bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic landscape and immune microenvironment features of FH-deficient renal cell carcinoma.
Authors: Sun Guangxi , Zhang Xingming , Pan Xiuyi , Zhu Sha , Liu Zhenhua , Zhao Jinge , Armstrong Cameron M. , Zhang Haoran , Huang Rui , Yin Xiaoxue , Zhang Mengni , Shen Pengfei , Dai Jindong , Shen Yali , Nie Ling , Wei Qiang , Li Xiang , Yao Jin , Chen Ni , Zeng Hao
Published: February 2020

717

Background: Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but aggressive subtype of RCC, and an understanding of their genomic landscape is lacking. Methods: Thirteen FH-deficient RCC and matched normal samples from our medical center were used for whole-exome sequencing and molecular profiling. Transcriptomic sequencing data were analyzed from The Cancer Genome Atlas (TCGA) RCC samples and two independent datasets of FH-mutated RCC. For each patient in our cohort, clinical outcomes were recorded, with median follow-up until March, 2019. Results: We identified FH-deficient RCC had high mutation burden, frequent somatic mutations in MUC4, MUC16, ANKRD6 and PRDM16 and germline pathologic FANCD2 mutation. In contrast to mainly RCC subtypes, FH-deficient RCC exhibited elevated mutational signatures of homologous recombination deficiency (7/13, 53%) and microsatellite instability (4/13, 30%). Moreover, we revealed that FH-deficient RCC was characteristic of an immunogenic tumor type, with high tumor-specific neoantigen burdens, enhanced immune cells infiltration but immunosuppressive microenvironment. In our cohort, 11 patients received systematic treatments; 63% (5/8) responded poorly to antiangiogenic or anti-mammalian target of rapamycin agents, but all (6/6) achieved benefit from immune checkpoint blockade monotherapy or combination with antiangiogenic agents. Conclusions: Our study provides a better understanding of the mutational landscape of FH-deficient RCC, highlighting the potential of immunotherapy for treating this patient populations.
Association of serum iron and response to immune checkpoint inhibitors (ICIs) in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Rathi Nityam , Stenehjem David D. , Agarwal Neeraj , Hahn Andrew W , Sirohi Deepika , Sharma Prayushi , Koh Mei Yee , Maughan Benjamin Louis
Published: February 2020

723

Background: ICIs have improved survival in mRCC patients (pts), yet response rates (RR) to these treatments are variable. Biomarkers predictive of response to ICIs may improve outcomes for mccRCC pts. Genes that promote tumor-specific iron accumulation such as hepcidin (HAMP) or transferrin (TF) are significantly correlated with decreased overall survival in clear cell RCC (TCGA-KIRC). Iron deficiency in cancer patients is positively correlated with tumor stage and inversely proportional to treatment response (PMID: 23567147). Here, we investigate whether serum iron profile may be associated with response to ICIs in mccRCC pts. Methods: Clinical data was obtained from an mRCC registry at the Huntsman Cancer Institute, University of Utah. Analyses were limited to mccRCC pts who had serum iron studies within 6 months before initiating an ICI and had been assessed for RR. ICIs included nivolumab + ipilimumab, atezolizumab, or nivolumab alone. Responses were defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by RECIST criteria. Clinical benefit (CB) was defined as CR + PR + SD. Descriptive statistics were used to assess associations between iron stores and response to ICIs and IMDC criteria. Results: 36 pts met all aforementioned eligibility criteria (29 were of IMDC intermediate risk, 7 were of IMDC poor risk). 5 pts received a first-line ICI, and the remaining 31 pts received ICIs as salvage therapy. Pts with CB had a significantly higher median serum iron level compared to those with no CB (59 vs 38.5 ug/dL; p=0.024). Furthermore, pts with normal transferrin saturation (TSAT %) were more likely to derive CB from ICIs (p=0.048). No association was found between serum ferritin (a marker of inflammation and tissue iron) and response to ICIs. Conclusions: In this hypothesis-generating study, increased serum iron, and TSAT levels within the normal range are associated with an increased likelihood of response to ICIs in pts with mccRCC. Once validated, these results may establish serum iron profile as a predictive marker of response to ICIs, in addition to providing the rationale for ruling out iron deficiency before starting ICIs.
Soluble PD-L1 as a marker of progressive disease on nivolumab in kidney cancer.
Authors: Mahoney Kathleen Margaret , Ross-Macdonald Petra B. , Shukla Sachet A. , Braun David A. , Song Linan , Veras Eliseo , Wind-Rotolo Megan , Van Allen Eliezer Mendel , McDermott David F. , Hodi F. Stephen , Choueiri Toni K. , Freeman Gordon J.
Published: February 2020

