bluuebunny/crossref_metadata_2025 huggingface dataset:
Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Analysis of clinical and genomic subgroups from the JAVELIN Bladder 100 trial.
Authors: Powles Thomas , Petrylak Daniel P. , Park Se Hoon , Sridhar Srikala S. , Caserta Claudia , Thiery Vuillemin Antoine , Lee Hyo Jin , Bellmunt Joaquim , Yamamoto Yoshiaki , Aragon-Ching Jeanny B. , Huang Bo , Ching Keith A. , Davis Craig B. , Di Pietro Alessandra , Loriot Yohann , Grivas Petros
Published: June 2021

4520

Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in patients (pts) with advanced UC that had not progressed on 1L platinum-based chemotherapy (HR, 0.69 [95% CI: 0.56, 0.86; 1-sided P= 0.0005]). We report post hoc analyses in previously unreported clinical and genomic subgroups. Methods: In JAVELIN Bladder 100 (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without progression after 4-6 cycles of 1L gemcitabine + cisplatin or carboplatin, and were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). The primary endpoint was OS, in all randomized pts and pts with PD-L1+ tumors (Ventana SP263 assay). In this exploratory analysis, we analyzed OS in disease stage and site subgroups, in pts with PD-L1+ tumors who received 1L gemcitabine + carboplatin, and in genomic subtypes (RNAseq whole-transcriptome profiling of tumor tissue) defined using data from The Cancer Genome Atlas (TCGA 2017). Interaction tests were not performed. Results: Prolonged OS was observed in the avelumab + BSC arm vs the BSC alone arm in pts with upper or lower tract tumors, metastatic or locally advanced (LA) and unresectable disease (prior to chemotherapy), and lymph node-only disease post-chemotherapy (Table). OS was also prolonged with avelumab + BSC in pts in PD-L1+ tumors who had received 1L gemcitabine + carboplatin, consistent with findings in the overall population. In genomic subtypes, the OS benefit for avelumab + BSC was apparent across TCGA subtypes except luminal. Conclusions: An OS benefit was seen for avelumab 1L maintenance + BSC vs BSC alone across subgroups of interest. Results are consistent with previously reported findings, further supporting avelumab 1L maintenance as a standard of care for pts with advanced UC that has not progressed with 1L platinum-containing chemotherapy. Clinical trial information: NCT02603432. [Table: see text]
Health care disparities and barriers to palliative care among metastatic renal cell carcinoma patients: An NCDB analysis.
Authors: Wadiwala Janvi , Patel Mausam , Li Chenghui , Maraboyina Sanjay , Safar Ahmed , Kim Thomas
Published: June 2021

4545

Background: Palliative care improves quality of life for both patients and caregivers but may be underutilized due to socioeconomic barriers to access. An NCDB analysis was performed to analyze the effect of socioeconomics on palliative care receipt among patients with metastatic renal cell carcinoma. Methods: A retrospective hospital-based analysis was performed using the National Cancer Database to identify variables that significantly affect receipt of palliative care among patients diagnosed with metastatic renal cell carcinoma diagnosed between 2004 and 2016. Sub-cohort analysis was also performed among patients with the most severe disease. Multivariate binominal logistic regression was performed to determine the association of underlying socioeconomics with receipt of palliative care. The odds of receiving palliative care based on socioeconomic factors was reported as odds ratios (OR) with 95% CI. Results: There were 50405 patients meeting inclusion criteria with 40448 (80.2%) undergoing no palliation and 9957 (19.8%) undergoing palliative care. Both Black and Spanish/Hispanic patients had decreased odds of receiving palliative care (OR, 0.816, 95% CI, 0.753 to 0.885 and OR, 0.599, 95% CI, 0.540 to 0.665, respectively). Increasing age, papillary histology, increasing income, and increasing distance were also significantly associated with decreased odds of receiving palliation while treatment at an integrated network cancer program or comprehensive community cancer program and higher educational attainment were associated with increased odds of receiving palliative care. Similar findings were demonstrated among patients with the most severe disease. Limitations include the retrospective design and potential underlying selection biases of this study. Conclusions: Significant associations between receipt of palliative care and socioeconomic factors exist among patients with metastatic renal cell carcinoma. In this study among patients with metastatic renal cancer, we found associations between socioeconomics and palliative care access including age, race, Spanish/Hispanic origin, income, education, and other factors.
Real-world outcomes in patients with metastatic clear cell renal cell carcinoma receiving front-line axitinib plus pembrolizumab versus ipilimumab plus nivolumab.
Authors: Zarrabi Kevin , Handorf Elizabeth A. , Miron Benjamin , Zibelman Matthew R. , Anari Fern , Ghatalia Pooja , Plimack Elizabeth R. , Geynisman Daniel M.
Published: June 2021

