Basal cell carcinoma misdiagnosed as urothelial cancer | RRU

Japan's MHLF Approves Padcev With Keytruda For First-line Treatment Of Radically Unresectable Urothelial Carcinoma

Astellas Pharma Inc., a pharmaceutical company conducting business in more than 70 countries around the world, announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approved Padcev (enfortumab vedotin [genetical recombination]) with MSD's Keytruda (pembrolizumab [genetical recombination]) as a combination therapy for the first-line treatment of adult patients with radically unresectable urothelial carcinoma. This is the first approved combination treatment for radically unresectable urothelial carcinoma in Japan to offer an alternative to platinum-containing chemotherapy, the current standard of care for first-line treatment.

In Japan, bladder cancer is the 9th most common cancer, with over 34,500 new cases diagnosed and 11,000 deaths reported from the disease in 2022. Particularly poor outcomes are associated with the latter stages of the disease, with global five-year survival rates of 39% and 8% for locally advanced and metastatic urothelial cancer, respectively.

The approval by the MHLW was supported by results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) which explored the efficacy and safety of enfortumab vedotin in combination with pembrolizumab in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Results showed that the treatment combination resulted in a median overall survival of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with platinum-containing chemotherapy, representing a 53% reduction in risk of death (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001). The median progression-free survival of 12.5 months (95% CI: 10.4-16.6) with the combination compared to 6.3 months (95% CI: 6.2-6.5) with chemotherapy represents a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: (0.38-0.54); P<0.00001). The safety results in EV-302 are consistent with those previously reported for this combination in EV-103 in cisplatin-ineligible patients with la/mUC. The most common (=3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin in combination with pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. No new safety issues were identified. During the EV-302 trial, approximately 30% of patients completed treatment with chemotherapy and then went on to receive maintenance therapy with avelumab, a PD-L1 inhibitor, which is reflective of current real world clinical practice. Results were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine.

Ahsan Arozullah, M.D., M.P.H., senior vice president, head of oncology development, Astellas, said: "Today's approval by Japan's MHLW expands the benefits of treatment with enfortumab vedotin in combination with pembrolizumab to patients living with radically unresectable urothelial carcinoma in Japan. These patients will now have an alternative to platinum-containing chemotherapy to treat this devastating disease, helping to improve patient outcomes, extend lives and give further hope to the patients and families that we serve."

In addition to this latest approval, enfortumab vedotin in combination with pembrolizumab was approved by the European Commission in August 2024 for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer, who are eligible for platinum-containing chemotherapy. Furthermore, in December 2023, the US Food and Drug Administration approved the use of the combination therapy for adult patients with locally advanced or metastatic urothelial cancer.

Astellas has already reflected the impact from the approval for enfortumab vedotin in Japan in its financial forecast for the current fiscal year ending March 31, 2025.

The EV-302 trial is an open-label, randomized, controlled phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.

The EV-302 trial is part of an extensive clinical programme evaluating this combination in multiple stages of urothelial cancer and other solid tumours. Findings from EV-302 were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine.

Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. Urothelial cancer accounts for 90% of global bladder cancers and can also be found in the renal pelvis, ureter, and urethra. If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease. Globally, approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.

Padcev (enfortumab vedotin [genetical recombination]) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. Non-clinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).

Padcev is indicated in Japan as monotherapy for the treatment of adult patients with radically unresectable urothelial carcinoma that has progressed after anti-cancer chemotherapy, and in combination with Keytruda (pembrolizumab) for the first-line treatment of adult patients with radically unresectable urothelial carcinoma.

EV-302 (NCT04223856) is an open-label, randomized, controlled phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).

Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective.

EV-203 (NCT04995419) is a phase 2, multicenter, single-arm bridging trial in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the trial.

EV-104 (NCT05014139) is a phase 1 trial exploring enfortumab vedotin in patients with non-muscle invasive bladder cancer (NMIBC). The trial will be conducted in two-parts, assessing dose escalation and dose expansion with enfortumab vedotin when administered intravesically as a monotherapy.

EV-202 (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter phase 2 trial investigating enfortumab vedotin alone in patients with previously treated advanced solid tumours. This trial also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/metastatic head and neck squamous cell carcinoma.

Astellas Pharma Inc. Is a pharmaceutical company conducting business in more than 70 countries around the world. The company is promoting the focus area approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on biology and modality.

Astellas and Pfizer have a clinical collaboration agreement with MSD to evaluate the combination of Astellas' and Pfizer's Padcev (enfortumab vedotin) and MSD's Keytruda (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. Keytruda is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).

NGS Underused In Advanced Prostate Cancer And Urothelial Cancer

Most patients with advanced prostate cancer or urothelial cancer are not undergoing next-generation sequencing (NGS), according to research published in JAMA Network Open.

Researchers assessed trends in NGS use among patients diagnosed with metastatic prostate cancer or advanced urothelial carcinoma between March 1, 2015, and December 31, 2022.

The study included 11,927 patients with metastatic prostate cancer, 29.3% of whom underwent NGS. The median time from diagnosis of metastatic disease to NGS was 13.2 months.

The rate of NGS in these patients rose from 19.0% in 2015 to 36.1% in 2020 but fell to 27.1% in 2022. The cumulative incidence of NGS at 1 year after diagnosis was 1.3% in 2015 and 32.7% in 2022.

