bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of biweekly gemcitabine in combination with capecitabine (GemCap) in elderly and frail patients (pts) with resected pancreatic cancer (PC).
Authors: Hakim Nausheen , Chi Jeffrey , Rehman Hasan , Nealon William , Deutsch Gary B , Newman Elliot , Anantha Sandeep , Coppa Gene , Deperalta Danielle , Rishi Arvind , Maloney Antonia , Moriarty Linda , Smith Melissa H , Jose Jyothi , Saif Wasif M.
Published: May 2020

4628

Background: ESPAC-4 study showed that GemCap conferred a survival benefit over gemcitabine monotherapy in resected PC patients. ESPAC-4 included patients with median age of 65 years (37-81) and ECOG performance status (PS) of 0 (43%), 1 (54%) and 2 (2%) who received a median cumulative dose of gemcitabine of 15,000 mg/m2, capecitabine. Here we present our experience with an adopted biweekly regimen of GemCap in patients who were ≥ 75 years and those who were deemed not suitable for ESPAC-4 regimen. Methods: Patients ≥ 75 years with resected PC, ECOG PS of 0-2 and no prior treatments were included. Patients were treated with a modified regimen of gemcitabine (1000-2000 mg/m2) every 2 weeks and capecitabine (800-1000 mg/m2) day 1-7 every 2 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS) and sites of recurrence. Toxicities were graded according to NCI CTCAE v5.0. Results: Thirty-five (22M, 13F) patients, ≥ 75 (median age 79) treated with biweekly Gem-Cap adjuvant treatment. 7 (28%) patients had ECOG PS of 1 and 28 (72%) had ECOG PS of 2. There were 5, 7 and 16 patients with stage I, II and III disease. Nine patients (25%) had R1 and 26 (75%) had R0 resection. The median PFS and OS were 8.0 months and 22.0 months. Nine (25%) had local recurrence, 21 (60%) had metastatic disease and 3 (8.6%) had NED. Two patients were lost to follow-up. The most frequent toxicities were grades 1-2 anemia (20%), thrombocytopenia (8%) and hand-foot syndrome (HFS) (10%). Grade ≥3 included diarrhea (4%) and HFS (1%) with no treatment-related discontinuations. Treatment compliance was 100%. Delays were necessary in 7% of cases and dose reduction was required in 4% of cases. There was no treatment related death. Conclusions: This schedule of biweekly GemCap regimen suggests an acceptable option in for elderly, frail patients with PC and warrants further exploration in patients not suitable for FOLFIRINOX, full dose GemCap or a clinical trial. This regimen required fewer dose reduction, omission or delays and allowed to administer pegylated-filgrastim. Previous studies have also shown decreased toxicity and equal efficacy of 7/7 schedule of capecitabine. Moreover, fewer visits to oncology and related expense do favor towards benefit. Additionally, this tolerable regimen is ideal to be combined with immunotherapy in clinical trials for this patient population.
Single-nucleus RNA-seq of frozen archival primary pancreatic ductal adenocarcinoma uncovers multi-compartment intratumoral heterogeneity associated with neoadjuvant treatment.
Authors: Hwang William L. , Jagadeesh Karthik , Guo Jimmy , Hoffman Hannah I. , Ashenberg Orr , Drokhlyansky Eugene , Van Wittenberghe Nicholas , Farhi Samouil , Schapiro Denis , Rodrigues Clifton , Ciprani Debora , Zollinger Daniel , Hong Theodore S. , Aguirre Andrew , Mino-Kenudson Mari , Rozenblatt-Rosen Orit , Fernandez-del Castillo Carlos , Liss Andrew , Jacks Tyler , Regev Aviv
Published: May 2020

4633

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease and existing molecular subtypes do not inform clinical decisions. Previously identified bulk transcriptomic subtypes of PDAC were often unintentionally driven by “contaminating” stroma. RNA extraction from pancreatic tissue is difficult and prior single-cell RNA-seq efforts have been limited by suboptimal dissociation/RNA quality and poor performance in the setting of neoadjuvant treatment. We developed a robust single-nucleus RNA-seq (sNuc-seq) technique compatible with frozen archival PDAC specimens. Methods: Single nuclei suspensions were extracted from frozen primary PDAC specimens (n = 27) derived from patients with (borderline)-resectable PDAC who underwent surgical resection with or without neoadjuvant chemoradiotherapy (CRT). Approximately 170,000 nuclei were processed with the 10x Genomics Single Cell 3’ v3 pipeline and gene expression libraries were sequenced (Illumina HiSeq X). Results: Distinct nuclei clusters with gene expression profiles/inferred copy number variation analysis consistent with neoplastic, acinar, ductal, fibroblast, endothelial, endocrine, lymphocyte, and myeloid populations were identified with proportions similar to corresponding multiplexed ion beam imaging. Non-negative matrix factorization revealed intra-tumoral heterogeneity shared across patients. Neoplastic cells featured eight distinct transcriptional topics characterized by developmental (epithelial, mesenchymal, endoderm progenitor, neural progenitor) and environmental (anabolic, catabolic, cycling, hypoxic) programs. CAFs exhibited four different transcriptional topics (activated/desmoplastic, myofibroblast, neurogenic, osteochondral). Differential gene expression and gene set enrichment analyses demonstrated that CRT was associated with an enrichment in myogenic programs in CAFs, activation pathways in immune cells, and type I/II interferons in malignant cells. CRT was also associated with a depletion in developmental programs within malignant cells. Conclusions: We uncovered significant intratumoral heterogeneity and treatment-associated differences in the malignant, fibroblast, and immune compartments of PDAC using sNuc-seq. Deconvolution of clinically-annotated bulk RNA-seq cohorts and characterization of intercellular interactions with receptor-ligand analysis and spatial transcriptomics are ongoing.
A phase I study of nanoliposomal irinotecan and 5-fluorouracil/folinic acid in combination with interleukin-1-alpha antagonist for advanced pancreatic cancer patients with cachexia (OnFX).
Authors: Hendifar Andrew Eugene , Kim Sungjin , Tighiouart Mourad , Hautamaki Emily , Kim Haesoo , Ng Camille , Liu Jar-Yee , Scher Kevin S. , Klempner Samuel J , Placencio-Hickok Veronica , Gresham Gillian , Gong Jun
Published: May 2020

