bluuebunny/crossref_metadata_2025 huggingface dataset:
Hereditary cancer genetic testing among patients with pancreatic cancer.
Authors: Taherian Nassim , Saam Jennifer , Larson Katie , Lancaster Johnathan M. , Permuth Jennifer
Published: May 2019

4134

Background: Pancreatic cancer (PC) is typically diagnosed at a late, untreatable stage, with a 5-year survival rate of only ~8%. Genetic testing for individuals with PC may aid in therapy decisions, as those with a germline or somatic pathogenic variant (PV) in a DNA-repair gene may benefit from PARP inhibitors. In addition, germline genetic testing for unaffected family members can identify high risk individuals who may be appropriate for surveillance studies. We assessed the results of hereditary cancer genetic testing among individuals with a personal history of PC and evaluated several possible risk factors. Methods: Individuals with PC who had germline testing for 25-29 cancer-susceptibility genes between September 2013 and November 2018 were included in this analysis (N = 1,676). Clinical characteristics were obtained from provider-completed test request forms and included personal cancer history (PHx), family cancer history (FHx), and age at diagnosis. Results: Overall, 12.6% (212/1676) of patients with PC carried a PV, most commonly in BRCA2 (3.8%), ATM (2.7%), and PALB2 (1.2%). PVs were more common in men and for individuals who had a PHx of additional cancer(s) (see Table). Age at PC diagnosis did not impact the positive PV rate. The PV positive rate was elevated among individuals with PC and at least two relatives with PC (15.1%) and for individuals with a FHx of cancer at an early age (14.2%). The PV positive rate remained > 10% regardless of nearly all other FHx characteristics evaluated, including the absence of any FHx (see Table). Conclusions: In this cohort, a substantial proportion of individuals with a PHx of PC carried PVs, regardless of age at diagnosis and personal and family cancer history. [Table: see text]
A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy (Bx).
Authors: Gao Jianjun , Karam Jose A. , Tannir Nizar M. , Campbell Matthew T , Slack Tidwell Rebecca , Ahrar Kamran , Rao Priya , Ng Chaan S. , Jonasch Eric , Matin Surena F. , Zurita Amado J. , Shah Amishi Yogesh , Shen Yu , Blando Jorge M. , Vence Luis M. , Basu Sreyashi , Zhao Hao , Allison James Patrick , Wood Christopher G. , Sharma Padmanee
Published: May 2019

4501

Background: Cytoreductive surgery (CS) including cytoreductive nephrectomy and metastasectomy provides clinical benefits to patients with MRCC. However, CS has not been evaluated in the setting of immune checkpoint (IC) therapy. We performed a pre-surgical/biopsy trial to evaluate biological and clinical activity of nivo +/- (bev or ipi) in patients with MRCC. Methods: In this open-label, randomized trial (NCT02210117), patients with MRCC w/o prior IC therapy and anti-VEGF therapy were randomized 2:3:2 to receive nivo (3mg/kg q2wks x3), nivo + bev (10mg/kg q2wks x3) or nivo + ipi (1mg/kg q3wks x2), followed by CS or Bx, and then nivo maintenance therapy up to 2 yrs. Clinical response per RECIST criteria was assessed at ≥12 wks. Pre- and post-treatment blood and tumors were obtained for correlative studies. Results: All of 105 patients have been accrued and 104 are evaluable for response. For all patients, best overall response (BOR = complete response [CR] + partial response [PR]) including surgery effect was 55% nivo, 44% nivo + bev, 43% nivo + ipi. Median PFS (95% confidence interval) was 14.5 months (5.5, not reached [NR]) nivo, 7.6 (4.8, 8.9) months nivo + bev, 7.5 (2.0, 12.4) months nivo + ipi. Overall survival (OS) at one year was 86% nivo, 73% nivo + bev, 83% nivo + ipi. Grade 3 or higher toxicities related to therapy were 38% for nivo, 42% for nivo + bev (including 18% hypertension), and 47% for nivo + ipi. For patients with CS, BOR including surgery effect was: 86% nivo, 88% nivo + bev, and 69% nivo + ipi. Median PFS was 17.3 months (6.1, NR) nivo, 7.6 (5.7, 10.3) months nivo + bev, 8.9 (2.9, 23.0) months nivo + ipi. OS at one year was 100% nivo, 94% nivo + bev, 92% nivo + ipi. Median OS has not yet reached with a median follow-up of 24.6 months. Immune and gene profiling analyses demonstrate: 1) tumor infiltrating CD8 T cells correlate with clinical responses to nivo or nivo + bev, but not to nivo + ipi; 2) tumor IFN pathway gene expression correlates with responses; and 3) PD-L1 status, tumor mutation or mutation burden, neoantigens did not correlate with response. Conclusions: IC therapy plus CS is safe and beneficial to patients with MRCC and therefore, warrants testing, along with a few correlative biomarkers, in a larger phase 3 trial. Clinical trial information: NCT 02210117.
Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): Update on Carmena trial with focus on intermediate IMDC-risk population.
Authors: Mejean Arnaud , Thezenas Simon , Chevreau Christine , Bensalah Karim , Geoffrois Lionnel , Thiery-Vuillemin Antoine , Cormier Luc , Lang Herve , Guy Laurent , Gravis Gwenaelle , Rolland Frederic , Linassier Claude , Timsit Marc-Olivier , Albiges Laurence , Oudard Stephane , Lebret Thierry , Treluyer jean-Marc , Colas Sandra , Escudier Bernard , Ravaud Alain
Published: May 2019

