bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between molecular subtype membership or hypoxia-associated gene expression signatures and clinical outcomes in the CALGB 90601 (Alliance) phase 3 clinical trial of gemcitabine and cisplatin (GC) plus bevacizumab (B) or placebo (P).
Authors: McConkey David James , Choi Woonyoung , Halabi Susan , Luo Bin , Al-Ahmadie Hikmat A. , Rosenberg Jonathan E. , Mountain Jack , Regazzi Ashley Marie , Fong Megan , Iyer Gopa , Van Allen Eliezer Mendel , Mouw Kent William , Wen Yujia , McCart Linda , Ballman Karla V. , Beltran Himisha , Morris Michael J.
Published: June 2022

4562

Background: Our previous work showed that basal tumors were associated with the best clinical outcomes in a Phase 2 clinical trial of neoadjuvant dose-dense MVAC plus B, and in other work we showed that basal tumors were enriched with hypoxia-associated gene expression signatures. Here we attempted to validate these findings in the C90601 Phase 3 clinical trial of GC plus B versus GC plus P. Methods: Whole transcriptome RNAseq was performed on all available tumors using Ion Torrent’s Ampliseq platform (n = 189). Tumors were assigned to molecular subtypes using 3 different classifiers - BASE47 (k=2), MDA oneNN (k=3), and the Consensus classifier (k=6). Tumor hypoxia signature enrichment was determined using 2 different gene expression signatures and gene set variation analysis (GSVA). The proportional hazards model was used to correlate molecular subtype calls and hypoxia signature enrichment with overall survival (OS) and progression-free survival (PFS) adjusting for stratification factors and treatment arm (for PFS). Results: The median OS & PFS by different signatures and the hazard ratios (HR) are presented in the Table. Conclusions: Predefined signatures associated with clinical benefit in the Phase-2 neoadjuvant clinical trial were not associated with benefit in C90601. Possible explanations include the lack of strong therapeutic effects of the treatments, potential heterogeneity (“subtype plasticity”) between the profiled tissue samples and the metastatic lesions under treatment pressure, and differences in biology associated with the disease states (muscle-invasive vs advanced/metastatic disease). Support: U10CA180821, U10CA180882, Department of Defense (CA160312), Genentech; ClinicalTrials.gov Identifier: NCT00942331. [Table: see text]
Preliminary results from phase Ib/II neoadjuvant CG0070 and nivolumab (N) for cisplatin (C)-ineligible muscle invasive bladder cancer (MIBC).
Authors: Li Roger , Spiess Philippe E. , Sexton Wade J. , Gilbert Scott Michael , Poch Michael Adam , Pow-Sang Julio M. , Zhang Jingsong , Dhillon Jasreman , Thomas Kerry , Borjas Gustavo , Bala Juliet , Grandi Paola , Burke James , Mule James J , Conejo-Garcia Jose , Jain Rohit K.
Published: June 2022

4574

Background: CG0070 is a replication-competent oncolytic adenovirus engineered to target RB deficient tumor cells and to express GM-CSF. CG0070 has previously demonstrated safety and efficacy against BCG-exposed high risk non-muscle invasive bladder cancer through tumor lysis and anti-tumor immune activation. We tested the safety and efficacy of CG0070 in combination with N as neoadjuvant therapy for MIBC in C-ineligible patients in this study (NCT04610671). Methods: C-ineligible pts with MIBC (cT2-4a, N≤1) were enrolled. Pts received 6 weekly intravesical CG0070 (1x1012vp) and 2 doses of N at wks 2 and 6, followed by radical cystectomy (RC). The primary objective is safety of CG0070+N as measured by CTCAEv5.0. Secondary objective is to assess pathologic response (PaR) (pT0N0). Exploratory objectives include the assessment of correlation between PaR with baseline 1) E2F expression; 2) immune infiltration; 3) PD-L1 expression; and 4) TLS expression. Results from a prespecified interim analysis following accrual of 15 patients is reported herein. Results: Between Nov 2020 and Jan 2022, 15 pts were enrolled with median age 75.5yrs, 73% male, 47% > cT2; 1 patient refused RC but was included in the ITT population. No DLTs were encountered. The overall rate of grade 3-4 AEs was 10/15 (75%), and the vast majority were related to RC (90%). Immune related AEs were seen in one pt, who had grade 2 autoimmune thyroiditis. There was no delay in time to RC and no unexpected surgical complications from treatment. PaR was observed in 6/13 (46%) evaluable pts, and an additional pt had negative post-treatment biopsy but refused RC. Conclusions: Neoadjuvant CG0070+N is safe and effective in C-ineligible pts with MIBC. This combination was well tolerated without any delays in RC and induced an overall response rate of 54%. Clinical trial information: NCT04610671. [Table: see text]
Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC).
Authors: Gupta Shilpa , Bellmunt Joaquim , Plimack Elizabeth R. , Sonpavde Guru P. , Grivas Petros , Apolo Andrea B. , Pal Sumanta K. , Siefker-Radtke Arlene O. , Flaig Thomas W. , Galsky Matt D. , Rosenberg Jonathan E. ,   Platinum-Ineligibility in Bladder Cancer Working Group
Published: June 2022