746

Background: Higher levels of soluble PD-L1 (sPD-L1) are associated with poor prognosis in patients with solid tumors including in renal cell carcinoma (RCC). Here we have tested whether in patients with advanced RCC, sPD-L1 levels are associated with PD-L1 expression on tumor tissue or with clinical outcomes on PD-1 blockade. Methods: Serum from 91 patients with advanced clear-cell RCC on a biomarker study of nivolumab (NCT01358721) obtained at baseline (Day 1), Day 29 and Day 63, was tested by SiMoa™ for sPD-L1 (capture mAb 298.12B1, detection mAb 339.4C10; Freeman laboratory and Quanterix). Tumor PD-L1 (tPD-L1) was assessed on pretreatment biopsies (Dako). Association of sPDL1 and tPD-L1 with clinical outcomes was analyzed, including best overall response by RECIST (BOR), objective response of >20% (OR), progression free survival (PFS), and overall survival (OS). Results quote Wilcoxon Rank Sum test or paired t-test with significance at P < 0.05. Results: Median sPD-L1 was highest in patients with progressive disease (PD) at all timepoints (Table). Compared to baseline, sPD-L1 levels significantly increased in patients with PD on Day 29 and Day 63, while sPD-L1 levels significantly decreased in patients with CR/PR on Day 63. In addition, we found significantly higher baseline sPD-L1 in patients with prior therapy compared to those who were treatment-naïve. High tPD-L1 was weakly associated with favorable OR, but also weakly associated with high baseline sPD-L1. Conclusions: Unlike tPD-L1, sPD-L1 levels may show promise for association with clinical response to nivolumab in RCC. In this exploratory study, sPD-L1 increase on-treatment was significantly associated with lack of OR, and may be of utility as an early marker for PD worthy of future validation. Analysis of RNASeq from patients’ tumor specimen is underway to assess whether high sPD-L1 with PD is associated with immune suppressive signatures.[Table: see text]
Renal biopsy cell cycle proliferation (CCP) score to predict adverse surgical pathology in renal cell carcinoma.
Authors: Tosoian Jeffrey J. , Feldman Adam S. , Abbott Madeline , Mehra Rohit , Tiemeny Placede , Wolf J. Stuart , Wu Shulin , Stone Steven , Wu Chin-Lee , Daignault Stephanie , Taylor Jeremy MG , Morgan Todd Matthew
Published: February 2020

747

Background: The role of renal mass biopsy (RMB) in risk stratifying patients with renal cell carcinoma (RCC) is unclear. We sought to determine whether the cell cycle proliferation (CCP) score from RMB can improve risk stratification of localized RCC. Methods: We identified patients with RCC who underwent RMB and subsequent partial/radical nephrectomy from 2000-2014. We used multivariable logistic regression to determine the association of patient-level variables and biopsy CCP score with adverse surgical pathology (Fuhrman grade 3-4, pT stage≥3, papillary type II histology, or evidence of metastasis at surgery). Effect size was estimated with odds ratios (OR) and discriminative performance with AUC. Results: Overall, 94 of 202 patients (46%) had adverse surgical pathology. On multivariable analysis, CCP score >0 was associated with 2.38-fold increased odds of adverse pathology (Table). Relative to the model omitting CCP score (AUC=0.70), the addition of CCP score as a continuous (AUC=0.731) or binary (AUC=0.730) variable yielded increased discriminative performance. Similar associations were observed in an analysis limited to patients with low-grade tumors on biopsy (bCCP: OR 2.44, p=0.024; cCCP: OR 1.57, p=0.11). In both models, increased lesion size on imaging was consistently associated with adverse pathology. Conclusions: Among patients with RCC, biopsy CCP score >0 was independently associated with adverse pathology, suggesting this classifier provides prognostic information beyond conventional pathologic data. Biopsy CCP score could be used to better guide patient-specific management.[Table: see text]
Phase II trial of a novel immunotherapy combination of pembrolizumab and HER2 bi-armed activated T cells (BATs) in metastatic castrate resistant prostate cancer.
Authors: Patel Meera , Lum Lawrence G. , Deol Abhinav , Thakur Archana , Heath Elisabeth I. , Chen Wei , Dobson Kimberlee , Fontana Joseph A. , Vaishampayan Ulka N.
Published: February 2020

