world APC patients eligible for olaparib, and to determine the PFS and overall survival (OS) after DC16. Methods: APC patients treated with first-line FFX in Alberta were identified (2011-2018). We conducted an analysis of baseline characteristics to identify factors associated with DC16. Results: We identified 165 APC patients treated with FFX with unknown BRCA 1/2 status, of which 56% were males and median age at diagnosis was 59 years (interquartile range 38-75 years). Of these, 72 (44%) had DC16. Normal LDH and ALP, and albumin more than 35 g/L were associated with a higher likelihood of having DC16 (table). The PFS of patients with DC16 was significantly higher than those with DC&lt;16 weeks (9.3 vs 2.5 months, HR=0.22, 95% CI 0.15-0.32, P&lt;0.001). In patients who had DC16, median PFS and OS from that point were 5.6 months and 17.9 months, respectively. Conclusions: Less than half of real-world patients treated with first-line FFX would be eligible for olaparib by the criteria of DC16 with FFX. Median PFS after DC16 is 5.6 months with FFX in patients with unknown BRCA 1/2 status. This provides a baseline for future trials evaluating maintenance strategies. Patients with APC and higher disease burden (higher ALP and LDH) and low albumin are less likely to have DC16. [Table: see text]

The Role of Metastasectomy in Urothelial Carcinoma: Where Are We in 2020?

Systemic therapy is the mainstay of treatment for metastatic urothelial carcinoma (UC). Responses to first-line platinum-based therapy tend to be short-lived with potential toxicity. Despite the approval of checkpoint inhibitors, the long-term prognosis for patients with metastatic UC remains dismal. Herein we report the case of a patient with a solitary pulmonary metastatic lesion of urothelial origin as the only site of metastatic disease who remained free of disease for more than 2 years without systemic therapy after metastasectomy. We review the literature discussing the role of combined surgical and medical management of oligometastatic UC. As our case illustrates, a growing body of evidence suggests a potential role for a multimodal approach in patients with oligometastatic UC.

ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy

Background: Little is known about the biological factors influencing ovarian cancer (OC) patient outcome, especially in older patients who are often underrepresented in clinical trials. We examined alterations in the transcriptomic profile of primary high-grade serous carcinoma (HGSC) samples from older OC patients (>70 years) receiving first-line platinum-based treatment to identify potential biomarkers for prediction of response to this therapy.Material and methods: Tumor samples from 50 HGSC patients were identified from a retrospective cohort, analyzed by gene expression array. The protein expression of selected biomarkers was examined using immunohistochemistry (IHC).Results: Gene expression profiling revealed 81 genes with significantly altered expression in patients experiencing progression after first-line platinum-based treatment within 6 months versus those who progressed later than 12 months. Expression of ankyrin repeat and PH domain 1 (ARAP1) was significantly lower in the group with early versus late progression (p ≤ .01). Correlation between ARAP1 expression and outcome was further confirmed by IHC staining in the discovery cohort (χ2-test, p = .004) and in independent validation cohorts. The sensitivity of ARAP1 allowed identification of 64.7% of patients with early progression in the discovery population, with a specificity of 78.6% and a negative predictive value of 78.6%. Multivariate regression analysis identified ARAP1 as an independent prognostic factor.Conclusions: This hypothesis generating study suggests that low expression of ARAP1 is an independent prognostic biomarker of shorter RFS in older patients with HGSC receiving first-line platinum-based antineoplastic therapy, which could be used to identify patients who should receive more intensive treatment and closer surveillance.

Multicenter retrospective study to evaluate the impact of trabectedin plus pegylated liposomal doxorubicin on the subsequent treatment in women with recurrent, platinum-sensitive ovarian cancer.

