bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma exosome microRNA-155 expression in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors: A potential biomarker of response to systemic therapy.
Authors: Soleimani Maryam , Thi Marisa , Saxena Neetu , Eigl Bernhard J. , Khalaf Daniel Joseph , Chi Kim N. , Kollmannsberger Christian K. , Nappi Lucia
Published: June 2021

4570

Background: The search for a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critically unmet need in the management of metastatic renal cell carcinoma (mRCC). We sought to evaluate the biomarker potential of plasma exosome microRNAs (miRNAs) implicated in RCC and in augmentation of the tumour microenvironment (TME) for such a role. Methods: Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and in 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and were used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to those of healthy volunteers and calculated using the 2ΔΔCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC pts and healthy volunteers according to best response to first line ICBT between responders (n = 27) v non-responders (n = 13). The cut-off value of significant expression was established by Youden’s index. Responders were defined as those patients experiencing complete response, partial response or stable disease and non-responders were those who experienced progressive disease. Results: The most common first line ICBT was nivolumab + ipilimumab (n = 32), followed by pembrolizumab + axitinib (n = 5), and avelumab + axitinib (n = 3). A significantly higher expression of miRNA-1233 (median 1.85 v 0.81 p = 0.008) and miRNA-155 [miR-155] (3.69 v 0.21 p = 0.006) were found in patients compared to healthy volunteers. Higher miR-155 expression was associated with higher Fuhrman grade (p = 0.002). There was no association with other clinical prognostic factors. MiR-155 was expressed at a significantly lower level in responders than in non-responders (median 0.61 v 35.29, p = 0.042). Response rate amongst patients with low and high expression of miR-155 (RQ ≤ 2.5) was statistically different (p = 0.042) and 84.2% of the pts with low miR-155 expression responded to the treatment. Conclusions: Lower expression of miR-155 was associated with response to ICBT in patients with mRCC. Functionally, miR-155 is involved in regulation and modulation of the TME. These results underscore the need for further work in this area to elucidate the role of this and other miRNAs as biomarkers of response in mRCC.
SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).
Authors: Agarwal Neeraj , Tangen Catherine , Hussain Maha H. A. , Gupta Shilpa , Plets Melissa , Lara Primo "Lucky" N. , Harzstark Andrea , Twardowski Przemyslaw , Paller Channing Judith , Zylla Dylan M. , Zibelman Matthew R. , Levine Ellis Glenn , Roth Bruce J. , Goldkorn Amir , Vaena Daniel A. , Kohli Manish , Crispino Tony , Vogelzang Nicholas J. , Thompson Ian Murchie , Quinn David I.
Published: June 2021

5001

Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]
Complementary detection of genomic alterations in metastatic castration-resistant prostate cancer (mCRPC) from CheckMate 9KD through analyses of tumor tissue and plasma DNA.
Authors: Sausen Mark , Baden Jonathan F. , Kalinava Natallia , Wang Xuya , Li Jun , Anguiano Esperanza , Unsal-Kacmaz Keziban , Wind-Rotolo Megan , Quinn Katie , Green George
Published: June 2021

5038

Background: Accurate analysis of the genomic alteration landscape within tissue- and plasma-derived tumor DNA using next-generation sequencing (NGS) may provide insights into specific patient populations that benefit from different therapies. The interchangeable use of tissue- and plasma-based assessments may benefit patients when tissue availability is limited, a common occurrence in individuals with mCRPC. To understand the potential sources of technical and biological variability in this setting, we performed comprehensive comparative analyses across 3 NGS platforms, using samples from patients enrolled in CheckMate 9KD, a phase 2 study of nivolumab combined with docetaxel, rucaparib, or enzalutamide for patients with confirmed mCRPC (NCT03338790). Methods: We performed retrospective integrated analyses of sequence and structural alterations identified through comprehensive genomic profiling (CGP) of DNA obtained from formalin-fixed, paraffin-embedded tissue specimens and cell-free DNA obtained from plasma. Tissue-based analysis was performed using the FoundationOne assay (F1, 395 genes), while the FoundationACT (FACT, 70 genes) and GuardantOMNI (OMNI, 500 genes) assays were used for plasma-based analysis. Analysis was performed on samples from 103 patients for which datasets from all 3 assays were available. Inter-platform analysis considered variants with ≥ 0.50% variant allele fraction and common to the shared pairwise targeted regions, while excluding synonymous variants. Results: Through broad profiling of DNA obtained from tissue and plasma, we uncovered previously identified recurrent alteration of AR, TP53, PTEN, and TMPRSS2 fusion with ETS genes. Additionally, we found that 42% (F1), 45% (FACT), and 34% (OMNI) of patients harbored a combination of germline and somatic mutations in homologous recombination repair pathway genes. Across all samples, median tumor mutational burden was 3.5 mutations per megabase (mut/Mb) by F1 and 8.6 mut/Mb by OMNI. Inter-platform variant analyses demonstrated concordance of 52% for F1 vs FACT, 40% for F1 vs OMNI, and 75% for FACT vs OMNI. Conclusions: Overall, these data demonstrate the value of integrated tissue and liquid biopsy profiling in mCRPC. Both technical and biological sources of variation, including panel size, mutation detection algorithms, variant annotation and reporting, analytical performance, circulating tumor DNA levels, and tumor heterogeneity, may be captured differently by tissue- and plasma-based techniques, accounting for the discordance in reported results. Clinical trial information: NCT03338790.
CheckMate 9KD cohort A1 final analysis: Nivolumab (NIVO) + rucaparib for post-chemotherapy (CT) metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pachynski Russell Kent , Retz Margitta , Goh Jeffrey C. , Burotto Mauricio , Gravis Gwenaelle , Castellano Daniel , Flechon Aude , Zschaebitz Stefanie , Shaffer David R. , Vazquez Limon Juan Carlos , Grimm Marc-Oliver , McCune Steven L. , Amin Neha P. , Li Jia , Wang Xuya , Unsal-Kacmaz Keziban , Saad Fred , Petrylak Daniel P. , Fizazi Karim
Published: June 2021