The study also included 6490 patients with advanced urothelial cancer, 32% of whom underwent NGS. The median time from diagnosis of advanced disease to NGS was 2.7 months.

The rate of NGS in these patients rose from 14.1% in 2015 to 48.8% in 2021 but fell to 46.6% in 2022. The cumulative incidence of NGS testing at 1 year after diagnosis was 6.9% in 2015 and 52.5% in 2022.

In both cohorts, the use of NGS differed by race and ethnicity, socioeconomic status, geographic location, and insurance status.

"The findings of this cohort study suggest that while the rate of NGS improved over time, the majority of patients … still did not undergo NGS testing," the researchers wrote. "Social determinants of health, such as race and ethnicity, SES [socioeconomic status], and insurance type, may be associated with access to NGS testing. Upon external validation, these hypothesis-generating data may help with understanding current disparities associated with NGS testing and improve access to standard-of-care approaches and therapies by shaping health care policies."

Disclosures: No funding source was reported. Some study authors disclosed conflicts of interest. Please see the original reference for complete disclosures.

This article originally appeared on Cancer Therapy Advisor

References:

Chehade CH, Jo Y, Gebrael g, et al. Trends and disparities in next-generation sequencing in metastatic prostate and urothelial cancers. JAMA Netw Open. Published online July 18, 2023. Doi:10.1001/jamanetworkopen.2024.23186

Keytruda Improves Disease-Free Survival In Some With Urothelial Carcinoma

Among patients with high-risk muscle-invasive urothelial carcinoma, postsurgical Keytruda extended the time some lived without signs of cancer.

Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery experienced notable improvements in disease-free survival (DFS, the time a patient lives without signs of cancer) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) when compared with patients who underwent observation after a 45-month follow-up, study findings have shown.

Findings from the phase 3 AMBASSADOR trial were presented during the 2024 ESMO Annual Congress by Dr. Andrea B, Apolo, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.

Study Highlights Adjuvant Keytruda significantly extended disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) compared to observation. The benefit of Keytruda was observed regardless of PD-L1 expression and lymph node status, suggesting its potential effectiveness for a wide range of patients. Patients with lower tract MIUC, primarily bladder cancer, demonstrated a more significant improvement in DFS with Keytruda compared to those with upper tract disease. While the final analysis of overall survival is pending, interim data suggest a potential benefit of Keytruda in extending the lives of patients with high-risk MIUC. The study reported manageable toxicity associated with Keytruda, making it a promising treatment option for patients with MIUC.

Urothelial carcinoma, as defined by the National Cancer Institute, begins in the urothelial cells lining the urethra, bladder, ureters, renal pelvis and other organs, and almost all bladder cancers are urothelial carcinomas.

"In this setting, [Keytruda] doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm," Apolo said during a presentation of the data in the intention-to-treat population that was published in The New England Journal of Medicine.

A total of 702 enrolled patients were randomly assigned to receive 200 milligrams of Keytruda every three weeks (354 patients) versus observation (348 patients) with dual primary end points of DFS and overall survival (OS, the time a patient lives regardless of disease status). Across both cohorts, the median age was 68 years, and the majority of patients were men (74.6%).

In the Keytruda arm, 57.3% of patients were PD-L1 positive compared with 57.8% of patients in the observation arm. In the Keytruda arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%) and urethra (1.7%) compared with the observation arm: 75.6%, 21% and 3.4%, respectively.

When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. "The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant [Keytruda]," Apolo added.

Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, "so it is hard to draw conclusions from these cohorts," Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status (if the cancer has spread to the lymph nodes), upper tract neoadjuvant therapy, ECOG performance status (evaluating a patient's ability to perform daily tasks) and histologic variants.

In all patients with N0 stage disease (cancer has not spread to the lymph nodes, with higher numbers indicating increasing spread to the lymph nodes), the hazard ratio (HR) for DFS was 0.53, meaning there was a 47% likelihood the disease would return compared with the observation group. In N1, the HR was 0.81, and for patients with N2/N3 stage disease, the HR was 0.71. "This was prognostic, but adjuvant Keytruda benefited all groups including N0 and N1, and N2 and N3," she continued.

Evaluation of lymph node stage by lower tract versus upper tract demonstrated that "patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant [Keytruda], regardless of N0 or N-plus status," Apolo said. "Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive," Apolo continued.

The investigators reported that the most common sites of metastatic disease occurrence (702 patients) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%) and liver (18%). Apolo noted that these recurrence sites were "interesting and hypothesis-generating."

In the primary analysis of the AMBASSADOR study, Keytruda showed a significant improvement in DFS versus observation after a 22-month follow-up.

The trial closed early due to the FDA approval of Opdivo (nivolumab) in high-risk MIUC after surgery. At that point, 34% of patients in the observation arm and 20% of patients in the Keytruda arm had received a non-protocol checkpoint inhibitor or withdrew consent. "The interim OS had been presented, although the final analysis of OS had not been performed because only 8% of events had been reached," Apolo said.

Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with Keytruda versus observation regardless of PD-L1 expression and lymph node status.

"Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant [Keytruda] as a therapeutic option in patients with high-risk MIUC," Apolo said.

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