97

Background: Immune checkpoint inhibitors (ICI) have demonstrated only modest efficacy in metastatic castrate resistant prostate cancer (mCRPC). Anti-HER2 and Anti-CD3 bispecific antibody armed activated T cells (HER2 BATs) demonstrated efficacy in prostate cancer cell lines, irrespective of HER2 expression status. Safety and preliminary responses in refractory mCRPC were noted in a phase I trial with HER2 BATs. Preclinical synergy was noted in prostate cancer with ICI and BATs. We conducted a phase II study with pembrolizumab and HER2 BATs that would potentially transform immune cells to exhibit cytotoxicity against prostate cancer. Methods: mCRPC patients with 0-1 performance status (PS) and normal liver, kidney and marrow function, pre or post docetaxel chemotherapy were eligible. Primary endpoint was 6 month progression free survival. Patients underwent apheresis for mononuclear cell collection which was shipped to the University of Virginia for manufacturing of HER2 BATs, which were infused twice weekly for 4 weeks. Pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 week prior to HER2 BATs infusion. Progression was determined by clinical evaluation, PSA, and radiologic assessment at 3 and 6 months and every 6 months thereafter. Results: Twelve patients have been enrolled on the study of which one withdrew consent. Median age was 69 years (Range 57 to 76 years). Five of 11 patients had prior docetaxel chemotherapy. Eight of 11 patients had bone and lymph node metastases, 1 had lymph node metastases only, and 2 had peritoneal metastasis. Median PSA was 111ng/ml [Range 5.2 - 378 ng/ml]. Five and 6 patients had PS of 0 and 1 respectively. The regimen was well tolerated with no unexpected toxicities. To date 3 of 6 patients have completed study treatment and remain progression free at 6 months, 1 death occurred due to an unrelated cause, and 2 patients progressed at 12 weeks of therapy. Two patients demonstrated an 88% and 36% PSA decline. Immune correlates will be presented. Conclusions: The combination regimen of pembrolizumab and BATs appears to be worthy of future exploration in a larger trial in mCRPC. Clinical trial information: NCT03406858.
MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.
Authors: De Bono Johann S. , Fleming Mark T. , Wang Judy Sing-Zan , Cathomas Richard , Williams Marna , Bothos John G. , Balic Kemal , Cho Song Hye , Martinez Pablo , Petrylak Daniel Peter
Published: February 2020

99

Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to < 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.
A phase I study to evaluate PSCA-targeting chimeric antigen receptor (CAR)-T cells for patients with PSCA+ metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dorff Tanya B. , Blanchard Suzette , Carruth Patti , Wagner Jamie , Kuhn Peter , Chaudhry Ammar , Adkins Lauren , Thomas Sandra , Martirosyan Hripsime , Chu Peiguo , Pal Sumanta K. , Forman Stephen J. , Priceman Saul
Published: February 2020

TPS250

Background: Although treatment options have improved, mCRPC remains highly lethal. Immunotherapy holds potential for durable remissions but not yet in mCRPC. CAR-T cell therapy has yielded cure for patients with refractory hematologic malignancies, and shows promise in solid tumors. Identifying and targeting the optimal antigen will be key to successful translation in solid tumors. Prostate stem cell antigen (PSCA) is highly expressed on prostate cancer cells, especially metastatic foci, and has limited expression on normal tissues. City of Hope has developed a second-generation PSCA CAR-T cell therapy containing an intracellular 4-1BB co-stimulatory domain (PSCA-BBζ) for first-in-human testing in men with mCRPC refractory to standard therapy (NCT03873805). Methods: The toxicity equivalence range (TEQR) design of Blanchard and Longmate will be used to evaluate select doses of PSCA-BBζ cells and determine the maximum tolerated dose (MTD). Doses include Cohort 1 = 100 million (M) CAR-T x 1 alone; Cohort 1b = 100M CAR-T x1 after lymphodepletion; Cohort 2 = 300M after lymphodepletion; Cohort 3 = 600M after lymphodepletion. 12 subjects will be accrued at the MTD. Eligibility: mCRPC treated with either abiraterone, enzalutamide or both; prior chemotherapy and/or radium223 allowed but not mandated. Tumor tissue, primary or metastatic, must stain positive for PSCA by IHC (Abcam 15168) and biopsy is repeated 28 days post infusion. Endpoints: Primary: all toxicities and dose-limiting toxicities defined as grade 3+ toxicity with attribution of possibly related or above, except CRS grade 3 resolved to < grade 2 within 72 hours or grade 3 encephalopathy resolved to baseline within 28 days. Secondary: persistence/expansion of CAR-T, response (soft tissue by RECIST, bone by PCWG3 criteria). Correlative studies include blood (immunophenotyping, cytokines, circulating tumor cell enumeration and PSCA expression), MRI (enhancement/diffusion changes in target lesions) and metastatic core biopsies (PSCA expression and local immune phenotype changes). Progress: 4 subjects have successfully manufactured PSCA-BBζ T cells; 1 completed treatment. Clinical trial information: NCT03873805.
A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.
Authors: Choudhury Atish Dipankar , Xie Wanling , Parikh Mamta , Lee Daniel , Kessler Elizabeth R. , Einstein David Johnson , Kochupurakkal Bose , Mouw Kent William , Van Allen Eliezer Mendel , Doyle L. Austin , D'Andrea Alan D. , Taplin Mary-Ellen , Shapiro Geoffrey
Published: February 2020