4577

Background: Treatment (tx) landscape has evolved significantly for cisplatin-ineligible mUC patients (pts). Carboplatin and gemcitabine followed by avelumab (Av) maintenance is the current preferred standard. Although pembrolizumab (P) and atezolizumab (At) were approved as 1L therapy for these pts in 2017, the FDA has now restricted the use of 1L P to “platinum ineligible” mUC pts. We previously suggested a consensus definition for “platinum-ineligible” pts with mUC (Gupta et al. ASCO GU 2019). We now updated the consensus definition for standard therapy and clinical trial eligibility in the current tx era. Methods: We surveyed 60 genitourinary medical oncologists in the US (similar cohort to 2019) using an online tool consisting of several clinical parameters used in our initial survey with additional questions related to current available tx options. Different age and creatinine thresholds in combination with ECOG PS along with other clinically relevant established criteria were analyzed. We compiled the responses to generate a consensus definition. Results: All 60 respondents provided 100% responses. Respondents (94%) reported using a carboplatin-based regimen followed by Av and 6% reported using carboplatin-based regimen followed by P for cisplatin-ineligible mUC pts. 17/60 (28.3%) and 29/60 (48.3%) checked PD-L1 status prior to using P or At respectively. Survey results for the most common responses are presented in the Table. Conclusions: Based on the survey, any mUC pt meeting one the following 5 parameters should be considered "platinum-ineligible”: ECOG PS > / = 3; Cr Cl < 30 ml/min; peripheral neuropathy > / =Grade 2; NYHA Heart Failure Class > 3; ECOG PS 2 AND Cr Cl < 30 ml/min. These criteria are proposed to guide treatment recommendations and standardization of eligibility criteria. [Table: see text]
Association of antibiotic therapy and treatment efficacy in urothelial cell carcinoma patients receiving immune checkpoint inhibitors.
Authors: Braun Avery , Deng Mengying , Handorf Elizabeth A. , Abbosh Philip
Published: June 2022

4578

Background: The content of gut microbiome has been linked to the effectiveness of immune checkpoint inhibitory (ICI) therapy in various cancer types. Antibiotic therapy (ABT) induces significant alterations in gut microbiota; however, only a limited number of single-institutional studies have examined the impact of ABT on ICI treatment. Utilizing a national database, we sought to provide ‘real world outcomes’ by investigating the association between ABT and ICI on overall survival (OS) and real-world progression free survival (rwPFS) in advanced urothelial carcinoma (aUC). Methods: We used the electronic health record (EHR)-derived de-identified FlatIron Health (FIH) database after Institutional Review Board approval was obtained, and included a waiver of informed consent to select 1491 subjects with aUC who received ICI therapy. Patient characteristics were described and compared between those with known ABT use and without known ABT use (in the 3 months pre/post ICI initiation), using ANOVA and Chi-square tests. rwPFS and OS were calculated from date of initiation of ICI to date of real-world progression/date of death. 3-month landmark Kaplan Meier methods and log-rank tests were used to estimate and compare rwPFS and OS between patients with-ABT and without-ABT, as well as patients with ABT use pre-ICI initiation, post-ICI initiation, and no known ABT use. Cox proportional models were used to investigate the association between rwPFS, OS, and antibiotic use, adjusting for patient characteristics. Results: In patients who received ICI, we included 407 patients who received ABT and 1084 who did not. Those who received ABT were younger (p < 0.001), more likely Caucasian (p = 0.046) and insured by Medicare (p < 0.001). rwPFS (median: 9.0 vs 10.0 months; p = 0.41) and OS (median: 14.0 vs 16.0 months; p = 0.073) were not significantly different between the with or without ABT subgroups. We included 101, 182, and 715 patients who received ABT prior to ICI, after ICI initiation, or did not receive ABT. When assessing timing of ABT, there was a significant difference in OS amongst pre-ICI initiation ABT, post-ICI initiation ABT and no known ABT groups (median: 17.0 vs 10.9 vs 16.0; p = 0.005). However, rwPFS (median: 10.1 vs 7.5 vs 10.0 months; p = 0.22) was not statistically different. Multivariable analysis identified no antibiotic use as a significant predictor of improved OS (HR 0.733, CI 0.598-0.898; p = 0.003). Other factors associated with OS were male gender (HR 1.158, Cl 1.005-1.335; p = 0.043) and receipt of extirpative surgery (HR 0.785, Cl 0.684-0.900; p < 0.001). Conclusions: This study identifies a potential negative association of ABT and OS, particularly after starting ICI. These results support the relevance of the gut microbiome on the efficacy of ICI treatment, may guide future efforts to improve the efficacy of ICI, and emphasize the importance of antibiotic stewardship.
Biomarkers of response to neoadjuvant atezolizumab with gemcitabine and cisplatin in muscle-invasive bladder cancer.
Authors: Lattanzi Michael , Solovyov Alexander , Lihm Jayon , Quinlan Colleen , Whiting Karissa , Li Hao , Al-Ahmadie Hikmat A. , Teo Min Yuen , Aggen David Henry , Ostrovnaya Irina , Regazzi Ashley Marie , Jihad Marwah , Bajorin Dean F. , Balar Arjun Vasant , Mortazavi Amir , Merghoub Taha , Iyer Gopa , Rosenberg Jonathan E. , Greenbaum Benjamin , Funt Samuel Aaron
Published: June 2022