5044

Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [Table: see text]
Circulating tumor DNA fraction (ctDNA%) to independently predict for clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Maurice-Dror Corinne , Fonseca Nicolette , Herberts Cameron , Fan William , Wyatt Alexander W. , Chi Kim N.
Published: June 2021

5049

Background: CtDNA% (the tumour-derived proportion of cell-free DNA (cfDNA)) is abundant in >60% of mCRPC pts and associates with adverse clinical prognostic factors. However, prognostic associations have not been comprehensively tested across clinical contexts. We evaluated the utility of ctDNA% as an independent prognostic biomarker in patients with mCRPC prior to first-line (1L) therapy. Methods: 410 treatment-naïve mCRPC pts had blood samples drawn prior to 1L therapy and followed prospectively for outcomes. Plasma cfDNA was subjected to deep targeted sequencing and ctDNA% was calculated using validated methods ( Annala, Cancer Discov, 2018 ). Overall survival (OS), PSA progression free survival (PSA PFS) and PSA declines ≥50% from baseline (PSA50 response rate (RR)) were stratified by ctDNA% and compared using Kaplan-Meier and Cox proportional hazards analysis. Results: Median age was 73 yrs. (range 45-98), the majority of pts had ECOG PS 0-1 (78%) and 9.5% had liver metastases at baseline. The most common 1L therapy employed was androgen receptor pathway inhibitors (90%). Median follow-up was 21 mo. (range 1-75) and median ctDNA% was 4.9% (range: 0-89%). Stratifying patients into high ctDNA (>30%) and Low ctDNA (≤2%) groups showed stronger association with OS and PSA PFS than grouping by median (Table). In a univariate comparison to pts with low ctDNA (≤2%), pts with high ctDNA% (>30%) had significantly shorter median PSA PFS, median OS and a lower PSA50 RR (Table). In a multivariable adjustment for clinical prognostic factors and cfDNA concentration, high ctDNA% remained strongly associated with OS (HR= 3.3, 95%CI: 2.1-5.3, p<0.001) and PSA PFS (HR: 3.7, 95%CI: 2.4-5.9, p<0.001). Although ctDNA% and total cfDNA concentration were correlated (R2=0.55), association with OS was stronger for ctDNA% than cfDNA concentration (stratified at median; HR: 2.9 (2.3-3.7), p<0.001 vs HR: 2.1 (1.7-2.6), p<0.001). Conclusions: In a large cohort of treatment-naïve mCRPC pts, ctDNA% prior to 1L treatment provided strong prognostic information independent of known clinical factors. These data further demonstrate the multipronged clinical utility of ctDNA-based profiling for actionable genomic alterations.[Table: see text]
Proliferation index and survival in men with prostate cancer starting long-term androgen deprivation therapy in the STAMPEDE clinical trial.
Authors: Mendes Larissa , Brawley Christopher D. , Grist Emily , Ali Adnan , Santos Vidal Sara , Parry Marina , Lall Sharanpreet , Atako Nafisah B. , Ishaq Sofeya , Richmond Malissa , Haran Aine , Hoyle Alex , Zakka Leila , Sweeney Christopher , Clarke Noel W. , Parmar Mahesh K. B. , James Nicholas D. , Brown Louise C. , Berney Daniel , Attard Gerhardt
Published: June 2021