4508

Background: Carmena was a randomized phase III trial, testing the benefit of CN followed by sunitinib (arm A) vs sunitinib alone (arm B), with stratification by MSKCC risk groups in 450 mRCC patients. Based on this trial, CN is not anymore recommended in mRCC (NEJM, Mejean et al, 2018). However there are questions about which patients could still benefit from CN, especially in intermediate risk group. In the present study, we investigated different subgroups from the Carmena trial to answer these questions. Methods: Carmena trial was initially stratified according to MSKCC risk groups. For the purpose of this analysis, we reclassified the patients based on IMDC risk groups. We also analyzed patients with one metastatic site vs more than one, as well as patients with secondary nephrectomy in arm B. Overall survival (OS) was the primary endpoint. Results: With a updated median FU of 61.5 months (mo), the median OS by ITT analysis was 15.6 vs 19.8 mo in arm A and B respectively stratified on MSKCC (HR 0.933 ; 95% CI [0.76- 1.15]) / stratified on IMDC (HR 0.957 ; 95% CI [0.78- 1.18]). Using IMDC risk group factors, 58.6% patients were intermediate and 41.4 % were poor risk. When looking at intermediate risk group only, 48.1% had only one risk factor (interval between diagnosis and treatment < 1y), with a median OS of 30.5 and 25.2 mo in arm A and B respectively (HR 1.24 [0.81 – 1.90]). By contrast, 51.9 % had two risk factors (mostly low hemoglobin, high corrected calcium or neutrophils), with a median OS of 16.6 and 31.2 mo in arm A and B respectively (HR 0.61 [0.41 – 0.91] p = 0.015). Regarding number of metastatic sites, 33% had only one metastatic site. Median OS was 23.6 and 22.7 mo in arm A and B respectively (HR 1.08 [0.75 – 1.57]. Finally, 40 patients had a secondary nephrectomy in arm B, with median OS of 48.5 mo [CI 95%: 27.9-64.4] vs 15.7 mo [CI 95%: 13.3-20.5] in patients who never had surgery. Conclusions: With longer FU, Carmena trial confirms that CN is not superior to sunitinib alone in ITT population, both with MSKCC and IMDC risk groups. However for patients with only one IMDC risk factor, CN might be beneficial. Number of metastatic site is not helpful to define good candidates for surgery. Finally, patients with secondary nephrectomy have very long OS, supporting this strategy. Clinical trial information: NCT00930033.
Interim analysis of ibrutinib plus paclitaxel for patients with advanced urothelial carcinoma previously treated with platinum-based chemotherapy.
Authors: Castellano Daniel E. , Morales-Barrera Rafael , Duran Ignacio , Keam Bhumsuk , Chung Ik Joo , Arkenau Hendrik-Tobias , Vaishampayan Ulka N. , Tuthill Mark , Gajate Pablo , Shin Sang Joon , Dang S. Paul , Ju Chia-Hsin , Lin Jennifer , Cole George W. , James Danelle Frances , Reig Oscar
Published: May 2019

4522

Background: Patients (pts) with advanced urothelial carcinoma (aUC) who progressed after platinum-based chemotherapy (PBCT) have a median overall survival (OS) of ~6 mo on CT and 8-10 mo on novel immune checkpoint inhibitors (ICIs). Treatment (tx) with ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase (BTK) with immunomodulatory properties, plus paclitaxel (pac) may improve outcomes for pts with aUC. Methods: Pts with aUC who had 1-2 prior tx (≥1 PBCT and/or ICIs) formed one cohort of this phase 1b/2 study. Recommended phase 2 dose per phase 1b was ibr 840 mg/d + weekly pac 80 mg/m2 in 21-d cycles; starting ibr dose of 560 mg/d. nanoString gene expression assay (NanoString Technologies) was used for preliminary assessment of ibr-targeted kinases in baseline tumor biopsies. Results: This interim analysis included the first 29 pts treated (ibr 840/560 mg/d, n = 25/4; median age 67 y). 52% had 2 prior regimens (prior PD-L1 inhibitors, 100%). Median time on study/tx was 7.2/2.3 mo (max tx: 11.5 mo). Unconfirmed overall response rate (ORR) was 41% (complete/partial response: 10%/31%). Disease control rate was 62%. ORR was 71% for 7 pts with only lymph node metastases; ORR was 36% for 14 pts with 1 prior tx and 47% for 15 pts with 2 prior tx. Median duration of response was 4.2 mo (90% CI: 1.9-7.1). Median progression-free survival was 3.6 mo (90% CI: 1.6-5.4). Median OS was 14.7 mo (90% CI: 7.7-15.9). Follow-up is ongoing for durability/survival with 6 pts alive without progression, including 4 still on ibr. 76% of pts had grade ≥3 adverse events (AEs); 4 discontinued ibr + pac due to AEs and 1 had major hemorrhage. Pac exposure was not impacted by ibr; pac geometric mean Cmax (2066 ng/mL) and AUC0-∞ (3813 ng·h/mL) were consistent with historical data. Preliminary tumor biopsy data showed a nonsignificant trend of higher BTK/ITK/BMX expression in tx responders; analyses are ongoing. Conclusions: Ibr + pac shows promising results for ORR/OS in pts with aUC previously treated with PBCT and ICIs. No unexpected safety signals were seen; ibr + pac seemed tolerable. Follow-up of these and additional pts will support the activity and safety of ibr + pac in this study. Clinical trial information: NCT02599324.
Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): Updated follow-up from KEYNOTE-057.
Authors: De Wit Ronald , Kulkarni Girish S. , Uchio Edward M. , Krieger Laurence Eliot Miles , Boormans Joost L. , Roumiguié Mathieu , Singer Eric A. , Bajorin Dean F. , Kamat Ashish M. , Grivas Petros , Seo Ho Kyung , Nishiyama Hiroyuki , Konety Badrinath R. , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , Balar Arjun Vasant
Published: May 2019