4634

Background: Interleukin-1-alpha (IL-1α) promotes tumor inflammation by shaping the tumor microenvironment, including tumor infiltrating myeloid cell recruitment, angiogenesis, and skewing and suppression of anti-tumor immunity. IL-1a inhibition in cancer subjects increased lean body mass and decreased fatigue, pain, and appetite loss. We report results of a single site phase 1 trial for an IL-1α antagonist (bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: A Bayesian adaptive design based on escalation with overdose control was used. Data are presented as frequency (percentage, %) for categorical variables and mean (± standard deviation) for continuous variables. Lean body mass (LBM) and fat mass were assessed at cycle 1 and 3, and T-test was used to assess changes. Results: Of 21 pts enrolled, 18 were evaluable. Median age was 68. Bermekimab in combination with nanoliposomal irinotecan (70 mg/m2) and 5-fluorouracil (2400mg/m2) was well tolerated at the highest dose level (12mg/kg). 10 pts experienced grade 3/4 toxicities including sepsis, anemia, hypokalemia, neutropenia, or leukopenia. There were no instances of grade 3/4 diarrhea. Ten pts (56%) had weight stability ( < 0.1 kg/BMI). Efficacy results include PR (n = 4, 22%), SD (n = 13, 72%), and PD (n = 1, 6%). PFS 7.7 m (95% CI: 4.34-12.73) and OS 10.5 m (95% CI: 5.79-17.70) were reported. LBM and fat mass change was -1.6 kg (± 2.0; p-value = 0.003) and -1.4 kg (± 1.7; p-value = 0.004). CRP was 20.4 (± 35.6) at cycle 1 and decreased significantly (p-value = 0.005). Serum VEGF decreased from C1 to C3 (p-value = 0.007). QLQ-PAN26 domains improved, particularly hepatic function (p = 0.04). FAACT scores improved for functional well-being (p = 0.02). Average daily step counts increased by 589 steps/day (p = 0.29) and resting heart rate decreased by 2.5 beats per minute (p = 0.005), as assessed by actigraphy. Conclusions: Bermekimab, nano-liposomal irinotecan and 5-fluorouracil in refractory pancreatic cancer patients with cachexia was well-tolerated with promising efficacy and improvements in patient performance. Clinical trial information: NCT03207724 .
First-line pembrolizumab (pembro) monotherapy in advanced non-clear cell renal cell carcinoma (nccRCC): Updated follow-up for KEYNOTE-427 cohort B.
Authors: Lee Jae-Lyun , Ziobro Marek , Suarez Cristina , Langiewitz Przemyslaw , Matveev Vsevolod Borisovich , Wiechno Pawel , Gafanov Rustem , Tomczak Piotr , Pouliot Frédéric , Donskov Frede , Alekseev Boris , Shin Sang Joon , Bjarnason Georg A. , Castellano Daniel , Du Xiaoqi , Perini Rodolfo F. , Rodriguez-Lopez Karla , McDermott David F. , Atkins Michael B.
Published: May 2020

5034

Background: KEYNOTE-427 (NCT02853344), a single-arm, open-label, phase 2 study, showed antitumor activity with first-line pembro monotherapy in nccRCC (cohort B). Studies of RCC and immune-oncology have shown that depth of tumor response may correlate with long-term benefit. We present the association between depth of response and OS plus updated efficacy and safety data in cohort B. Methods: Pts with histologically confirmed nccRCC, who did not receive prior systemic therapy, and who have measurable disease (RECIST v1.1) received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points were ORR (primary), DOR, and PFS (RECIST v1.1); OS; and safety. Association between depth of response, defined as maximum reduction from baseline in sum of target lesions, and OS was evaluated using a Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: Of 165 pts, 72% had papillary histology, 13% had chromophobe histology, and 16% were unclassified. Median time from enrollment to data cutoff was 18.7 mo (range, 9.9-26.0). ORR was 26.1% (95% CI, 19.5-33.5; 10 CRs, 33 PRs). Median (range) DOR was 15.3 mo (2.8-21.0+); 57.3% had DOR ≥12 mo. At 18-mo, PFS rate was 18.9% and OS rate was 67.0%. Most pts (58.8%) had some reduction in target lesions. Pts with a > 30% reduction in target lesions had an increased probability of survival (Table). ORR (95% CI) was similar for papillary (28.0% [20.1-37.0]) and unclassified (30.8% [14.3-51.8]) histology but lower for chromophobe (9.5% [1.2-30.4]). OS rates at 18 mo were 70.8%, 66.7%, and 50.0 in the papillary, chromophobe, and unclassified groups, respectively. Treatment-related AEs (TRAEs) occurred in 67.9% of all pts, primarily pruritus (19%), hypothyroidism (14%), and fatigue (14%). Grade 3-5 TRAEs occurred in 14% of pts; 2 pts died of TRAEs (pneumonia and cardiac arrest). Conclusions: First-line pembro monotherapy continued to show antitumor activity in nccRCC with no new safety concerns. In general, for pts who had greater reductions in target lesions, the trend was toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]
Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057.
Authors: Balar Arjun Vasant , Kamat Ashish M. , Kulkarni Girish S. , Uchio Edward M. , Boormans Joost L. , Bajorin Dean F. , Roumiguié Mathieu , Singer Eric A. , Krieger Laurence Eliot Miles , Grivas Petros , Seo Ho Kyung , Nishiyama Hiroyuki , Konety Badrinath R. , Nam Kijoeng , Zambon João Paulo , Kapadia Ekta , De Wit Ronald
Published: May 2020