5076

Background: Treatment intensification with docetaxel or abiraterone improved survival for advanced prostate cancer starting androgen deprivation therapy (ADT) in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE, NCT00268476) trial. However, survival and time-to-progression is highly variable on ADT, introducing the risk of unnecessary toxicity from additional treatments for some patients. Here we test the prognostic association of proliferation index using Ki67 scores in the control arm of the STAMPEDE population of high-risk localised (M0) and metastatic (M1) prostate cancer. Methods: Pre-ADT diagnostic needle biopsies were obtained from 517 men randomized in STAMPEDE arm A between 2006 and 2015. These were assessed for proliferation using an analytically optimised Ki67 immunohistochemistry assay. Ki67 was tested for associations with baseline clinico-pathological variables (Grade group, pre-ADT serum PSA and imaging metastatic burden) in univariable linear-regression models, and for associations with survival outcomes in multivariable Cox-regression models adjusted for these and additional confounding variables. Primary outcome measure was overall survival, secondary outcomes were prostate cancer-specific, failure-free, progression-free and metastatic progression-free survival. Results: Ki67 was available for 475 patients who received ADT only for at least 2 years ± radiotherapy. Of 202 M0, 74 were node positive. Of 273 M1, 116, 127 and 30 were respectively low, high and unknown radiological M1 volume. Ki67 score associated with higher Gleason (p=7.15x10-11) and presence of extra-pelvic metastases (p=1.41x10-8). Increasing Ki67 scores showed a strong linear association with poorer overall survival, with an estimated 2% increase in the hazard of death per percentage increase in the score (adjusted HR=1.02, 95% CI 1.01-1.02; p=1.04x10-5). There was also strong evidence that Ki67 associated positively with all secondary outcomes, including prostate cancer-specific survival (adjusted p=5.50x10-6) and metastatic progression-free survival (adjusted p=3.50x10-9). Conclusions: Ki67 immuno-score is strongly prognostic in clinically advanced prostate cancer independent of Gleason score and the other clinicopathological variables tested in this study. Ki67 is a clinically scalable assay that could improve selection for treatment intensification and provide a tool for screening patients most likely to benefit from further molecular investigation.
A phase II randomized controlled trial of exercise on biochemical progression in men with prostate cancer on active surveillance.
Authors: Kang Dong-Woo , Fairey Adrian S. , Boulé Normand G. , Field Catherine J. , Wharton Stephanie A. , Courneya Kerry S.
Published: June 2021

5080

Background: Men with prostate cancer (PCa) undergoing active surveillance (AS) are at increased risks of cardiovascular death and disease progression. Any intervention that can address these issues during AS would be highly beneficial. Clinical and preclinical studies have demonstrated the benefits of exercise to improve cardiovascular health in cancer patients and suggested the potential role of exercise in suppressing PCa progression in men with PCa undergoing AS. Therefore, the purpose of this study was to investigate the effects of exercise on cardiorespiratory fitness and biochemical progress of PCa in men with PCa on AS. Methods: The Exercise During Active Surveillance for Prostate Cancer (ERASE) Trial was a single-centre, two-armed, randomized controlled trial in Edmonton, Canada. 52 men with localized PCa who were undergoing AS were randomized to high-intensity interval training (HIIT; n = 26) or usual care (UC; n = 26). The HIIT group performed thrice-weekly, supervised, aerobic HIIT on a treadmill at 85-95% of peak cardiorespiratory fitness (VO2peak) for 12 weeks. The primary outcome was VO2peak, and the secondary and exploratory outcomes included biochemical progression of PCa (prostate-specific antigen [PSA]), PSA kinetics, and growth of prostate cancer cell line LNCaP. Results: 46/52 participants (88%) completed the postintervention VO2peak assessment and adherence to HIIT was 96%. Compared to UC, HIIT significantly improved VO2peak (adjusted between-group mean difference, 1.6 ml·kg-1·min-1; 95% confidence interval [CI], 0.3 to 2.9; p= 0.014). HIIT also significantly reduced PSA level (adjusted between-group mean difference, -1.1 ug/L; 95% CI, -2.1 to 0.0; p= 0.043) and PSA velocity ( p= 0.040), and suppressed LNCaP cell growth ( p =0.024). No significant differences were found in PSA doubling time ( p= 0.10) and testosterone ( p= 0.24). Conclusions: The ERASE Trial is the first randomized controlled trial to demonstrate the impact of HIIT exercise for improving physical fitness and inhibiting biochemical progression of PCa in men with localized PCa on AS. Our findings suggest that supervised aerobic HIIT may be a promising intervention in this clinical setting. Larger-scale randomized controlled trials are warranted to determine if improvements in physical fitness and PCa-related markers translate into improved long-term clinical outcomes in these men such as disease progression, receipt of radical treatments, posttreatment complications, and survival. Clinical trial information: NCT03203460.
Active surveillance of postradical prostatectomy biochemical recurrence: Long-term assessment of outcomes.
Authors: Ahlering Tom Edward , Huang Erica , Huynh Linda My , Su Huang Wei
Published: June 2021

