First-line Platinum-based Chemotherapy In Patients Research Articles

Difference of oncological efficacy between two immune checkpoint inhibitors following first-line platinum-based chemotherapy in patients with unresectable, metastatic, advanced urothelial carcinoma: a multicenter real-world Japanese cohort.

Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab. A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rateonICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup. ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from -29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT. Our study provides real-world evidence regarding difference of oncological efficacy between maintenanceavelumab and subsequentpembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT.

Abstract CT090: DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas

Abstract Background Neuroendocrine carcinomas (NECs) have limited treatment options. DLL3 is highly expressed in NECs and is a promising treatment target. In an ongoing phase 1 trial (NCT04429087), BI 764532, a DLL3/CD3 IgG-like T-cell engager, was tolerable with clinical activity in patients with DLL3-positive (+) tumors, including those with small cell lung cancer and other NECs. Purpose DAREON™-7 (NCT06132113), a phase 1, open-label, dose-escalation (Part A) and dose-expansion (Part B) trial, aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE)/recommended phase 2 dose (RP2D), and the safety and efficacy of BI 764532 + platinum and etoposide in patients with DLL3+ NEC. Experimental design Part A: ~25 patients will receive intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide (CE) until intolerable toxicity, or progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or for a maximum of 36 months. BI 764532 dose escalation will be guided by a Bayesian logistic regression model with overdose control. Part B: 2 cohorts (~15 patients each) will receive BI 764532 at the RDE/RP2D + CE or cisplatin/etoposide (carboplatin/etoposide or cisplatin/etoposide are the most-used standard of care [SOC] regimens). Key inclusion criteria: patients must have no prior systemic treatment for DLL3+ locally advanced or metastatic NEC (extrapulmonary or unknown primary) or large cell NEC of the lung except for 1 cycle of standard platinum/etoposide regimen as first-line treatment prior to entering the treatment period of the trial; patients with localized NEC or resectable disease who received prior adjuvant therapy can participate in the trial if they experienced a treatment-free interval of >6 months prior to the diagnosis of metastatic disease; and patients must have at least 1 measurable lesion as defined per RECIST v1.1. Patients must be adequate candidates to receive platinum/etoposide as the SOC treatment. Primary endpoints: occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation (Part A) and on-treatment (Part B) periods. Secondary endpoints: occurrence of DLTs and adverse events during the on-treatment period (Part B), and efficacy measured by objective response and duration of response (Part B). Enrollment is ongoing. Citation Format: Jaume Capdevila, Timon Vandamme, Patricia Niccoli, Saori Mishima, Ken Kato, Yiyuan Ma, Ping Sun, Lijiang Geng, Ulrich M. Lauer. DAREON™-7: A phase 1, open-label, dose escalation and expansion cohort trial of the delta-like ligand (DLL3)-targeting T-cell engager BI 764532, plus first-line platinum-based chemotherapy in patients with DLL3-positive (+) neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT090.

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).

TPS714 Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .

Application of statistical machine learning in biomarker selection

In the recent JAVELIN Bladder 100 phase 3 trial, avelumab plus best supportive care significantly prolonged overall survival relative to best supportive care alone as first-line maintenance therapy following first-line platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). Discovering biomarkers using genomic profiling to understand potential patient heterogeneity is essential to help improve patient care with precision medicine. For the JAVELIN Bladder 100 trial, it is unclear which variable selection methods can most reliably identify biomarkers to inform patient care because the dataset is characterized by high collinearity and low signal. The aim of this paper was to evaluate available selection methods and their ability to discover prognostic and predictive biomarkers in patients with aUC receiving first-line maintenance therapy. A simulation study evaluated the performance of popular variable selection approaches for high-dimensional data including penalized regression models, random survival forests, and Bayesian variable selection methods. For Bayesian variable selection methods, a modified Bayesian Information Criterion (BIC) thresholding rule was proposed in addition to the traditional BIC thresholding rule. These methods were applied to the JAVELIN Bladder 100 dataset to investigate potential biomarkers associated with survival benefit. Results from the simulations demonstrated the strengths and limitations of the different methods. The variable selection methods demonstrated low false discovery rates under different conditions. However, their performance declined in the presence of high collinearity. Using the JAVELIN Bladder 100 data, we identified some potentially significant biomarkers across multiple models. Several lasso-related methods were able to identify potentially biologically meaningful variables in the trial. Some variable selection methods (such as stochastic search variable selection and random survival forest) may not be well suited to this type of data due to the presence of extreme collinearity and low signal. Future research should explore novel variable selection methods that may be more suitable for identifying prognostic and predictive biomarkers in this population.Trial registration: ClinicalTrials.gov Identifier: NCT02603432.

Phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy following first-line platinum-based chemotherapy in patients with advanced biliary tract cancer (BTC): BilT-02.

4113 Background: Gemcitabine, cisplatin and durvalumab followed by maintenance durvalumab is standard of care first-line (1L) therapy for patients (pts) with advanced BTC. In this trial, we investigated the combination of a PARP inhibitor with anti-PD1 antibody in absence of progression after at least 4 months of standard 1L platinum-based chemotherapy. Methods: Pts with advanced BTC, ECOG PS 0-1 and absence of progression on 1L platinum-based therapy were enrolled on a phase 2 trial to receive rucaparib 600 mg PO BID in combination with nivolumab 240 mg IV Q2 weeks every 28 days for up to 2 years. The primary endpoint was 4-month progression-free survival (PFS) rate from the date of first study treatment with an alternative hypothesis of 85%. Secondary endpoints included median PFS and overall survival (OS) from first study treatment (PFS1, OS1) as well as from start date of first-line chemotherapy (PFS2, OS2), best overall response, and safety. Results: 31 pts were enrolled of which 14 (45%) were women, 25 (80.6%) Caucasian and 24 (77.64%) with ECOG 1. Primary disease site was intrahepatic, extrahepatic hilar and distal, and gallbladder cancer in 21 (67.7%), 4 (12.9%), 1 (3.2%) and 4 (12.9%), respectively. 1L platinum-based treatment included gemcitabine/cisplatin based in 26 (83.9%), FOLFOX in 3 (9.7%) and carboplatin/paclitaxel in 1 (3.2%) pts. Mean (range) cycles of rucaparib and nivolumab were 6.75 (1-24) and 5.9 (1-24). The median follow-up time is 28.7 months using reverse censoring methodology. PFS rate at 4 months was 54.8% (95% CI, 36-70.3), comparable to the 63% null estimate based on ABC-02 trial. Median PFS1 and OS1 are estimated to be 4.6 months (95% CI, 3.7-6.2) and 15.9 months (95% CI, 9.8-24.1). Median PFS2 and OS2 calculated from date of 1L chemotherapy are estimated as 9.9 months (95% CI, 8.3-11.3) and 21.4 months (95% CI, 14.8-26.7). Two (6.4%) pts had partial response (with IDH R132G and KRAS G12D) as best response with stable disease in an additional 22 (71%) pts. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 15 (48.4%) pts, including 1 patient who died on therapy due to possibly-related immune-related myocarditis. The most common grade 2 or greater TRAEs included fatigue (9, 29.0%), anemia (7, 22.6%), neutropenia (6, 19.3%), elevated AST (5, 16.1%) and elevated ALT (4, 12.9%). Reasons for treatment discontinuation included death (2), progression (27), adverse event (1) while 1 patient completed 2 years of study treatment. Conclusions: The primary endpoint of PFS rate at 4 months was not met but the preliminary measures of PFS1 and OS1 are much longer than expected, and hypothesis generating for rational combination of PARP inhibitor with maintenance immunotherapy in this rare cancer. Exploratory endpoint of association of genomic analysis with efficacy is ongoing and will be discussed. Clinical trial information: NCT03639935 .

Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 > 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 < 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression <50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).

TPS4609 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Clinical trial information: NCT05092958 .