5041

Background: Pembro was recently approved for the treatment of HR NMIBC based on results from the phase 2 KEYNOTE-057 (NCT02625961) study. Herein we present safety, efficacy, and posttreatment outcomes with > 2 y follow-up from KEYNOTE-057 cohort A. Methods: Patients with histologically confirmed HR BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy (RC) received pembro 200 mg Q3W for up to 2 y or until disease recurrence, progression, or unacceptable toxicity. The primary end point was complete response rate (CRR). Key secondary end points were duration of response (DOR) and safety. Results: Overall, 102 patients were initially enrolled, and 96 were included in the efficacy analysis. Median time from enrollment to data cut off was 28.4 months (range, 18.2-40.5). CRR was 40.6% (95% CI, 30.7-51.1), and median DOR was 16.2 months (range, 0+ to 30.4+). Among 39 patients with CR, 18 (46.2%) had a DOR ≥12 months. No patient’s disease progressed to muscle-invasive or metastatic bladder cancer while on study treatment. Median PFS and OS were not reached. At 12 months, PFS was 82.7% and OS was 97.9%. A total of 36 patients (37.5%) underwent RC after discontinuation from study treatment, which included 9 of 22 patients (40.9%) who had recurrence after initial CR and 27 of 57 (47.4%) nonresponders. Of the 36 who underwent RC, 33 (91.6%) had no pathological upstaging to MIBC and 3 (8.3%) had at least pT2 disease at time of RC. For subsequent treatments other than RC, 27 of 96 (28.1%) patients received additional intravesical therapy (eg, BCG, gemcitabine, or mitomycin), 21 of 96 (21.9%) underwent local procedures (eg, TURBT), and 3 of 96 (3.1%) received systemic therapy (eg, pembro). In 102 patients treated with pembro, treatment-related AEs (TRAEs) occurred in 67 (65.7%) patients; most frequently reported TRAEs were fatigue, pruritus, and diarrhea (10.8% each). Grade 3/4 TRAEs occurred in 13 patients (12.7%), and 21 patients (20.6%) experienced immune-mediated AEs. There were no grade 5 TRAEs. Conclusions: After > 2 y of follow-up, durable and clinically meaningful activity of pembro was observed in patients who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or opted out of RC. Pembro did not seem to limit the opportunity for subsequent therapies, including RC. The safety profile was consistent with what is reported in the literature. Clinical trial information: NCT02625961 .
Detection of urothelial carcinoma using plasma cell-free methylated DNA.
Authors: Nuzzo Pier Vitale , Spisak Sandor , Berchuck Jacob E , Baca Sylvan , Korthauer Keegan , Nassar Amin , Abou Alaiwi Sarah , Bakouny Ziad , Flippot Ronan , Steinharter John A. , Curran Catherine , Lee Gwo-Shu Mary , Waikar Sushrut , Pomerantz Mark , De Carvalho Daniel , Sonpavde Guru , Freedman Matthew L. , Choueiri Toni K.
Published: May 2020

5046

Background: Methylation profiling of circulating cell-free DNA (cfDNA) is a promising approach for non-invasive tumor detection due to the presence of tissue-specific epigenetic signatures that are detectable in cfDNA. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMedDIP-seq) is a sensitive, low-input, cost-effective, bisulfite-free approach to profiling cfDNA methylomes, capable of detecting and classifying various tumor types. We tested the feasibility of cfMeDIP-seq to detect urothelial carcinoma (UC) in plasma samples. Methods: We performed cfMeDIP-seq on plasma samples from 43 patients (pts): 18 metastatic UC (UC) pts, 12 pre-cystectomy non-metastatic UC pts, and 13 cancer-free controls. Six (50%) of pre-cystectomy cases were non-muscle invasive UC. cfDNA was immunoprecipitated and enriched using an antibody targeting 5-methylcytosine and PCR-amplified to create a sequence-ready library. The top differentially methylated regions (DMRs) between UC and control samples were used to train a regularized binomial generalized linear model using 80% of the samples as a training set. The 20% of withheld test samples were then assigned a probability of being UC or control. This process was repeated 100 times. Results: The average amount (standard deviation) of cfDNA isolated from 1 ml of UC plasma samples was 29.2 (27.4) ng/µL and 8.02 (3.58) ng/µL in cancer-free controls. We identified 9,826 DMRs in plasma samples at an adjusted p-value of < 0.01, which partitioned UC and control samples. Iterative training and classification of held out samples using the top 300 DMRs resulted in a mean AUROC of 0.987. Conclusions: cfMeDIP-seq is an interesting new approach for non-invasive detection of UC. cfMeDIP-seq demonstrates high sensitivity to detect UC across all stages of UC, including non-muscle invasive disease.
Multicenter analysis of serum tumor markers, treatment patterns, and relapse in patients with testicular cancer in clinical stage IS.
Authors: Brandt Maximilian Peter Johannes Karl , Ruf Christian Guido , Dieckmann Klaus Peter , Syring Isabella , Ruckes Christian , Hiester Andreas , Albers Peter , Christian Bolenz , Heidenreich Axel , Haferkamp Axel , Zengerling Friedemann , Paffenholz Pia
Published: May 2020

5052

Background: Testicular germ cell tumors (TGCT) in clinical stage I (CSI) are tumors confined to the testis without evidence of metastasis. Around 50% of all TGCT patients present with elevated serum tumor markers (TM) such as alpha-feto protein (AFP), beta-humanochoriongonadotropin (ß-HCG) and lactate-dehydrogenase (LDH). After ablatio testis, TMs usually return to normal according to half-life kinetics, however, in clinical stage IS (CSIS) TMs remain elevated or increase after surgery. Follow-up data on CSIS is scarce and our study aims to assess clinical characteristics and oncologic outcomes in a large TGCT cohort. Methods: In this multicenter study we collected data from 5 tertiary referring hospitals in Germany, included patients with CSIS and evaluated TM levels, treatment and the primary outcome relapse-free survival. False CSIS was defined as documented CSIS but TMs that returned to normal after respective half-life kinetics. Differences between predefined groups (chemotherapy, TM, true/false CSIS) was analyzed with fisher’s exact and chi-square test. Results: Overall, 2616 patient data files were analyzed. Forty-three patients (1.6%) were documented as CSIS of which 27 (63%) were true and 16 (37%) false CSIS. Six (14%) had seminomas and 37 (86%) non-seminomas. In the true CSIS group AFP, ß-HCG, AFP plus ß-HCG and LDH were elevated in 13, 6, 3 and 2 cases. Four true CSIS patients received surveillance, 21 had 3x or 2x courses of BEP (bleomycin, etoposide and cisplatin) and 2 carboplatin. Within the false CSIS group, 2 patients were treated with surveillance, 10 received 3x BEP, one 3x PEI (cisplatin, etoposide and ifosfamid) and 3 had carboplatin. Chi-Square test revealed no difference between true or false CSIS classification in respect to application of chemotherapy (any chemotherapy, p = 0.83). Relapse-free survival after 5 and 10 years was 88.9% and 77.8%, respectively. Three patients in the true CSIS group relapsed (2 seminomas had carboplatin, 1 non-seminoma had surveillance). All relapses were treated with 3 courses of BEP with no documented death in the CSIS population. Conclusions: Overall, less than 2% of all TGCT were documented CSIS of which 37% were falsely classified. We report a high proportion of relapse-free survival in CSIS treated with surveillance or BEP with a high heterogeneity in treatment patterns. Correct classification of CSIS remains of critical importance to avoid toxicity for patients that could be safely treated with surveillance.
Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.
Authors: Malone Eoghan Ruadh , Lewin Jeremy Howard , Wang Lisa , Lau Susan , Hamilton Robert James , Hansen Aaron Richard , Jarvi Keith , Zhang Wenjiang , Chen Eric Xueyu , Bedard Philippe L.
Published: May 2020

5056

Background: Cisplatin is highly curative treatment for testicular cancer. Most survivors develop azoospermia immediately after cisplatin with recovery expected in 50% at 2 years and 80% at 5 years. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, however, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility. Methods: Testicular cancer survivors previously treated with cisplatin were enrolled, relapsed disease treated with salvage chemotherapy was excluded. Semen samples were collected to assess semen quality. Repeat semen collections were performed if azoo- or oligospermia was noted. Serum and semen Platinum levels were determined using HPLC-tandem mass spectrometry. DNA Fragmentation Index (DFI) was measured. Results: From 11/2017 to 12/2019, 38 pts (median age 32 years; range: 19-52; median BSA 2.03; range: 1.81-2.61) were enrolled, 31 were treated with 3 cycles of Bleomycin, Etoposide, Cisplatin. Median cumulative cisplatin dose was 300 mg/m2 (range: 274-404). Median serum platinum concentration was 0.1 ng/mL (range: 0-22.6) at a median of 11 months (range 0.5-36) post treatment completion. Median semen platinum concentration was 0.5 ng/mL (range: 0.2-28.7) at a median of 14 months (range: 1.3-40) post treatment completion. Semen platinum levels were higher in semen than in blood drawn at the same time (p = 0.03). Semen platinum levels were associated with time from last cisplatin dosing (r = -0.34; p = 0.09) but not cumulative cisplatin dose (r = -0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = -0.15, p = 0.46). DFI was associated with time from last cisplatin dosing (r = 0.55, p = 0.08) but not with semen platinum level (r = -0.32, p = 0.33). In 4 pts with serial semen samples available, semen platinum level decreased with time, sperm concentration and motility increased. Conclusions: Platinum can be detected in semen in long-term testicular cancer survivors at higher levels than matched blood samples. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer, further studies are needed to assess the relationship between platinum persistence in semen and recovery of fertility post chemotherapy.
TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC).
Authors: Pal Sumanta K. , Escudier Bernard , Atkins Michael B. , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Needle Michael N. , McDermott David F. , Rini Brian I.
Published: May 2020

5062

Background: Tivozanib (T) is a potent and highly selective VEGFR inhibitor. TIVO-3 is a phase 3 study designed to compare the efficacy and safety of T with those of sorafenib (S) as 3rd and 4th line therapy in patients with metastatic RCC. Methods: Subjects with RCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint inhibitor (CPI); TKI plus other) then randomized in a 1:1 ratio to T or S. Results: The 2 arms were well balanced for demographics and prior cancer history. 60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 26% had prior treatment with a CPI. Patients treated with T demonstrated PFS superiority compared to S, 5.6 (95% CI 7.3 - 5.3) v. 3.9 mos (95% CI 5.6 – 3.7; HR 0.73; p=0.02). ORR was 18% for T compared to 8% for S (p=0.02). 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. The predefined, interim analysis for OS performed two years after enrollment was closed had a HR of 0.99 based on 227 events. The final analysis will be presented based on an estimate of 263 events. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this heavily-treated/relapsed or refractory RCC population and is better tolerated than S. Final OS data will be updated prior to presentation. Clinical trial information: 02627963 .
Phase I clinical trials as a therapeutic option for patients with metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W , Alhalabi Omar , Meric-Bernstam Funda , Naing Aung , Jonasch Eric , Msaouel Pavlos , Piha-Paul Sarina Anne , Hong David S. , Pant Shubham , Yap Timothy A , Campbell Erick , Le Hung , Tannir Nizar M. , Roszik Jason , Subbiah Vivek
Published: May 2020

5073

Background: Immune checkpoint inhibitors, multi-kinase VEGF agents, and mTOR inhibitors are approved for mRCC. Due to the overlapping mechanisms of action of the twelve approved therapies for mRCC, select patients are referred for phase I clinical trials after progression on multiple lines of treatment. We sought to evaluate the efficacy of phase I trials in patients with mRCC. Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center. Baseline clinical characteristics and outcomes data were retrospectively collected. The historical control was a study of 1112 patients with mRCC who received third-line treatment in the IMDC database (PMID: 27318422). Time to event endpoints were calculated using Kaplan-Meier methods. Hazard ratios (HR) were calculated using the Cox proportional hazard model. Results: Between 2014 and 2019, there were 106 cases where 82 patients with mRCC were enrolled in a phase I clinical trials (40 unique trials). 30% (32/108) of the cases were in patients with non-clear cell RCC (nccRCC), and the most prevalent nccRCC histologies were papillary (n = 7) and renal medullary carcinoma (n = 7). The median number of prior systemic therapies was 2 (range 0-9). Across the entire cohort, median PFS was 5.9 months (m), median OS was 31.2 m, and the ORR was 23% (Table). In patients who received at least two prior lines of therapy (n = 70), the median PFS was 4.8 m and median OS was 24.9 m. In patients with metastatic nccRCC, median OS, PFS, and ORR were numerically lower, but statistically did not contradict the supposition that these outcomes did not differ from ccRCC (Table). Conclusions: In the largest pooled phase I clinical trial experience for patients with mRCC, phase I trials may have therapeutic value when compared to historical controls, where median PFS was 3.9 m, median OS was 12.4 m, and ORR was 10.5%. Patients with all histologies of mRCC may derive clinical benefit from phase I clinical trials, yet patients with ccRCC had numerically better outcomes. Patients with mRCC should be considered for phase I clinical trials. [Table: see text]
Immune infiltration and angiogenesis as markers of outcome in the post-nephrectomy setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).
Authors: Hakimi A. Ari , Voss Martin H , Kuo Fengshen , Silagy Andrew W. , Marker Mahtab , Reising Albert , Millholland John , Chan Timothy An-thy , Russo Paul , Motzer Robert J.
Published: May 2020

5082

Background: Defined stromal and immune features of the tumor microenvironment (TME) have proven relevant for outcomes with systemic therapy in advanced clear cell renal cell carcinoma (ccRCC). We hypothesized that these may matter beyond therapeutic applications and could be relevant much earlier in the disease course. We sought to study the TME in high risk ccRCC patients undergoing definitive surgery. Methods: Clinical, pathologic, immunohistochemical, and whole-genome microarray data were acquired on 236 out of 769 patients in the Placebo arm of PROTECT trial (NCT01235962 - pazopanib vs placebo). Transcriptomic scores assessing angiogenesis and myeloid infiltration with individual annotations above/below median were used to categorize patients into four groups (angiogenesis high vs. low; myeloid high vs. low). We tested categorical association with disease free (DFS) and overall survival (OS) using logrank testing and assessed interdependence with relevant clinicopathologic variables, including the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Tumors from236 patients were available for analysis. Overall, 37% developed metastatic recurrence and 81% were alive at last follow up. On univariate analysis increasing tumor stage, higher UISS score, and angiogenesis/myeloid subgroups (high – H and low – L) were associated with worse DFS and OS (all p values <0.05). On multivariate analysis TME subgroups remained significant for worse DFS and OS (Table). Conclusions: Microenvironmental subgroups stratified into angiogenic and myeloid expression profiles carry independent prognostic significance and should be further explored to guide future biomarker-directed adjuvant trials. Clinical trial information: NCT01235962 . [Table: see text]
Breast cancer index (BCI) predicts benefit of two-and-a-half versus five years of extended endocrine therapy in HR+ breast cancer patients treated in the ideal trial.
Authors: Liefers Gerrit-Jan , Noordhoek Iris , Treuner Kai , Putter Hein , Zhang Yi , Meershoek – Klein Kranenbarg Elma , Wong Jenna , Van De Velde Cornelis J. H. , Schnabel Catherine A.
Published: May 2020

