ABSTRACT
PURPOSE: Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution. EXPERIMENTAL DESIGN: Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment. RESULTS: FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2). CONCLUSIONS: FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.
Subject(s)
Carcinoma, Transitional Cell , Cell-Free Nucleic Acids , Urinary Bladder Neoplasms , Humans , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/pathology , Receptor, Fibroblast Growth Factor, Type 3/genetics , Treatment Outcome , GenomicsABSTRACT
PURPOSE: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.
Subject(s)
Adenocarcinoma , Carcinoma, Transitional Cell , Colorectal Neoplasms , Urinary Bladder Neoplasms , Adenocarcinoma/genetics , Carcinoma, Transitional Cell/genetics , Colorectal Neoplasms/pathology , Genomics/methods , Humans , Phenotype , Retrospective Studies , Urinary Bladder/pathology , Urinary Bladder Neoplasms/geneticsABSTRACT
INTRODUCTION: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. RESULTS: One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (Subject(s)
Carcinoma, Small Cell
, Urinary Bladder Neoplasms
, Carcinoma, Small Cell/pathology
, Chemotherapy, Adjuvant
, Cystectomy
, Genomics
, Humans
, Neoadjuvant Therapy
, Retrospective Studies
, Urinary Bladder/pathology
, Urinary Bladder Neoplasms/drug therapy
, Urinary Bladder Neoplasms/genetics
, Xeroderma Pigmentosum Group D Protein
ABSTRACT
Enfortumab Vedotin (EV) is FDA-approved for advanced urothelial cancer in patients previously treated with platinum-based chemotherapy and a checkpoint inhibitor. We conducted a real-world study to determine the extent of EV wastage in a single institution and assessed the financial impact of EV wastage annually in the United States. Systematic examination of the usage and wastage of all standard-of-care EV treatments administered to urothelial cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) between 1 January 2020 and 31 December 2020 was performed. Drug wastage was calculated by subtracting the actual administered dose from the total dose in an optimal set of vials. We built a pharmacoeconomic model to assess the financial impact of EV wastage annually in the US using the January 2021 Average Sales Prices from the Centers for Medicare and Medicaid Services. Sixty-four patients were treated with standard-of-care EV, with a median of 11 doses per patient (range 1-28). Wastage occurred in 46% of administered doses (367/793), with a mean waste per dose of 2.9% (0-18%). The average drug wastage cost per patient was $3127 ($252/dose). The annual cost of EV wastage in the US is estimated to be $15 million based on wastage data from a single center in the US. In summary, EV wastage due to available vial sizes was 2.9%, which falls under acceptable thresholds. While the percentage of EV wastage is relatively low, waste-minimizing practices may reduce the financial toxicity for the individual patient and for society.
ABSTRACT
BACKGROUND: The worldwide Coronavirus disease 2019 (COVID-19) public health pandemic has restructured clinical care of patients with cancer throughout the world. The specific changes in the management of genitourinary (GU) cancers in different cancer centers owing to COVID-19 are not known, and some clinical scenarios remain controversial. We conducted an opinion survey to determine what changes in cancer treatment strategies are occurring owing to the COVID-19 pandemic. MATERIALS AND METHODS: A 20-item online survey was sent on May 25, 2020 to 170 expert GU medical oncologists from Europe and North America. The survey solicited responses to changes in GU cancer management in the setting of the COVID-19 pandemic. Data was collected and managed via a secure REDCap Database. RESULTS: Surveys were completed by 78 (45.8%) of 170 GU oncologists between May 25, 2020 and June 25, 2020. Clinical practice changes owing to COVID-19 in at least one scenario were reported by 79.1% of responders, most pronounced in prostate cancer (71.8%) and least pronounced in urothelial cancer (23%). Preferences for change in management varied by country, with 78% (37/47) of United States oncologists indicating a change in their practice, 57% (4/7) of Canadian oncologists, and 79% (19/24) of European oncologists. CONCLUSIONS: This study suggests international practice changes are occurring in GU cancer care during the COVID-19 pandemic. The variability in practice changes between countries may reflect differences in COVID-19 case load during the time point of data collection. These results, based on expert opinion during this rapidly changing crisis, may inform the oncologic community regarding the effects of COVID-19 on GU cancer care.