Clinical Implications of BRCA Mutations in Advanced Biliary Tract Cancer

Introduction: Current standard chemotherapy for biliary tract cancer (BTC) has limited survival benefits, and the need for targeted therapies is increasing. This study investigated the genetic profiles and clinical implications of BRCA mutations in patients with advanced BTC. Methods: Targeted high-throughput sequencing was performed on samples obtained from 25 patients with advanced BTC who had received palliative first-line platinum-based chemotherapy. Results: Of the 25 patients, 16 (64.0%) were younger than 65 years of age and 16 (64.0%) were male. The BTC cases consisted of intrahepatic cholangiocarcinoma (9, 36.0%), extrahepatic cholangiocarcinoma (5, 20.0%), and gallbladder cancer (11, 44.0%). The median overall survival (OS) and progression-free survival (PFS) of all patients were 11.9 months (95% confidence interval [CI]: 9.2–14.6) and 5.6 months (95% CI: 3.8–7.3), respectively. Genomic alterations in TP53 (52.0%), BRCA (36.0%), ATM (32.0%), ERBB2 (24.0%), NOTCH1 (20.0%), and FGFR3 (20.0%) were frequently reported. TP53 and ATM mutations were associated with OS (TP53: hazard ratio [HR] 2.719, 95% CI: 1.074–6.881, p = 0.035; ATM: HR 2.780, 95% CI: 1.091–7.082, p = 0.032). Patients with BRCA mutations had a slightly improved PFS compared to those with intact BRCA (6.7 months [range, 2.7–10.7 months] vs. 5.3 months [range, 3.6–7.0 months], p = 0.090). However, there was no significant difference in OS between groups (BRCA mutant vs. intact: 10.6 months [range, 3.6–17.6 months] vs. 11.9 months [range, 7.5–16.3 months], p = 0.252). BRCA mutations were significantly associated with PFS in the multivariate analysis (HR 0.150, 95% CI: 0.034–0.655, p = 0.012). Conclusion: This study demonstrated that BRCA mutations might have a role as predictive biomarkers for palliative first-line platinum-based chemotherapy in patients with advanced BTC.

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial cancer (mUC) (Alliance A032001).

TPS4607 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Support: U10CA180821, U10CA180882, U24CA196171,U10CA180863 (CCTG); Clinical trial information: NCT05092958.

Androgen Receptor Expression Is a Predictor of Poor Outcome in Urothelial Carcinoma

BackgroundSeveral preclinical and clinical studies demonstrated a strong correlation between androgen receptor (AR) signaling and bladder tumorigenesis. This study aims to evaluate the prognostic significance of AR expression in metastatic urothelial carcinoma (mUC).MethodsSamples from a phase III trial (LaMB, NCT00949455) which compared maintenance lapatinib versus placebo after completion of first-line platinum-based chemotherapy in patients with HER 1/2-positive mUC of the bladder were collected. Corresponding baseline and follow-up data included patients enrolled in the study and those who screen failed. AR expression was assessed independently by a single pathologist who was blinded to the study. Samples were grouped according to AR expression (negative vs. positive) and correlated with baseline tumor characteristics and survival.ResultsOf the 446 screened samples in the LaMB study, 90 were retrospectively analyzed for AR expression. There were no correlations between AR expression and tumor stage (r = −0.10), tumor grade (r = 0.05) at diagnosis, or subsequent treatment with lapatinib (r = −0.04). The median progression-free survival was 6 months (95% CI, 3.20–6.80) in the AR-negative group and 5 months (95% CI, 3.41–6.59) in the AR-positive group [HR 0.54 (95% CI, 0.31–0.92), p = 0.02]. Similarly, patients with AR-negative disease had more favorable overall survival (OS) with 16 months (95% CI, 6.6–25.4) and 11 months (95% CI, 7.0–15.0) in the AR-positive group [HR 0.55 (95% CI, 0.31–0.98), p = 0.04]. In the multivariate analysis, AR expression was significantly associated with worse OS (p = 0.045).ConclusionsAR expression is a predictor of poor outcome and presents a targetable alteration in patients with mUC.

