Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)

SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (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. Pembrolizumab 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.

EV-302 is a landmark Phase III, global, open-label, randomized trial comparing the efficacy and safety of Enfortumab vedotin and Pembrolizumab with the efficacy and safety of platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma. A total of 886 eligible patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 and Pembrolizumab 200 mg IV on day 1 of every 3-week cycle (N=442) or chemotherapy consisting of Gemcitabine and either Cisplatin or Carboplatin (N=444), determined on the basis of eligibility to receive cisplatin, for a maximum of 6 cycles. The maximum number of Pembrolizumab cycles allowed was 35 and there was no maximum number of cycles set for Enfortumab vedotin. The treatment groups were well balanced. The median age was 69 yrs and randomization was stratified according to eligibility to receive Cisplatin (eligible or ineligible), PD-L1 expression status (High-CPS 10 or more versus Low-CPS less than 10), and liver metastases (present or absent). The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included Overall Response Rate (ORR) as assessed by BICR, Duration of Response, and Safety. As of the data cutoff date, the median duration of follow-up for survival was 17.2 months.

The PFS was significantly longer in the Enfortumab vedotin plus Pembrolizumab group compared to the chemotherapy group (median duration 12.5 months versus 6.3 months; HR=0.45; P<0.001), representing a 55% reduction in the risk of disease progression or death. Enfortumab vedotin plus Pembrolizumab also substantially improved median OS, and the median OS was 31.5 months compared to 16.1 months with chemotherapy (HR=0.47; P<0.001) representing a 53% reduction in the risk of death. These PFS and OS benefits were consistent between the intention-to-treat population and all the prespecified subgroups, including those defined according to Cisplatin eligibility status and PD-L1 expression status. The Overall Response Rate (ORR) in the Enfortumab vedotin plus Pembrolizumab group was 67.7%, significantly higher than the 44.4% ORR observed with chemotherapy alone (P<0.001), with a Complete Response rate of 29.1% versus 12.5% respectively. The median Duration of Response was Not Reached in the Enfortumab vedotin plus Pembrolizumab group and was 7.0 months in the chemotherapy group.

Treatment-related adverse events of Grade 3 or higher occurred in 55.9% of the patients in the Enfortumab vedotin plus Pembrolizumab group, and was 69.5% in the chemotherapy group. The most common treatment-related adverse events of any grade in the Enfortumab vedotin plus Pembrolizumab group were peripheral sensory neuropathy, pruritus and alopecia, whereas the most common such events in the chemotherapy group were anemia, neutropenia and nausea.

It was concluded that treatment with Enfortumab vedotin plus Pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, emerging as a potential new standard of care, irrespective of Cisplatin eligibility. The results from this study mark a significant paradigm shift in the management of locally advanced or metastatic urothelial carcinoma, offering new hope for patients and clinicians alike.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. Powles T, Valderrama BP, Gupta S, et al. for the EV-302 Trial Investigators. N Engl J Med 2024;390:875-888.

SUMMARY: The FDA on March 6, 2024, approved Nivolumab (OPDIVO®) in combination with Cisplatin and Gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of all urothelial cancers, and the latter can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Platinum-based chemotherapy remains the standard of care for the first line treatment of unresectable or metastatic urothelial carcinoma. Cisplatin-based chemotherapy is preferred over Carboplatin-based chemotherapy for eligible patients and has a response rate of over 40%, with a median Overall Survival (OS) of approximately 15 months. These responses, however, are not durable. To date, no novel agent has improved Overall Survival when added to platinum-based chemotherapy, for first-line treatment of metastatic urothelial carcinoma. There is an unmet need for more effective treatment.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Nivolumab presently is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma after previous platinum-based chemotherapy, as well as for adjuvant treatment of high-risk muscle-invasive urothelial carcinoma after radical resection.

Based on the data from Phase II studies, CheckMate 901 clinical trial was conducted to evaluate the benefit of a combination of Nivolumab plus Gemcitabine and Cisplatin, as compared with Gemcitabine and Cisplatin alone, in patients with previously untreated advanced urothelial carcinoma. CheckMate 901 is an international, open-label, randomized, Phase III trial, consisting of 2 parts. In the first part which is summarized below, Nivolumab plus Gemcitabine and Cisplatin was compared with Gemcitabine and Cisplatin alone, in patients with previously untreated, unresectable or metastatic urothelial carcinoma. In the second part of this study, which is ongoing, patients were assigned to receive either Nivolumab plus Ipilimumab or platinum-based chemotherapy.

In the current trial, 608 patients (N=608) with previously untreated unresectable or metastatic urothelial carcinoma were randomized assigned 1:1 to receive either Nivolumab 360 mg IV in combination with Cisplatin and Gemcitabine every 3 weeks for up to six cycles, followed by Nivolumab 480 mg IV every 4 weeks until disease progression, unacceptable toxic effects, or up to a maximum of 2 years, or Gemcitabine and Cisplatin alone every 3 weeks for up to six cycles. Patients who discontinued Cisplatin alone could be switched to Gemcitabine and Carboplatin for the remainder of the platinum-doublet cycles up to six cycles in total. Randomization was stratified by tumor PD-L1 expression and presence of liver metastasis. Patient characteristics were well-balanced between the two study groups. The median patient age was 65 years. The primary tumor site was the bladder in 75% of patients. 37% of patients had a high tumor PD-L1 expression (1% or more) and 21% of patients had evidence of liver metastases. The dual Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Objective response rate (ORR) per BICR was an exploratory endpoint.