4551

Background: Front-line treatment for patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) has undergone rapid advances in the last five years. This evolution has led to uncertainty about the optimal first line combination regimen. Herein, we compare real-world outcomes in pts treated with either axitinib/pembrolizumab (A/P) or ipilimumab/nivolumab (I/N) reported by International Metastatic RCC Database Consortium (IMDC) score. Methods: The nationwide Flatiron Health electronic health records-derived database was used to select pts diagnosed with mRCC and treated with front-line A/P or I/N from 2018-2020. The primary endpoints were overall-survival (OS) and real-world progression free survival (rwPFS). The survival analyses were adjusted using propensity score-based Inverse Probability of Treatment weighting, providing balance on age, gender, insurance, race, IMDC, practice type, and nephrectomy. Survival was assessed from beginning of therapy, and survival by treatment groups was compared using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. Disease characteristics between the treatment groups were compared using chi-square and T-tests. Results: 821 pts received frontline A/P (n=259) or I/N (n= 562). Demographics and clinical parameters were similar between the two cohorts. Median age was 66 years, 73% were male, and 54.9% had a nephrectomy. 459 pts had all IMDC criteria factors available, 242 pts had missing factors but enough to define as intermediate/poor risk, 120 pts had unknown IMDC risk. Adjusted median OS was not statistically different: mOS for A/P was not reached (NR) while I/N was 22 mo (95% CI, 19.8-NR; p=0.40). Twelve-month survival was 68.5% for A/P treated pts and 65.8% for I/N treated pts (P=0.41). Twelve-month rwPFS was 41.4% for A/P treated pts and 39.7% for I/N treated pts (P=0.14). No statistical difference in survival was seen within IMDC risk strata (see table). Conclusions: In this retrospective, real-world study of pts treated with front-line A/P or I/N, 12-month survival was not statistically different irrespective of IMDC risk. Longer follow-up will be necessary to discern any significant differences.[Table: see text]
Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial.
Authors: Apolo Andrea B. , Powles Thomas , Burotto Mauricio , Bourlon Maria Teresa , Hsieh James J , Basso Umberto , Shah Amishi Yogesh , Suarez Cristina , Porta Camillo , Barrios Carlos H. , Gurney Howard , Kessler Elizabeth R , Retz Margitta , George Saby , Escudier Bernard , Zhang Joshua , Simsek Burcin , Scheffold Christian , Motzer Robert J. , Choueiri Toni K.
Published: June 2021

4553

Background: First-line N+C significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in aRCC patients (pts) in the phase 3 CheckMate 9ER trial, leading to FDA approval of N+C in this setting. A deeper understanding of how baseline disease characteristics may impact clinical outcomes with N+C vs S may inform clinical decision making. Methods: Pts with clear cell aRCC were randomized to N 240 mg IV Q2W + C 40 mg PO QD vs S 50 mg PO QD (4 weeks of 6-week cycles). In this post hoc exploratory analysis, PFS, OS, and ORR were evaluated across pt subgroups defined by baseline IMDC risk status, organ sites of metastases (mets), number of organs with any lesions, or target lesion size. Consistent with primary/secondary efficacy endpoints in ITT pts, PFS and ORR were evaluated per RECIST v1.1 by blinded independent central review in subgroups. Results: Median follow-up in ITT pts was 23.5 months. PFS, OS, and ORR (including complete response [CR]) outcomes are summarized in the table across subgroups: IMDC risk (favorable [FAV], intermediate [I], poor [P]); number of organs with ≥ 1 target/nontarget lesion (T/NT; 1 and ≥ 2); sum of diameters of target lesions (sDTL; < and ≥ median [72.1 mm]), and in pts with liver, bone, or lung mets. The PFS HR favored N+C vs S and median (m) PFS was longer with N+C vs S across all subgroups. The OS HR also favored N+C vs S across most subgroups. ORR ranged from 38%–66% (N+C) vs 10%–44% (S) across subgroups, and CR benefits were seen with N+C in most subgroups. Additional outcomes including landmark OS and response details in subgroups will be reported. Conclusions: Consistent with outcomes in ITT pts, efficacy benefits with N+C vs S were observed regardless of IMDC risk status, organ site of mets, or extent of tumor burden at baseline. These results support N+C as a new first-line treatment option for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]
Dynamic changes of the immune infiltrate after neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).
Authors: Bex Axel , Abu-Ghanem Yasmin , Van Thienen Johannes V. , Graafland Niels , Lagerveld Brunolf , Zondervan Patricia , Beerlage Harrie , van Moorselaar Jeroen , Kockx Mark , Van Dam Pieter-Jan , Szabados Bernadett , Blank Christian U. , Powles Thomas , Haanen John B. A. G.
Published: June 2021