4530

Background: Upregulation of the PD-1 pathway has been observed in BCG-unresponsive NMIBC, suggesting that pembro may be beneficial. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study (NCT02625961); updated results for pts with carcinoma in situ (CIS) with or without papillary tumors (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary tumors who received adequate BCG therapy and were unable/refused to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts who developed HR NMIBC or progressive disease during treatment were required to discontinue. Key end points were complete response rate (CRR), duration of response, and safety. Results: 102 pts (median age, 73 years; CIS alone, 63.7%; median number of prior BCG instillations, 12) had enrolled in cohort A as of enrollment cutoff. Median (range) duration of follow-up was 15.8 mo (4.6-28.2) ; 3-mo CRR was 40.2% (95% CI, 30.6-50.4) by central assessment. Among 41 pts who had CR at 3 mo, median CR duration was 12.7 mo (range, 0+ to 20.5+ mo); 75.4% had a CR duration ≥ 6 mo; 52.6% had a CR duration ≥12 mo (Kaplan-Meier method); 24 pts (58.5%) maintained CR at last follow-up, and 15 (36.6%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle-invasive or metastatic disease. CRR was 44.6% for pts with CIS alone (n = 65), 41.7% for CIS with T1 tumors (n = 12), and 28.0% for CIS with high-grade Ta tumors (n = 25). Treatment-related adverse events (AEs) occurred in 66 (64.7%) pts; most frequent (≥10%) were pruritus (10.8%), diarrhea (10.8%), and fatigue (9.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.7%) pts. Immune-mediated AEs occurred in 19 (18.6%) pts. Conclusions: Pembro continued to show encouraging antitumor activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial information: NCT02625961.
Increasing use of neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC): Prognostic impact of non-standard of care (SOC) regimens.
Authors: Nyame Yaw A. , Holt Sarah K , Winters Brian , Psutka Sarah P. , Dash Atreya , Schade George R , Lin Daniel W. , Diamantopoulos Leonidas Nikolaos , Grivas Petros , Yu Evan Y. , Gore John L. , Wright Jonathan L.
Published: May 2019

4532

Background: Cisplatin-based NAC can prolong overall survival (OS) in patients (pts) with MIBC. Utilization of NAC has increased to about 20% of pts with MIBC over the last decade. We evaluated NAC utilization with and without SOC cisplatin-based combination regimens and oncologic outcomes using registry data. Methods: This is a population-based analysis of linked SEER-Medicare data (2004-2011). We identified 4534 pts with MIBC (cT2-4N0-1) undergoing radical cystectomy (RC). Based on pharmacy records data, pts were stratified into 3 groups: SOC, non-SOC, and immediate cystectomy (IC). We used descriptive statistics to compare groups, and multivariate logistic regression to define factors associated with receiving SOC NAC. Competing risk bladder cancer-specific mortality (BCSM) incidence curves were generated and KM analysis was used to assess OS from time of RC. The impact of NAC on OS was evaluated with Cox regression analysis. Results: 694 (15.3%) pts received NAC, increasing from 11% in 2004 to 24.8% in 2011, with 345 (50%) receiving non-SOC, e.g. gemcitabine/carboplatin (49.3%), gemcitabine alone (21.2%), carboplatin alone (14.8%), cisplatin alone (8.4%), and methotrexate/vinblastine/ adriamycin/carboplatin (0.8%). On logistic regression, increasing age (OR 0.91, 95%CI 0.88 – 0.94, p < 0.0001), Hispanic/Latin ethnicity (OR 0.49, 95%CI 0.22 – 1.10, p = 0.08), and ≥moderate renal dysfunction (OR 0.20, 95%CI 0.08 – 0.51, p < 0.001) were associated with lower odds of SOC NAC. Non-SOC NAC was associated with higher BCSM (competing risk) and lower OS (KM) vs. IC and SOC NAC. On multivariable analysis, non-SOC NAC was associated with higher risk of BCSM (HR 1.35, 95%CI 1.06 – 1.72, p = 0.01) and lower OS (HR 1.38, 95%CI 1.11 – 1.70, p = 0.003) vs. SOC NAC. Conclusions: About 50% of pts receiving NAC were not treated with SOC regimens. Non-SOC NAC was associated with higher bladder cancer death risk. This stresses the role of SOC NAC ideally in a multidisciplinary expert setting, as well as the need for timely RC and neoadjuvant clinical trials, including cisplatin-ineligible pts.
Gemcitabine plus carboplatin versus gemcitabine plus oxaliplatin in cisplatin unfit patients with advanced urothelial carcinoma: A randomized phase II study (COACH, KCSG GU10-16).
Authors: Lee Jae-Lyun , Kim Bong-Seog , Lim Ho Yeong , Kim Hee Jun , Park Inkeun , Choi Yoon Ji , Park Kyong Hwa , Lee Kyung Hee , Yoon Shinkyo , Hong Bumsik , Hong Jun Hyuck , Ahn Hanjong
Published: May 2019