Meta-Analysis of Therapy of Cinobufacini Capsule Adjunct with First-Line Platinum-Based Chemotherapy for the Treatment of Advanced NSCLC

Background Cinobufacini capsule, an anticancer traditional Chinese patent medicine, has been widely used as adjunctive treatment to platinum-based chemotherapy in patients with advanced NSCLC. Purpose To evaluate the efficacy and safety of cinobufacini capsule combined with first-line platinum-based chemotherapy for advanced NSCLC. Study Design. A systematic review and meta-analysis of eight outcome measures selected for this study were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Methods A comprehensive literature search was conducted in 7 electronic databases to identify all the relevant randomised controlled trials. Cochrane handbook 5.1.0 was applied to evaluate the quality of included trials, and the RevMan 5.3 and Stata 15.1 software were used to combine the trials for data analysis and assess the publication bias. Results From the 19 studies reviewed, a total of 1,564 patients were included. Compared with first-line platinum-based chemotherapy alone, cinobufacini capsule combined with chemotherapy showed significant effects in improving ORR (RR = 1.49, 95% CI (1.33, 1.66)), 1-year survival rate (RR = 1.44, 95% CI (1.28, 1.63)), and 2-year survival rate (RR = 1.78, 95% CI (1.42, 2.22)), raising the percentages of CD3+ cells (SMD = 1.25, 95% CI (1.05, 1.45)), CD4+ cells (SMD = 1.52, 95% CI (1.33, 1.71)), and ratio of CD4+/CD8+ (SMD = 1.36, 95% CI (1.17, 1.54)), and reducing chemotherapy toxicity including leukopenia (RR = 0.61, 95% CI (0.51, 0.72)), thrombocytopenia (RR = 0.52, 95% CI (0.41, 0.67)), and vomiting (RR = 0.79, 95% CI (0.70, 0.88)). Conclusion Cinobufacini capsule may increase the therapeutic effectiveness, improve cellular immune function, and reduce the toxicity of first-line platinum-based chemotherapy in patients with NSCLC. These results require confirmation by further rigorously designed randomised controlled trials (RCTs).

Rovalpituzumab Tesirine as a Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With Extensive-Stage–SCLC: Results From the Phase 3 MERU Study

IntroductionRovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage–SCLC after platinum-based chemotherapy. MethodsMERU was a phase 3 randomized, double-blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors. ResultsMedian age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84–1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T significantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (≥20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema (26%), photosensitivity reaction (25%), fatigue (25%), nausea (22%), and dyspnea (21%). ConclusionsBecause of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage–SCLC.

Maintenance chemotherapy is effective in patients with metastatic triple negative breast cancer after first-line platinum-based chemotherapy

Platinum-based chemotherapy (PBCT) has gained an important position as a first-line treatment for metastatic triple-negative breast cancer (mTNBC). We assessed whether maintenance chemotherapy maintenance was superior to observation after first-line PBCT in patients with mTNBC. A total of 265 patients with mTNBC who had exhibited non-PD after 4-6 cycles of firstline PBCT at the Fudan University Shanghai Cancer Center from January 2008 to April 2019 were retrospectively analyzed. 107 patients who did not receive additional treatment were defined as the control observation group, and the remaining 158 patients who continued to receive maintenance therapy were defined as the maintenance treatment group. The median progression-free survival (PFS) time in the maintenance group was 9.63 months, which was significantly longer than the PFS time of 7.47 months in the observation group (HR 0.49, 95% CI: 0.37-0.67, P<0.0001). The median overall survival (OS) of the observation group and the maintenance group was 25.37 months and 31.27 months, respectively (HR 0.65, 95% CI: 0.44-0.95, P=0.019). The survival benefit was still present after adjusting baseline characteristics. Moreover, multivariate analyses suggested that maintenance chemotherapy is an independent predictive factor for both PFS and OS. Interaction and stratified analyses showed no difference in the PFS with between the single-drug maintenance strategy, single agent or doublet group and the doublet-drug maintenance group. The most common adverse event in this study was hematologic toxicity. Except for hand-foot syndrome (0 vs. 7.6%, P=0.004), the incidence of other adverse events was not significantly different between the observation and maintenance groups. After achieving non-PD with the first-line PBCT in mTNBC patients, chemotherapy maintenance may provide OS benefit prior to the era of biologicals.