4584

Background: We previously reported the clinical outcomes of a positive multi-center phase II trial of neoadjuvant gemcitabine (G) and cisplatin (C) plus atezolizumab (A) in patients with muscle-invasive bladder cancer (Funt, et al. JCO 2022). In this and another trial of neoadjuvant GC with pembrolizumab (Rose et al, JCO 2021), PD-L1 positivity by immunohistochemistry was not predictive of non–muscle-invasive downstaging ( < pT2N0). Therefore, we investigated other pre-treatment tissue-based genomic and gene expression biomarkers of response and resistance. Methods: 36 pts had pre-treatment tissue available for genomic analysis. We performed targeted hybridization capture DNA sequencing using the CLIA-certified MSK-IMPACT platform and whole transcriptome RNA sequencing. We examined genomic and gene expression biomarkers which have been previously investigated in the context of neoadjuvant cisplatin-based chemotherapy or anti-PD-1/L1 immunotherapy for MIBC, including tumor mutation burden (TMB), a DNA damage response (DDR) 9-gene panel (NCT03609216) associated with response to neoadjuvant chemotherapy, and an 8-gene cytotoxic T cell transcriptional signature associated with response to neoadjuvant A (tGE8; Powles et al, Nature Medicine 2019). We also evaluated TGF-β pathway activation, which was associated with resistance to A in pts with metastatic BC (Mariathasan et al, Nature 2018). Putative biomarkers were assessed for correlation with < pT2N0, the trial’s primary endpoint. Results: DNA was available from all 36 pts, and RNA met quality control metrics for 29 pts. TMB was significantly higher in pts with < pT2N0 (median 16 mut/Mb, IQR 12-25) versus ≥ pT2N0 (median 10 mut/ Mb, IQR 8-10; p < 0.01). A single patient had a TMB > 200 Mut/Mb with a POLE hotspot mutation and achieved pT0N0; TMB was still significantly higher in responders after omission of this patient (p < 0.01). Nine of 25 pts (36%) with < pT2N0 had a deleterious DDR mutation versus 1 of 10 pts (10%) with ≥ pT2N0 (p = 0.13). While tGE8 was significantly increased in patients with < pT2N0 compared to those without (p = 0.01), TGF-β pathway activation was not increased in pts with ≥ pT2N0 (p = 0.99). Conclusions: TMB and the tGE8 cytotoxic T cell transcriptional signature were associated with response to combination GC+A in muscle-invasive bladder cancer. More detailed molecular analyses will be reported. Clinical trial information: NCT02989584.
Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.
Authors: Witjes Alfred , Bajorin Dean F. , Galsky Matt D. , Gschwend Jürgen E. , Tomita Yoshihiko , Lebret Thierry , Pérez-Valderrama Begoña , Bamias Aristotelis , Collette Sandra , Zhang Joshua , Nasroulah Federico , Shariat Shahrokh F.
Published: June 2022

4585

Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]
Quantifying the absolute benefit of neoadjuvant chemotherapy followed by definitive therapy in patients with muscle-invasive bladder cancer: A systematic review and meta-analysis.
Authors: Ikram Waleed , Naqvi Syed Arsalan Ahmed , Raina Ammad , Fatima Ezza , Siddiqi Rabbia , Islam Mahnoor , Asghar Noureen , Khakwani Kaneez Zahra Rubab , Khan Ahsan Masood , Hussain Syed A. , Bryce Alan Haruo , Riaz Irbaz Bin , Singh Parminder
Published: June 2022