4534

Background: We investigated the activity and safety of first-line gemcitabine-oxaliplatin (GemOx) compared with gemcitabine-carboplatin (GCb) in cisplatin-ineligible patients with advanced UCCC. Methods: Treatment naïve, cisplatin-ineligible patients with advanced UCCC were randomly assigned to GemOx [gemcitabine 1,000 mg/m2, oxliplatin 100 mg/m2 on day 1 (D1) every 2 weeks] or GCb (gemcitabine 1,000 mg/m2 on D1 and D8, carboplatin AUCC 4.5 on D1 every 3 weeks) stratified by ECOG performance status (PS) and visceral metastases. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Between January 2011 and Mar 2017, 80 patients were enrolled; 39 patients and 40 patients were allocated to GCb and GemOx arm, respectively. Median age was 72 years (range 46-84) in GCb arm and 72.5 (55-85) in GemOx arm. ECOG PS was 2 in 41% (GCb arm) and 43% (GemOx arm), and median GFR was 45 ml/min (interquartile range 36-56) in GCb and 47 ml/min (37-56) in GemOx arm. ORR were 48.7% and 55.0% in GCb and GemOx, respectively. With a median follow-up duration of 37.8 months, median PFS and OS in GCb and GemOx arm were 5.5 months (95% CI, 4.8-6.2) vs. 4.4 months (95% CI, 2.7-6.1) and 9.1 months (95% CI, 5.2-13.0) vs. 11.0 months (95% CI, 6.9-15.0), respectively. Grade 3 leukopenia, neutropenia and fatigue were significantly more common in GCb arm (26% vs. 3%, p=0.003; 33% vs. 10%, p=0.014; 15% vs. 3%, p=0.057) while any grade neuropathy was more common in GemOx (8% vs. 60%, p<0.001). Conclusions: GemOx has showed comparable efficacy with GCb and favorable hematologic toxicity profile. GemOx may be used as a new option for UCCC patients who are not suitable for platinum-containing chemotherapy. Clinical trial information: NCT01487915.
FGFR-altered, advanced urothelial carcinoma (UC) and response to chemotherapy prior to receiving erdafitinib.
Authors: Necchi Andrea , Siefker-Radtke Arlene O. , Zhong Bob , Mahadevia Parthiv Jasvant , Santiago-Walker Ademi E. , De Porre Peter , Loriot Yohann
Published: May 2019

4542

Background: FGFR-altered, advanced UC has predominantly a luminal 1 subtype, which is associated with lower response rates to immunotherapy and possibly also to chemotherapy. Objective response rates (ORR) for first-line cisplatin-based regimens, such as gemcitabine-cisplatin (gem/cis) and methotrexate-vinblastine-doxorubicin-cisplatin (MVAC), historically range between 45-60% and for gemcitabine-carboplatin (gem/carbo) 35-45%. However, the ORR on chemotherapy for the ~20% of patients with FGFR-altered tumors is unknown. Methods: BLC2001 (NCT02365597) is an ongoing global open-label phase 2 study of the pan-FGFR inhibitor erdafitinib in patients with locally advanced or metastatic UC with specific FGFR2/3 gene alterations. Patients who had received first-line (1L) or second-line (2L) chemotherapy for advanced UC were identified. Investigator-reported ORR (complete + partial responses) and median time to progression (TTP) on these pretreatments were analyzed. Results: Of 210 patients treated with erdafitinib in BLC2001, 191 had received prior systemic therapy including 184 and 83 patients who had received 1L and 2L chemotherapy, respectively. ORR were 29.3% (54/184; 95% CI 22.8%, 35.9%) to 1L chemotherapy and 24.1% (20/83; 95% CI 14.9%, 33.3%) to 2L chemotherapy. 1L therapy consisted of gem/cis in 94 patients, gem/carbo in 59 patients, and MVAC in 22 patients, with ORR (95% CI) of 35.1% (25.5%, 44.8%), 25.4% (14.3%, 36.5%), and 22.7% (5.2%, 40.2%), respectively. In the 2L setting, of 46 patients who had received a regimen containing a taxane (paclitaxel or docetaxel) or vinflunine, 8 patients (17.4%; 95% CI 6.4%, 28.3%) achieved an objective response. Median TTP was 7.16 mo (95% CI 6.18, 7.49) after 1L chemotherapy (7.6 mo for gem/cis, 6.3 mo for gem/carbo, and 5.3 mo for MVAC) and 4.35 mo (95% CI 3.3, 5.5) after 2L chemotherapy (3.6 mo for taxane or vinflunine). Conclusions: In this post-hoc analysis, the overall ORR to prior 1L chemotherapy was lower, but within the range expected based on historical data. Further investigation into the response to chemotherapy in FGFR alteration positive patients is warranted and may be useful for the development of 1L trials of combination therapy. Clinical trial information: NCT02365597.
Erdafitinib in high-risk patients (pts) with advanced urothelial carcinoma (UC).
Authors: Park Se Hoon , Loriot Yohann , Zhong Bob , Hussain Syed A. , Mahadevia Parthiv Jasvant , De Porre Peter , Siefker-Radtke Arlene O.
Published: May 2019

4543

Background: The pan-FGFR inhibitor erdafitinib exhibited a robust objective response rate (ORR) and tolerability among pts with FGFR2/3-altered advanced UC in the BLC2001 (NCT02365597) phase 2 study (Siefker-Radtke ASCO 2018 #4503). Here we report a post hoc subgroup analysis to explore efficacy among high-risk pts. Methods: The analysis included 99 BLC2001 pts who received the optimized dose regimen of 8 mg/d continuous (pharmacodynamically guided uptitrated to 9 mg/d per serum phosphate). Results for ORR, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed by select baseline variables, with high-risk defined as age >75 y, ECOG PS 2, hemoglobin <10 g/dL, visceral metastases, and 2 or 3 Bellmunt risk factors. Results: Efficacy results (Table) show investigator-assessed ORR >36% and median PFS >5 mo across all subgroups except ECOG PS 2. OS data are immature but generally follow the trend of PFS. With the exception of ECOG 2, there were no differences in G3/4 serious AE proportions by subgroup. Conclusions: The post hoc subgroup findings support that erdafitinib generally provides comparable efficacy in high-risk pts with FGFR-altered advanced UC as the overall population. Clinical trial information: NCT02365597. [Table: see text]
Immune correlates of CD73 expression in patients with urothelial carcinoma (UC).
Authors: Lin Edwin , Nussenzveig Roberto , Hahn Andrew W , Yandell Mark , Harshman Lauren Christine , Agarwal Neeraj , Tripathi Abhishek
Published: May 2019