Efficacy and safety of Kanglaite injection combined with first-line platinum-based chemotherapy in patients with advanced NSCLC: a systematic review and meta-analysis of 32 RCTs.

As a Chinese medicine injections, Kanglaite injection (KLT) is a complementary or alternative therapy for first-line platinum-based chemotherapy. However, the effect that certain factors, including the dose of KLT, chemotherapy cycles, evaluation criteria, or supportive treatment, have on the efficacy of the objective response rate (ORR), median survival time (MST), and adverse reactions is still unknown. Eight databases were systematically searched from the inception dates to December 1, 2019, using the keywords Kanglaite, chemotherapy, and non small cell lung carcinoma to identify randomized clinical trials (RCTs). Analyses were performed using Review Manager 5.3 and Stata 15.1. There were 32 randomized controlled trials, involving 2,577 participants, that fulfilled the inclusion criteria. Compared with first-line platinum-based chemotherapy alone, KLT combined with chemotherapy could increase the ORR [risk ratio (RR), 1.41 (95% CI: 1.28 to 1.56); absolute risk difference (ARD), 0.13 (95% CI: 0.1 to 0.17)], decrease the risk ratio of adverse reactions [nausea and vomiting: RR, 0.58 (95% CI: 0.42 to 0.81); ARD, -0.17 (95% CI: -0.26 to -0.08); leukopenia: RR, 0.61 (95% CI: 0.44 to 0.86); ARD, -0.16 (95% CI: -0.24 to -0.08)], prolong MST, and increase disease control rate and Karnofsky performance status. According to the subgroup analyses, KLT combined with cisplatin or paraplatin plus paclitaxel (TP) failed to demonstrate a significant association with the ORR. And when lacking the use of supportive treatment, this combination would not decrease the RR of both adverse reactions compared with chemotherapy alone. KLT plus first-line platinum-based chemotherapy, except when chemotherapy regimens were TP, increased efficacy and quality of life in patients with advanced NSCLC. We are unsure whether this combination offers a low risk of adverse reactions. Additional high-quality RCTs are warranted to assess the effects of the combined therapy further.

Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial

Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: phase III POLO trial

Transcriptional Activation of Gstp1 by MEK/ERK Signaling Confers Chemo-Resistance to Cisplatin in Lung Cancer Stem Cells.

Lung cancer management remains a challenge due to its asymptomatic and late presentation when it is metastatic. The clinical response to the first-line platinum-based chemotherapy in patients with advanced lung cancer is disappointing due to the development of chemoresistance. Chemoresistance is a complex phenomenon. Mechanistic research using experimental models has yielded limited clinical results to help increase understanding for overcoming resistance. While the role of lung CSCs in conferring multidrug resistance has been postulated, experimental evidence remains associative and lacks in depth mechanistic inquisition. In the present study, using mouse and human lung adenocarcinoma cell lines and their respective paired CSC derivative cell lines that we generated, we identified cancer stem cell component of lung adenocarcinoma as the source that confers multidrug resistance phenotype. Mechanistically, Gstp1 confers cisplatin resistance in mouse and human lung CSC models, both in vitro and in vivo. Further, transcriptional activation of Gstp1 expression by MEK/ERK signaling underlies cisplatin resistance in lung CSC cells. Moreover, we show that GSTP1 expression is a poor diagnostic and prognostic marker for human lung adenocarcinoma, thus is of high clinical relevance. Taken together, we have provided mechanistic understanding of the lung CSC in mediating chemoresistance.