4594

Background: Cisplatin based neoadjuvant chemotherapy (NAC) followed by definitive therapy improves survival in patients with muscle invasive bladder cancer (MIBC). However, the clinical benefit of NAC might vary with the choice of definitive therapy. Therefore, we assessed the absolute benefit of NAC followed by radical cystectomy or radical radiotherapy separately using the totality of evidence. Methods: MEDLINE and EMBASE were systematically searched to identify randomized trials assessing cisplatin based neoadjuvant chemotherapy followed by either radical cystectomy or definitive radiotherapy in patients with MIBC. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). Treatment effects were expressed as hazard ratios (HR) with 95% confidence interval (CI). Incidence rate ratios were calculated to estimate time to event outcomes for trials not reporting HR. A random-effects DerSimonian-Laird meta-analysis was conducted. Absolute effects were then obtained using baseline risks from the control arm of RCTs. Results: Of 4887 studies identified, 13 trials with 2529 patients were included in this meta-analysis. Most trials included patients with T2-4 and N0 patients and only 3 trials included patients with node positive disease. Total of 180 (47%) DFS events were observed with NAC+RC compared to 213 (56%) events in RC alone (HR: 0.72; 95% CI: 0.59-0.89) and 346 (58%) OS events were observed with NAC+ RC compared to 385 (52%) events in RC alone (HR: 0.80; 95% CI: 0.69-0.92). Total of 186 (70%) DFS events were observed with NAC + radiotherapy compared to 205 (71%) events in radiotherapy alone (HR: 0.91; 95% CI: 0.74-1.12) and 263 (58%) OS events were observed with NAC+ radiotherapy compared to 294 (61%) events in radiotherapy alone (HR:0.93; 95% CI: 0.79-1.08). Conclusions: The choice of definitive therapy after cisplatin-based NAC impacts survival in patients with MIBC. RC after NAC improved DFS (114 fewer events per 1000 events) and OS (76 fewer per 1000 events) whereas radiotherapy after NAC showed no survival benefit. [Table: see text]
Influence of darolutamide on cabazitaxel systemic exposure.
Authors: Buck Stefan , Guchelaar Niels A.D. , de Bruijn Peter , Moghaddam-Helmantel Inge M. Ghobadi , De Hoop Esther Oomen , Westgeest Hans M. , Hamberg Paul , Mathijssen-van Stein Danielle , Lolkema Martijn P. , Koolen Stijn L.W. , De Wit Ronald , Mathijssen Ron H.J.
Published: June 2022

5038

Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC0-24h). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]
Adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: 8-year follow-up of the randomized ASTRRA trial.
Authors: Baek Soo Yeon , Noh Woo Chul , Ahn Sei-Hyun , Kim Hyun-Ah , Ryu Jai Min , Kim Seung Il , Lee Eun-Gyeong , Im Seock-Ah , Jung Yongsik , Park Min Ho , Park Kyong Hwa , Kang Su Hwan , Jeong Joon , Park Eunhwa , Kim Sung Yong , Lee Min Hyuk , Kim Lee Su , Lim Woosung , Kim Seonok , Kim Hee Jeong
Published: June 2022

506

Background: Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial, at 63 months median follow-up, showed that the addition of 2 years of ovarian function suppression (OFS) to Tamoxifen (TAM) significantly improved disease-free survival (DFS) compared with TAM alone in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. We report updated long-term outcomes from ASTRRA trial with 106.4 months median follow-up. Methods: This study is a post-trial follow-up of the ASTRRA trial, which randomly assigned 1,298 patients with breast cancer in a 1:1 ratio to receive TAM only (n = 647) or TAM + OFS (n = 635). The primary endpoint was DFS and secondary endpoint was overall survival (OS). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% confidence interval (CI) from Cox-regression model. Results: At 106.4 months of median follow-up, there continues to be a statistically significant reduction in DFS event rate in favor of the TAM+OFS group. The estimated 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (HR 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between two groups. The estimated 8-year OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). The results of DFS and OS between the two groups defined from the time of random assignment to the time of events were also similar. Conclusions: These data demonstrate consistent survival advantages of adding OFS 2 years to TAM treatment over time, with the long-term follow-up reported to date. This study finding suggest that adding OFS to TAM should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. Longer follow-up is needed to fully evaluate the OS benefit.
Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: Meta-analysis of individual participant data from randomized trials.
Authors: Vale Claire Louise , Fisher David , Godolphin Peter , Rydzewska Larysa H , Boher Jean-Marie , Burdett Sarah , Chen Yu-Hui , Gravis Gwenaelle , James Nicholas D. , Liu Glenn , Murphy Laura , Parmar Mahesh K. B. , Rogozinska Ewelina , Sfumato Patrick , Sweeney Christopher , Sydes Matthew R. , Tombal Bertrand F. , White Ian R , Tierney Jayne F. ,   The STOPCAP M1 Collaboration
Published: June 2022

5070

Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p<0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p<0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p<0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]
An open label, nonrandomized, multisite phase II trial combining bevacizumab, atezolizumab, and rucaparib for the treatment of previously treated recurrent and progressive endometrial cancer.
Authors: Bradley William Hampton , Hayes Monica Prasad , Taylor Nicolas , Rader Janet Sue , Bishop Erin , Hopp Elizabeth , McAlarnen Lindsey Allison , Liegl Melodee , Simpson Pippa , Uyar Denise
Published: June 2022