TPS252

Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191). Clinical trial information: NCT03517969.
Phase III study of pembrolizumab (pembro) plus olaparib versus enzalutamide (enza) or abiraterone acetate (abi) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who progressed on chemotherapy: KEYLYNK-010.
Authors: Yu Evan Y. , Park Se Hoon , Huang Yi-Hsiu , Bennamoun Mostefa , Xu Lu , Kim Jeri , Antonarakis Emmanuel S.
Published: February 2020

TPS256

Background: Pembro, a PD-1 inhibitor, and olaparib, a PARP inhibitor, have some single-agent antitumor activity in mCRPC. The phase 1b/2 KEYNOTE-365 study (NCT02861573) showed promising activity with pembro and olaparib in pts with mCRPC unselected for homologous recombination deficiency, warranting further investigation. Methods: KEYLYNK-010 (NCT03834519) is a phase 3 trial to evaluate efficacy and safety of pembro + olaparib in molecularly unselected enza- or abi-pretreated pts with mCRPC who progressed with taxane chemotherapy. An estimated 780 pts will be randomly assigned 2:1 to receive pembro 200 mg IV every 3 wk plus olaparib 300 mg orally twice daily or abi 1000 mg orally once daily + prednisone/prednisolone 5 mg orally twice daily (enza-pretreated pts) or enza 160 mg/day orally (abi-pretreated pts). Stratification will be by prior treatment (abi/enza) and measurable disease (yes/no). Adults (≥18 y) with histologically confirmed mCRPC who progressed on androgen deprivation therapy ≤6 mo of screening, and an ECOG PS of 0 or 1 are eligible. Pts previously received either abi or enza (but not both) as well as 1 docetaxel-based regimen. Pts are required to provide tumor tissue for biomarker analysis. Responses will be assessed by CT/MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 9 wk during the first year and every 12 wk thereafter. Treatment will continue with up to 2 y of pembro (35 cycles) and olaparib or abi/enza until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are OS and rPFS. Secondary end points are time to initiation of subsequent anticancer therapy; ORR, and DOR per PCWG3-modified RECIST v1.1 by BICR; time to PSA progression; time to first symptomatic skeletal event; time to radiographic soft tissue progression; time to pain progression; and safety. Exploratory end points are identification of molecular (genomic, metabolic, or proteomic) biomarkers indicative of response. Accrual began May 2, 2019. Clinical trial information: NCT03834519.
TALAPRO-2: A placebo-controlled phase III study of talazoparib (TALA) plus enzalutamide (ENZA) for patients with first-line metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Azad Arun , Fay Andre P. , Carles Joan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Lin Xun , Quek Ruben G.W. , Czibere Akos , Fizazi Karim
Published: February 2020

TPS264

Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/2 and traps PARP on DNA, preventing DNA damage repair (DDR) and causing death of cells with DDR mutations (eg BRCA1/2). TALA is approved in multiple countries for germline BRCA1/2-mutated HER2- advanced breast cancer. ENZA is an established therapy for CRPC. PARP1 activity has been shown to support AR function, suggesting that co-blockade of PARP1 may synergize with AR-directed therapy, regardless of DDR deficiency. A combination of TALA with ENZA in mCRPC may improve clinical outcomes in patients with or without DDR-deficient tumors. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate efficacy, safety, pharmacokinetics, and patient (pt)-reported outcomes (PROs) of the combination. Methods: Enrollment goal is 1037 pts (19 pts, part 1 dose-finding; 1,018 pts, part 2 placebo-controlled). Key eligibility criteria: age ≥18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status ≤1, no brain metastases, and no prior life-prolonging systemic therapy in nonmetastatic CRPC or mCRPC state. Prior docetaxel or novel hormonal therapy (excluding novel AR inhibitors) in castration sensitive (CSPC) setting is allowed. The randomized double-blind portion will evaluate safety, efficacy, and PROs of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Randomization is stratified by prior NHT or docetaxel for CSPC (yes/no) and DDR mutation status (deficient vs nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v.1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8–12 weeks thereafter. rPFS will be compared between two arms by a 1-sided stratified log-rank test. Pt recruitment is ongoing in multiple regions including US, Europe/Eastern Europe, Israel, South America, South Africa, and Asia Pacific region. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.
FIGHT-205: Phase II study of first-line pemigatinib (PEMI) plus pembrolizumab (PEMBRO) versus PEMI alone versus standard of care (SOC) for cisplatin (CIS)—Ineligible urothelial carcinoma (UC) with FGFR3 mutation or rearrangement.
Authors: Galsky Matt D. , Powles Thomas , Dreicer Robert , Kitamura Hiroshi , Asatiani Ekatherine , Howe Jason , Zhen Huiling , Oliveira Natalia , Necchi Andrea
Published: February 2020