A Real-World Study of Maintenance Chemotherapy vs. Observation in Patients with Metastatic Triple Negative Breast Cancer after Achieving Disease Control with First-Line Platinum-Based Chemotherapy

Background: The platinum-based chemotherapy (PBCT) has gained its important position in the first-line treatment of metastatic triple-negative breast cancer (mTNBC). We accessed whether maintenance chemotherapy is superior to observation after first-line PBCT in patients with mTNBC. Patients and Methods: From January 2008 to November 2016, a total of 232 patients with mTNBC exhibited disease control with 4-6 cycles of first-line PBCT in the Fudan University Shanghai Cancer Center were retrospectively analyzed. 87 patients remained without any treatment were defined as a control observation group, and the remaining 145 patients continued to receive maintenance therapy were allocated into the maintenance treatment group. Findings: The median PFS time in the maintenance group was 9.6 months, which was significantly longer than the 7.7 months in the observation group (HR 0.47, 95% CI 0.34-0.65, P<0.0001). The median OS in the two groups was 23.9 months and 30.1 months, respectively (HR 0.67, 95% CI 0.45-0.98, P=0.029). Interaction and stratified analyses showed no difference in the PFS between the single drug maintenance group and the doublet drug maintenance group. The most common adverse event in this study was the hematologic toxicity. Except hand-foot syndrome (0 vs. 8.3%, P=0.003), the incidence of other adverse events was not significantly different between the two groups. Interpretation: After achieving disease control with first-line PBCT in mTNBC patients, maintenance chemotherapy is recommended. Funding Statement: This study was supported by the Shanghai Municipal Science and Technology Commission Guidance Project, P.R. China (contract no. 18411967800)；Shanghai Municipal Commission of Health and Family Planning (grant no. 201640069); Shanghai Natural Science Foundation (grant no. 17ZR1405700); and research grant from Shanghai Hospital Development Center (grant no. SHDC12018X03). Declaration of Interests: The Author(s) declare(s) that there is no conflict of interest. Ethics Approval Statement: This study was approved by the Regional Ethics Committee of our hospital and informed consent was obtained from all patients.

Expression of ERCC1, Bcl-2, Lin28a, and Ki-67 as biomarkers of response to first-line platinum-based chemotherapy in patients with high-grade extrapulmonary neuroendocrine carcinomas or small cell lung cancer.

BackgroundSmall cell lung cancer (SCLC) and high-grade extrapulmonary neuroendocrine carcinomas (EPNEC) share similar histopathological features and treatment, but outcomes may differ. We evaluated in our study the expression of biomarkers associated with response rate (RR) to chemotherapy and overall survival (OS) for these entities.Materials and MethodsThis is a multicentre retrospective analysis of advanced EPNEC and SCLC patients treated with platinum-based chemotherapy. Paraffin-embedded tumour samples were reviewed by a single pathologist and tested for immunohistochemistry (IHC) expression of Ki-67, ERCC1, Bcl-2, and Lin28a. All images were evaluated by the same radiologist and RR was determined by RECIST 1.1.ResultsFrom July, 2006 to July, 2014, 142 patients were identified, being 82 (57.7%) SCLC and 60 (42.3%) EPNEC. Clinical characteristics and median Ki-67 (SCLC: 60%; EPNEC: 50%; p = 0.86) were similar between the groups. RR was higher for SCLC patients (86.8% versus 44.6%; p<0.001), but median OS was similar (10.3 months in SCLC and 11.1 months in EPNEC; HR 0.69, p = 0.07). Bcl-2 expression was higher in SCLC patients (46.3% versus 28.3%, p = 0.03) and was associated with worse prognosis in EPNEC (median OS 8.0 months versus 14.7 months; HR 0.47, p = 0.02).ConclusionEPNEC patients presented inferior RR to platinum-based chemotherapy than SCLC but tended to live longer. Neither ERCC1, Lin28, or Ki-67 were prognostic or predictive for RR in EPNEC or SCLC. High Bcl-2 expression was associated with poor prognosis in EPNEC patients.

A phase III study of rovalpituzumab tesirine maintenance therapy following first-line platinum-based chemotherapy in patients with extensive disease small cell lung cancer (ED SCLC).