4573

Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a front-line standard of care for metastatic RCC. Neoadjuvant use of these combinations is associated with tumor downsizing, but dynamic effects on key immune biomarkers are uncertain. We report early dynamic changes in the tumour immune environment after neoadjuvant treatment with avelumab/axitinib. Methods: Neoavax is an open label, single arm, phase II trial, investigating 12 weeks of neoadjuvant avelumab/axitinib prior to nephrectomy in patients with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4N0-1M0). Partial primary tumour response (RECIST 1.1) occurring in ≥25% is the primary endpoint. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and major histocompatibility complex class I (MHC-I) were compared on paired samples (pre-treatment biopsy and nephrectomy) (NCT03341845). Results: Paired, sequential tissue from the first 24 patients was analysed for immune biomarker expression. Of these patients, 70% were ≥pT3a, 30% pN1, 58% had ISUP/WHO grade ≥3 with 8% sarcomatoid features. Compared to pre-treatment biopsy there was a significant increase in PD-L1 (p = 0.0002) and CD8+ expression (p = 0.0003) after therapy, whereas changes in CD8/GZMB+, MHC-I and CD8/CD39+ were not significant. Furthermore, neoadjuvant avelumab/axitinib therapy was associated with a significant decrease in Foxp3+ cells (p = 0.009). Conclusions: 12 weeks of neoadjuvant axitinib/avelumab treatment in ccRCC leads to significant dynamic changes in the tumour microenvironment for CD8+, PD-L1 and Foxp3+ expression. High baseline Foxp3+ infiltration is associated with an unfavorable outcome in the majority of solid tumours. The significant on-treatment decrease in Foxp3+ may account for the positive interaction seen between VEGF targeted therapy and immune checkpoint inhibitors in mRCC. If these cells represent regulatory T cells (Tregs), activated CD4 T cells or fragile Tregs remains to be determined. Clinical trial information: NCT03341845.
Clinical utility of FDG PET-CT in stage 1 and advanced testicular seminoma.
Authors: Conduit Ciara , Hofman Michael S , Lewin Jeremy Howard , Toner Guy C. , Tran Ben
Published: June 2021

5027

Background: Testicular seminoma is highly curable; however, treatments can cause long-term morbidity in survivors. Following chemotherapy for advanced seminoma, positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose together with computerised tomography (PET-CT) can identify patients with residual masses who do not need additional treatment. Its role in detecting recurrence during active surveillance, particularly in patients with small indeterminate masses, is unknown. We assessed the clinical utility of PET-CT in testicular seminoma undergoing active surveillance for stage 1 disease and following curative-intent treatment for advanced disease. Methods: An institutional database was interrogated to identify patients with testicular seminoma who underwent PET-CT between 2000-2020. Demographic, clinicopathological, PET-CT findings and outcome data were retrieved. The positive predictive value (PPV) of PET-CT for correctly identifying disease recurrence was calculated, with disease recurrence (true positive) defined as progressive radiological change, response to treatment or histological confirmation. Negative predictive value (NPV) was calculated for correctly identifying non-recurrence (true negative) at 24-months post PET-CT. Results: We identified 193 PET-CT in 181 stage 1 patients. Of these, 18 (10%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. Of the 138 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 96%. In the subset of PET-CT conducted for suspicion of recurrence in stage 1 patients (n = 71: abnormal imaging n = 65, elevated markers n = 4, other clinical suspicion n = 2), 16 (23%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. In this subset, the NPV is 93% at 24 months (3 recurrences in 44 negative PET-CT). We also identified 154 PET-CT in 77 post-treatment, advanced stage patients. Of these, 69 (45%) PET-CT were positive, with 51 correctly diagnosing recurrence, PPV 74%. Of the 66 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 92%. In the subset of PET-CT performed for suspicion of recurrence following treatment for advanced disease (n = 61: abnormal imaging n = 49, elevated markers n = 5, other clinical suspicion n = 7), 41 (67%) PET-CT were positive, with 36 correctly diagnosing recurrence, PPV 88%. In this subset, the NPV is 94% at 24 months (1 recurrence in 17 negative PET-CT). Conclusions: At our centre, PET-CT has a very high PPV for recurrence, particularly in stage 1 disease, and a very high NPV for non-recurrence in all disease settings. In the subset of PET-CT performed for suspicion of recurrence, PPV is > 88% and NPV is > 93%. The role of PET-CT should be considered in patients with suspicion of recurrence where it may prevent over-treatment in up to 70% patients in stage 1 or 30% in advanced disease.
Outcomes of patients with germ cell tumors diagnosed with stage I disease who subsequently received high dose chemotherapy (HDCT) with peripheral stem cell transplant (PBSCT) following failure of initial therapy for metastatic disease: The Indiana University experience.
Authors: Benzinger Stephen B , Ashkar Ryan , Abonour Rafat , Abu Zaid Mohammad Issam , Adra Nabil , Einhorn Lawrence H. , Hanna Nasser H.
Published: June 2021