5081

Background: Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of distant metastatic progression/prostate cancer death, resulting in potential complications & expenses of overtreatment. Little has been published on management decisions & outcomes of active surveillance (AS). We characterize our long term experience with AS following post-RP BCR without radiation/androgen deprivation therapy. Methods: From June 2002 - September 2019, 1865 men underwent RP. 406 experienced BCR; of these, 138 (34%) were observed without treatment intervention. BCR defined as PSA>0.2 ng/dl, x2. PSAs checked every 1-3 months and entered into a PSADT graph. Men were considered to be formally AS after 3+ years of increasing DT following RP. Men with decreasing DT were treated and censored. Results: The table depicts demographics of the AS patients; median follow-up was 7.3 years (IQR: 4.6-10.6) post-RP. Of patients on AS, average age was 63.7 +/- 7.2 years and 86%, 48%, 40%, 51% and 14% were GG 1 through 5, respectively. Current DT of AS patients averages 20 months, with 0% PCSM. Only 10% of patients with decreasing DT began treatment after average 4 years following BCR. Conclusions: Of 406 patients experiencing post-RP BCR, 34% of patients are effectively managed with AS, with 0% PCSM across all GG. Presently 69 (50%) AS men have been under observation for 7.3 to 18 years. This suggests that significant portion of patients display benign recurrence, characterized by increasing DT following BCR and can be managed safely with observation alone.[Table: see text]
Dose escalation for mitigating diarrhea: Ranked tolerability assessment of anti-diarrheal regimens in patients receiving neratinib for early-stage breast cancer.
Authors: Marx Gavin M. , Chien Amy Jo , García-Sáenz José A. , Chan Arlene , Ruiz-Borrego Manuel , Barcenas Carlos Hernando , Thirlwell Michael P. , Trudeau Maureen E. , Bose Ron , Egle Daniel , Pistilli Barbara , Wassermann Johanna , Cheong Kerry A. , Semsek Dieter , Singer Christian F. , Hunt Daniel , Khambholja Utpal , Xu Feng , Shah Naisargee , Brufsky Adam
Published: June 2021

536

Background: The primary tolerability concern with neratinib (NERLYNX®; N), an irreversible pan-HER tyrosine kinase inhibitor, is diarrhea. Data from the multi-cohort, open-label, phase 2 CONTROL trial [Barcenas et al. Ann Oncol 2020] demonstrated significant improvement in grade 3 diarrhea and diarrhea-related discontinuations vs the ExteNET trial, which did not mandate anti-diarrheal prophylaxis. We report a systematic analysis of tolerability in CONTROL and ExteNET. Methods: Patients (pts) ≥18y with stage I–IIIc HER2+ breast cancer received N (240 mg/d po for 1y) after trastuzumab-based adjuvant therapy and were enrolled sequentially into cohorts assessing different modalities to mitigate diarrhea. Cohorts with complete data were included: loperamide (L); L+budesonide (BL); L+colestipol (CL); CL as needed (CL-PRN); and N dose escalation (DE; 120 mg/d on d1–7, 160 mg/d on d8–14, and 240 mg/d thereafter). Integrated ranking (IR) analysis was performed on 13 endpoints in 4 domains (exposure, diarrhea, adverse events [AEs], quality of life [QoL]) identified with input from clinicians; cohorts were ranked from 1 (best) to 5 (worst). Index scores (IS) based on individual pt data from CONTROL were calculated as supportive analysis to confirm selection of the regimen with best overall tolerability, which was then compared with ExteNET. Results: Of the 5 CONTROL cohorts evaluated, DE ranked best for most endpoints. Average ranks per IR method: L 3.4; BL 3.2; CL 3.0; CL-PRN 3.3; DE 2.0. The IS analysis supported DE as the cohort with best overall tolerability. Comparison of CONTROL DE vs ExteNET showed improvement in tolerability in all domains (table). Conclusions: These analyses suggest superiority of weekly DE vs other anti-diarrheal strategies. A lower rate of grade 3 diarrhea was observed with CONTROL DE vs ExteNET (13.3 vs 39.9%, respectively), as well as a comparable or improved AE profile. The data also reveal greater compliance with N (fewer early discontinuations, longer treatment duration, higher cumulative dose) and reduced impact on QoL with DE, suggesting improved tolerability. Clinical trial information: NCT02400476. [Table: see text]
Postoperative adjuvant dose-dense chemotherapy with bevacizumab and maintenance bevacizumab after neoadjuvant chemotherapy for advanced ovarian cancer: A phase II AGOG/TGOG trial.
Authors: Chen Wei-Chun , Chou Hung-Hseuh , Yang Lan-Yan , Huang Huei-Jean , Chang Wei-Yang , Lin Hao , Wu Ren-Chin , Chen Min-Yu , Qiu J. Timothy , Huang Kuan-Gen , Chao Angel , Chang Ting-Chang , Lai Chyong-Huey
Published: June 2021

