The FDA on June 30, 2020 approved BAVENCIO® for maintenance treatment of patients with locally advanced or metastatic Urothelial Carcinoma (UC) that has not progressed with first-line Platinum-containing chemotherapy. BAVENCIO® is a product of EMD Serono, Inc.
Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)
JELMYTO® (Mitomycin)
The FDA on April 15, 2020 approved JELMYTO® for adult patients with low-grade upper tract urothelial cancer. JELMYTO® is a product of UroGen Pharma.
FDA Approves KEYTRUDA® for BCG-Unresponsive, High-Risk Non-Muscle Invasive Bladder Cancer
SUMMARY: The FDA on January 8, 2020, approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS) with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy.
The American Cancer Society estimates that for 2020, about 81,400 new cases of bladder cancer will be diagnosed in the US and about 17,980 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but is less common in women and the average age at the time of diagnosis is 73. Approximately 50% of all bladder cancers are non-invasive or in situ cancers. Patients with high-risk, Non-Muscle Invasive Bladder Cancer that has become unresponsive to BCG treatment, are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes.
KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. KEYTRUDA® is presently approved by the FDA for the treatment of patients with locally advanced or metastatic Urothelial carcinoma who are not eligible for Cisplatin-containing chemotherapy or for those with disease progression during or following platinum-containing chemotherapy, based on its durable antitumor activity in this patient group. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting that KEYTRUDA® may be of benefit in this group of patients.
This new FDA approval for KEYTRUDA® was based on the KEYNOTE-057 study, which is a multicenter, single-arm trial that enrolled 148 patients with high-risk NMIBC, of whom 96 patients had BCG-unresponsive CIS with or without papillary tumors. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Eligible patients had received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy. All patients had undergone TransUrethral Resection of Bladder Tumor (TURBT) to remove resectable disease. Patients with residual Carcinoma In Situ, not amenable to complete resection were permitted. Patients received KEYTRUDA® 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The median age was 73 years and the median number of prior BCG instillations was 12. More than half of patients (56.9%) had a PD-L1 Combined Positive Score (CPS) of less than 10, and most patients in this analysis had refused prior cystectomy. The Primary end point was Complete Response Rate (CRR) as defined by negative results for cystoscopy with TURBT/biopsies as applicable, urine cytology, and CT Urography imaging. Secondary end points included Duration of Response and Safety.
At a median follow up was 28 months the Complete Response Rate was 41% and the median Duration of Response was 16.2 months. Forty-six percent (46%) of responding patients experienced a Complete Response lasting at least 12 months. The most frequent adverse reactions were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, peripheral edema and hypothyroidism.
It was concluded from this study that KEYTRUDA® had encouraging activity in bladder cancer patients, with high-risk, BCG-unresponsive Carcinoma in Situ, with or without papillary tumors. The authors added that this study demonstrates that immune activation with systemically administered treatment can result in local activity in the bladder, as well as long-term durable remissions of cancer.
Keynote 057: Phase II trial of Pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). Balar AV, Kulkarni GS, Uchio EM, et al. J Clin Oncol 37, 2019 (suppl 7S; abstr 350)
KEYTRUDA® (Pembrolizumab)
he FDA on January 8, 2020 approved KEYTRUDA® for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS), with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy. KEYTRUDA® is a product of Merck & Co. Inc.
PADCEV® (Enfortumab vedotin-ejfv)
The FDA on December 18, 2019 granted accelerated approval to PADCEV® for adult patients with locally advanced or metastatic urothelial cancer who have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) inhibitor, and a Platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. PADCEV® is a product of Astellas Pharma US, Inc.
FDA Grants Accelerated Approval to PADCEV® for Metastatic Urothelial Cancer
SUMMARY: The FDA on December 18, 2019, granted accelerated approval to PADCEV® (Enfortumab vedotin-ejfv), for adult patients with locally advanced or metastatic urothelial cancer who have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand1 (PD-L1) inhibitor, and a Platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The American Cancer Society estimates that in 2019, approximately 80,470 new cases of Bladder Cancer will be diagnosed and 17,670 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen and a Check Point Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.
PADCEV® is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Following binding to Nectin-4 on the cell surface, PADCEV® becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. In a Phase I dose-finding study of PADCEV®, the Objective Response Rate (ORR) was 42% among patients with advanced urothelial cancer, who previously received treatment with a PD-1/PD-L1 inhibitor.