At a median follow up of 33.6 months, there was a statistically significant improvement in both Overall Survival and Progression Free Survival for Nivolumab in combination with Cisplatin and Gemcitabine followed by Nivolumab, compared to Cisplatin and Gemcitabine alone. The median OS was 21.7 months for patients who received Nivolumab in combination with Cisplatin and Gemcitabine and 18.9 months for those who received Cisplatin and Gemcitabine alone, (HR=0.78; P=0.02). Overall survival was 70.2% and 62.7%, respectively, at 12 months and 46.9% and 40.7%, respectively, at 24 months. The median PFS was 7.9 months and 7.6 months, respectively (HR=0.72; P=0.0012). The PFS was 34.2% and 21.8%, respectively, at 12 months and 23.5% and 9.6%, respectively, at 24 months.

The Objective Response Rate and Complete Response Rates were 57.6% and 21.7% respectively with Nivolumab combination therapy, versus 43.1% and 11.8% with Gemcitabine and Cisplatin alone. The median duration of Complete Response was 37.1 months with Nivolumab combination therapy and 13.2 months with Gemcitabine and Cisplatin alone. The most common treatment-related Adverse Events with the Nivolumab combination were anemia, nausea, and neutropenia.

It was concluded that a combination of Nivolumab with Gemcitabine and Cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma, compared to Gemcitabine and Cisplatin alone. The researchers added that this study provides evidence of the benefit of concurrent administration of an immune checkpoint inhibitor and chemotherapy in improving Overall Survival in this patient population.

Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. van der Heijden MS, Sonpavde G, Powles T, et al., for the CheckMate 901 Trial Investigators. N Engl J Med 2023; 389:1778-1789.

SUMMARY: The FDA on December 16, 2022, approved ADSTILADRIN® (Nadofaragene firadenovec-vncg) for adult patients with high-risk Bacillus Calmette-Guérin (BCG) unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS) with or without papillary tumors. According to the American Cancer Society, 81,180 new cases of bladder cancer were diagnosed in 2022 and 17,100 died 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 years. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. The current standard intervention for superficial bladder cancers-Non-Muscle Invasive Bladder Cancer (NMIBC) involves removing the bladder tumor and intravesical treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, for patients with high-risk Non-Muscle Invasive Bladder Cancer, including those with Carcinoma in Situ, High Grade T1, or large-volume or recurrent Ta tumors, to reduce the risk of recurrence. Although 80% of patients have an initial complete response to BCG, more than half of patients have recurrence and progression within the first year, and develop resistance to BCG. These patients 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. The development of a safe, effective and durable intravesical treatment remains a critical unmet need for patients who want to avoid radical cystectomy or systemic immunotherapy.

ADSTILADRIN® (Nadofaragene firadenovec-vncg) is a nonreplicating recombinant adenovirus vector-based gene therapy, that delivers a copy of the human Interferon alfa-2b gene to the patient’s bladder urothelial cells. This novel gene therapy approach provides a longer duration of exposure of the urothelium to Interferon alfa-2b, by allowing the urothelial cells to produce Interferon on an ongoing basis. The safety and efficacy of intravesical ADSTILADRIN® for patients with BCG-refractory and relapsing non-muscle-invasive bladder cancer, was demonstrated in Phase I and Phase II clinical trials. The present study was conducted to evaluate the efficacy and safety of intravesical ADSTILADRIN® in a larger population of patients with BCG-unresponsive Non-Muscle Invasive Bladder Cancer.

This Phase III multicenter, open-label, single-arm trial enrolled 157 patients with high-risk Non-Muscle Invasive Bladder Cancer, 98 of whom had BCG-unresponsive Carcinoma in Situ, evaluable for response. A single-arm design was adopted as there is no standard treatment for this patient population. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) 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 BCG. Patients received ADSTILADRIN® 75 mL intravesical instillation (3 x 1011 viral particles/mL) once every three months up to 12 months, unacceptable toxicity, or recurrent high-grade NMIBC. Patients without high-grade recurrence were allowed to continue ADSTILADRIN® every three months. The major efficacy outcome measures were Complete Response (CR) at any time and Duration of Response (DoR). CR was defined as negative cystoscopy with applicable TransUrethral Resection of Bladder Tumor (TURBT) and biopsies, and urine cytology. Random bladder biopsies of five sites were conducted in patients remaining in CR at 12 months.

The Complete Response Rate was 51%, the median Duration of Response was 9.7 months and 46% of responding patients remained in Complete Response for at least one year. The most common grade 3 adverse reaction was micturition urgency (1%). Most of patients experienced Grade 1 Adverse Events which included mild fatigue and bladder spasms. The most common Grade 3 toxicity was urinary urgency noted in 1% of patients.

This study has demonstrated that Intravesical delivery of the adenoviral vector containing the human recombinant Interferon alfa-2b gene was associated with promising efficacy outcomes, with an acceptable safety profile. ADSTILADRIN® is a novel treatment option and alternative to chemotherapy and systemic therapies and is the first FDA-approved gene therapy for bladder cancer.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin