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• W4319072016 abstract "Bladder Cancer: Bladder CancerAntibody-drug conjugates (ADC) may have the most significant impact when it comes to bladder cancer, especially when used in combination with checkpoint inhibitors, according to researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. This information points to results from the EV-103/KEYNOTE-869 clinical trial (NCT03288545) that demonstrate the synergy between an antibody-drug conjugate and checkpoint inhibitor in urothelial cancer treatment. The researchers evaluated for antitumor activity of enfortumab vedotin monotherapy and in combination with pembrolizumab in previously untreated cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (la/mUC). The Phase I/II trial data show that combination therapy in patients with la/mUC had an overall response rate (ORR) of 64.5 percent and significant tumor shrinkage in nearly every patient in the study, including several (10.5%) who achieved complete remission. Patients also seemed to respond regardless of PD-L1 or NECTIN4 expression, according to the researchers. The study was led by Jonathan E. Rosenberg, MD, medical oncologist and Chief of the Genitourinary Oncology Service at MSKCC, who presented the results at the clinical trial at the ESMO 2022 conference.Jonathan E. Rosenberg, MD: Jonathan E. Rosenberg, MD“Enfortumab is known to be an active drug in refractory urothelial cancers with a response rate of 40 percent in that setting and prolonged survival in randomized trials compared to conventional chemotherapy,” Rosenberg said. “It's also known that pembrolizumab improves survival in refractory urothelial cancer.” While enfortumab vedotin and pembrolizumab as monotherapy have each shown anti-tumor activity with a survival benefit in pretreated patients with la/mUC, there still is a critical need for effective and tolerable first-line therapies, Rosenberg noted. Enfortumab vedotin is an ADC that contains monomethyl auristatin E (MMAE), which is the most commonly used cytotoxin in the development of ADCs. Pembrolizumab is a humanized antibody used in cancer immunotherapy. In an earlier study, EV-103/KEYNOTE-869 dose-escalation cohort and expansion Cohort A, enfortumab vedotin plus pembrolizumab showed encouraging safety and efficacy outcomes, including a response rate of 73.3 percent that was “unheard of” and “formed the rationale for the current confirmatory study,” Rosenberg said. The new study was not designed as a comparative analysis of the individual therapies on la/mUC. Rather, it looked at confirming the data that combining enfortumab vedotin and pembrolizumab would lead to a similar response rate and understanding of the activity of enfortumab vedotin monotherapy in the same population of cisplatin-ineligible patients. In addition to confirming the findings from Cohort A, the exceptional outcomes demonstrated in Cohort K have prompted federal regulators to consider awarding accelerated approval of enfortumab vedotin and pembrolizumab for la/mUC, Rosenberg told Oncology Times. “Preclinical evidence suggested there would be synergy immunologically between enfortumab vedotin and the checkpoint blockade, both in the laboratory and in studies with other antibody conjugates containing MMAE,” he said. “MMAE appears to produce immunogenic cell death, which is a process where the immune system is better able to recognize antigens of dying cells compared to other ways that cells die where the immune system may not be stimulated. I think the research validates that when you combine them, the immune checkpoint inhibitor, in this case, pembrolizumab, likely allows for better recognition and amplifies the immune response than if the immune drug is given by itself.” Lessons for Success Rosenberg, along with other colleagues, conducted multiple clinical trials that lead to the FDA approval for enfortumab vedotin, including one that resulted in Breakthrough Therapy Designation in 2019 for the treatment of patients with la/mUC with disease progression following immunotherapy and chemotherapy. In 2020, enfortumab vedotin and pembrolizumab earned Breakthrough Therapy Designation for patients with unresected advanced or metastatic urothelial carcinoma, based on results from EV-103/KEYNOTE-869 dose-escalation cohort and expansion Cohort A. In this study, patients with la/mUC were randomized 1:1 to enfortumab vedotin (1.25 mg/kg) as monotherapy on Day 1 and Day 8, or in combination with pembrolizumab (200 mg) on Day 1 of 3-week cycles. The primary endpoint was confirmed ORR per RECIST v1.1 by a blinded independent central review. Secondary endpoints included duration of response (DOR), safety, and treatment-related adverse events (TRAEs). There were 149 patients included in the study, including 76 treated with enfortumab vedotin plus pembrolizumab and 73 with enfortumab vedotin monotherapy. The patients were predominantly male and about 60 percent had impaired performance status. More than 80 percent presented with visceral disease and approximately 40 percent were PD-L1 high. A total of 64.5 percent of patients responded to the enfortumab vedotin plus pembrolizumab combination and median DOR was not reached. The confirmed ORR for enfortumab vedotin monotherapy was 45.2 percent with a median DOR (95% CI) of 13.2 months. A total of 18 patients experienced a serious TRAE in the combination therapy group along with 11 patients in the monotherapy group. Three TRAEs leading to death (3.9%) occurred in the combination group and 2 (2.7%) in the monotherapy group. While skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, none