5029

Background: Pts with stage I testicular germ cell tumors (GCT) have a 15-year DFS of 99%. However, 1% are not cured, despite orchiectomy and systemic therapy at relapse. Predictive variables for relapse in this small population have not been identified. Methods: Pts undergoing HDCT with PBSCT as salvage therapy for relapsed GCT after an initial diagnosis of stage I disease managed with orchiectomy and surveillance were evaluated from a database at Indiana University. Patient demographics, disease characteristics, adherence to standard surveillance guidelines for stage I disease, prognostic variables, treatment received in the first-line setting, pattern of relapse, and outcomes were analyzed. Results: From 1/92 to 10/19, 71 pts (34 seminoma, 37 NSGCT) initially diagnosed with stage I GCT managed with orchiectomy and surveillance but subsequently relapsed and eventually required HDCT with PBSCT were identified. Median f/u time was 5.1 years (range, 1.1-18.8). Median age was 34.1. First-line chemo consisted of BEP or EP in most pts. Risk category at relapse: good/intermediate/poor (52/8/11). Pattern of initial relapse included 22 (seminoma n=13, NSGCT n=9) with RPLN only. Relapse and death after HDCT occurred in 2 of these 22 pts. Strict adherence to standard surveillance guidelines was observed in 62/71 pts. Relapse and/or death after HDCT occurred in 3 of 9 with inadequate surveillance follow-up. At a minimum of 1 yr follow-up, 54 of 71 (76%) remain alive, including 47 (66%) who have no evidence of disease (NED). Conclusions: Most patients in this series progressed despite appropriate surveillance and first-line chemotherapy. Pattern of relapse was also not indicative of further progression in most patients. Further investigation should evaluate disease biology that puts patients with potentially easily curable disease at risk of multiple relapses.[Table: see text]
Diagnostic performance of Gallium-68 prostate-specific membrane antigen (PSMA) PET/CT imaging in early-relapsed prostate cancer: Phase 3, prospective, multicenter study (IAEA-PSMA study).
Authors: Cerci Juliano J , Fanti Stefano ,   IAEA Prostate Working Group
Published: June 2021

5078

Background: Biochemical recurrence (BCR) is a clinical challenge in prostate cancer (PCa) patients with impact on defintion of subsequent therapies. The use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) presents better accuracy than standard imaging practice. This phase3, prospective, multicentric, international study evaluates the diagnostic performance and clinical impact of PSMA-PET/CT in evaluating BCR in PCa. Methods: Patients with PCa who have undergone primary definitive treatment and with rising PSA were recruited in the study. Overall 17 centers from 15 countries (Azerbaijan, Brazil, Colombia, India, Israel, Italy, Jordan, Lebanon, Malaysia, Mexico, Pakistan, Poland, South Africa, Turkey, and Uruguay) were involved. Images and data were centrally reviewed; data were collected for PSMA site of findings, positivity rate, defined as the percentage of patients with a positive 68Ga-PSMA PET/CT taking into account the composite standard: pathology, correlative imaging, PSA response, with at least 6 mo. clinical follow-up, and impact on patient management by determining changes in the treating physician’s documented clinical plans before and after 68Ga-PSMA PET/CT. Results: Were enrolled 1198 patients and presented final data from 1004 patients. 68Ga-PSMA PET/CT was positive in 654/1004 patients (65.1%); lesions were identified as: prostate/prostatic bed only in 13.7% cases; pelvic lymph nodes only 20.5%, and with any metastatic disease in 27.0%. There was a correlation between PSMA-PET/CT positivity and Gleason score (p<0.001): detection rate was 371/613 (60.5%) in patients with Gleason 7, 130/196 (66.3%) in Gleason 8, 140/180 (77.8%) in Gleason 9 and 13/15 (86.7%) in Gleason 10. There was also significant correlation between lesions identification and PSA values (p<0.001): detection rate was 21/41 (51.2%) for PSA <0.2, 84/188 (44.7%) for PSA between 0.2-0.5, 124/232 (53.4%) for PSA 0.5-1.0, 158/235 (67.2%) for PSA ≥1 and <2, 171/206 (83.0%) for PSA ≥2 and <4, and 96/102 (94,1%) in PSA 4 to 10. Also, treatment was modified based on PSMA results in 56.8% of patients. The 68Ga-PSMA PET/CT positivity was consistent and not statistically different among the countries. Conclusions: This is the largest multicenter trial on 68Ga-PSMA PET/CT detected local and metastatic recurrence in most men with BCR. 68Ga-PSMA PET/CT results changed the recommended treatment approaches in the majority of patients. This study confirms the reliability of PSMA PET in BC and the worldwide feasibility of such approach.
Predict the benefit of metronomic capecitabine maintenance in early-stage triple-negative breast cancer: Results from the SYSUCC-001 study.
Authors: Yuan Zhongyu , Hua Xin , Li Wang-Zhong , Huang Heng , Cai Li , Lin Ying , Zhang Lehong , Chen Qianjun , Huang Jia-Jia , Bi XiWen , Xia Wen , Wang Shu-Sen , Xu Fei , Hong Ruoxi , Jiang Kuikui , Shi Yanxia , Xue Cong , An Xin , Tang Jun , Wang Xi ,   The South China Breast Cancer Group (SCBCG)
Published: June 2021