Debulking surgery, followed by taxane/platinum-based chemotherapy has traditionally been the first-line treatment for advanced ovarian cancer. However, most patients will experience recurrence afterwards, and receive subsequent lines of therapy. It has been proposed that extending the treatment-free interval of platinum can improve the response to a subsequent platinum-based chemotherapy, and reduce associated toxicities in women with recurrent, platinum-sensitive ovarian cancer. The aim was to determine the impact, in clinical practice, of trabectedin with pegylated liposomal doxorubicin (trabectedin/PLD) on the subsequent platinum-based therapy in these patients, and to explore the prognosis for breast cancer gene status and the expression of diverse genes. This was a multicenter, retrospective, postauthorization study that involved 79 patients. Germline or somatic mutations of breast cancer gene 1/2 were present in 21.5%. The median time between trabectedin/PLD and the onset of the subsequent treatment was 6.7 months. The overall response rate during the trabectedin/PLD period was 36.7%. In the subsequent first-line platinum-based therapy, the overall response rate was 51.4%. Progression-free survival and overall survival were 11.8 and 25.4 months, respectively, from the onset of trabectedin/PLD treatment. Partially platinum-sensitive (between 6 and 12 months) and platinum-sensitive patients (treatment-free interval of platinum≥12 months) showed no differences in progression-free survival and overall survival. Grade 3 neutropenia and asthenia were reported in 15.2 and 10.1% of patients, respectively. Most frequent adverse events in more than 10% of patients were neutropenia (45.6%), asthenia (43.0%), nausea (25.3%), and anemia (13.9%). The intercalation with a nonplatinum regimen may improve the response to a subsequent platinum-based therapy in women with recurrent, platinum-sensitive ovarian cancer.

&lt;p&gt;Heterogeneity of targeted lung lesion predicts platinum-based first-line therapy outcomes and overall survival for metastatic triple-negative breast cancer patients with lung metastasis: a “PET biopsy” method&lt;/p&gt;

Background: Platinum-based chemotherapy is widely used as first-line therapy for metastatic triple-negative breast cancer (mTNBC). Intratumor heterogeneity derived from fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is a potential predictor of treatment outcomes and the prognosis of breast cancer. However, the presence of multiple lesions and complex calculation methods leads to difficulties in the clinical use of this parameter for metastatic breast cancer. The aim of this study is to provide a convenient and effective measurement of intratumor heterogeneity to predict treatment outcomes for mTNBC patients with lung metastasis.Patients and methods: We enrolled mTNBC patients with lung metastasis who underwent 18F-FDG PET/CT scans before first‐line therapy from three clinical trials (NCT01287624, NCT02341911 and NCT02546934). Apart from the regular FDG parameters, including standard uptake value (SUV), total lesion glycolysis (TLG) and metabolic tumor volume (MTV), we defined the lung index as the SUVmean divided by the difference between the SUVmax and SUVmean for the targeted lung lesion. The MTV was automatically exported from the manual delineation using software based on an adaptive threshold of SUV intensity >2.5 within the contouring margin. The TLG was calculated using the following formula: TLG=SUVmean×MTV. Progression‐free survival (PFS) and overall survival were estimated by the Kaplan–Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazard model.Results: The data from 31 patients were available for analysis. The median PFS of low-lung index (LI) patients was 8.1 months, which was significantly longer than that of high-LI patients (HR=3.3, 95% CI 1.5–7.3, p=0.003). Patients with low TLG had a significantly better PFS than those with high TLG (HR=2.6, 95% CI 1.2–5.8, p=0.014). Patients with low TLG had significantly longer overall survival than those with high TLG (31.2 months vs 13.9 months, HR=3.1, 95% CI 1.2–8.6, p=0.029). Multivariate analysis confirmed the predictive value of LI and TLG.Conclusions: This study proposed a new “PET biopsy” method to evaluate the intratumor heterogeneity of mTNBC on pretreatment 18F-FDG PET/CT scans and indicated the predictive value of LI and TLG for first-line platinum-based treatment outcomes and overall survival. These findings could help clinicians recognize patients who are likely to not only have a favorable response to platinum-based therapy but also a good prognosis.

Real-world characterization of advanced/metastatic non-small cell lung cancer (aNSCLC) patients (pts) with rapid disease progression (RDP).

e20706 Background: Despite advances in therapy, recent observational data shows that aNSCLC pts with RDP continue to have a poor prognosis. This retrospective, observational study characterizes the demographic, molecular, &amp; treatment profile of pts with RDP. Methods: Adult aNSCLC pts receiving first-line (1L) platinum-based (Pt) therapy between 01/2014 - 12/2018 were identified in the COTA Real-World Evidence database and assigned to RDP (n = 280) &amp; non-RDP (n = 1,212) cohorts based on time to progression during 1L Pt therapy (≤ 12 and &gt; 12 weeks, respectively). Results: Of 1,492 eligible pts, the incidence of RDP was 19%. Mean age (±SD) was 64.6 (10.9) and 66.1 (10.2) in the RDP and non-RDP group, respectively (p = 0.04). Data showed RDP patients had higher percentage of stage IV disease at diagnosis (77 v 72, p &lt; 0.01), higher histologic grade G3/G4 (37 v 29, p = 0.01), and PD-L1 negative (&lt; 1% expression) status (p = 0.01). Table shows molecular profiling across cohorts. No notable difference in treatment patterns across 1L and 2L was observed. Conclusions: This study identifies stage IV disease at diagnosis, higher grade, &amp; PD-L1 negative ( &lt; 1% expression) as potential risk factors for RDP. A better understanding of this poor prognosis cohort may offer an opportunity to better optimize therapies &amp; outcomes. [Table: see text]

