Author: RR

FDA Approves OPDIVO® in Combination with Chemotherapy for the First Line Treatment of Advanced Urothelial Carcinoma

RR

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.

AMTAGVI® (Lifileucel)

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The FDA on February 16, 2024, granted accelerated approval to AMTAGVI®, a tumor-derived autologous T cell immunotherapy, for adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. AMTAGVI® is a product of Iovance Biotherapeutics, Inc.

Stockholm3 Blood Test Identifies Aggressive Prostate Cancer

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

PSA (Prostate Specific Antigen) is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on PSA levels remains controversial, and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. PSA test CANNOT distinguish between aggressive and benign cancer. As a result, many men have to undergo unnecessary follow-ups with a biopsy of the prostate. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. PSA test is also difficult to interpret, and PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer.

Stockholm3 is a blood test that combines 5 protein biomarkers, 101 genetic markers, and clinical data with an advanced algorithm, in order to detect almost 100% of aggressive prostate cancers at an early stage. The Stockholm3 test has been validated in over 75, 000 men and has been used in health systems in Sweden, Norway, Finland, Germany, Switzerland, UK and Turkey, and results have been published in international peer-reviewed journals. Evidence suggests that Stockholm3 is more effective at predicting risk than PSA testing alone, for men aged 45-74 with PSA of at least 1.5ng/ml. Several studies have shown that the application of this test can reduce the number of biopsies by 32%, without compromising the diagnostic capacity of intermediate grade prostate cancers (Gleason 7 or higher), in comparison with the use of the PSA value 3 ng/ mL as cut-off value for biopsy recommendation. However, none of the validation studies included ethnically diverse population.

SEPTA is a prospective trial conducted to validate Stockholm3 in an ethnically diverse population, for prostate cancer risk stratification, and determine whether it could achieve noninferior sensitivity and superior specificity in this diverse population. This trial included men who were referred for prostate biopsy at North American sites from 2019 to 2023. Study participants had no previous diagnosis of prostate cancer. This study also used bio-banked specimens from 2008 to 2020. The cohort comprised 912 enrolled men and 1,217 with bio-banked blood. The median age was 63 years, 46% were White, 24% Black, 16% Asian and 14% were Hispanic.

This trial had 2 prespecified Primary goals: 1) Demonstrate noninferiority of the test in detecting Clinically Significant Prostate Cancer (defined as Gleason Grade group 2 or more), compared to PSA testing. 2) Prove superior specificity of the test versus PSA testing, thereby reducing the number of biopsies in men with benign or Gleason Grade group 1 biopsies. A Secondary goal was to evaluate Stockholm3 and PSA across ethnic subgroups. The study assessed Stockholm3 performance using prespecified thresholds and compared it to PSA across different ethnic subgroups. Statistical analysis plans were established before data analysis.

It was noted that the median PSA and Stockholm3 values among the participants were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies, and 20% had a prior benign biopsy. On biopsy, 29% were diagnosed with Clinically Significant Prostate Cancer, 14% with Gleason Grade group 1 cancer, and 57% with benign findings. The detection rate for Clinically Significant Prostate Cancer varied across ethnic groups: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%).

Overall, Stockholm3 value 15 or higher demonstrated noninferiority to a PSA value of 4 ng/mL or higher and nearly three times superior specificity. These results were consistent across ethnic subgroups. The researchers noted that using a Stockholm3 value of 15 or higher would have reduced benign and Gleason Grade group 1 biopsies by 45% overall and between 42-52% across ethnic subgroups, compared to PSA of 4 ng/ml or higher.

The study concluded that in an ethnically diverse population, Stockholm3 could significantly reduce unnecessary biopsies and diagnoses of low-grade tumors, while maintaining similar sensitivity to PSA, for detecting Clinically Significant Prostate Cancer. The results suggest that
Stockholm3 could improve risk stratification and reduce harms associated with prostate cancer screening in diverse populations.

Stockholm3 validation in a multi-ethnic cohort for prostate cancer (SEPTA) detection: A multicentered, prospective trial. Vigneswaran HT, Eklund M, Discacciati A, et al. J Clin Oncol 42, 2024 (suppl 4; abstr 262). DOI 10.1200/JCO.2024.42.4_suppl.262. Abstract#262.