TPS592

Background: Fibroblast growth factor receptor (FGFR) 3 gene alterations (GAs) are involved in UC pathogenesis. Pts with metastatic UC and FGFR3 GAs express low programmed cell death ligand 1 (PD-L1) levels; combination with FGFR inhibitors may confer added benefit via tumor-direct and immunomodulatory effects. Preliminary data from a phase 2 monotherapy trial of PEMI (INCB054828), a selective, potent, oral FGFR1–3 inhibitor, confirmed efficacy in previously treated relapsed/refractory pts with UC and FGFR3 GAs (NCT02872714). FIGHT-205, a randomized, open-label, phase 2 study, will assess efficacy and safety of PEMI + PEMBRO vs PEMI alone vs SOC (carboplatin [CARB] + gemcitabine [GEM] or PEMBRO alone) in CIS-ineligible metastatic/unresectable UC with FGFR3 mutation/rearrangement (NCT04003610). Methods: Eligible pts are adults with confirmed metastatic/unresectable UC; ≥1 measurable target lesion (per RECIST v1.1); platinum (PT)/CIS-ineligible; centrally confirmed FGFR3 mutation/rearrangement; ECOG PS ≤2. Exclusions include prior selective FGFR inhibitor, anti-PD-1/PD-L1/2, or co-inhibitory T-cell receptor directed agent; chemotherapy (except adjuvant, neoadjuvant); clinically significant corneal/retinal disorder; Ca/PO4 homeostasis disorder/systemic mineral imbalance with ectopic calcification; untreated CNS metastases. Pts will be randomized (1:1:1) to 3 groups: PEMI 13.5 mg QD (continuous, 21-d cycle) + PEMBRO 200 mg Q3W, PEMI alone (same dose), or SOC (GEM [1000 mg/m2 on D1 + D8] + CARB [AUC 5 (or 4.5) on D1 or D2] Q3W or PEMBRO [same dose] if PD-L1 score high/PT-ineligible). PEMI titration to 18 mg starting at cycle 2 is required for pts without hyperphosphatemia (serum PO4 >5.5 mg/dL) and grade ≥2 treatment-related AEs during cycle 1. Hyperphosphatemia will be managed by diet modifications, PO4 binders, diuretics, or dose adjustments. PEMI will continue until progression/unacceptable toxicity. Primary endpoint is progression-free survival. Secondary endpoints are overall survival, objective response rate, duration of response, safety, and quality of life. Clinical trial information: NCT04003610.
Avelumab as single agent for patients with metastatic or locally advanced urothelial cancer PD-L1+ unfit for cisplatin: The ARIES study.
Authors: Iacovelli Roberto , Buti Sebastiano , Buttigliero Consuelo , De Vivo Rocco , Caserta Claudia , Ferraú Francesco , Galli Luca , Martelli Valentino , Masini Cristina , Mattioli Rodolfo , Merler Sara , Milesi Laura , Naglieri Emanuele , Ricotta Riccardo , Rizzo Mimma , Sacco Cosimo , Santini Daniele , Tambaro Rosa , Verri Elena , Santoni Matteo
Published: February 2020

TPS596

Background: Urothelial cancer (UC) is the ninth most common cancer worldwide, this tumour has a poor prognosis when in advanced stage. Cisplatin-based chemotherapy is considered the most effective treatment but more than 50% of patients are considered not eligible ( cis-unfit) for this regimen and have a median survival of only 6-9 months. In the past years, the most used chemotherapy regimen for cis-unfit patients was the combination of carboplatin and gemcitabine. Two single arm studies tested the anti-PD-L1/PD1 monoclonal antibodies atezolizumab and pembrolizumab and reported a response rate of 25% with good safety profile in an unselected population for PD-L1 expression. Recently, atezolizumab alone showed longer OS compared to carboplatin-gemcitabine regimen. Avelumab is another fully human anti-PD-L1 IgG1 antibody already tested in urothelial and in other cancers with a promising safety and efficacy profile. Methods: The single arm, phase II ARIES trial (NCT03891238), aims to evaluate the activity and efficacy of avelumab in patients with metastatic or locally advanced UC considered cis-unfit with PD-L1 expression ≥5%. Overall survival is the primary endpoint. Cis-unfit definition includes at least one of the following characteristics (i) ECOG-Performance status=2; (ii) creatinine clearance <60 ml/min; (iii) grade ≥2 peripheral neuropathy or hearing loss; (iv) disease progression within six months after a previous adjuvant/neoadjuvant treatment with cisplatin-based therapy. Avelumab will be administered at standard dose of 10 mg/kg in 1-hour intravenous infusion every 2 weeks (Q2W). Sixty-seven patients will be enrolled, and supportive care is allowed during the study. Avelumab may be continued after radiological progression of disease at physician’s discretion if an improvement of symptoms or not new symptoms will be reported. The study is currently ongoing in twenty centres in Italy. Clinical trial information: NCT03891238.
Efficacy of atezolizumab concurrent with radiotherapy in patients with muscle-invasive bladder cancer (MIBC) (SOGUG-2017-A-IEC(VEJ)-4).
Authors: Vázquez-Estévez Sergio , Fernandez Calvo Ovidio , Alvarez-Fernandez Carlos , Bonfill Teresa , Domenech Montserrat , GarcIa SAnchez JosE , García José Miguel Jurado , Madueño Francisca Martínez , Romero-Laorden Nuria , Sevillano Elena , Núñez Cristina
Published: February 2020