Subject(s)
COVID-19/prevention & control , Medical Oncology/methods , Telemedicine , Urogenital Neoplasms , COVID-19/epidemiology , COVID-19/psychology , Expert Testimony , Humans , Internet , Medical Oncology/trends , Pandemics , Public Health , SARS-CoV-2 , Surveys and Questionnaires , Urogenital Neoplasms/diagnosis , Urogenital Neoplasms/therapy , Urology/organization & administrationABSTRACT
BACKGROUND: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC. METHODS: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified. RESULTS: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively. CONCLUSIONS: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Immune Checkpoint Inhibitors/therapeutic use , Mutation , Neoadjuvant Therapy/mortality , Urinary Bladder Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/genetics , Young AdultABSTRACT
BACKGROUND: Immune checkpoint blockade has made a significant impact on the clinical outcomes of patients with metastatic urothelial carcinoma (UC). However, evidence for this approach in patients with non-UC of the urinary tract is limited. METHODS: This was a phase II open-label study of durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for four cycles followed by durvalumab 1500 mg every 4 weeks. Eligible patients had metastatic non-UC with ECOG PS 0-1 regardless of prior therapy (except small cell carcinoma who were pretreated). The primary endpoint was overall response rate per RECIST v1.1. A Simon's minimax two-stage design was employed, with 13 patients planned for stage one. Pre-treatment tumors underwent PD-L1 staining and next-generation sequencing. RESULTS: Thirteen patients were treated, including seven small cell carcinoma, three squamous cell carcinoma, and three adenocarcinoma. Eleven patients had visceral metastases. No responses were observed; 11 patients had PD and 2 patients had SD. Median PFS was 1.8 months (95% CI, 1.25-not reached [NR]) with a median follow-up of 7.38 months (range, 5.23-21.99 months). Median OS was 6.97 months (95% CI, 4.34-NR). One patient's tumor was PD-L1 positive and all sequenced tumors (n = 8) were microsatellite stable. Grades 3-4 treatment-related adverse events occurred in 38.4% of patients. CONCLUSIONS: In a poor prognosis cohort of patients with non-UC, durvalumab and tremelimumab lacked clinical activity while demonstrating a manageable safety profile.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Small Cell/drug therapy , Carcinoma, Squamous Cell/drug therapy , Urologic Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Small Cell/pathology , Carcinoma, Squamous Cell/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Response Evaluation Criteria in Solid Tumors , Survival Rate , Urologic Neoplasms/pathologyABSTRACT
BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.
Subject(s)
Aminopyridines/therapeutic use , Morpholines/therapeutic use , Phosphatidylinositol 3-Kinase/therapeutic use , Urologic Neoplasms/drug therapy , Aged , Aged, 80 and over , Aminopyridines/pharmacology , Cell Line, Tumor , Female , Humans , Male , Middle Aged , Morpholines/pharmacology , Neoplasm Metastasis , Phosphatidylinositol 3-Kinase/pharmacologyABSTRACT
INTRODUCTION: The aim of this study was to determine drug delivery/toxicity, and pathologic/surgical outcomes of patients with muscle-invasive bladder cancer (MIBC) receiving neoadjuvant gemcitabine-cisplatin (GC) plus radical cystectomy-pelvic lymph node dissection (RC-PLND). PATIENTS AND METHODS: Chemotherapy and surgical/pathologic outcomes were retrospectively analyzed with 5-year survival follow-up at a referral center. Post-neoadjuvant chemotherapy (NAC) pathologic endpoints included complete response (pT0N0), residual non-MIBC (pTa/Tis/T1N0), and ≥ MIBC (≥ pT2 and/or N+). Associations of pathologic/surgical findings with overall survival (OS), disease-free survival (DFS), and surgical management with RC-PLND were analyzed (Cox regression). RESULTS: Clinical T2a-T4aN0M0 MIBC patients (n = 154) from January 2000-October 2012 received GC plus RC-PLND. Patients (n = 117; 76%) received GC × 4 and 136 (88%) GC × 3. Five-year OS was 61% (95% confidence interval [CI], 53-71). Median number of resected lymph nodes (LNs) was 19. Down-staging was observed as follows: pT0N0: 21%; pTa/Tis/T1N0: 25%, with similar 5-year OS (85% and 89%, respectively). Five-year OS for < pT2 versus ≥ pT2 residual disease was 87% (95% CI, 78%-98%) versus 38% (95% CI, 27%-53%); P < .001. Post-NAC stage ≥ pT2 (HR, 6.79; 95% CI, 2.63-17.53; P < .001), positive LN (HR, 3.64; 95% CI, 1.84-7.19; P < .001), and positive margins (HR, 4.15; 95% CI, 1.68-10.25; P = .002) were associated with increased risk of all-cause death (multivariable analysis). An HR of 0.97 (95% CI, 0.94-1.00) was observed for each additional node removed, but this effect was not statistically significant (P = .056). CONCLUSIONS: Neoadjuvant GC achieves meaningful pathologic responses. Patients with ≥ pT2 residual disease, positive margins, or positive LN post-chemotherapy have inferior survival.