5510

Background: Patients with metastatic recurrent endometrial cancer have limited effective therapies. Single agent pembrolizumab is utilized in mismatch repair deficient (MMRd) patients, while the combination of lenvatinib and pembrolizumab is now more commonly used in MMR intact patients who have progressed after chemotherapy combinations. This trial investigated a novel three drug regimen. Methods: Patients with recurrent endometrial cancer not amenable to curative intent surgery or radiation after one or two lines of therapy were eligible regardless of histology. This study is a multicenter, open-label, nonrandomized phase II trial. All subjects initially received the three-drug combination of rucaparib, bevacizumab, and atezolizumab. The primary goal of this trial was to estimate the overall response rate in these patients, and secondarily to estimate the progression-free and overall survival of patients treated with this triplet combination. Total enrollment was 30, with the first six subjects participated in a safety lead-in. Treatments until progression, toxicity, or clinician choice. Subjects could continue past progression if, in the estimate of the treating clinician and subject, clinical benefit was being provided. Subjects were eligible for analysis if they received at least one cycle and had one post-dose tumor assessment. The ORR assumption was 27% with a lower bound of 14%. Results: 30 subjects were enrolled between 07/2019 and 06/2021. Of these 26 were evaluable. Median follow up at cut off was 14.9 months. 23 subjects had clinical benefit, with 1 (4%) with CR, 9 (39%) with PR, and 13 (57%) with stable disease as best response. Overall median event-free (progression or death) was 5.3 (95% CI 2.7-7.9) months and overall survival 13.3 (95% CI NA) months at cut off. Median duration of therapy was 4.4 months (IQR 1.7-7.3), with 4 subjects remaining on study directed therapy at data cut off. Histology distribution was 50% serous, 20% endometrioid, and 13% carcinosarcoma. 19 pts were White, 8 African American, 2 identified as Asian, 1 unknown. In the MMR deficient patients, event-free probability was 11.9 months. Grade 3 or 4 treatment related adverse events occurred in 50% patients. Conclusions: To our knowledge, this trial represents the first use of a non-chemotherapy-based triplet therapy for recurrent endometrial cancer. The combination of rucaparib, bevacizumab, and atezolizumab may safely be used to treat recurrent/persistent endometrial cancer. This combination demonstrates clinically meaningful improvement in response, with acceptable toxicity. Enhanced response to therapy was seen in MMR deficient subjects. Clinical trial information: NCT03694262.
Safety and efficacy of MORAb-202 in patients (pts) with platinum-resistant ovarian cancer (PROC): Results from the expansion part of a phase 1 trial.
Authors: Nishio Shin , Yunokawa Mayu , Matsumoto Koji , Takehara Kazuhiro , Hasegawa Kosei , Hirashima Yasuyuki , Kato Hidenori , Ikezawa Hiroki , Nomoto Maiko , Hayato Seiichi , Otake Yohei , Miura Takuma , Yonemori Kan
Published: June 2022

5513

Background: MORAb-202 is an antibody-drug conjugate consisting of farletuzumab (an antibody that binds to folate receptor alpha [FRα]) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin-B–cleavable linker. The dose-escalation part of this phase 1 study confirmed antitumor activity in pts with ovarian cancer (Shimizu 2021, CCR); based on efficacy and safety, MORAb-202 0.9 mg/kg and 1.2 mg/kg Q3W were chosen as doses for the expansion part of this study in pts with PROC. Methods: The primary objective for the expansion part of this phase 1 study conducted in Japan was to define the safety and tolerability of MORAb-202. Secondary objectives included PK characterization and efficacy assessment (best overall response, objective response rate, progression-free survival, and overall survival). Eligible pts included those who had received ≤2 regimens of chemotherapy after diagnosis of PROC, had measurable disease per RECIST v1.1, and an ECOG PS of ≤1. Pts (except those with high grade serous histology) in the expansion phase were required to be FRα positive. The expansion phase began at the 0.9 mg/kg dose (Cohort 1); Cohort 2 (1.2 mg/kg) was initiated after safety assessment of Cohort 1 was completed. Tumor responses were assessed per RECIST v1.1 by investigator. Results: Twenty-four pts were treated in Cohort 1 and 21 pts were treated in Cohort 2. Grade ≥3 TEAEs occurred in 33.3% of pts in Cohort 1 and 28.6% of pts in Cohort 2. The most common TEAE was interstitial lung disease (ILD)/pneumonitis at both dose levels (Cohort 1: 37.5% [n=9; 8 with grade 1, 1 with grade 2]; Cohort 2: 66.7% [n=14; 6 with grade 1, 7 with grade 2, 1 with grade 3]). Other common TEAEs of any grade were nausea (25.0%; 33.3%), pyrexia (33.3%; 42.9%), malaise (16.7%; 28.6%), and headache (12.5%; 47.6%), in Cohorts 1 and 2, respectively. ORR was 25.0% and 52.4% in Cohorts 1 and 2, respectively (Table). Antitumor activity was observed across FRα-expression levels (<50% and ≥50%) and will be presented. Conclusions: In the PROC population, antitumor activity was seen with both the MORAb-202 0.9 mg/kg and 1.2 mg/kg doses. While pt numbers were small, efficacy was observed irrespective of FRα-expression levels. ILD/pneumonitis was the most common TEAE and was low grade in most pts. Dose optimization is ongoing to maximize the benefit/risk profile of MORAb-202. Clinical trial information: NCT03386942. [Table: see text]
Efficacy and safety of QL1706, a novel dual immune checkpoint blockade containing a mixture of anti-PD1 IgG4 and anti-CTLA4 IgG1 antibodies, for advanced cervical cancer: Cohort data from a phase 1b trial.
Authors: Liu Jihong , Liu Naifu , Wang Danbo , Li Dapeng , Fang Cheng
Published: June 2022