TPS601

Background: Radical cystectomy (RC) is the standard of care for patients with T2-T4a MIBC. Organ-preserving treatment is an alternative for patients who wish to attempt bladder preservation therapy or are ineligible for cystectomy. This includes maximal transurethral resection of bladder tumour, external beam radiation therapy (EBRT) and concurrent chemotherapy. The 5 and 10 year OS and disease specific survival (DSS) rates in contemporary RC series are comparable to that reported in bladder-preserving series. Due to EBRT can mediate inmunoestimulatory effects and that radiotherapy has been used in combination with different treatment regimens, a considerable interest has been attracted by combinatorial regimens involving EBRT plus checkpoint inhibitors. The purpose of the present study is to explore feasibility and activity of the combination of atezolizumab associated with EBRT after TURBT in the treatment of localized MIBC with preservation intent. Methods: The primary endpoint of this study is to assess the efficacy of atezolizumab concurrent with EBRT in terms of pathological complete response. The secondary endpoints include OS, DSS, disease free survival, bladder intact disease-free survival, number of patients (pts) with muscle invasive and non-muscle invasive local failure, the rate of distance metastases, the rate of pts with bladder preserved, the rate of immediate or late salvage cystectomy and safety profile and tolerability of the combination. Biomarkers will be evaluated as exploratory endpoints. Elegibility criteria include pts with histologically-confirmed diagnosis of MIBC in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient’s choice, unfit for cisplatin and PS (ECOG) 0-2. Pts will receive atezolizumab 1.200 mg by IV infusion on Day1 of each cycle every 3 weeks for a total of 6 treatment courses, concurrent with EBRT 60 Gy in 30 fractions over 6 weeks at 2 Gy/day. With 35 evaluable pts and a pCR of 80%, the 95%CI of the estimation would be 0.62–0.92. The study will be stopped if we do not achieve at least 9 pCR among the first 13 evaluable pts. Otherwise, the study will continue until 39 pts. Clinical trial information: 2018-004348-47.
Adding mitomycin to Bacillus Calmette-Guérin as adjuvant intravesical therapy for high-risk, nonmuscle-invasive urothelial bladder cancer (BCGMM; ANZUP 1301).
Authors: Liow Elizabeth Chien Hern , Hayne Dickon , Stockler Martin R. , Martin Andrew James , Sengupta Shomik , Anderson Paul , Ford Kate , Frydenberg Mark , Gorzeman Margot , Green Will , Grummet Jeremy , Hawks Cynthia , Krieger Laurence Eliot Miles , Ischia Joseph , McCombie Steve , Patel Manish , Davis Ian D. ,   The Bladder, Urothelial, and Penile (BUP) Cancer Sub-Committee of the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2020

TPS602

Background: Adjuvant intravesical bacillus Calmette-Guérin (BCG) decreases disease recurrence and progression in people with high-risk, non-muscle invasive urothelial bladder cancer (NMIBC), however recurrence occurs in 30% despite optimal therapy. Recent meta-analyses evaluating addition of intravesical mitomycin (MM) to BCG showed lower rates of recurrence and cancer-specific mortality in people with NMIBC who received combination regimens. Good quality randomized trials to definitively test this combination are lacking. The BCGMM trial (NCT02948543) will be the largest study to date evaluating this approach in people with high-risk NMIBC. Methods: This open-label phase 3 trial aims to randomize 500 participants, stratified by stage, site of disease, and presence of carcinoma in-situ, to Arm A (BCG induction weekly x6 then monthly x10) or Arm B (BCG + MM weekly x9 then monthly x9). This study is powered to detect a 10% improvement in 2-year disease free survival (DFS) at 5% level of significance with 85% power. Stage 1 of this study, designed to recruit 130 patients to determine rates of treatment completion, activity reflected by cystoscopic findings at 3 months, adverse events, resource use, and health related quality of life, has completed enrolment and successfully established feasibility of this trial protocol. Stage 2, aiming for a further 370 patients, will inform on additional endpoints including differences in DFS, time to recurrence and progression, overall survival, and potential predictive biomarkers, is estimated to complete accrual in December 2020. Successful treatment completion, defined as 75% or more of planned treatment doses, has been achieved in 76% of patients treated in the experimental arm of Stage 1, compared to 60% in those allocated BCG alone. Clinical trial information: NCT02948543.
A multicenter phase II study of avelumab in patients with locally advanced or metastatic penile cancer (PC) who are unfit for, or have progressed on or after platinum-based chemotherapy: (ALPACA).
Authors: Alqaisi Husam , Winquist Eric , Mukherjee Som , Canil Christina M. , Fallah-Rad Nazanin , Sridhar Srikala S.
Published: February 2020