5540

Background: The objective of this study is to evaluate the safety and efficacy of adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after neoadjuvant chemotherapy (NAC) and interval debulking surgery (IDS) for stage III/IV ovarian, tubal, and primary peritoneal cancer. Methods: This phase II clinical trial using Simon's minimax two-stage design was conducted. At the first stage, 13 subjects were enrolled, and the trial would proceed to second stage if ≤3 subjects discontinued treatment for study-defined significant adverse events (AEs). Patients with stage III/IV ovarian, tubal, and primary peritoneal cancer deemed not feasible for primary cytoreductive surgery were enrolled after 3 to 4 cycles of NAC and IDS without disease progression. NAC could be either weekly paclitaxel (80mg/m2) (dose-dense) plus 3-weekly carboplatin (AUC5-6) or 3-weekly conventional schedule. After IDS, postoperative dose-dense adjuvant chemotherapy for 3 cycles at least (best to 6 cycles), and 3-weekly bevacizumab 15mg/kg was given since postoperative cycle 2. Further 3-weekly maintenance bevacizumab 15mg/kg was given intravenously for 17 cycles. Results: Of the 22 enrolled subjects, 13 (59.1%) had no gross lesion after IDS. Of the 13 subjects enrolled on the 1st stage, one study-defined significant AE occurred, therefore the trial proceeded to the 2nd stage (n = 9). The median progression-free survival (PFS) was 22.1 months (95% confidence interval [CI], 13.7 – 30.5), and the median overall survival (OS) was 49.2 months (95% CI, 33.8 – 64.6). Peritoneal Cancer Index score at entering abdomen during IDS was significant for PFS (>12 vs ≤ 12: p = 0.003). One of the 22 subjects did not receive any study treatment. In the safety analysis (n = 21), grade 3/4 AEs included thrombocytopenia of 38.1%, neutropenia 71.4%, and anemia 28.6%. Study-defined significant AEs of bowel perforation, poor-healing wound, and hypertension were found in 1 case each, respectively. Conclusions: This phase II trial demonstrated adding bevacizumab to dose-dense adjuvant chemotherapy with bevacizumab maintenance after NAC was feasible with tolerable toxicity and comparable PFS/OS as compared to other studies using bevacizumab in the NAC phase or dose-dense scheduling throughout. Clinical trial information: NCT02022917.
Open-label, multicenter, phase 1b/2 study of rebastinib in combination with paclitaxel to assess safety and efficacy in patients with advanced or metastatic endometrial cancer.
Authors: Janku Filip , Hamilton Erika P. , Mathews Cara Amanda , Chu Christina , Diamond Jennifer Robinson , Hays John L. , Arend Rebecca Christian , Cristofanilli Massimo , Jewell Andrea , Reichmann William , Kuida Keisuke , Achour Haroun , Ruiz-Soto Rodrigo , Richardson Debra L.
Published: June 2021

5576

Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( > 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.
Trends in breast cancer mortality according to molecular subtypes: A population-based study.
Authors: Han Yunan , Xu Shuai , Colditz Graham A. , Toriola Adetunji T.
Published: June 2021

572

Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.
Evaluation of sensitivity to endocrine therapy index (SET2,3) for response to neoadjuvant endocrine therapy (NET) and subsequent prognosis.
Authors: Symmans William Fraser , Du Lili , Hoskin Tanya L. , Anurag Meenakshi , Ma Cynthia X. , Bedrosian Isabelle , Hunt Kelly , Ellis Matthew James , Suman Vera Jean
Published: June 2021