Subject(s)
Cystectomy , Urinary Bladder Neoplasms , Cisplatin , Deoxycytidine/analogs & derivatives , Humans , Lymph Node Excision , Muscles , Neoadjuvant Therapy , Retrospective Studies , Treatment Outcome , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/surgery , GemcitabineABSTRACT
Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m2 on day 1 and cisplatin 35 mg/m2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cystectomy , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Female , Filgrastim/administration & dosage , Humans , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Invasiveness , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Polyethylene Glycols/administration & dosage , Prospective Studies , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , GemcitabineABSTRACT
Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.
Subject(s)
Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , DNA Damage/genetics , DNA Repair/genetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Urologic Neoplasms/drug therapy , Urologic Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/immunology , Biomarkers, Tumor/genetics , Female , Humans , Male , Middle Aged , Mutation , Programmed Cell Death 1 Receptor/immunology , Progression-Free Survival , Prospective Studies , Urologic Neoplasms/immunologyABSTRACT
OBJECTIVE: To examine germline single nucleotide polymorphisms (SNPs) as markers of response to gemcitabine platinum (GP) combination chemotherapy in urothelial carcinoma (UC). METHODS: Saliva or blood was prospectively collected from 216 patients treated with GP for UC of the bladder between 1991 and 2011. Based on reported associations with gemcitabine and cisplatin response or putative mechanisms of gemcitabine or cisplatin/carboplatin activity, we selected SNPs of interest and were able to genotype 59 SNPs (using the SequenomMass ARRAYiPLEX platform) in 261 patients randomly split 2/3 into a training set (n = 174) and 1/3 into a test set (n = 87). Logistic regression was used to test the association between response to GP and SNPs. RESULTS: The median age at diagnosis was 64 years (range: 28 - 85) for the discovery set and 67 years (range: 30 - 84) for the validation set. Males composed 76% and 69%, and white non-Hispanics composed 88% and 91% of the training and test validation sets, respectively. Three SNPs on GALNTL4 (rs7937567, rs12278731, and rs9988868) and one intergenic SNP (rs1321391) were significantly associated with response to GP in the training set and were used to build a SNP score. However, when assessed in the test set, the SNP score was not significantly associated with response. CONCLUSION: Multiple SNPs selected from previous studies failed to predict response to GP in this cohort. Larger studies capable of accounting for population-based allele frequency heterogeneity may be required for replication of genetic alterations important to pharmacogenomics.â©.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carboplatin/pharmacokinetics , Carcinoma/drug therapy , Cisplatin/pharmacokinetics , Deoxycytidine/analogs & derivatives , N-Acetylgalactosaminyltransferases/genetics , Pharmacogenomic Variants , Polymorphism, Single Nucleotide , Urinary Bladder Neoplasms/drug therapy , Urothelium/drug effects , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/blood , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma/genetics , Carcinoma/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cisplatin/blood , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Female , Genotype , Humans , Introns , Logistic Models , Male , Middle Aged , Models, Genetic , N-Acetylgalactosaminyltransferases/metabolism , Pharmacogenetics , Phenotype , Prospective Studies , Treatment Outcome , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urothelium/pathology , Gemcitabine , Polypeptide N-acetylgalactosaminyltransferaseABSTRACT
BACKGROUND: Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs. OBJECTIVE: We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting. METHODS: Patients received gemcitabine 800âmg/m2 and cisplatin 35âmg/m2 on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5âmg QOD, DL2:5âmg daily, DL3:10âmg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination. RESULTS: 12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1 *(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1 * had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached). CONCLUSIONS: The maximum tolerated dose was reached at the lowest dose level, 5âmg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity.