4548

Background: Checkpoint inhibitors have improved outcomes in UC. However, response rates are low and additional mechanisms of immune evasion need to be ascertained. CD73 (encoded by NT5E) converts extracellular AMP to adenosine, which exerts an immunosuppressive effect in the tumor microenvironment by inhibiting infiltrating T and NK cells. Utilizing The Cancer Genome Atlas (TCGA) bladder cancer dataset, we evaluated correlations between NT5E expression and the immune milieu in UC. Methods: RNA-seq data from 411 primary UC tumor samples were obtained from the TCGA. Patients were split into low, intermediate, and high NT5E expression groups (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean). A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged expression of 18 previously validated genes (Ayers et al, 2017). NT5E expression was compared between tumors with high and low TIS scores and among the TCGA molecular subtypes. Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes and compared between NT5E expression groups (Charoentong et al, 2017). The Mann-Whitney U test assessed statistical significance, and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression was significantly higher in tumors with a high TIS score compared to those with low TIS score (P<0.0001) and correlated with expression of other immune checkpoints such as PD-L1, IDO and LAG-3 (each P<0.01). Patients with basal/squamous subtype had the highest NT5E expression compared to luminal or neuronal subtypes. High NT5E expression was associated with increased infiltrating NK cells, neutrophils, Tregs and decreased Type 2 T helper cells. Conclusions: High expression of NT5E in UC patients with an inflamed tumor phenotype was associated with an increase in infiltrating Tregs, and the basal/squamous subtype. Our findings highlight a potential role of CD73-adenosine pathway as a mechanism of immune evasion and a novel therapeutic target in UC. Further studies to assess the clinical impact of NT5E expression on outcomes in UC patients treated with immunotherapy are needed. AT and NA: equal contribution.
An FDA analysis of the association between adverse events and outcome in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody.
Authors: Weinstock Chana , Maher Virginia Ellen , Fernandes Laura L. , Tang Shenghui , Agrawal Sundeep , Brave Michael Holman , Ning Yang-Min , Singh Harpreet , Suzman Daniel L. , Xu James , Goldberg Kirsten B. , Sridhara Rajeshwari , Ibrahim Amna , Theoret Marc Robert , Beaver Julia A. , Pazdur Richard
Published: May 2019

4549

Background: To assess the relationship between tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. The datasets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the Investigator. Immune-mediated adverse events were defined as AESIs treated with topical or systemic corticosteroids. Results: In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti-PD-1/L1 antibody while a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared to those with no related AESI [hazard ratio (HR) 0.42; 95% CI: 0.37, 0.49]. Fifty-seven percent of responding patients with a related AESI reported a related AESI prior to documentation of response. Conclusions: Patients who responded to treatment with an anti-PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not appear to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.
A pilot presurgical study evaluating anti-PD-L1 durvalumab (durva) plus anti-CTLA-4 tremelimumab (treme) in patients (pts) with high-risk muscle-invasive bladder carcinoma (MIBC) who are ineligible for cisplatin-based neoadjuvant chemotherapy (NAC).
Authors: Gao Jianjun , Siefker-Radtke Arlene O. , Navai Neema , Campbell Matthew T , Slack Tidwell Rebecca , Guo Charles , Kamat Ashish M. , Matin Surena F. , Araujo John C. , Shah Amishi Yogesh , Msaouel Pavlos , Blando Jorge M. , Vence Luis M. , Duan Fei , Basu Sreyashi , Singh Shalini , Zhao Hao , Allison James Patrick , Dinney Colin P.N. , Sharma Padmanee
Published: May 2019

4551

Background: In MIBC pts, especially in those with high risk features including lymphovascular invasion, hydronephrosis, T3b disease, or variant histology, cisplatin-based NAC followed by cystectomy improves overall survival as compared with cystectomy alone. However, it is estimated that over 50% of pts with MIBC are ineligible for cisplatin-containing therapy. Therefore, we propose this pre-surgical trial with durva + treme for this population of pts. Methods: This is a single-arm, pre-surgical clinical trial with durva + treme in pts with localized, high-risk MIBC (cT2-T4a) who are ineligible for cisplatin-based NAC due to decreased renal function, neuropathy, hearing loss, or heart failure; or refuse cisplatin-based NAC (NCT02812420). Each patient receives durva (1500 mg) plus treme (75 mg) on weeks 1 and 5. Pts then undergo surgery at week 9-11. Pre- and post-treatment blood and tumor samples are collected for correlative biological analyses. Results: Twenty eight of 35 pts have been enrolled on this trial. Twenty-one pts have completed cystectomy as of 11/16/19. Of these 21 pts, 9 (43%) had pathologically complete response (pCR) and two (10%) had pathologic T1N0 (pT1) disease (≤pT1N0 rate = 52%). Fourteen of 21 (67%) had down-staging of disease. Of note, 10 of these 21 pts had 3-D mass (T3) on exam under anesthesia or clinical T4a disease; 5 of these 10 pts (50%) had pCR and one (10%) had pT1 disease (≤pT1N0 rate = 60%). Only 5 of 28 (17%) pts developed grade 3 immune related toxicity including hepatitis and amylase/lipase elevation, and two (7%) resulted in surgery delay for > 30 days. Immune profiling with CyTOF analysis of baseline peripheral blood indicates that pts with pCR have significantly lower frequency of a Th2 subset as compared to pts with up-staging of disease. In addition, gene expression profiling analysis of baseline tumor tissues demonstrates a significantly less immunosuppressive microenvironment in pts with pCR as compared to pts with up-staging of disease. Conclusions: Our data indicate that durva plus treme is an effective and safe neoadjuvant therapy for pts with MIBC ineligible for cisplatin-based therapy. Therefore, neoadjuvant therapy with durva + treme and a number of potential biomarkers warrant testing in a larger phase 3 trial. Clinical trial information: NCT 02812420.
Causes of patient ineligibility in clinical trials of metastatic urothelial cancer.
Authors: Ison Gwynn , Maher Virginia Ellen , Weinstock Chana , Agrawal Sundeep , Brave Michael Holman , Ning Yang-Min , Singh Harpreet , Xu James , Ibrahim Amna , Beaver Julia A. , Pazdur Richard
Published: May 2019