580

Background: Patients (pts) in Cohort A of the American College of Surgeons Oncology Group Z1031 (Alliance) trial of NET for cStage II-III breast cancer were randomized to anastrozole [ANA], letrozole [LET] or exemestane [EXE] for 16-18 weeks (wks). In Cohort B, pts chose between ANA and LET and switched to chemotherapy or surgery if a tumor biopsy after 2-4 wks of NET had Ki67 >10%. Treatments after surgery were not defined by the trial protocol. SET2,3 measures nonproliferation gene expression related to estrogen and progesterone receptors adjusting for a baseline prognostic index that combines clinical tumor and nodal stage and a 4-gene molecular subtype (RNA4) defined by ESR1, PGR, ERBB2 and AURKA. High SET2,3 in a pre-treatment biopsy using cStage information is defined as SET2,3 >1.77. Methods: 379 pts had gene expression data from a research tumor biopsy prior to NET (Agilent 44K microarrays). A bioinformatician blinded to pt treatment and clinical outcomes determined SET2,3. The trial statistician then examined the association between SET2,3 and pharmacodynamic response at 2-4 wks (N=141, Cohort B): Ki67 ≤10% and complete cell cycle arrest (CCCA Ki67 ≤2.7%); pathologic outcomes in pts who completed NET: ypStage 0/1 (N=329, Cohorts A&B), PEPI-0 rate (N=155, Cohort B); and event-free survival (EFS) post-registration (N=244, Cohorts A&B). We used Fisher’s exact tests to assess whether responses, and Cox modeling to evaluate whether EFS, differed with respect to SET2,3 status. Results: High SET2,3 in 48% of pts (183/379) was associated with older age (median: 66 vs 63 years; p=0.012); cStage II (95% vs 75%; p <0.001); and pre-NET Ki67 ≤10% (37% vs 20%; p< 0.001) in pts with low SET2,3. In Cohort B, pts with high SET2,3 had a higher rate of pharmacodynamic response in their tumor at wk 2-4 than pts with low SET2,3 (Table). In the subset of Cohort B pts with wk 2-4 Ki67 ≤10%, pre-treatment SET2,3 trended numerically higher in pts who achieved PEPI-0 score (p=0.049) but the proportion achieving PEPI-0 did not differ by SET2,3 high/low status (Table). EFS was significantly longer for pts with high SET2,3 than pts with low SET2,3 (HR[H/L]: 0.52; 95% CI: 0.34-0.80; p=0.003). Conclusions: An exploratory analysis of Z1031 data demonstrated that the rate of pharmacodynamic suppression of proliferation by NET at 2-4 wks was greater and EFS was longer for pts with breast cancer expressing high SET2,3 disease than pts with low SET2,3. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Clinical trial information: NCT00265759. [Table: see text]
Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Saba Nabil F. , Roe Denise , Bauman Jessica R. , Kaczmar John M. , Bhatia Aarti K. , Muzaffar Jameel , Julian Ricklie Ann , Wang Steven , Bearelly Shethal , Baker Audrey , Steuer Conor Ernst , Giri Anshu , Burtness Barbara , Centuori Sara , Caulin Carlos , Saboda Kathylynn , Obara Stefanie , Chung Christine H.
Published: June 2021

6015

Background: Cetuximab (C), an anti-EGFR monoclonal antibody (mAb), is approved for advanced HNSCC but benefits a minority. Crosstalk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways is a known resistance mechanism. HGF is also immunosuppressive within the tumor microenvironment. A Phase I study confirmed the safety of C and ficlatuzumab (F), an IgG1 anti-HGF mAb, with preliminary efficacy and biomarker data suggesting that dual pathway inhibition may overcome tumor-intrinsic or immune cetuximab resistance. Methods: The primary objective of this phase II randomized, non-comparative trial was to evaluate the efficacy of F (20 mg/kg every 2 wks), with or without C (500 mg/m2 every 2 wks), in pan-refractory, advanced HNSCC. Eligibility criteria included recurrent/metastatic HNSCC, performance status (PS) 0-1, C resistance (defined as progression on or within 6 months of exposure), and resistance to or ineligibility for platinum and anti-PD1 mAb. Randomization was stratified by HPV status and center. The primary endpoint was median progression-free survival (mPFS). An arm was deemed worthy of further study if the lower bound of the 90% 1-sided confidence interval (CI) excluded the historical control of 2 months. Secondary objectives included overall response rate (ORR) in the overall and HPV-stratified populations. A Bayesian continuous monitoring rule for futility was applied. Results: 60 patients were randomized and 58 treated between Jan 2018 and Dec 2020 (27 to F; 33 to FC). Baseline characteristics were balanced across major prognostic variables including age, PS, HPV status, platinum resistance, and PD1 mAb exposure. Median time since prior cetuximab was 3.5 months (range 0-48 months). Grade ≥3 adverse events attributed to F included: pneumonitis (2); edema (3); diarrhea (1); LFT elevation (1); rash (2); electrolyte abnormality (2). The Table presents efficacy data. The F arm stopped for futility after 26 evaluable subjects accrued. The FC arm completed accrual and met the primary endpoint; 32 evaluable subjects had mPFS of 3.6 months (lower bound 90% 1-sided CI: 2.3 months) and ORR of 19% (6/32). All responses were in HPV- subjects, including 2 complete (CR) and 4 partial responses (PR) to the FC combination and 1 PR to F monotherapy. The mPFS and ORR for the HPV- population (n = 16) on FC were 3.8 months and 38% (6/16). Mechanistic signaling and immune biomarkers are under analysis. Conclusions: The well-tolerated FC combination met the primary PFS endpoint in pan-refractory, advanced HNSCC with notable activity in HPV- HNSCC, warranting phase III investigation. Clinical trial information: NCT03422536. [Table: see text]
Expansion cohort validation of a clinical predictive model for head and neck cancer survival in patients treated with immune checkpoint inhibitors.
Authors: Laliotis Georgios I. , Issa Majd , Klamer Brett , Karivedu Vidhya , Bhateja Priyanka , Dibs Khaled , Mladkova Nikol , Pan Xueliang Jeff , Old Matthew O. , Gamez Mauricio , Grecula John C. , Jhawar Sachin R , Mitchell Darrion L , Baliga Sujith , Carrau Ricardo , Rocco James William , Blakaj Dukagjin , Bonomi Marcelo Raul
Published: June 2021