512

Background: For postmenopausal women with hormone receptor positive (HR+) breast cancer, the optimal duration of extended endocrine therapy (EET), after completing 5 years of initial aromatase inhibitor (AI)–based adjuvant therapy, remains unclear. BCI [HOXB13/IL17BR (H/I)] is a gene expression-based biomarker that has been demonstrated to predict EET benefit in the MA.17 and Trans-aTTom studies in patients treated with adjuvant tamoxifen. The current study examined the ability of BCI (H/I) to predict endocrine benefit from 2.5 vs. 5 years of extended letrozole in the IDEAL trial. Methods: All patients with available tumor specimens were eligible for this blinded prospective-retrospective study. The primary endpoint was Recurrence-Free Interval (RFI). Median follow-up was 9.1 years from randomization. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the differential benefit of EET with statistical significance of the interaction between BCI (H/I) and treatment assessed by likelihood ratio test. Results: 908 HR+ patients (73% pN+, median 59y, 45% pT1, 48% pT2, disease free at 2.5 years) were included, with 88% and 68% receiving prior treatment with an AI or chemotherapy, respectively. BCI by H/I status (High vs. Low) was significantly predictive of response from extended letrozole in the overall (N = 908) and pN+ (N = 664) cohorts. Notably, BCI (H/I) predicted EET benefit in patients that received any primary adjuvant therapy with an AI (N = 794). Treatment to biomarker interaction was significant in the overall (p = 0.045), pN+ (p = 0.029) and any prior AI (p = 0.025) cohorts, adjusted for age, pT stage, grade, nodal status, prior endocrine therapy and prior chemotherapy. Conclusions: Novel findings from this study demonstrate that BCI predicts endocrine benefit from extended letrozole in postmenopausal patients treated with primary adjuvant AI. These results support the growing body of evidence that BCI by H/I status predicts preferential endocrine response in distinct subgroups of patients, and further support its role as an important genomic tool to inform the risk-benefit regarding duration of extended endocrine therapy. Clinical trial information: NTR3077, BOOG 2006-05, Eudra-CT 2006-003958-16 . [Table: see text]
Validation of MAF biomarker for response prediction to adjuvant bisphosphonates in 2 clinical trials: AZURE and NSABP-B34.
Authors: Paterson Alexander H. G. , Anderson Stewart J. , Gomis Roger , Jean-Mairet@inbiomotion.com Joel , Tercero Juan-Carlos , Lucas Peter , Mamounas Eleftherios P.
Published: May 2020

513

Background: An Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis indicates that adjuvant bisphosphonates increase time to bone recurrence and survival in postmenopausal breast cancer patients, but results of individual trials have been inconclusive. Retrospective analyses of AZURE, a trial of adjuvant zoledronic acid, showed MAF (a transcription factor of the AP-1 family) amplification status predicted bisphosphonate benefit independently of menopause for invasive disease-free survival (IDFS) and overall survival (OS). Validation of MAF amplification status as a potential companion diagnostic for adjuvant bisphosphonates was confirmed using NSABP-B34 specimens. Methods: The randomized, placebo-controlled NSABP B-34 study of women with stage 1-3 breast cancer were assigned to adjuvant systemic therapy plus oral clodronate 1600 mg daily or placebo for 3 years. The primary endpoint was disease-free survival (DFS) with overall survival (OS) as a secondary outcome. MAF amplification was assessed by fluorescence in-situ hybridization on anonymized sections of breast tumor tissue in all patients with tumor samples and performed in a laboratory blind to treatment assignment. Protocol and analysis plans were pre-specified. Disease outcomes were analysed using intention to treat principles. Results: 2496 B-34 patients contributed tumor samples (from 2001-2004), of whom 1883 (75%) were evaluable (947 placebo and 936 clodronate). 1515 (80%) tumors were MAF negative (766 placebo and 749 clodronate) and 368 were MAF positive. At median follow-up of 108 months, MAF was prognostic for DFS, OS and bone-metastasis-free survival in the control group (MAF-positive vs MAF-negative: HRDFS=1·39, 95%CI 1·01-1·92; p=0.045; HROS=1·59, 95%CI 1·08-2·33; p=0.018; HRBM=2·03, 95%CI 1·13-3·68; p=0.016). In patients with MAF-negative tumors, clodronate gave higher DFS and OS than controls at 60 months (HRDFS=0·70, 95%CI 0·51-0·94; p=0.020 and HROS=0·59, 95%CI 0·37-0·93; p=0.024), the latter maintained through follow-up (HROS=0·74, 95%CI 0·54-1.00; p=0.047), but not in patients with MAF-positive tumors - consistent with previous AZURE results. Conclusions: MAF benefit prediction from adjuvant bisphosphonates was confirmed using specimens from 2 randomized clinical trials (AZURE and NSABP-B-34) conducted and analyzed in similar manner using the same validated tests and clinical endpoints. These results are evidence towards introducing MAF testing into clinical practice.
Comprehensive profiling of androgen receptor-positive (AR+) triple-negative breast cancer (TNBC) patients (pts) treated with standard neoadjuvant therapy (NAT) +/- enzalutamide.
Authors: Lim Bora , Seth Sahil , Huo Lei , Layman Rachel M. , Valero Vicente , Thompson Alastair Mark , White Jason B , Litton Jennifer Keating , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Rauch Gaiane M , Murthy Rashmi Krishna , Ding Qingqing , Symmans William Fraser , Zhao Li , Zhang Jianjun , Tripathy Debu , Moulder Stacy L. , Ueno Naoto T.
Published: May 2020