TPS8583 Background: SCLC embodies 15-20% of lung cancers. Patients (pts) are staged with either limited or extensive disease; the standard front-line treatment for the latter is chemotherapy with carbo- or cisplatin combined with etoposide or irinotecan. Response rates are high with limited duration. Recurrence may be attributable to chemo-resistant tumor initiating cells (TICs). Delta-like protein 3 (DLL3) is an inhibitory Notch receptor ligand identified as a novel target in SCLC TICs. DLL3 is highly expressed in SCLC but not normal tissue. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate composed of a DLL3-targeting IgG1 monoclonal antibody tethered to a DNA cross-linking toxin. Rova-T has shown activity in recurrent/relapsed ED SCLC patients (Rudin et al., Lancet Oncol, 2016). Given DLL3 expression in TICs, exploration of Rova-T front-line maintenance strategies in ED SCLC is warranted. The postulated mechanism of action of Rova-T and its clinical activity indicate potential to improve progression-free and overall survival in this setting. Methods: This is a Phase 3, randomized, double-blind, placebo-controlled, international study (NCT03033511, no pts enrolled yet as of 7 February 2017). Approximately 740 ED SCLC pts will be enrolled to include ~480 pts with high DLL3 expression. Eligibility: pts ≥ 18 years; histologically or cytologically confirmed ED SCLC with ongoing clinical benefit (complete/partial response or stable disease) after 4 cycles of 1st line platinum-based therapy; definitively treated CNS metastases allowed; &gt; 3 but ≤ 9 wks between the administration of the last cycle of platinum-based chemotherapy and randomization; available tumor tissue for DLL3 expression testing; ECOG performance score 0-1. Pts will be randomly assigned 1:1 to receive 0.3 mg/kg Rova-T or placebo on Day 1 of each 6-wk cycle, omitting every 3rd cycle. Primary objectives: determine if Rova-T improves progression-free and overall survival. Secondary objectives: assess Rova-T antitumor activity by determining objective response rate, clinical benefit rate, duration of response, and changes in pt reported outcomes. Clinical trial information: NCT03033511.

Molecular analysis of cell-free DNA to identify distinct molecular mutational burden and its effect on first-line chemotherapy in patients with NSCLC from a phase III trial.

e20660 Background: To investigate the predictive significance of molecular mutational burden via genetic analysis of circulating cell-free DNA (cfDNA) in NSCLC patients treated with first-line platinum-based chemotherapy. Methods: Eligible patients were enrolled in a phase III trial (NCT01560195). Blood samples were collected at baseline, every two cycles of chemotherapy and at disease progression. Both cfDNA fragment and genomic DNA were isolated and subjected to enrichment for a 1.15M size panel covering exon regions from 1,086 genes. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: Forty-eight patients were enrolled. 17 genes alterations were frequently found from 15 patients (training set). Patients with partial response (PR, n = 3) had significantly lower total mutational burden of these genes than that with stable disease (SD, n = 9) and progression disease (PD, n = 3) (P &lt; 0.05). Based on these results, we further developed a predictive model including 6 genes ( PIK3CA, KIF5B, CD74, XRCC1, MTHFR and KRAS) in the validation set (n = 33). The results showed that the mutational burden of 6-genes panel had the promising predictive yield in patients with PR (n = 7) vs. SD+PD (n = 25) (AUC = 0.962, P = 0.000), PR vs. SD (n = 18) (AUC = 0.960, P = 0.000) and SD vs. PD (n = 8) (AUC = 0.964, P = 0.003). Notably, there was no significant difference in the baseline cfDNA concentration among patients with PR, SD and PD (P &gt; 0.05). Patients with PR experienced a reduction of molecular mutational burden of cfDNA while patients with SD or PD experienced no change or increased molecular mutational burden of cfDNA after two or four cycles of chemotherapy. However, it did not reach the statistically significant difference. Conclusions: The current study demonstrated that molecular characteristics of cfDNA was significantly associated with the effect of first-line platinum-based chemotherapy in patients with NSCLC. The mutational burden of six-genes panel had the promising predictive value in NSCLC patients treated with first-line chemotherapy.