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Background: Anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death 1 (PD-1) antibodies have synergistic effect. QL1706 is a novel dual immune checkpoint blockade containing a mixture of anti-PD-1 IgG4 and anti-CTLA4 IgG1 antibodies produced by a single cell line. QL1706 showed promising anti-tumor activity in multiple solid tumors. Here we reported the cervical cancer cohort data from the phase 1b trial of QL1706 (NCT05171790). Methods: Eligible patients had a pathologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, with recurrent or metastatic, immunotherapy-naive disease at the time of enrollment. Patients were required to have ≥one lesion measurable by RECIST v1.1 and disease that had relapsed after a first-line, platinum-based regimen. Patients were included regardless of PD-L1 expression status at baseline. Patients received intravenous QL1706 5.0 mg/kg q3w (i.e., recommended phase 2 dose, defined in a phase 1a trial), for up to 24 months. The primary endpoint was confirmed overall response rate (ORR) per RECIST v1.1 by investigator. The secondary endpoints included disease control rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety, etc. Results: As of Dec 31, 2021, totally 53 patients with cervical cancer were enrolled (median age, 52 years [range 33-72]). Median follow-up was 5.6 months. Most patients (45 [85%]) had ECOG performance status of 1. Histological breakdown was squamous cell carcinoma (44 [83%]) and adenocarcinoma (nine [17%]). 33 (62%) patients had received one prior chemotherapy, 20(38%) patients had received ≥two prior chemotherapy. The confirmed ORR was 28% (95% CI 17%-42%; 15 patients), including one (2%) complete response and 14 (26%) partial response, with median duration of response not reached (95% CI 2.8 months-not estimable). Disease control was observed in 29 (55%; 95% CI 40%-68%) patients. Median PFS was 4.2 months (95% CI 1.7-6.9), and 6-month PFS rate was estimated as 37% (95% CI 24%-51%). Treatment-related adverse events (TRAE) were observed in 40 (75%) patients. Nine (17%) experienced grade ≥3 TRAE. The most common TRAE were rash (eight [15%]), hyperthyroidism (eight [15%]), and pyrexia (seven [13%]). Three (6%) patients suffered TRAE leading to dose discontinuation. The immune-related TRAE and serious TRAE were observed in 28 (53%) and eight (15%) patients, respectively. Conclusions: QL1706 demonstrated promising and durable clinical activity, with favorable tolerability in patients with recurrent and/or metastatic cervical cancer. Further investigations in this setting are continuing. Clinical trial information: NCT05171790.
Risk of contralateral breast and other cancers in patients with invasive lobular breast cancer.
Authors: Choong Grace Mei Yee , Savitz Samuel T. , Giridhar Karthik , Haddad Tufia C. , Ruddy Kathryn Jean , Boughey Judy Caroline , Goetz Matthew P. , Couch Fergus , Yadav Siddhartha
Published: June 2022

555

Background: Women with early-stage breast cancer (BCa) are living longer, and survivorship issues including second primary cancers (SPCs) are therefore increasingly important. This study seeks to determine the risk of SPCs, including contralateral breast cancer (CBCa), in women with early-stage invasive lobular carcinoma (ILC). Methods: The study population consisted of women with BCa diagnosis between 2000-2018 within the NCI Surveillance, Epidemiology, and End Results (SEER v 3.2.9) registry and between 2000-2021 in the Mayo Clinic Cancer Registry. In the SEER registry, the standardized incidence ratios (SIR) for SPCs were estimated for adult women with histologically confirmed early stage (I-III) ILC compared to the development of any primary cancer in the general population. For reference, SIRs for SPCs for a similar patient population with invasive ductal carcinoma (IDC) of the breast were also estimated. For comparison of CBCa between ILC and IDC, follow up records from the Mayo Clinic Cancer Registry were evaluated among adult women who underwent lumpectomy or unilateral mastectomy for early stage ILC or IDC. A multivariable Cox proportional hazards regression was performed to compare the risk of CBCa between ILC and IDC while adjusting for the age at diagnosis, race/ethnicity and estrogen receptor status of the primary tumor. Results: An increased incidence (p<0.05) of any SPCs and second BCa was noted for both ILC and IDC compared to the expected rate of primary cancer in the general population (Table). Interestingly, women with ILC were observed to have a significantly increased incidence of subsequent gastric cancer which was not seen for women with IDC. An SIR >1.5 was noted for subsequent risk of sarcoma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) for both ILC and IDC (Table). In the Mayo Clinic Cancer Registry of 2,218 women with ILC and 14,629 women with IDC meeting the inclusion criteria, the 5-year risk of CBCa was 2.6% and 1.5% (log rank statistic p-value =0.001) for ILC and IDC respectively. A significantly increased risk of CBCa was noted in women with ILC (Hazard Ratio 1.82, 95% CI 1.34-2.47, p<0.001) compared to women with IDC in the multivariable analysis. Conclusions: Women with ILC may have an increased risk of SPC and second BCa compared to the risk of any primary cancer in the general population. The increased incidence of gastric cancer and the higher risk of CBCa in ILC survivors compared to women with IDC is intriguing and needs to be investigated further including evaluation of the role of germline genetic factors. [Table: see text]
Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial.
Authors: Labidi-Galy Sana Intidhar , Rodrigues Manuel , Sandoval Jose L. , Kurtz Jean Emmanuel , Heitz Florian , Mosconi Anna Maria , Romero Ignacio , Berger Regina , Nagao Shoji , Vergote Ignace , Parma Gabriella , Nøttrup Trine Jakobi , Rouleau Etienne , Garnier Georges , El-Balat Ahmed , Zamagni Claudio , Martín-Lorente Cristina , Pujade-Lauraine Eric , Fiévet Alice , Ray-Coquard Isabelle Laure
Published: June 2022