6030

Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will die within two years of diagnosis. We have shown that pretreatment clinical characteristics may predict overall survival (OS). Here, we expand our analysis to a total of 201 pts. Methods: Between January 15,2016 and April 9, 2020, 201 pts with R/M HNSCC were treated with ICI as first, second line and beyond. Data on p16 status, hemoglobin (Hb), albumin, lactate dehydrogenase (LDH), neutrophil, platelet and lymphocyte count was recorded initially. OS was defined from the start of ICI to death. Progression Free Survival (PFS) was defined from the start of ICI to disease progression (PD) or death. A nomogram was created using the rms package to generate individualized survival prediction. Results: 201 pts were analyzed, sex: 154 male (77%), 47 female (23%), median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), ipilimumab+nivolumab 10 (5%). Line of therapy: First: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), others 72 (36%). p16 status: negative 132 (66%), positive 69 (34%). Laboratory values: Median neutrophil count: 4.58 (IQR: 3.43-6.47), Median lymphocyte count: 0.69 (IQR: 0.47-1.08), Median Platelet count: 229 (IQR: 187-300), hemoglobin (Hb) normal/low 101/100 (50%/50%), albumin: normal/low 156/45 (78%/22%), LDH: normal/high 124/77 (62%/38%). Overall response rate: 36 (18%). Median OS: 12 months (CI: 9.4-14.8), median PFS: 4 months (CI: 3.5-5.7). The variables associated with OS were neutrophil count (high) [HR 1.28 (1.08 – 1.51), p=0.004], lymphocyte count (high) [HR 0.75 (0.60 – 0.95), p=0.015], albumin (low) [HR 2.06 (1.37 – 3.10), p<0.001], hemoglobin (low) [HR 1.64 (1.14 – 2.35), p=0.007], LDH (high) [HR 1.78 (1.23 – 2.56), p=0.002] and p16 status (positive) [HR 0.58 (0.39-0.87), p=0.009]. Using the prognostic index of the chosen model, we stratified patients into three risk groups at the 33rd and 66th percentile. Median OS in the good risk group was 24 months (CI: 18.5-NR), average risk group 13.8 months (CI: 11-20), poor risk group 2.3 months (CI: 1.7-4.4). The discrimination of the model after internal validation was c-index of 0.72. Conclusions: A small percentage of R/M HNSCC pts treated with ICI have good long-term survival outcomes. In a larger cohort, we internally validated the utilization of a simple, inexpensive and widely accessible nomogram based on clinical and laboratory variables which can predict OS in this patient population.
Outcomes and prediction of lethal recurrence after transoral robotic surgery for HPV+ head and neck cancer.
Authors: Basu Devraj , Shimunov David , Cohen Roger B. , Lin Alexander , Swisher-McClure Samuel , Lukens John Nicholas , Bauml Joshua , Hartner Lee P. , Aggarwal Charu , Duvvuri Umamaheswar , Rajasekaran Karthik , Chalian Ara , Rassekh Christopher , Cannady Steven , Newman Jason , O'Malley Bert W. , Weinstein Gregory S. , Gimotty Phyllis A. , Brody Robert
Published: June 2021

