ESMO 2023: LBA6
Exciting results from the EV-302 phase 3 trial suggest that the partnership between Seagen and Astellas’ antibody-drug conjugate Padcev and Merck’s renowned oncology treatment Keytruda may be a harmonious breakthrough in the field of bladder cancer.
Several weeks ago, the medical community buzzed with anticipation when Seagen and Astellas revealed the improved outcomes of their combination therapy compared to the standard of care for previously untreated bladder cancer patients. However, the critical data remained undisclosed, leaving the medical community intrigued. Finally, during a presentation at the European Society of Medical Oncology (ESMO) Congress in Madrid, the eagerly awaited numbers were unveiled, lending strong support to the potential transformation offered by this combination, described by Seagen’s R&D chief, Dr. Roger Dansey, as “practice changing.”
In the EV-302 trial, which involved 886 bladder cancer patients eligible for cisplatin or carboplatin-containing chemotherapy, the Keytruda-Padcev combo significantly reduced the risk of death by an impressive 53% compared to standard chemotherapy. The median overall survival (OS) for patients receiving the combination reached 31.5 months, a substantial improvement over the 16.1 months observed in the chemotherapy group. Furthermore, the combination showed substantial success in progression-free survival (PFS), reducing the risk of disease progression or death by 55%. Patients on the combination therapy enjoyed a median progression-free survival of 12.5 months, while those on chemotherapy only saw 6.3 months without progression.
In terms of secondary outcomes, the results indicated that patients treated with a combination of enfortumab vedotin and pembrolizumab achieved a significantly higher confirmed objective response rate (ORR) at 68% compared to the 44% ORR in patients receiving chemotherapy. Within the enfortumab vedotin plus pembrolizumab group, 29.1% of patients had a complete response, and 38.7% experienced a partial response, while in the chemotherapy group, these figures were 12.5% for complete responses and 32.0% for partial responses. Moreover, the duration of response (DOR) was notably longer in the enfortumab vedotin plus pembrolizumab group, with the median DOR not being reached, as opposed to the 7 months median DOR in the chemotherapy group.
“The remarkable findings presented today demonstrate that the combination of enfortumab vedotin and pembrolizumab could offer longer survival and more time without disease progression for patients with advanced urothelial cancer. The presentation of this data is an important milestone for this patient population, and we look forward to continued discussions with regulatory authorities as we work to expedite bringing this therapy to those who need it most.”
– Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
The objective response rate in the EV-302 trial was another notable success, with the combination prompting a response in 67.7% of patients, outperforming the 44.4% response rate seen in the chemotherapy group.
In terms of safety, the combination displayed a favorable profile, with 55.9% of patients experiencing severe treatment-related adverse events. In contrast, 69.5% of patients on chemotherapy endured grade 3 or higher adverse events in 6.8% of cases. Skin reactions were the most common adverse events reported in the combination group, affecting 15.5% of patients.
The Keytruda-Padcev combo could impact patients eligible for cisplatin-based chemotherapy, irrespective of their PD-L1 status. In April, the combination received accelerated FDA approval for treating first-line cisplatin-ineligible patients, and the expansion of its label to include the cisplatin-eligible population could potentially double Padcev’s global market to over $5 billion.
However, while the data are promising, analysts at Leerink Partners caution that more research is needed to determine the full extent of the combo’s effectiveness, especially across various subgroups. To become the standard of care, it must demonstrate benefits that surpass those achieved with platinum-based chemotherapy, they noted.
One critical aspect of the EV-302 trial that analysts are watching closely is the hazard ratio (HR), which quantifies the probability of death or disease progression in the treatment group relative to the control group over a specified time. With hazard ratios of 0.47 for OS and 0.45 for PFS, indicating a 53% reduction in death risk and a 55% reduction in disease progression risk, the analysts are eager to see if further data will show even more substantial improvements in specific patient groups.
Conclusion
In the EV-302 study, enfortumab vedotin and pembrolizumab demonstrated significant success by meeting both primary endpoints of overall survival (OS) and progression-free survival (PFS) when compared to platinum and gemcitabine chemotherapy. Patients treated with this combination experienced a substantial extension in OS, with a median of 31.5 months, representing a 53% reduction in the risk of death compared to chemotherapy. PFS also showed marked improvement, with a median of 12.5 months and a 55% reduction in the risk of cancer progression or death. These positive outcomes were consistent across various patient subgroups. The safety profile, while showing some Grade 3 or higher adverse events, was consistent with previous reports and did not reveal any new safety concerns. Overall, the results underscore the potential of enfortumab vedotin and pembrolizumab as an effective and well-tolerated treatment option for patients with advanced urothelial cancer.