This FDA approval was based on the results from the pivotal Phase II EV-201 study, which is an open-label, single-arm, multicenter trial in which 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy were enrolled. Patients received PADCEV® 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle, until disease progression or unacceptable toxicity. The median age was 69 years. The Primary endpoint was ORR as assessed by blinded Independent Central Review. Secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Safety and Tolerability.
The ORR was 44%, with 12% Complete Responses and 32% Partial Responses. Overall, 84% of evaluable patients showed some degree of tumor shrinkage. The responses were noted at a median of 1.8 months after treatment initiation and the median Duration of Response was 7.6 months. These objective responses were seen in all patient subgroups evaluated, including those with poor prognostic features. The median PFS was 5.8 months, and the median Overall Survival was 11.7 months. The most common adverse reactions were fatigue, alopecia, decreased appetite and peripheral neuropathy. Blood glucose levels should be monitored closely in patients with, or at risk, for diabetes mellitus or hyperglycemia.
It was concluded from this study that treatment with PADCEV® demonstrated clinically meaningful Objective Response Rate, in patients with advanced metastatic urothelial cancer, who received prior treatment with a PD-1 or PD-L1 inhibitor and Platinum-based chemotherapy, thus fulfilling an unmet need. PADCEV® is the first Nectin-4-directed Antibody-Drug Conjugate to receive FDA approval, and a Phase III study is underway comparing PADCEV® against standard single-agent chemotherapy, in patients with advanced, previously treated metastatic urothelial cancer. EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. Petrylak DP, Balar AV, O’Donnell PH, et al. DOI: 10.1200/JCO.2019.37.18_suppl.LBA4505 Journal of Clinical Oncology 37, no. 18_suppl (June 20, 2019) 4505-4505.
FDA Approves BALVERSA® for Metastatic Urothelial Carcinoma
SUMMARY: The FDA on April 12, 2019 granted accelerated approval to BALVERSA® (Erdafitinib) for patients with locally advanced or metastatic Urothelial Carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations,that has progressed during or following platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Patients should be selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. The FDA also simultaneously approved the THERASCREEN® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a companion diagnostic for this therapeutic indication.
FGFRs are a family of Receptor Tyrosine Kinases, which may be upregulated in a variety of malignancies. The Fibroblast Growth Factor/Fibroblast Growth Factor Receptor (FGF/FGFR) signaling pathway regulates embryogenesis, adult tissue homeostasis, angiogenesis and wound repair, and is also pivotal in cell functions, including proliferation, differentiation, apoptosis and migration. Deregulated FGF/FGFR activations have been associated with developmental disorders and cancer progression. Following binding with a ligand, FGFRs activate downstream signaling pathways such as the Mitogen Activated Protein Kinase (MAPK), Signal Transducer and Activator of Transcription (STAT), the PhosphoInositide-3-Kinase (PI3K)/Akt pathways, and PLC-DAG-PKC pathway. FGFR isoforms have been shown to result in oncogenic FGFR signaling, which in turn promotes tumorigenesis. FGFR3 mutations have been described in approximately 75% of low-grade papillary bladder cancers, and FGFR3 overexpression has been noted in 42% of muscle-invasive bladder cancers. FGFR1 amplification has also been found in 3% of urinary bladder cancers. Patients with FGFR alterations have poor outcomes when treated with available therapies and these alterations occur in 20% of patients with metastatic Urothelial Carcinoma.
BALVERSA® (Erdafitinib) is a once-daily, oral, pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor. The approval of BALVERSA® was based on data from a cohort of 87 patients, enrolled in Study BLC2001, which is a multicenter, open-label, single-arm trial. Enrolled patients had locally advanced or metastatic Urothelial Carcinoma that had progressed during, or following at least one prior chemotherapy regimen, and had FGFR genomic alterations such as FGFR3 gene mutations or FGFR2 or FGFR3 gene fusions. Ten percent of patients were chemo naïve, 47% percent of patients had received two or more prior lines of therapy and 80% of patients had visceral metastases. Approximately 97% patients had prior Platinum based therapy and 24% of patients had received anti–PD-1/PD-L1 treatment. The median patient age was 67 years. Patients received BALVERSA® at a starting dose of 8 mg PO once daily. Patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17 (41% of the patients) had their dose increased to 9 mg once daily. Treatment was continued until disease progression or unacceptable toxicity. The Primary end point was Objective Response Rate (ORR).