TPS7

Background: Squamous cell carcinoma of the penis is a rare and highly aggressive malignancy. Combination platinum-based chemotherapy is the standard of care in the metastatic setting. However, it is poorly tolerated and outcomes are dismal, underscoring an urgent unmet need for novel strategies. Since, penile cancers are often HPV-mediated and frequently overexpress PDL1, there is strong rationale to test the PDL1 inhibitor Avelumab, which is a well-tolerated drug in the setting of metastatic PC. Methods: This is a multicenter, single arm, phase 2 study of Avelumab (10mg/kg IV every 2 weeks) in patients with locally advanced or metastatic PC unfit for or progressed on platinum-based chemotherapy. A Simon’s two-stage design will be used where 9 patients will be enrolled in stage 1. If there is at least 1 response defined by iRECIST (complete response [iCR], partial response [iPR], or stable disease [iSD]) the study will proceed to stage 2, where an additional 15 patients will be enrolled. The primary objective is to demonstrate the anti-tumor activity of avelumab by objective response rate (ORR) according to (iRECIST). Secondary endpoints include: PFS, OS in patients determined to have PD-L1 positive tumors (including infiltrating immune cells) by the GMP verified Dako PD-L1 IHC 22C3 pharmDx test with thresholds of <1%, 1-49%, and ≥ 50% to define PD-L1 positivity, and in all enrolled patients. Secondary objectives also include assessing pathologic complete response rate (pCR) for patients undergoing surgery in the treatment time course, evaluation of safety and immunogenicity profile of Avelumab. The study is now open and actively accruing with further centres opening imminently. Funding Source: Pfizer. Clinical trial information: 03391479.
PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Zhang Tian , Ballman Karla V. , Choudhury Atish Dipankar , Chen Ronald C. , Watt Colleen , Wen Yujia , Zemla Tyler , Emamekhoo Hamid , Vaishampayan Ulka N. , Morris Michael J. , George Daniel J. , Choueiri Toni K.
Published: February 2020

TPS760

Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN trials. Combination immunotherapy with VEGF therapies have shown benefit in the JAVELIN 101 and KEYNOTE 426 trials over sunitinib. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter, phase 3 trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1mg/kg and NIVO 3mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, IMDC intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480mg IV every 4 weeks, pts with progression of disease (PD) switch to CABO 60mg oral daily, and pts with non-CR/non-PD are randomized to NIVO 480mg IV every 4 weeks versus NIVO 480mg IV every 4 weeks with CABO 40mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS rate will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include PFS, 12-month CR rate, ORR based on RECIST 1.1 and irRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR and association of IL-6 with treatment benefit will be assessed. Other tissue-based and plasma-based biomarkers are planned. Updated enrollment will be presented. Clinical trial information: NCT03793166.
CASSIOPE: A real-world study assessing the use of cabozantinib for the treatment of advanced renal cell carcinoma (aRCC) after vascular endothelial growth factor (VEGF)-targeted therapy in Europe.
Authors: Staehler Michael D. , Hamberg Paul , Bigot Pierre , Suárez Cristina , Barthelemy Philippe , Eymard Jean-Christophe , Laramas Mathieu , Taguieva Pioger Naila , Gross-Goupil Marine , Rink Michael , Masini Cristina , De Vivo Rocco , Gajate Pablo , Azzabi Ashraf , Procopio Giuseppe
Published: February 2020