517

Background: The luminal androgen receptor (LAR) subtype of TNBC has a low pathologic complete response (pCR) rate after NAT. We determined the pCR rate of the enzalutamide and paclitaxel (ZT) regimen for pts with anthracycline-insensitive AR+ TNBC (NCT02689427), and related biomarkers. Methods: ARTEMIS (NCT02276443) is a non-randomized trial to determine if NAT can be used to personalized therapy. Pts received 4 cycles of doxorubicin-based NAT (AC). Pts with insensitive disease by imaging were offered clinical trials as the second phase of NAT based upon molecular profiling of pre-treatment biopsies. Immunohistochemistry (IHC) of AR+≥10% was the threshold for selecting ZT (enzalutamide 160 or 120 mg PO qD + paclitaxel 80 mg/m2 qW for 12 cycles). pCR was determined by surgery after NAT. Trial had two-stage Phase II design, and we report the completed first stage. We evaluated the concordance between Vanderbilt LAR subtype by molecular profiling (microarray and RNAseq) and IHC %AR+ cells. Frequency of PI3K pathway alterations within the LAR subtype was assessed. Results: 267 pts had tumors profiled by IHC, 220 by microarray, 187 by RNAseq and 197 by whole exome sequencing. 96 pts had post-AC RNAseq. LAR scores from both RNAseq and microarray profiling (n = 139) were highly concordant (R = 0.89, P < 0.001) and identified ~10% of TNBCs tested as LAR. The %AR+ cells from IHC correlated with LAR subtype scores according to RNAseq (R = 0.6, P < 0.001), with a cut-point of ≥30% AR+ having the best concordance with LAR subtype. Unlike other subtypes, by serial profiling, LAR TNBCs did not change subtype signatures after exposure to AC. LAR TNBCs had low rates of pCR (23%) and high rates of PI3K pathway activating aberrations (85%); however PI3K aberrations did not correlate with pCR. Seventeen patients with AC-insensitive TNBC received ZT. Five of 15 patients (33.3%) had responses (pCR or RCB-I). Toxicities are Grade (Gr) 4 syncope (n = 1), Gr3 abnormal liver function (n = 2), Gr3 neutropenia (n = 4). IHC & LAR subtype scores did not statistically associate with response to ZT (P = 0.8, P = 0.9). However, all responders to ZT had an upregulated androgen response pathway (ssGSEA Z > 1) as measured by transcriptomic analysis in pre-treatment biopsies analysis (P = 0.05, ppv = 0.56, npv = 1). Conclusions: The LAR TNBC subtype has a low pCR rate to NAT. Among pts with AC-insensitive TNBC, baseline upregulated androgen response pathway and LAR subtype may benefit from the ZT regimen, potentially by PI3K targeting. Clinical trial information: NCT02689427 .
Dementia risk among post-menopausal women treated with endocrine therapy for early-stage breast cancer in Ontario, Canada.
Authors: Blanchette Phillip S. , Lam Melody , Le Britney , Richard Lucie , Shariff Salimah , Pritchard Kathleen I. , Raphael Jacques , Vandenberg Theodore A. , Fernandes Ricardo , Desautels Danielle , Chan Kelvin K. , Earle Craig
Published: May 2020

521

Background: The association between anti-estrogen therapy and risk of dementia remains controversial. We performed a population-based real-world study investigating the association between endocrine therapy use and dementia. Methods: We used health administrative data collected from post-menopausal women (aged ≥66 years) who were diagnosed with breast cancer and started on adjuvant endocrine therapy from 2005-2012. Patients were classified by use of either an aromatase inhibitor or tamoxifen and followed to measure an unadjusted cumulative incidence of developing dementia. A multivariable analysis adjusting for age, income quintile, medical comorbidities, and duration of endocrine therapy was completed using a Cox-proportional hazards model. Results: We identified 12,077 patients of whom 73% were treated with an aromatase inhibitor and 27% with tamoxifen. The median age was 73 years (IQR 69-78), 64% of patients were treated with lumpectomy, and 19% received adjuvant chemotherapy. The unadjusted event rate for developing dementia was Hazard Ratio (HR)= 0.70 (95% confidence interval (CI)=0.63-0.78, p-value<0.0001) among patients receiving an aromatase inhibitor versus tamoxifen and the 5-year dementia incidence rate was 7.4% versus 9.2% respectively. Our multivariable analysis showed a significant decrease in the rate of dementia in patients treated with an aromatase inhibitor compared to tamoxifen (HR=0.88, 95% CI 0.78-0.98, p-value=0.02) with a median of 5.9 years of follow-up. Factors associated with the development of dementia included older age, previous history of ischemic heart disease, diabetes, hypertension and stroke. Duration of endocrine therapy and previous use of adjuvant chemotherapy were not associated with dementia in our study. Conclusions: This investigation indicates that use of aromatase inhibitors compared to tamoxifen is associated with a lower risk of developing dementia among post-menopausal breast cancer patients. Further prospective studies investigating the neurocognitive effects of endocrine therapy are warranted.
Tumor-infiltrating lymphocytes in ipsilateral breast tumor recurrences predict prognosis.
Authors: Stenmark Tullberg Axel , Nimeus-Malmström Emma , Killander Fredrika , Sjöström Martin , Puttonen Henri A.J. , Feng Felix Y , Kovacs Aniko , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: May 2020

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Background: The antitumoral immune response is dynamic and changes with tumor progression. Previous studies show that immunohistochemical (IHC) assessment of TILs in local recurrences can predict prognosis. It is not clear how adjuvant radiotherapy (RT) can alter the local immune response or if gene expression analyses of TILs in recurrences can provide prognostic information. Methods: Matched biopsies from primary tumors and ipsilateral breast tumor recurrences (IBTRs) from the randomized SweBCG91RT trial were assessed for TILs. Analyses were performed using gene expression (86 matched pairs) and IHC assessment (126 matched pairs). Results: The median time to IBTR was 8.0 years among irradiated patients and 3.6 years among unirradiated patients. In the gene expression analyses, higher absolute values of CD8+ T cells, CD4+ effector memory and CD8+ effector memory T cells in the recurrence could significantly predict a decreased risk of subsequent distant metastasis. In addition, a net increase of these cells in the IBTR compared to the primary tumor was associated with a significantly lower risk of metastasis. TILs did not change significantly between the matched tumors for the whole group or among irradiated patients versus unirradiated patients in the gene expression or IHC analyses. Surprisingly, the group with unchanged TILs levels as measured by IHC had the lowest risk of metastasis while an increase or a decrease in TILs was significantly associated with an increased risk. Conclusions: Cytotoxic and memory T cells in the recurrence protect against subsequent distant metastasis although IHC measurement of TILs could not confirm these results. No significant differences in TILs infiltration between irradiated versus unirradiated patients could be determined in the recurrences. Further analyses including changes of subtypes between the primary tumor and the recurrence will be presented.
TheraP: A randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603).
Authors: Hofman Michael S , Emmett Louise , Sandhu Shahneen Kaur , Iravani Amir , Joshua Anthony M. , Goh Jeffrey C. , Pattison David A. , Tan Thean Hsiang , Kirkwood Ian D. , Ng Siobhan , Francis Roslyn J. , Gedye Craig , Rutherford Natalie K. , Zhang Alison Yan , McJannett Margaret Mary , Stockler Martin R. , Violet John A. , Williams Scott , Martin Andrew James , Davis Ian D.
Published: May 2020