The ORR was 32.2%, with Complete Responses in 2.3% and Partial Responses in 29.9%. Median response duration was 5.4 months. Responding patients included those patients who had previously not responded to anti PD-L1 or PD-1 treatment. The most common adverse reactions were increased serum phosphate, stomatitis, fatigue, increased serum creatinine, diarrhea, onycholysis, increased liver function studies and hyponatremia.
The authors concluded that treatment with BALVERSA® resulted in high Response Rates among patients with chemorefractory metastatic Urothelial Carcinoma with FGFR genomic alterations. BALVERSA® is the first approved personalized treatment, targeting susceptible FGFR genetic alterations, fulfilling an unmet need for these poor prognosis patients. First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). Siefker-Radtke AO, Necchi A, Park SH, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503)
BALVERSA® (Erdafitinib)
The FDA on April 12, 2019 granted accelerated approval to BALVERSA® (Erdafitinib) for patients with locally advanced or metastatic Urothelial Carcinoma, with susceptible FGFR3 or FGFR2 genetic alterations,that has progressed during or following Platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant Platinum-containing chemotherapy. Patients should be selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. The FDA also simultaneously approved the THERASCREEN® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a companion diagnostic for this therapeutic indication. BALVERSA® is a product of Janssen Pharmaceutical Companies.
KEYTRUDA® (Pembrolizumab) and TECENTRIQ® (Atezolizumab)
The FDA on August 16, 2018 updated the prescribing information for these two agents, to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are Cisplatin-ineligible. FDA approved two different companion diagnostic tests, the Dako PD-L1 IHC 22C3 PharmDx Assay (Dako North America, Inc.) as a companion diagnostic for treatment with KEYTRUDA® and Ventana PD-L1 (SP142) Assay® (Ventana Medical Systems, Inc.) as a companion diagnostic test for treatment with TECENTRIQ®.
KEYTRUDA® Improves Overall Survival in Advanced Urothelial Carcinoma
SUMMARY: The American Cancer Society estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a platinum based chemotherapy regimen. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.
The FDA approved KEYTRUDA® (Pembrolizumab) in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA subsequently in July 2017 granted an accelerated approval to frontline KEYTRUDA® for patients with locally advanced or metastatic urothelial carcinoma, who are not eligible for cisplatin-containing chemotherapy. KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. 
KEYNOTE-045 trial is an open-label, multicenter, phase III study in which 542 patients with advanced urothelial carcinoma who had progressed on prior therapies were randomly assigned to receive KEYTRUDA® or investigator's choice of Paclitaxel, Docetaxel, or Vinflunine. Eligible patients had histologically or cytologically confirmed urothelial carcinoma and had progressed on no more than 2 prior systemic therapies, including a platinum based regimen. Patients were randomly assigned in a 1:1 ratio to receive KEYTRUDA® 200 mg every 3 weeks (N=270) or investigator's choice of Paclitaxel 175 mg/m2 , Docetaxel 75 mg/m2, or Vinflunine 320 mg/m2, every 3 weeks (N=272). The primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS), and the secondary endpoints included Objective Response Rate (ORR) and Safety. Efficacy was assessed in all patients as well as in patients with a PD-L1 Combined Positive Score (CPS) of 10% or more. (CPS is the percentage of PD-L1-expressing tumor and inflammatory cells).
In an updated analysis, with a median follow up of 22.5 months for both treatment groups, the median OS with KEYTRUDA® was 10.3 months compared with 7.4 months with chemotherapy (HR=0.70; P=0.0003) and among patients with a Combined Positive Score of 10% or more, the OS was 8.0 versus 5.2 months respectively (HR=0.58; P=0.003). The OS benefit was noted regardless of age, liver metastases, hemoglobin, visceral disease, and choice of chemotherapy. The 18 month OS rate was 33.2% with KEYTRUDA® versus 19.7% with chemotherapy. There was however no significant difference in the median PFS between the two treatment groups. The ORR was 21.1% with KEYTRUDA® and 11.0% with chemotherapy and the responses with KEYTRUDA® were more durable than with chemotherapy. The median response duration of response was not reached in the KEYTRUDA® group versus 4.4 months in the chemotherapy group. Treatment-related Adverse Events of any grade occurred in 62% of patients in the KEYTRUDA® group and 91% of patients in the chemotherapy group. Discontinuation due to toxicities occurred in 7.1% versus 12.5% of KEYTRUDA® vs chemotherapy patients, respectively.
It was concluded that KEYTRUDA® is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. De Wit R, Vaughn DJ, Fradet Y, et al. Annals of Oncology (2017) 28 (suppl_5): v605-v649. 10.1093/annonc/mdx440