TPS770

Background: Cabozantinib, an inhibitor of multiple receptor tyrosine kinases including VEGF receptor 2, and MET and AXL receptors, is approved for the treatment of aRCC in the USA and, in Europe, in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy. The METEOR trial investigated cabozantinib as second-line (2L) or later-line therapy and showed improved progression-free survival (PFS), objective response rate and overall survival vs everolimus. Adverse events (AEs) associated with cabozantinib were generally manageable in METEOR; dose interruptions and reductions occurred in 70% and 60% of patients, respectively. Here we present the design of the CASSIOPE study which aims to assess the real-life use of cabozantinib as 2L or third- or later-line (≥ 3L) therapy for aRCC. Methods: CASSIOPE is an ongoing, European, prospective, non-interventional study in adults with aRCC who have received ≥ 1 prior VEGF-targeted therapy and are initiating cabozantinib as 2L or ≥ 3L therapy according to Summary of Product Characteristics. The primary endpoint is the proportion of patients with dose modifications (interruption, reduction or discontinuation) due to AEs. Secondary endpoints include additional drug utilization parameters, effectiveness (overall best response, PFS), and healthcare resource utilization associated with managing treatment-related AEs. Overall, 680 patients (340 on 2L therapy; 340 on ≥ 3L therapy) will be enrolled to assess the 2-sided 95% confidence interval of the primary endpoint with a precision of ± 5%, assuming a 75% dose modification rate and ≤15% of starting doses lower than 60 mg. Visits will be based on the site's clinical practice, with a maximum follow-up of 12 months after treatment initiation, even if treatment is continued. Data collection started in April 2018. As of 9 October 2019, 336 patients have been enrolled. The overall study duration is expected to be 36 months. An interim analysis is planned when ≥ 340 patients have completed ≥ 3 months follow-up from treatment initiation. The study is funded by Ipsen Pharma. Clinical trial information: NCT03419572; EUPAS19464.
CaboPoint, a phase II, open-label study of cabozantinib as second-line therapy for patients with clear cell metastatic renal cell carcinoma (RCC), whose disease progressed after therapy with checkpoint inhibitors (CPIs).
Authors: Albiges Laurence , Schmidinger Manuela , Taguieva Pioger Naila , Pérol David , Grünwald Viktor
Published: February 2020

TPS772

Background: Cabozantinib, a tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptors, MET and AXL, is approved for the treatment of advanced RCC (in the USA) in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy (in Europe). Here we present the design of the CaboPoint study evaluating the efficacy and safety of cabozantinib in patients with clear-cell metastatic RCC, whose disease progressed after CPI therapy. Methods: CaboPoint is a phase II, open-label (OL), single-arm study of cabozantinib in adults with unresectable, locally advanced or metastatic RCC with a clear-cell component, whose disease progressed after CPI therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate, evaluated by independent review committee. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. Change in disease-related symptoms and safety/tolerability will also be assessed. During the pre-treatment period, potential participants will attend a screening visit within 15 days of treatment initiation to determine eligibility status. During the treatment period, a target of 250 eligible patients (n = 125 per cohort) at 50 sites across AT, CH, DE, ES, FR, NL and UK will receive OL cabozantinib (60 mg once daily; self-administered at home) for up to 18 months after the last recruited patient has received their first dose. Safety assessments will be conducted every 2 weeks up to week 4, and every 4 weeks thereafter. Patients may continue on cabozantinib after disease progression if clinical benefit is observed. During the post-treatment follow-up period, patients who discontinue early will be contacted at visits every 12 weeks to assess survival status and subsequent anticancer therapy. Each cohort will have an interim analysis when 60% of the patients have reached 12 months of follow-up. The study is funded by Ipsen Pharma. Clinical trial information: NCT03945773.
Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients
Authors: Cheema Huma Arshad , Rasool Iqra Ghulam , Anjum Muhammad Nadeem , Zahoor Muhammad Yasir
Published: February 2020

Objective: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients.

Methods: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children’s Hospital Lahore.

Results: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe.

Conclusion: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families.

doi: https://doi.org/10.12669/pjms.36.3.467

How to cite this:Cheema HA, Rasool IG, Anjum MN, Zahoor MY. Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients. Pak J Med Sci. 2020;36(3):479-484. doi: https://doi.org/10.12669/pjms.36.3.467

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nuclear distributions, rms radii and form factors with the harmonic oscillator shell model
Authors: Kosmas T. S. , Vergados J. D.
Published: February 2020

General expressions for calculating nuclear distributions (proton, charge, matter and momentum), mean radii and nuclear form factors are derived by extending recent related works. They are based either on the simple harmonic oscillator shell model or on its modification in which fractional occupation probabilities of the surface orbits are used to fit the experimental elastic electron scattering data. The 40Ca and the values of partial occupation method is applied to the spherical nucleus probabilities are compared with those determined from experimental reaction data.
Relative probability of recoilless Λ-production in nuclei in the plane-wave impulse approximation
Authors: Grypeos M. E. , Lalazissis G. A. , Massen S. E. , Panos C. P.
Published: February 2020

The problem of estimating the relative probability Ρ of recoilless Λ production in nuclei by means of the (K-,π-) reaction is investigated in the plane-wave impulse approximation, which leads to approximate expressions of the "Debye-Waller type". The values of the relevant average overlap integrals between Λ and neutron normalized harmonic oscillator wave func­ tions are close to 1.
A Democratic Mapping between the Shell Model and the IBM
Authors: Skouras L. D. , Van Isacker P. , Nagarajan M. A.
Published: February 2020

A method is proposed to connect states of the shell model and the interacting boson model and derive the boson model hamiltonian from shell-model data. This novel mapping technique is based on the properties of the shell-model overlap matrix. An application to the /7/2 shell is presented and the results of the new mapping are compared with the standard OAI results.