ABSTRACT
BACKGROUND: The current study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable urothelial carcinoma (UC) who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev); or gemcitabine and cisplatin (GCis). METHODS: Patients with UC who were treated with GCbBev on protocol were analyzed prospectively and 2 contemporary control cohorts receiving GCb or GCis were evaluated retrospectively. VTE was defined as either venous or arterial (myocardial infarctions or cerebral vascular accidents) thrombosis. VTEs were considered to be related to treatment if they occurred during treatment or within 4 weeks of the completion of treatment. Associations with chemotherapy regimen were tested using either the Fisher exact test or Kruskal-Wallis test. Clinical factors associated with VTEs were analyzed using conditional logistic regression stratified by treatment regimen. RESULTS: Among 198 patients, VTEs occurred in 13 of 51 patients treated with GCbBev (26%), 22 of 92 patients treated with GCb (24%), and 8 of 55 patients treated with GCis (15%). Patient characteristics were significantly different between the treatment cohorts in terms of age, prior cystectomy, tumor location near pelvic vessels, Khorana risk group, and receipt of antiplatelet therapy. The incidence of VTE and type of VTE (arterial vs venous) did not differ by type of chemotherapy. Prior cystectomy was associated with an increased risk of VTE (odds ratio, 2.2; 95% confidence interval, 1.0-4.9 [P = .047]). CONCLUSIONS: The incidence of VTE in Cis-treated patients was similar to prior reports. However, the VTE rate in Cb-treated patients was > 20%, a figure not previously defined in patients with UC and higher than expected. This high incidence of both Cis-related and Cb-related VTEs warrants greater awareness by treating physicians and deserves further study. Cancer 2016;122:712-721. © 2015 American Cancer Society.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Myocardial Infarction/epidemiology , Stroke/epidemiology , Urologic Neoplasms/drug therapy , Venous Thromboembolism/epidemiology , Aged , Bevacizumab/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Transitional Cell/pathology , Carcinoma, Transitional Cell/secondary , Case-Control Studies , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Humans , Incidence , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Kidney Pelvis/pathology , Logistic Models , Male , Middle Aged , Prospective Studies , Retrospective Studies , Ureteral Neoplasms/drug therapy , Ureteral Neoplasms/pathology , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Urologic Neoplasms/pathology , GemcitabineABSTRACT
BACKGROUND: Pemetrexed is a commonly used treatment for platinum-resistant advanced urothelial carcinoma (UC) based on objective response rates of 8% and 28% in two small phase II studies. To address the discrepancy in reported response rates and to assess efficacy and toxicity outside of a clinical trial setting, we performed a large retrospective analysis of pemetrexed use at Memorial Sloan Kettering Cancer Center. We also investigated candidate prognostic factors for overall survival in this setting to explore whether the neutrophil-lymphocyte ratio (NLR) had independent prognostic significance. PATIENTS AND METHODS: Patients receiving pemetrexed for platinum-resistant advanced UC between 2008 and 2013 were identified. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to determine response rate. Kaplan-Meier and Cox regression analyses were used to examine the association of various factors with efficacy and survival outcomes. Hematologic toxicity and laboratory abnormalities were recorded. RESULTS: One hundred and twenty-nine patients were treated with pemetrexed. The objective response rate was 5% (95% confidence interval: 1%-9%), and the median duration of response was 8 months. Median progression-free survival (PFS) was 2.4 months, and the 6-month PFS rate was 14%. There was no significant difference in response rate by age, Eastern Cooperative Oncology Group (ECOG) performance status, or number of prior therapies. On multivariable analysis, ECOG performance status (p < .01), liver metastases (p = .02), and NLR (p < .01) had independent prognostic significance for overall survival. CONCLUSION: This 129-patient series is the largest reported data set describing pemetrexed use in advanced UC. Activity was modest, although discovery of molecular biomarkers predictive of response would be valuable to identify the small subset of patients who do gain significant benefit. Overall, the data highlight the urgent need to develop novel therapies for these patients.