Treatment patterns and overall survival in metastatic urothelial carcinoma in a real-world, US setting

BackgroundMetastatic urothelial carcinoma (mUC) treated with chemotherapy is associated with poor survival; however, as the field of immuno-oncology continues to evolve, new immunotherapies have recently become available. The current study aimed to assess real-world characteristics, treatment patterns, and overall survival (OS) of patients with mUC treated in the United States (US). MethodsWe conducted a retrospective, observational analysis of patients with mUC from the Flatiron Health longitudinal database from 2011 to 2017. Treatment patterns of patients who started systemic first-line therapy (1 L cohort) or second-line therapy following platinum-based first-line therapy (2 L cohort) were described using medication order and administration data. Kaplan-Meier analyses were used to assess OS from the start of first- and second-line therapy in the 1 L and 2 L cohorts, respectively. ResultsA total of 1811 patients qualified for the 1 L cohort (median age [range], 72 [32–84] years); 476 met the criteria for the 2 L cohort (median age [range], 71 [40–84] years). The most common first- and second-line therapies were carboplatin + gemcitabine (n = 562 [34.6%]) and atezolizumab (n = 90 [13.1%]), respectively, in the 1 L cohort. Median OS was 12.7 months (95% confidence interval [CI] 11.8, 13.4) in the 1 L cohort and 8.3 months (95% CI 7.2, 8.9) in the 2 L cohort. ConclusionsConsistent with clinical trial results, survival was poor in this real-world study in patients with mUC, indicating a continued unmet need. As immunotherapy becomes more commonplace in the treatment of mUC, future studies are needed to understand its real-world impact on survival.

Avelumab treatment for metastatic urothelial carcinoma in the phase Ib JAVELIN Solid Tumor Study: Updated safety and efficacy analysis with ≥ two years of follow-up.

425 Background: Avelumab, a human anti‒PD-L1 IgG1 antibody, is approved for the treatment of metastatic urothelial cancer (mUC) progressing after platinum chemotherapy in the US, Canada, and Israel. Here, we report an updated pooled analysis of 2 cohorts of avelumab-treated patients (pts) with mUC from the JAVELIN Solid Tumor study (NCT01772004). Methods: Pts with mUC whose disease had progressed after platinum-based therapy or were cisplatin ineligible received avelumab 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (NCI CTCAE v4.0). Results: As of April 2018, 249 pts had received avelumab and had been followed for ≥2 years (median 2.7 years). Median treatment duration was 12.0 weeks (IQR, 6.0-32.1), and 12 pts (4.8%) remained on treatment. Confirmed ORR in all evaluable pts (n = 242) was 16.5% (95% CI: 12.1%-21.8%; complete response in 4.1%). Median DOR was 20.5 mo (95% CI: 9.7-not estimable), and the Kaplan-Meier (K-M) estimate of 12-mo DOR was 65.4% (95% CI: 47.0%-78.8%). Median PFS was 1.6 mo (95% CI: 1.4-2.7 mo), median OS was 7.0 mo (95% CI: 5.9-8.5 mo), and the K-M 12-mo and 24-mo OS rates were 35.9% (95% CI: 29.9%-42.0%) and 20.1% (95% CI: 15.2%-25.4%), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 71.1% of pts (177/249), most commonly infusion-related reactions (24.1%), fatigue (18.1%) and rash (18.1%). Grade ≥3 TRAEs occurred in 11.6% of pts (29/249), most commonly fatigue (1.6%), elevated lipase (1.6%), and pneumonitis (1.2%). Ten pts (4.0%) discontinued avelumab due to a TRAE. There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab showed durable clinical activity and had a manageable safety profile in pts with mUC. A phase 3 trial of avelumab in the maintenance setting after first-line platinum-based therapy for mUC is ongoing. Clinical trial information: NCT01772004.