521

Background: Recent clinical trials and meta-analysis have suggested the benefit of adding capecitabine to standard chemotherapy in early-stage triple negative breast cancer (TNBC). We aimed to develop an individualized prediction model to quantify the clinical benefit of metronomic capecitabine maintenance in TNBC. Methods: Patients from the SYSUCC-001 trial, randomized to standard treatment with or without metronomic capecitabine maintenance, were pooled. Candidate covariates included age, tumor size, lymph node, histological grade, Ki-67 percentage, lymphovascular invasion, chemotherapy regimen and capecitabine medication. The primary endpoint was disease-free survival (DFS). The nonlinear effect of continuous covariate was modelled by restricted cubic spline. We developed a survival prediction model using the Cox proportional hazards model. Results: A total of 434 patients were recruited (306 in development cohort and 128 in validation cohort). The estimated 5-year DFS in the development cohort and validation cohort were 77.8% (95% CI, 72.9-82.7%) and 78.2% (95% CI, 70.9-85.5%), respectively. Age and lymph node had significant nonlinear effects on DFS. Four covariates significantly associated with DFS in the final prediction model were age, lymph node, lymphovascular invasion and capecitabine medication. The model demonstrated suitable calibration and fair discrimination ability with a C-index of 0.722 (95% CI, 0.662-0.781) and 0.764 (95% CI, 0.668-0.859) in the development cohort and validation cohort, respectively. We design an easy-to-use online calculator based on the model, capable of predicting capecitabine maintenance benefit. Conclusions: The evidence-based prediction model could identify those patients who most warrant metronomic capecitabine maintenance and thus help treatment decision making in daily clinical practice. Clinical trial information: NCT01112826.
Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.
Authors: Blayney Douglas W. , Shi Yuankai , Adamchuk Hryhorii , Feng David , Zhang Qingyuan , Du Lihua , Huang Lan , Mohanlal Ramon
Published: June 2021

533

Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC <0.5 cells × 10E9/L) in early-stage BC (node positive or node negative with a high risk of recurrence) pts. 221 pts with ECOG status 0 or 1 received Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Central laboratory ANC was assessed at Covance in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Primary objective was to compare the percentage (%) of pts with a Duration of Severe Neutropenia (DSN) of 0 days [that is % of pts with no Grade (Gr) 4 neutropenia (N)] in C1 in each arm. Key secondary endpoints were DSN and ANC Nadir in C1. We also evaluated safety (AE frequency and Grade). Conclusions: Adding Plin to Peg offers superior CIN protection compared to Peg alone and also has a superior safety profile by lowering over 20% of grade 4 AE. The effect size of the CIN protection in the combination is also correlated to clinical meaningful FN reduction compared to peg alone. Clinical trial information: NCT03531099. [Table: see text]
Cost-effectiveness of the Oncotype DX Breast Recurrence Score test in postmenopausal women with node-positive early breast cancer based on the RxPONDER trial.
Authors: Berdunov Vladislav , Millen Steve , Paramore Andrew , Reynia Sarah , Fryer Nina , Griffin Jane , Georges Nadia
Published: June 2021

534

Background: The Oncotype DX test is a predictive and prognostic multigene assay used to guide adjuvant chemotherapy in HR+/HER2- early breast cancer. The ability of the Oncotype DX test to predict the benefit of chemotherapy in node-positive early breast cancer was demonstrated in SWOG-8814. This evidence, in combination with findings from a bespoke analysis of the TransATAC study, informed an economic evaluation of the Oncotype DX test by the National Institute for Health and Care Excellence in the UK. This study examined the impact of new evidence from the RxPONDER trial on the cost-effectiveness of the Oncotype DX test in postmenopausal women with node-positive early breast cancer. Methods: The cost-effectiveness of the Oncotype DX test compared to clinical risk tools only in postmenopausal HR+/HER2- early breast cancer was estimated using a model in Microsoft Excel. The pre-RxPONDER analysis using the old cut points (RS 0-17, RS 18-30, RS 31-100) was informed by TransATAC and SWOG-8814. The model was updated with 5-year probability of distant recurrence as first site estimates based on new RS cut points (RS 0-25, RS 26-100) from RxPONDER. The impact on incremental lifetime costs and quality-adjusted life-years (QALYs) gained was examined based on the list price for the Oncotype DX test in the UK. Results: The impact of adding data from RxPONDER into the cost-effectiveness analysis is summarized in the table below. Conclusions: The RxPONDER trial demonstrated that the addition of chemotherapy to endocrine therapy had no benefit for distant recurrence in postmenopausal women with RS 0-25, regardless of clinical features, which suggests that most patients with 1-3 positive nodes can be safely spared adjuvant chemotherapy. In the model this was reflected in reduced cost of chemotherapy and higher QALYs from avoiding short and long-term adverse effects of chemotherapy. Targeted chemotherapy of a minority (17%) of patients with RS 26-100 reduced the cost of distant recurrence and improved survival based on the model results. RxPONDER provides direct evidence to inform the probability of distant recurrence with endocrine and chemo-endocrine therapy, whilst previous models have had to synthesize multiple sources of DRFI and chemotherapy treatment effect. Future studies should examine the impact of the RxPONDER findings on chemotherapy treatment decision-making in routine clinical practice.[Table: see text]
PD-L1 expression and TOP3A mutation as prognostic factors for adjuvant chemotherapy in triple negative breast cancer.
Authors: Wang Xue , Yuan Peng , Du Feng , Cui Lina , Zheng Fangchao , Yue Jian , Zhang Bei , Wang Jiayu , Fan Ying , Ma Fei , Xu Binghe
Published: June 2021