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Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, the addition of maintenance olaparib (ola) to bevacizumab (bev) in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for pts with HRD-positive tumors including a BRCA1/ BRCA2 mutation (BRCAm; Ray-Coquard et al. NEJM 2019). Preclinical data suggest that pts with mutations (mut) in the RING domain of BRCA1 are less sensitive to ola. The magnitude of benefit from ola + bev, according to the location of mut in the functional domains (FD) of BRCA , remains to be explored. Methods: Pts with newly diagnosed advanced HGOC in response after platinum-based chemotherapy + bev received maintenance bev (15 mg/kg q3w for 15 months [mo]) + either ola (300 mg bid for 24 mo) or placebo (pbo). In this post hoc exploratory analysis, PFS was analyzed in pts with BRCAm according to mut location in the FDs of BRCA1 (RING, DNA-binding domain [DNA-BD], or BRCA1 C terminus [BRCT]) and BRCA2 (RAD51-BD; DNA-BD). Results: Among the 806 randomized pts, 235 (29.2%) harbored a BRCAm: 160 (19.9%) with a BRCA1 mut and 76 (9.4%) with a BRCA2 mut. BRCA1 mut in FDs of RING, DNA-BD and BRCT were detected in 19 (11.8%), 41 (25.6%) and 34 (21.2%) pts, respectively. BRCA2 mut were detected in FDs of RAD51-BD and DNA-BD in 37 (48.7%) and 14 (18.4%) pts, respectively. With a median follow-up of 25.5 mo, 24-mo PFS rates and hazard ratios (HRs) according to mut locations are reported in the Table. In pts with a BRCA1 DNA-BD mut, 24-mo PFS was 89% and 14% (ola + bev vs pbo + bev; HR 0.08, 95% confidence interval [CI] 0.02–0.26) compared with 64% and 24% for pts with mut in RING + BRCT + other domains (HR 0.33, 95% CI 0.19–0.57). In pts with BRCA2 mut, 24-mo PFS for pts with mut in the DNA-BD was 91% vs 100% (ola + bev vs pbo + bev) compared with 82% and 44% for pts with mut in RAD51-BD + other domains (HR 0.21, 95% CI 0.08–0.54). Conclusions: In this exploratory analysis, pts with newly diagnosed advanced HGOC and a BRCAm had a PFS benefit from maintenance ola + bev regardless of mut locations in BRCA1/BRCA2. Sensitivity to ola + bev maintenance was particularly high for pts with mut in the DNA-BD of BRCA1. Pts with a mut in the DNA-BD of BRCA2 commonly had excellent outcomes. Clinical trial information: NCT02477644. [Table: see text]
Camrelizumab plus apatinib in patients with advanced or recurrent endometrial cancer after failure of at least first-line therapy: Interim results of a single-arm phase II trial.
Authors: Wang Huaying , Tian Wenjuan , Ren Yulan , Jing Chuyu , Shan Boer
Published: June 2022