6047

Background: Increasing use of transoral robotic surgery (TORS) for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is likely to impact recurrence patterns and outcomes. Profiling HPV+ HNSCC recurrences after TORS and identifying features predictive of lethal outcome would facilitate tailoring adjuvant therapy and guide surveillance post-therapy. This study uses long term follow-up of patients at the first institution to bring TORS into clinical use to describe the recurrence patterns, distinguish outcomes associated with distinct patterns, and create a risk model for lethal recurrence. Methods: This retrospective cohort study at a single academic tertiary center analyzed 634 consecutive, treatment-naïve HPV+ HNSCC patients receiving TORS and neck dissection for clinical features at presentation and pathologic traits identified by surgical resection. The main outcomes were distant metastatic recurrence (DMR) and locoregional recurrence (LRR). Multivariate logistic regression with backward stepwise elimination was used to identify features associated with recurrence. Results: 6.5% of patients developed DMR at a median of 12.4 months after surgery and had a 5-year overall survival (OS) of 52.5% (95% CI, 33.9%-68.2%), whereas the 6.2% patients developing LRR alone had 5-year OS of 83.3% (95% CI, 66.2%-92.2%; P =.01). After recurrence, 5-year progression-free survival was 24.7% (95% CI, 11.4%-40.7%) for DMR cases and 85.7% (95% CI, 65.1-94.6%) for cases with LRR alone (P <.001). Comparing recurrent cases to recurrence-free controls showed DMR to be independently associated with positive surgical margins (AOR 5.7; 95% CI, 2.1-15.7) and advanced clinical stage at presentation (AOR 6.5; 95% CI, 1.9-23.0). Positive margins increased DMR risk by 4.2-fold and reduced 5-year disease-free survival (P <.001) in early-stage cases (Table), which comprised 95% of the cohort. By contrast, isolated LRR was associated with failure to receive indicated adjuvant therapy and was usually controllable by salvage therapy. Conclusions: Based on the largest single institution cohort reported to date, long term oncologic outcomes for HPV+ HNSCCs after TORS are excellent overall. While DMR is often fatal, LRR is salvageable with durable disease control. In addition to standard staging criteria, positive margins indicate substantially higher risk of DMR but not LRR. A risk model for DMR that incorporates margin status after TORS is relevant for guiding clinical trial design and whole-body surveillance.[Table: see text]
Endostar combined with intensity-modulated radiotherapy in low-risk local advanced nasopharyngeal carcinoma: A phase II, randomized, multicentric clinical trial.
Authors: Kang Min , Lin Shaomin , Zhu Haisheng , Liao Sihui , Huang Haixin , Yu Bin , Wang Hongqian , Liu Meilian , Zhu Jinxian , Huang Guang , Zhang Tingting , Yang Zhendong , Zhou Pingting , Zhou Ziyan , Qin Yutao , Wei Zhuxin , Du Qinghua , Zhao Changhong , Shen Mingjun , Wang Rensheng
Published: June 2021

6050

Background: A Phase II, randomized, prospective, multicentric trial was conducted to evaluate the efficacy and safety of Endostar plus radiotherapy in patients with low-risk local advanced nasopharyngeal carcinoma (NPC). This study reported the preliminary results of NCT02237924. Methods: From 09/2014 to 08/2016, patients with low-risk local advanced NPC were randomly treated with Endostar plus radiotherapy (ERT group, n=60) and concurrent chemoradiotherapy (CCRT group, n=60). Primary endpoint was the 5-year overall survival (OS) rate. The secondary endpoints were 3-year OS rate, progression free survival (PFS) rate, loco-regional recurrence free survival (LRRFS) rate and distance metastasis free survival (DMFS) rate. Results: After a median follow-up of 47 months, 3-year OS rate were 93.2% and 79.3% (p=0.032), 3-year PFS rate were 89.8% and 70.6% (p=0.011), 3-year DMFS rate were 93.2% and 80.7%, in two groups, respectively (P=0.042). 3-year LRRFS rate were 96.6% and 92.0% in two groups, respectively (but P=0.565). For short-term curative effects, CR rate were 71.2% and 60.0% for primary tumor, 74.6％and 63.3％for cervical lymph nodes, in two groups, respectively (P < 0.05). Moreover, the incidences of adverse events were significantly lower in ERT group compared with in CCRT group. The grade 3/4 Hyponatraemia (0 [0%] vs 3 [5%], p=0·04), the grade 1/2 vomiting (10 [16.7%] vs 52 [86.7%], p=0.000), dry mouth (45 [75.0%] vs 56 [93.3%], p=0.012), leukopenia (22 [36.7%] vs 42 [70.0%], p=0.000) and weight loss (30 [50.0%] vs 45 [75.0%], p=0.005). No patients died of treatment-related causes. Conclusions: OS, PFS, and DMFS rates can be improved, adverse events be reduced, with better tolerability, by Endostar plus radiotherapy, when compared to concurrent chemoradiotherapy for local advanced low-risk NPC. Clinical trial information: NCT02237924. [Table: see text]