Subject(s)
Carcinoma, Transitional Cell/drug therapy , Drug Resistance, Neoplasm/drug effects , Pemetrexed/administration & dosage , Urinary Bladder Neoplasms/drug therapy , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/pathology , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Pemetrexed/adverse effects , Platinum/administration & dosage , Prognosis , Treatment Outcome , Urinary Bladder Neoplasms/pathology , Urothelium/pathologyABSTRACT
BACKGROUND: The complete remission (CR) rate with salvage systemic therapy for urothelial carcinoma (UC) is unclear, and its value as an intermediate end point and association with survival are unknown. MATERIALS AND METHODS: Data from phase II trials of salvage chemotherapy and/or biologic agents were pooled. Data regarding response, overall survival (OS), progression-free survival (PFS), time from prior chemotherapy, hemoglobin, performance status, and liver metastasis status were collected. Cox proportional hazards regression was used to evaluate the association of CR and other prognostic factors with outcomes. RESULTS: A total of 789 of 818 patients enrolled in 12 phase II trials had evaluable data. CR and partial response were seen in 14 (1.8%) and 109 (13.8%) patients. Median (95% confidence interval) OS for those with a CR was 21.5 (14.2-34.3) months, compared with 6.7 (6.0-7.0) months in those without a CR (P < .001). Median (95% confidence interval) PFS for those with a CR was 15.7 (8.2-27.1) months, compared with 2.6 (2.4-2.8) months for those without a CR (P < .001). Prior cisplatin and time from prior chemotherapy of ≥ 3 months were associated with CR (P < .05). The presence of poor prognostic factors and suboptimal response to prior therapy did not preclude CR. CONCLUSION: CR occurs in 1.8% of patients receiving salvage therapy for advanced UC and is strongly associated with durable OS and PFS. CR warrants validation as an intermediate end point and may help select agents for further investigation and tumors for molecular interrogation.
Subject(s)
Biological Products/therapeutic use , Salvage Therapy/methods , Urologic Neoplasms/drug therapy , Urothelium/pathology , Aged , Clinical Trials, Phase II as Topic , Disease-Free Survival , Female , Humans , Male , Middle Aged , Proportional Hazards Models , Prospective Studies , Retrospective Studies , Survival Analysis , Treatment Outcome , Urologic Neoplasms/mortality , Urologic Neoplasms/pathology , Urothelium/drug effectsABSTRACT
UNLABELLED: What's known on the subject? and what does the study add?: No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention. In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required. OBJECTIVE: To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC). PATIENTS AND METHODS: The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks). In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center. The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate. A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤ 50%, as opposed to the alternative hypothesis of ≥ 70%. RESULTS: The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months. No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS. CONCLUSIONS: Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed. Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Sirolimus/analogs & derivatives , Urinary Bladder Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Carcinoma, Transitional Cell/secondary , Clinical Trials, Phase II as Topic , Everolimus , Female , Humans , Male , Middle Aged , Sirolimus/therapeutic use , Urinary Bladder Neoplasms/pathologyABSTRACT
PURPOSE: Although gemcitabine and carboplatin (GCa) is a standard option for patients with advanced urothelial cancer (UC) who are ineligible for cisplatin, outcomes remain poor. This trial evaluated the efficacy and safety of bevacizumab with GCa in advanced UC. PATIENTS AND METHODS: Patients with Karnofsky performance status of 60% to 70%, creatinine clearance less than 60 mL/min, visceral metastasis, or solitary kidney were eligible and received a lead-in dose of bevacizumab 10 mg/kg followed 2 weeks later by gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin at area under the [concentration-time] curve (AUC) 5.0 or 4.5 and bevacizumab 15 mg/kg on day 1 every 21 days for six cycles. Patients achieving at least stable disease (SD) continued bevacizumab 15 mg/kg every 21 days for 18 additional cycles. The study was powered to detect a 50% improvement in median progression-free survival (PFS) over a historical control. RESULTS: Fifty-one patients, median age 67 years (range, 42 to 83 years), were enrolled onto the study and were evaluable for toxicity. Twenty (39%) experienced grade 3 to 4 toxicity, and 10 (20%) had thromboembolic events (deep venous thrombosis or pulmonary embolism). Four received one or fewer cycles leaving 47 evaluable for outcomes. Twenty-three (49%) achieved response (three complete; 20 partial), and 11 had SD. Median PFS was 6.5 months (95% CI, 4.7 to 7.8 months); PFS was greater in the carboplatin AUC 5.0 group (P = .04). Median overall survival (OS) was 13.9 months. CONCLUSION: The 95% one-sided lower confidence bound of 4.77 months for median PFS did not meet the predesignated PFS of more than 4.8 months considered sufficient for further study. Median OS was greater than expected. An ongoing phase III trial in patients who are eligible for therapy with cisplatin will define the role of bevacizumab in UC.