5500

Background: LuPSMA is a radiolabeled small molecule that delivers therapeutic β-radiation to PSMA-expressing tumors. Encouraging efficacy and safety has been shown in non-randomized studies of mCRPC. TheraP is a randomized phase II trial comparing LuPSMA vs cabazitaxel in men with mCRPC progressing after docetaxel. Methods: Men with mCRPC, and imaging with 68Ga-PSMA-11 and 18F-FDG PET/CT that confirmed high PSMA-expression and no sites of FDG-positive/PSMA-negative disease, were randomly assigned (1:1) to LuPSMA (6-8GBq q6weeks up to 6 cycles) vs cabazitaxel (20mg/m2 q3weeks up to 10 cycles); stratified by disease burden (>20 vs ≤20 sites), prior novel antiandrogens (NAA; abiraterone or enzalutamide), and study site. The primary endpoint was PSA response rate (PSA50-RR) defined by ≥50% reduction. Secondary efficacy endpoints included PSA-progression-free survival (PSA-PFS) and overall survival (OS). Data cut-off was 31DEC19 at this first pre-specified analysis. Results: 200 (median age 72 y, prior NAA 91%, >20 lesions 78%) of 291 PET screened men were randomised to LuPSMA (N=99) or cabazitaxel (N=101). 17 patients withdrew or died before receiving study treatment (1 LuPSMA vs 16 cabazitaxel). The PSA50-RR was higher in those assigned LuPSMA than cabazitaxel (65/99 [66%; 95%CI 56-75] vs 37/101 [37%; 95%CI 27-46]; P<0.001). At a median follow-up of 11.3 months, LuPSMA significantly improved PSA-PFS (HR 0.63, 95%CI 0.45-0.88, P=0.007; 143 events with next pre-specified analysis planned after 170 events). Efficacy results were similar when analyses were restricted to per-protocol treated men. OS data remains immature (57 deaths). Grade III-IV adverse events (AEs) occurred in 31/98 (32%) LuPSMA-treated men vs 42/85 (49%) in cabazitaxel-treated men. Discontinuations for toxicity occurred in 1/98 (1%) LuPSMA vs 3/85 (4%) cabazitaxel-treated. There were no treatment-related deaths. Conclusions: In men with docetaxel-treated mCRPC, LuPSMA was more active (PSA50-RR) than cabazitaxel with relatively fewer G3-4 AEs and PSA-PFS favoring LuPSMA. Clinical trial information: NCT03392428 .
Accuracy of 68Ga-PSMA-11 for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic lymph node dissection: A multicenter prospective phase III imaging study.
Authors: Hope Thomas A , Armstrong Wesley R , Murthy Vishnu , Lawhn Heath Courtney , Behr Spencer , Barbato Francesco , Ceci Francesco , Farolfi Andrea , Schwarzenboeck Sarah , Unterrainer Marcus , Zacho Helle , Cooperberg Matthew R. , Nguyen Hao Gia , Carroll Peter , Reiter Robert Evan , Holden Stuart , Fendler Wolfgang Peter , Eiber Matthias , Czernin Johannes , Calais Jeremie
Published: May 2020

5502

Background: To determine the accuracy of 68Ga-PSMA-11 PET for the detection of pelvic nodal metastases (N1) compared to histopathology at time of radical prostatectomy (RP). Methods: This is a prospective multicenter single-arm open-label phase 3 imaging trial. Patients with intermediate to high risk prostate cancer (PCa) considered for RP with lymph node dissection (PLND) were enrolled at the University of California, Los Angeles (UCLA) and at the San Francisco (UCSF) (NCT03368547, NCT02611882, NCT02919111), and underwent one 68Ga-PSMA-11 PET. The primary endpoint was the sensitivity (Se) and specificity (Sp) of 68Ga-PSMA-11 PET for the N1 detection compared to PLND histopathology (reference-standard) on a per patient basis using nodal region-based correlation. Each scan was read by three blinded independent central readers (BICR). Consensus was based on majority rule. Results: From December 2015 to August 2019, 633 patients underwent one 68Ga-PSMA-11 PET for primary staging, and 277/633 (44%) subsequently underwent RP and PLND. The median initial PSA was 11.1 [0.04-147]. 75/277 patients (27%) had N1 disease per histopathology. Using a regional based analysis, Se, Sp, positive predictive value (PPV) and negative predictive value (NPV) for N1 detection was 0.40 [0.34, 0.46], 0.95 [0.92, 0.97], 0.75 [0.70, 0.80], 0.81 [0.76, 0.85], respectively. Se was higher for patients with higher PSA: 0.29 [0.24, 0.35] for PSA < 11 ng/ml versus 0.48 [0.42, 0.54] for PSA > 11. Se was higher when the nodes were larger: 0.30 [0.25, 0.36] for nodes < 10 mm versus 0.68 [0.63, 0.74] for nodes > 10. The average node size in true positive patients was 10 mm versus 4 mm in false negative patients. Conclusions: In intermediate to high risk PCa patients who underwent RP and PLND, 68Ga-PSMA-11 PET detected pelvic nodal metastases with a sensitivity of 0.40 and a specificity of 0.95. Higher PSAs and larger node size correlated with increased sensitivity. Clinical trial information: NCT03368547, NCT02611882, NCT02919111 .