4556

Background: Registrational trials of PD-1/PD-L1 inhibitor therapy help inform clinicians and patients about the expected outcomes of patients receiving these drugs. However, the clinical trial population does not reflect all patients with the underlying disease. There have been ongoing efforts to expand eligibility criteria for clinical trial enrollment that are expected to mitigate some of these factors. We reviewed four registrational trials of PD-1/PD-L1 inhibitor therapy to better understand why patients were deemed ineligible for trial enrollment and whether expanded eligibility criteria may have addressed the reasons for ineligibility. Methods: We reviewed four trials that led to approval of PD-1/PD-L1 inhibitor therapy. These trials screened 1931 and enrolled 1253 patients with metastatic or locally advanced urothelial cancer who had previously received platinum-based therapy. We examined the datasets to determine patient demographics and reasons for trial ineligibility. Results: There were no differences in the demographics characteristics of patients who were eligible or ineligible for study treatment. However, when compared to the SEER database the screened population was younger, and minorities were under-represented. Causes of patient ineligibility included: 1) Lack of Tumor Tissue/PD-L1 Low Tumor Staining (23%), 2) Underlying Disease characteristics were not met (19%), 3) Laboratory Abnormalities (18%), 4) Excluded Co-morbid Conditions (16%), 5) Poor Performance Status (15%), 6) Refused Consent (10%), 7) Other (7%), and 8) Incorrect Prior Therapy (5%). Conclusions: Clinical trial accrual should be representative of all patients with the underlying disease. Changes in trial eligibility criteria such as less stringent requirements concerning tumor tissue (when possible), co-morbid conditions, laboratory abnormalities, and performance status may improve patient accrual. These, when added together, formed the majority of the reasons for clinical trial ineligibility.
RNAseq and DNA whole-exome sequence analysis reveal novel response signatures to IO treatment in muscle invasive bladder cancer (MIBC) patients.
Authors: Mayhew Gregory , Shibata Yoichiro , Uronis Joshua M , Hayward Michele C , Rose Tracy L , Kim William Y. , Perou Charles M. , Lai-Goldman Myla , Milburn Michael Vance
Published: May 2019

4558

Background: Objective: To examine in a cohort of anti-PD-(L)1 immune checkpoint inhibitors (ICP) treated urothelial cancer patients a strategy combining treatment outcomes with molecular alterations, pathways, and immune/tumor microenvironment features to determine potential responder and rapid-progression signatures. Methods: De-identified clinical history and treatment outcomes were collected on 109 MIBC patients treated with ICP agents. Archived FFPE samples from these patients were obtained and processed for mRNAseq, exome-seq, tumor mutation burden (TMB), microsatellite instability (MSI) and mutation panel testing. Comprehensive tumor/immune profiling is being analyzed in the context of ICP treatments and RECIST 1.1 outcomes. A 60 gene MIBC 4-typer expression subtyper and other response associated predictors are used to stratify and identify positive/negative ICP response indicators. Results: 109 patients were identified (median age 75, 64% male, 78% white, 17% black). 74% of patients had received prior platinum-based chemotherapy, and 12% had received 2 or more prior lines of therapy. At initiation of ICP, 28% of patients had hemoglobin < 10, 30% had liver metastases, and 59% had ECOG performance status > 0. Mutation analysis of the first 66 patients showed TP53 (n = 34, 52%), FGFR (n = 17, 26%), CDKN2A (n = 13, 20%) and RB1 (n = 12, 18%) as the top alterations. No patients (0/8) with known pathogenic mutations in FGFR3 (S249C and TACC3-fusion) responded to ICP. Of patients with T2 staging prior to ICP (37/66), overall survival was markedly shorter (2.7 years) in those possessing FGFR3 mutations (n = 6/37) compared to that for FGFR3 WT patients (5.7 years, n = 31/37; p = 0.045). Further analyses of molecular features relative to treatment outcomes are ongoing to characterize response signatures. Conclusions: Our preliminary cohort of patients with pathogenic FGFR3 alterations showed 0% favorable response to ICP. We are expanding on this observation with further comprehensive molecular analyses and retrospective treatments/outcomes data. We anticipate identifying expression signatures that reflect ICP patient responder/non-responder signatures that may aid in future therapy decisions.
A reduced pazopanib dose with food: Is it more patient-friendly and does it reduce drug costs?
Authors: Lubberman Floor , Gelderblom Hans , Hamberg Paul , Vervenne Walter , Mulder Sasja F. , Jansman Frank , Colbers Angela , Van Der Graaf Winette T.A. , Burger David , Luelmo Saskia , Moes Dirk Jan A.R. , Van Herpen Carla M.L.- , Van Erp Nielka P.
Published: May 2019

4564

Background: Pazopanib has been licensed for advanced soft tissue sarcoma and metastatic renal cell carcinoma in a fixed oral daily dose of 800mg taken fasted. We hypothesized that ingesting pazopanib with food may improve patients’ comfort and reduce gastro-intestinal adverse events. Moreover, a food intervention, resulting in a better absorption, can lead to a lower dose, which could significantly reduce treatment costs. Methods: Part 1 of the study was performed to determine whether 600mg pazopanib taken with a continental breakfast was bioequivalent to 800mg pazopanib taken fasted. In part 2, differences in GI-toxicity and patient satisfaction were assessed by the cancer-therapy-satisfaction-questionnaire after both intake regimens. Finally, patient’s preference for either intake regimen was asked. Results: 16 patients were included in the bioequivalence study. The geometric mean ratio (fed/fasted) of the area under the plasma concentration time curve was 1.10 (90% CI 1.00-1.19), maximum peak concentration was 1.12 (90% CI 1.02-1.22) and pazopanib trough concentration was 1.10 (90% CI 1.02-1.18). In part 2, 60 patients were included. No differences were seen in the occurrence of GI-toxicities under both intake regimens. Patients seem to be more positive about their feelings about side effects (72.3(95% CI 68.1-76.5) vs 68·2 (62.7-73.6); p=.092) and satisfaction with therapy scores were higher (84.7(95% CI 81.4-87.9) vs 81.9 (78.7-85.2); p= .059) when pazopanib was taken with food. 41 (68%) of the patients preferred the intake with continental breakfast. Conclusions: Intake of 600mg pazopanib with food results in bioequivalent exposure and was preferred over a standard pazopanib dose without food. Moreover, with this simple food intervention a large cost reduction can be realized in patients treated with pazopanib. Clinical trial information: NCT02138526.
Comparative genomic profiling from tumor tissue and circulating tumor DNA (ctDNA) in 111 patients (Pts) with metastatic clear cell renal cell carcinoma.
Authors: Kotecha Ritesh , Gedvilaite Erika , Murray Samuel J. , Motzer Robert J. , Tsui Dana , Voss Martin Henner
Published: May 2019

4565

Background: Circulating tumor DNA (ctDNA) assessment is a non-invasive approach for genomic interrogation of solid tumors. As a novel tool, key benchmarks for applications in metastatic clear cell renal cell carcinoma (mccRCC) are yet to be determined. To understand the utility of ctDNA, we performed a large cohort analysis using a comparative genomics approach integrating matched primary tissue and ctDNA genomic data. Methods: Pts with prior tumor mutational profiles generated via next generation sequencing (NGS) from nephrectomy or metastatic specimens underwent single-time point plasma collection. Targeted NGS sequencing with MSK-IMPACT was performed on tumor and ctDNA with subsequent bi-directional cross genotyping using Waltz 2.0. All pts had matched germline comparison from peripheral blood; clinical data was extracted from medical record. Liberal (1-2 reads) and stringent (≥3 reads) filters were applied, with a cut-off of < 30% allele frequency to remove germline mutations. Results: 111 mccRCC pts, of whom available IMDC-risk was favorable (35%), intermediate (60%), and poor-risk (5%) were included for analysis. The median time between tissue and ctDNA collection was 23 months (R: 1-177), and 96% of patients had undergone nephrectomy prior to ctDNA collection. In primary tissue sequencing, 64/111 (58%) from nephrectomy and 42/111 (42%) from metastatic sites, 569 unique alterations were identified across the whole cohort, with a median of 4 mutations/pt (R:1-23). RCC-specific alterations included VHL (88%), PBRM1 (48%), SETD2 (34%), KDM5C (17%), TP53 (14%). Across the cohort, 176 alterations were identified in ctDNA. With cross genotyping, ctDNA alterations concordant with primary tumors were detected in 20% (22/111 pts, 28 unique alterations) using stringent criteria with a median of 1 mutation/pt (R:1-2). Using liberal criteria, concordance with primary tumors was 59% (66/111 pts, 142 unique alterations) with a median of 2 mutations/pt (R: 1-8). Conclusions: This large cohort study matching oncogenomics from tumor and ctDNA highlights complexities and challenges of applying liquid biopsy in biomarker development in mccRCC.
Retrospective analysis of the safety and efficacy of immune checkpoint inhibitors (CPI) among patients (pts) with pre-existing autoimmune disorders (AD) and renal cell carcinoma (RCC) or urothelial carcinoma (UC).
Authors: Martinez Chanza Nieves , Xie Wanling , Issa Majd , Dzimitrowicz Hannah Elizabeth , Tripathi Abhishek , Beuselinck Benoit , Lam Elaine Tat , Zakharia Yousef , McKay Rana R. , Shah Sumit , Mortazavi Amir , Harrison Michael Roger , Choueiri Toni K. , Harshman Lauren Christine
Published: May 2019