were serious. “One of the lessons from the study for physicians as they get more familiar with prescribing enfortumab vedotin either alone or in combination with pembrolizumab is that monitoring for side effects is a key factor in successfully treating patients,” Rosenberg said. “Patients early on in their course of treatment can have severe skin reactions, some that can even be life-threatening,” he added. “They were not seen in this study, but that does not mean they can't happen. But they definitely have been seen with monotherapy. So I think that's important for physicians to be aware of.” Promising Survival Curve The earlier study, Cohort A, was a non-randomized, 45-patient study evaluating the safety, feasibility, and effectiveness of the drug combination with a greater than 2-year survival in patients who historically had a median patient survival of 9-12 months. In Cohort K, the treatment duration was longer with the combination therapy than with enfortumab vedotin monotherapy. The longer-term time-to-event endpoints in the study are not mature, however, so it is premature to make any broad conclusions about the combination therapy, although the results are encouraging, Rosenberg noted. “There aren't enough patients that have been followed long enough to really understand the overall survival outcomes and progression-free survival yet from Cohort K, so that would be a current limitation,” he said. “But the shape of the survival curve appears to be similar to what we saw with Cohort A, suggesting that Cohort K will ultimately the early findings.” Nearly all of the patients in the study had tumor reductions (97.9%). “We also saw patients respond regardless of their PD-L1 levels, which, in bladder cancer, has not performed all that reliably in terms of predicting response to immune checkpoint blockade,” Rosenberg said. Patients treated in the new study also seemed to respond regardless of NECTIN4 expression. The gene expression is thought to be necessary for bladder cancer cells to be sensitive to enfortumab vedotin. “There were responders with NECTIN4 and responders without NECTIN4 expression,” he said. The toxicity profile, meanwhile, “was largely additive,” Rosenberg said. “In other words, it was the toxicity of the enfortumab vedotin plus the toxicity of the pembrolizumab. However, there were more skin reactions with the combination of the two, which is a common side effect for both drugs. But the treatment toxicities generally were not limiting,” he explained. Whether there is true synergy between enfortumab vedotin and pembrolizumab has not been established. “My own personal feeling is that there is synergy, but it is a very hard thing to prove,” Rosenberg said. “We really need to get a better sense of time-to-event endpoints in the study and a much longer follow-up to have a better understanding of that.” Changing the Paradigm In metastatic urothelial cancer, the current treatment paradigm is gemcitabine and platinum-based chemotherapy followed by avelumab maintenance for responders. If people have progression after chemotherapy, then they receive pembrolizumab. That treatment approach is the standard of care and has improved survival rates, Rosenberg noted. “But the nice thing about enfortumab vedotin plus pembrolizumab is that so many people have tumor shrinkage,” he added. “That rapid growth you sometimes see initially with urothelial cancer is blunted by the fact that you are giving such potent therapy,” Rosenberg explained. “And with 97 percent of patients with tumor reduction, I think it is likely that this is going to supersede the paradigm of chemotherapy followed by maintenance for most patients as time goes on.” The confirmatory Phase III study, EV-302, is comparing enfortumab vedotin to chemotherapy alone in patients with previously untreated advanced urothelial cancer and will determine whether this is a treatment option for all patients with metastatic disease, not just cisplatin-ineligible patients. Furthermore, results from two other Phase III trials “may move this up to the perioperative setting,” Rosenberg said. The Phase III study, KEYNOTE-905/EV-303, is comparing perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin and cystectomy to cystectomy alone in cisplatin-ineligible patients with muscle-invasive bladder cancer, while KEYNOTE-B15/EV-304 is comparing enfortumab vedotin and pembrolizumab to neoadjuvant cisplatin-based chemotherapy. Meanwhile, in addition to monitoring for skin reactions, physicians should watch for peripheral neuropathy in patients, which is a toxicity of the MMAE-containing enfortumab vedotin, Rosenberg noted. “Some cisplatin-ineligible patients are ineligible for the chemotherapy because of neuropathy. Therefore, enfortumab vedotin plus pembrolizumab may not be optimal for them either and that is something to think about as they are considering patients if this does become FDA-approved,” he said. “Bladder cancer, for many years, decades in fact, had not seen many treatment advances. But since about 2016, there has been a cascade of [FDA] approvals showing multiple agents with significant activity in this disease. As a result, patients are living longer and hopefully better with metastatic cancer. And I think enfortumab vedotin plus pembrolizumab probably could improve outcomes even further compared to where we are today.” Chuck Holt is a contributing writer. Top 10 Best Hospitals for Cancer" @default.
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• W4319072016 title "Combination Therapy Shrinks Nearly All Tumors in Bladder Cancer Trial" @default.
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