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Background: For advanced or recurrent endometrial cancer (EC), therapeutic options remain scarce. Immune or antiangiogenic monotherapy has shown moderate efficacy in EC. Preclinical and clinical data showed that camrelizumab (an anti-PD-1 antibody) plus apatinib (a selective VEGFR2 inhibitor) markedly enhanced anti-tumor efficacy in multiple solid tumors. This study was designed to assess the efficacy and safety of the combination of camrelizumab and apatinib as second-line or above therapy for advanced or recurrent EC. Methods: This was an open-label, single-arm, phase II trial conducted in China. Patients with advanced or recurrent EC who progressed after at least first-line therapy received camrelizumab (200 mg, intravenously, q2w) plus apatinib (250 mg, orally, qd). Using a minimax Simon two-stage design, 21 patients were enrolled at stage I and if a complete or partial response was observed in at least four patients, the enrollment would be continued to 40 patients. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included time to objective response (TTR), disease control rate (DCR), duration of Response (DoR), progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF) and safety. Here, the results of stage I are reported. Results: Between January 20, 2020 and July 8, 2021, 21 patients were enrolled. The median age was 57 years (range 29–72). Thirteen patients (61.9%) had ECOG PS of 0, and eight patients (38.1%) received at least two prior therapies. As of November 9, 2021, the median follow-up time was 13.5 months (IQR 11.3-16.3). Among 21 evaluable patients, the confirmed ORR was 47.6% (95% CI 25.7%-70.2%) with complete response in one patient (4.8%) and partial response in nine patients (42.9%); eight patients had stable disease for a DCR of 85.7% (95% CI 63.7%-97.0%). The median PFS was 11.8 months (95% CI 5.2-14.4). Treatment-related adverse events (TRAEs) of any grade and of grade ≥ 3 were reported in 21 (100%) patients and 10 (47.6%) patients, respectively. The most common grade ≥ 3 TRAEs included gamma-glutamyltransferase increased (six [28.6%]), direct bilirubin increased (four [19.0%]), alanine aminotransferase increased (three [14.3%]), aspartate aminotransferase increased (three [14.3%]) and hyperglycaemia (three [14.3%]). Four patients (19.0%) experienced reactive cutaneous capillary endothelial proliferation, all of which were grade 1-2. No treatment-related deaths were reported. Conclusions: Camrelizumab plus apatinib demonstrated promising antitumor activity and a manageable safety profile in patients with advanced or recurrent EC after failure of at least first-line therapy. Clinical trial information: ChiCTR2000031932.
Biomarkers for response to immunotherapy in triple-negative breast cancer: Differences between survival and pCR biomarkers.
Authors: Denkert Carsten , Schneeweiss Andreas , Rey Julia , Karn Thomas , Braun Michael , Huober Jens Bodo , Sinn Hans-Peter , Zahm Dirk Michael , Hanusch Claus , Marmé Frederik , Furlanetto Jenny , Thomalla Joerg , Blohmer Jens U. , van Mackelenbergh Marion , Staib Peter , Jackisch Christian , Fasching Peter A. , Sinn Bruno Valentin , Untch Michael , Loibl Sibylle
Published: June 2022

583

Background: Immunotherapy is entering clinical practice as a promising new neoadjuvant therapeutic approach in triple-negative breast cancer, and it is important to identify biomarkers to focus this therapy on those patients that have the highest benefit. Interestingly, an improved survival outcome is observed in pCR and non-pCR patients, which raises the hypothesis that biomarkers might also be different for pCR prediction as well as prognosis. In this study, we investigated this hypothesis in the neoadjuvant GeparNuevo trial. Methods: A total of 174 patients were randomized to receive neoadjuvant chemotherapy with durvalumab vs. placebo. HTG EdgeSeq mRNA analysis was performed for a total of 2549 genes in 162 pretherapeutic core biopsies. In addition, tumor-infiltrating lymphocytes (stromal and intratumoural) as well as PD-L1 protein expression was evaluated by IHC. We systematically compared the distant disease-free survival (DDFS) of 5 predefined gene signatures (including the GeparSixto immune signature) as well as 12 single mRNA markers identified in previous projects between treatment arms using univariate Cox proportional-hazard regression analyses. In addition, exploratory biomarker analyses were performed. Results: The PSIP1 gene expression (per 1 unit hazard ratio [HR]: 0.58 95%CI 0.41-0.83; p=0.002), TAP1 (per 1 unit HR: 0.68 95%CI 0.48-0.95; p=0.025) as well as stromal TILs (sTILs) (per 10% HR: 0.73 95%CI 0.56-0.95; p=0.019) were significant for improved DDFS in the complete cohort. In the placebo arm PSIP1 (HR 0.50 95%CI 0.29-0.87; p=0.014) as well as sTILs (HR 0.73 95%CI 0.53-0.99; p=0.044) were significant for improved DDFS. In the durvalumab arm, the gene expression of PSIP1 (HR 0.54 95%CI 0.31-0.94; p=0.029), PD-L1/CD274 (per 1 unit HR: 0.41 95%CI 0.21-0.77; p=0.006), CD38 (per 1 unit: HR 0.52 95%CI 0.29-0.92; p=0.026) as well as the GeparSixto immune signature (per 1 unit HR: 0.51 95%CI 0.27-0.97; p=0.041) were significant for improved DDFS, with a positive test for interaction with treatment arm for PD-L1/CD274 (interaction p=0.020). Additional analyses, including multivariate Cox regressions for DDFS as well as systematic comparisons for biomarkers for DDFS and for pCR, will be presented. Conclusions: Our analysis suggests that biomarkers for immune response are linked to improved survival with neoadjuvant durvalumab therapy and that in this setting, survival biomarkers are not identical to pCR biomarkers. The results are a basis for a further dissection of the contribution of pCR to survival effects of immunotherapy.