4571

Background: RCC and UC pts with clinically significant AD were generally excluded from CPI trials due to potential AD exacerbation. Thus, the safety and clinical activity of CPI in AD pts are not well characterized. Methods: We retrospectively collected data from RCC and UC pts with AD treated with CPI at 9 centers. Adverse events (AEs) were assessed using CTCAEv5 criteria. Objective response rate (ORR) was assessed by RECIST principles. Overall survival (OS) was estimated by Kaplan Meier. Results: Of 103 pts (57 RCC & 46 UC) with a broad spectrum of AD such as psoriasis (22%), thyroiditis (20%), rheumatoid arthritis (13%), polymyalgia rheumatica (8%), inflammatory bowel disease (6%), multiple sclerosis (3%) and lupus (3%), most received CPI as 1st or 2nd line (77% RCC, 93% UC) and anti-PD-1/L1 monotherapy (65% RCC, 98% UC). At CPI start, 36 had clinically active AD (all grade 1-2) and 4(11%) requiring systemic immunosuppression. AD exacerbations occurred in 37% (n = 38); most frequent: arthritis (12% RCC, 24% UC), rash (11% RCC, 9% UC). New onset immune related (ir) AEs occurred in 36% (n = 37); most frequent: colitis (12% RCC, 4% UC), rash (11% RCC, 9% UC), hypothyroid (each 7%), nephritis (7% UC). Table details timing and management. Median followup was 12.5 (1-52) mos for RCC and 14.5 (1-53) mos for UC. Median time on CPI was 6 mos (1-36) RCC and 4 mos (0.5-40) UC. At data cutoff, 39 RCC & 36 UC had discontinued CPI; 16% for toxicity. ORR was 31% for RCC and 35% for UC. 1 yr-OS rate was 74% (95%CI 58-84) for RCC and 60% (95%CI 43-74) for UC. Conclusions: AD exacerbations or new irAEs occurred in 37% and 36% respectively and were generally manageable. Only a minority required CPI cessation due to toxicity. [Table: see text]
Systemic therapy for advanced clear cell renal cell carcinoma (ccRCC) after progression on immune-oncology plus VEGF targeted therapy combinations (IO-VEGF).
Authors: Ged Yasser , Gupta Ruby , Duzgol Cihan , Shapnik Natalie , Redzematovic Almedina , Kotecha Ritesh , Voss Martin Henner , Feldman Darren R. , Akin Oguz , Patil Sujata , Motzer Robert J. , Rini Brian I. , Lee Chung-Han
Published: May 2019

4576

Background: IO-VEGF combinations are the backbone for current and future therapeutic developments in RCC with several IO-VEGF regimens reporting positive results in phase 3 trials. However, limited data exists on outcomes to subsequent therapy in patients progressing on IO-VEGF regimens. Methods: A retrospective analysis was performed on patients with ccRCC at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic Cancer Institute who initiated systemic therapy post IO-VEGF regimens including combinations with VEGFR tyrosine kinase inhibitors (IO-TKI) and combinations with anti-VEGF monoclonal antibodies (IO-mAB). Patients treated on unreported clinical trials were excluded from the outcomes analysis. The primary objective was to evaluate the overall survival (OS) post IO-VEGF. The secondary objectives included objective response rate (ORR) and progression-free survival (PFS) according to RECIST v1.1. Kaplan-Meier methods and the log-rank test were used to evaluate time from start of systemic therapy post IO-VEGF to the event of interest. Results: Fifty-nine patients were treated after discontinuation of IO-VEGF regimens. Prior IO-VEGF regimens included IO-mAB (n = 35, 59%) and IO-TKI (n = 24, 41%). IMDC scores at the start of next line of therapy were favorable in 20%, intermediate in 60% and poor in 20%. Next line of therapy included VEGFR-TKI monotherapy (n = 45, 76%), VEGFR-TKI based combinations (n = 6, 10%), mTOR inhibitors (n = 3, 5%), and unreported clinical trials (n = 5, 9%). VEGFR-TKI containing regimens (n = 51) included cabozantinib (n = 22), axitinib (n = 17), lenvatinib/everolimus (n = 4), pazopanib (n = 4), and others (n = 4). Median OS was 24.5 months (95% CI 12-NE) with a 12 months OS rate of 63%. The ORR was 27% (14/51) and the median PFS was 6.8 months (95% CI 4.8-11). No difference in post IO-VEGF OS was observed when comparing IO- TKI vs IO-mAB (log rank p = 0.7). Conclusions: Post combination IO-VEGF treatment, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs continue to show clinical activity similar to historic experiences of patients post VEGF monotherapy.
First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal-cell carcinoma (mRCC): Results from the international mRCC database consortium (IMDC).
Authors: Dudani Shaan , Graham Jeffrey , Wells Connor , Bakouny Ziad , Pal Sumanta K. , Dizman Nazli , Donskov Frede , Porta Camillo , de Velasco Guillermo , Hansen Aaron Richard , Iafolla Marco Adelmo James , Beuselinck Benoit , Vaishampayan Ulka N. , Wood Lori , Liow Elizabeth Chien Hern , Yan Flora , Yuasa Takeshi , Bjarnason Georg A. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: May 2019

4577

Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L IO-VEGF (IOVE) inhibitor combinations. Comparative data between these two strategies are limited and the efficacy of subsequent therapies remains unknown. Methods: Using the IMDC dataset, patients (pts) treated with any 1L IOVE combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 188 pts received 1L IO combination therapy: 113 treated with IOVE combinations and 75 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups. When comparing IOVE combinations vs ipi-nivo, 1L response rate (RR) was 33% vs 40% (p=0.39), time to treatment failure (TTF) was 14.3 (95% CI 9.2-16.1) vs 10.2 months (95% CI 6.7-15.1, p=0.23), and median overall survival (OS) was not reached (NR) (95% CI 22.3-NR) vs NR (95% CI 35.1-NR, p=0.17). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.71 (95% CI 0.46-1.12, p=0.14) and the HR for death was 1.74 (95% CI 0.82-3.68, p=0.14). Second-line (2L) treatments were varied. In pts receiving subsequent VEGF-based therapy, 2L RR was lower in the IOVE (n=20) versus ipi-nivo (n=20) cohort (15% vs 45%; p=0.04), though 2L TTF was not significantly different (3.7 vs 5.4 months, p=0.40, n=55). The use of IO post IOVE was uncommon and 3/5 pts had PD as best response; 2/5 had PR/SD but their 1L IOVE exposure was short at <3 months. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as lOVE combinations and ipi-nivo have comparable 1L RR, TTF and OS. Most pts received VEGF-based therapy in the 2L. In this group, 2L RR was greater in pts who received ipi-nivo, though there was no difference in 2L TTF. [Table: see text]