541

Background: Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is markedly heterogeneous and lacks specific targets. The aim of this study is to explore potential predictors and therapeutic targets based on clinical and genetic characteristics. Methods: 138 patients with triple-negative breast cancer after surgical treatment were 1:1 randomly assigned to the paclitaxel combined with carboplatin (TCb) group or the epirubicin combined with cyclophosphamide sequential paclitaxel (EC-T) adjuvant chemotherapy group. PD-L1 was retrospectively analyzed by surgically resected specimens, and 733 cancer-related genes were detected by NGS. Pathway enrichment analysis was performed using DAVID for functional enrichment genetic alterations. Cox regression models and Kaplan-Meier were used to evaluate disease-free survival (DFS). Results: In this study, there was no significant difference in DFS between the TCb and EC-T groups. 31 (22.5%) of 138 TNBC patients were positive for PD-L1 expression, including 15 (10.9%) patients positive for PD-L1 in tumor cells (TCs) and 29 (21.0%) patients positive for PD-L1 in tumor-infiltrating immune cells (TICs). Patients with positive PD-L1 expression, either in TCs or TICs, achieved better DFS [HR=0.13 (95% CI: 0.02-0.93), p=0.016], the difference was also shown in the EC-T group [HR=0 (95% CI: 0- inf), p=0.037], but not in the TCb group [HR=0 (95% CI: 0.04-2.1), p=0.189]. In addition, we identified 7 patients with mutations in DNA topoisomerase IIIα(TOP3A), a homologous recombination (HR)-related gene, and patients with mutations in this gene had worse DFS than those without mutations [HR=4]. However, there was no statistically significant association between BRCA mutation and response to either therapeutic regimens. Conclusions: In this TNBC patient population, immunohistochemistry (IHC) and NGS analyses identified potential prognostic markers. PD-L1 positive and TOP3A mutation were significantly associated with early triple-negative breast cancer prognosis.
Survival following locoregional recurrence in breast cancer by clinical subtype.
Authors: Allen Kirsten , Lohrisch Caroline A. , Le Dan , Diocee Rekha M. , Speers Caroline , Nichol Alan , Taylor Sara Kristina
Published: June 2021

543

Background: We sought to explore the impact of locoregional recurrence (LRR) on survival in breast cancer (BC) patients in British Columbia treated in the modern era. Methods: A retrospective cohort study design identified patients diagnosed with stage I-III BC from 04/2005-12/2013 treated with surgery and who had a subsequent LRR. Exclusions were death or distant metastasis within 120 days of LRR, bilateral previous/synchronous BC, and other invasive cancers. After LRR, overall survival (OS) and factors associated with OS, including clinical subtype and adjuvant therapy (AdTx), were examined. We defined clinical subtypes as: Luminal (Lum) A-estrogen receptor (ER) and progesterone receptor (PR) positive, HER2 negative, and grade 1 or 2; Lum B-as Lum A but grade 3, or as Lum A but only one of ER or PR positive; triple negative (TNBC)-ER and PR and HER2 negative; and HER2 positive (with any ER, PR). In the absence of earlier LRR, we defined adequate AdTx as: (a) TNBC: >=50% of planned chemotherapy (Chx), (b) HER2 positive: >=50% of planned Chx and >=8 cycles of anti-HER2 therapy, (c) Lum A, B: >=4 years of endocrine therapy and (d) after partial mastectomy or positive final margins: >=50% of radiation therapy dosage. Results: The final cohort had 492 patients with a median follow-up of 7.2 years from LRR and 11.8 years from diagnosis. LRR was local in 69.3% (n=341) and regional +/- local in 30.7% (n=151). Compared with local only, regional recurrences were associated with higher T and N stage, grade, and Lum status (p<=0.01). Biomarkers were re-evaluated at LRR in 82% and changed from initial diagnosis in 32% of those tested: ER expression 3.8% gain, 6.1% loss; PR expression 9.1% gain, 15.1% loss; HER2 overexpression 3.7% gain and 4.8% loss. Over half of patients (n=255, 52%) did not receive adequate AdTx, either by choice or recommendation. A similar proportion with local vs. regional recurrence had inadequate AdTx. Time to death from 1st LRR did not vary significantly between local vs. regional recurrences (median 2.7 years). OS after LRR was lowest in TNBC (median 3.1 years, 24.2% 10-year OS) and longest in Lum A (median not reached, 64.7% 10-year OS) (Table). Conclusions: Our data provide rates of OS after LRR in the era of modern adjuvant therapy. OS after LRR varied by clinical subtype, with TNBC faring the worst, and Lum A the best. Over half had not received adequate AdTx. Despite similar treatment options, OS after LRR was significantly longer for Lum A than B subtypes, underscoring the need for therapy tailored to biology. OS was low in all other subtypes, emphasizing the importance of avoiding LRR.[Table: see text]
Optimal treatment duration of bevacizumab (BEV) combined with carboplatin and paclitaxel in patients (pts) with primary epithelial ovarian (EOC), fallopian tube (FTC) or peritoneal cancer (PPC): A multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR 17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890).
Authors: Pfisterer Jacobus , Joly Florence , Kristensen Gunnar , Rau Joern , Mahner Sven , Pautier Patricia , El-Balat Ahmed , Kurtz Jean Emmanuel , Canzler Ulrich , Sehouli Jalid , Heubner Martin L. , Hartkopf Andreas D. , Baumann Klaus , Hasenburg Annette , Hanker Lars Ch. , Belau Antje , Schmalfeldt Barbara , Denschlag Dominik , Park-Simon Tjoung-Won , Harter Philipp
Published: June 2021

