Seagen/Astellas plans to expand their Antibody Drug Conjugate (ADC), Padcev in additional bladder cancer settings?

Padcev (Enfortumab vedotin) for the treatment of locally advanced or metastatic urothelial cancer, Adcetris (Brentuximab vedotin) for the treatment of several types of CD30-expressing lymphomas, and Tivdak (Tisotumab vedotin) for the treatment of recurrent or metastatic cervical cancer are the three ADCs that Seagen is currently commercializing.

Padcev is a Nectin-4-directed antibody and microtubule inhibitor combination that is currently approved for third-line metastatic urothelial cancer treatment. However, the companies want to advance this drug to the front line. Ongoing registrational trials for PADCEV in the first-line metastatic setting are supported by preliminary encouraging data. As per the data presented from the EV-103/Keynote-869 study Padcev as monotherapy demonstrated meaningful efficacy outcome results as neoadjuvant treatment in patients.  According to the results published, investigators reported a pathological complete response (pCR) rate of 36.4% (n=22) among those treated with Padcev, as well as a pathological down staging (pDS) rate of 50%.

Analyst Opinion: Based on the positive performance of Padcev in neoadjuvant Muscle-invasive bladder cancer (MIBC), it’s possible that its potential in this sector may provide patients with a new treatment option. The EV-104 study of PADCEV as monotherapy in non-muscle invasive bladder cancer has commenced enrolment. In addition, Astellas and Merck are pursuing two phase III studies in muscle-invasive bladder cancer that are exploring Padcev in conjunction with Keytruda as a perioperative therapy in diverse populations. Patients who are cisplatin-eligible are enrolled in the EV-304 study, whereas those who are cisplatin-ineligible are enrolled in the EV-303 trial. For Padcev, expansion to neoadjuvant setting is not the end, as the companies are also anticipating Cohort K data from the EV-103/Keynote-869 study, in which Padcev in combination with Keytruda is being evaluated in first-line cisplatin-ineligible Urothelial cancer. The company anticipates expedited approval in this line of setting, with data readout in the second half of this year. Furthermore, Seagen is testing Padcev in combination with Keytruda in first-line cisplatin-eligible and cisplatin-ineligible metastatic urothelial cancer. EV-302 is intended to be a confirmatory trial for Cohort K, as well as supporting global marketing applications. The EV-302 phase III trial is planned to finish enrolling patients in 2022, and favorable results from this research might pave the way for global submissions. Now that we know Padcev will most likely work in a cisplatin-incompatible setting, it is indeed time to discuss its potential competitors, such as PD-L1 inhibitor Bavencio (Pfizer and Merck), which is approved as maintenance therapy for patients who have responded to one round of platinum-containing chemotherapy. Bavencio is for patients who are not eligible for cisplatin but can receive carboplatin, platinum chemotherapy. Prior accelerated approvals for Keytruda and Tecentriq in front-line bladder cancer were, on the other hand, questioned and challenged after confirmatory studies failed. However, the FDA’s Oncologic Drugs Advisory Committee agreed in April 2021 to retain Keytruda (as a first-line bladder cancer treatment for those who are cisplatin-ineligible and carboplatin-ineligible) and Tecentriq (as a first-line treatment for cisplatin-ineligible patients) accelerated approvals in bladder cancer. The company may benefit from their continuous attempts to grow Padcev’s label.

“I think the most meaningful efficacy outcome is pathologic complete response rate. In other studies, that has been potentially deemed as a surrogate for overall survival. To me, that is most indicative of how active this drug is in this setting.” – Expert Opinion