5501

Background: GOG-0218 established the addition of BEV 15 mg/kg every 3 weeks (q3w) for 15 months to standard front-line chemotherapy for advanced ovarian cancer, but the optimal BEV duration remained unknown. We report primary results from a randomized phase 3 trial designed to address this question. Methods: Eligible pts with FIGO stage IIB–IV EOC, FTC, or PPC and ECOG PS ≤2 underwent primary cytoreductive surgery followed by 6 cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin AUC 5 q3w) and BEV (15 mg/kg q3w). Pts were randomized to receive BEV for either 15 months (standard arm BEV15) or 30 months (experimental arm BEV30), stratified by FIGO stage/residual tumor (stage IIB–IIIC/no residual tumor vs stage IIB–IIIC/residual tumor or stage IV). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST v1.1. Secondary endpoints were overall survival (OS), objective response rate, quality of life, safety, and tolerability. The trial was designed with 80.2% power to detect a hazard ratio (HR) of 0.66 favoring BEV30 (2-sided log-rank test, 5% significance level, 10% dropout rate) after 697 PFS events. The trial was funded by F. Hoffmann-La Roche Ltd., performed according to ENGOT model A. Results: From Nov 2011 to Aug 2013, 927 women (83% with EOC) from 161 centers were randomized. Baseline characteristics were balanced between arms; median age was 61 years, 96% had ECOG PS 0/1, 58% had no residual tumor, and 77% had high-grade serous histology. Serious adverse events of special interest for BEV occurred in 51/448 pts (11%) vs 61/442 pts (14%) receiving BEV15 vs BEV30, respectively: hypertension (2.7%/4.5%), thromboembolic event (2.2%/3.2%), fistula (3.1%/1.1%), gastrointestinal perforation (0.2%/0.9%), proteinuria (0.7%/1.4%), hemorrhage (0.2%/0.9%), and myocardial infarction (0%/1.1%). Efficacy is shown in the table. Conclusions: Longer treatment with BEV for up to 30 months improves neither PFS nor OS in pts with primary EOC, FTC, or PPC. Therefore BEV treatment duration of 15 months remains standard of care. Clinical trial information: NCT01462890. [Table: see text]
Olaparib treatment (Tx) in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSR OC) by BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: Overall survival (OS) results from the phase II LIGHT study.
Authors: Mathews Cara Amanda , Simpkins Fiona , Cadoo Karen Anne , Liu Ying L , Provencher Diane M. , McCormick Colleen , ElNaggar Adam , Altman Alon D , Gilbert Lucy , Black Destin , Kabil Nashwa , Bennett James , Munley Jiefen , Yu Judy , Aghajanian Carol
Published: June 2021

5515

Background: LIGHT (NCT02983799) evaluated olaparib Tx in pts with PSR OC in cohorts with known BRCAm and HRD status. We report the final OS analyses. Methods: We conducted anopen-label, non-randomized, multicenter study of pts with PSR OC and ≥1 prior line of platinum-based chemotherapy (CTx). Pts were assigned to one of 4 cohorts: germline (g) BRCAm; somatic (s) BRCAm; HRD +ve (non-BRCAm); and HRD -ve. Genomic instability score (GIS) and gBRCAm status were determined by Myriad myChoice and BRACAnalysis CDx tests, respectively. HRD +ve tumors were defined by a GIS ≥42. Pts received olaparib Tx (starting dose 300 mg bid) until disease progression or unacceptable toxicity. OS was a secondary endpoint and was analyzed at 12 months (mo) after the primary analysis and 18 mo after the last pt was enrolled. Safety was assessed in pts who received ≥1 dose. Results: Data cut-off (DCO) was Aug 27, 2020. Of 272 enrolled pts, 271 received olaparib; of these, 270 had measurable disease at baseline and were included in efficacy analyses (Table). At DCO, 40% of pts had died (maturity) with a median follow-up in censored pts of 26.3 mo. Kaplan–Meier 18-mo OS rates were 86%, 88%, 79%, and 60% in the gBRCAm, sBRCAm, HRD +ve (non-BRCAm), and HRD -ve cohorts, respectively. Platinum-based CTx was the most common first subsequent Tx and was received by 39% pts after olaparib discontinuation. At DCO, the median duration of Tx was 7.4 mo and 244 pts had discontinued treatment, mainly due to disease progression (72%); 5% discontinued due to treatment-emergent adverse events (TEAEs). The only TEAE leading to discontinuation in >1 pt was nausea (2 pts). Serious TEAEs were reported in 25% of pts. The most common serious TEAE was small intestinal obstruction (6%). Three adverse events of special interest occurred, each in 1 pt (<1%): acute myeloid leukemia (post discontinuation), pneumonitis, and pulmonary fibrosis. Conclusions: In the final OS analysis, 18-mo OS ranged from 60–88% across the 4 cohorts. Consistent with the primary analysis, the 18-mo OS rate was highest in the BRCAm cohorts (similar OS in g and sBRCAm); among pts without a BRCAm, 18-mo OS was highest in the HRD +ve cohort. No new safety signals were observed compared with the primary analysis and with prior olaparib studies. Clinical trial information: NCT02983799. [Table: see text]
Anlotinib plus sintilimab in patients with recurrent advanced cervical cancer: A prospective, multicenter, single-arm, phase II clinical trial.
Authors: Xu Qin , Chen Chuanben , Sun Yang , Huang Zhangzhou , Lin Yibin , Liu Jing , Li Li , Li Zirong , Pan Junping , Chen Ying
Published: June 2021

5524

Background: It is difficult for patients with recurrent advanced cervical cancer to obtain clinical benefits after the failure of standard chemotherapy. However, antiangiogenic therapy combined with immune checkpoint inhibitors have become a promising strategy for advanced cervical cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumour angiogenesis and proliferative signalling. Sintilimab is a fully humanized, high-affinity monoclonal antibody against programmed cell death-1 (PD-1). This phase II, single-arm study (ChiCTR1900023015) aims to evaluate the efficacy and safety of anlotinib plus sintilimab in patients with recurrent advanced cervical cancer. Methods: Patients who have received at least once platinum-based chemotherapy, histopathologically confirmed recurrent advanced cervical cancer (including squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma), more than 1% PD-L1 expression, ECOG 0-1 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and sintilimab was administered intravenously (200mg once every 3 weeks). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2019 and February 2021, 42 patients with a median age of 52 years (range:47-58), FIGO histopathological stage I (11.9%), II (31.0%), III (33.3%), IV (9.5%) and undiagnosed (14.3%) were enrolled. 39 of these patients were evaluable. In the efficacy-evaluable population (n = 39), the therapeutic evaluation showed that 2 and 20 patients achieved complete response and partial response respectively, yielding the ORR of 56.4% (22/39, 95% CI:40.2 to 71.5). The DCR was 94.9% (37/39, 95% CI:80.7 to 98.8). The median response time was 1.6 months. The median PFS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included hypothyroidism (33.3%), hypertension (23.8%), AST (21.4%), diarrhea (19.0%), ALT (16.7%), hand-foot syndrome(14.3%), hypertriglyceridemia (14.3%) and anemia (11.9%). The grade 3 AEs were hypertension (4.8%), hyponatremia (4.8%), immune pneumonia (2.4%) and immune myocarditis (2.4%). No higher AEs and treatment-related death were observed. Conclusions: Anlotinib plus sintilimab showed a promising efficacy with a favorable toxicity profile for patients with recurrent advanced cervical cancer. We will report more data in the future. Clinical trial information: ChiCTR1900023015.
A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.
Authors: Jackson Camille Catherine , Cantrell Leigh , Erickson Britt Kristina , Moore Kathleen N. , Duska Linda R. , Richardson Debra L. , Landrum Lisa Michelle , Holman Laura L. , Walker Joan L. , Mannel Robert S. , Moxley Katherine M. , Queimado Lurdes , Ding Kai , Cohoon Andrew , Vesely Sara , Dockery Lauren E.
Published: June 2021

5527

Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.