Seagen  and Astellas Pharma’s Padcev (enfortumab vedotin) has investigators optimistic about its potential success in first-line (1L) and second-line (2L) urothelial carcinoma (UC), but they noted potential obstacles. Still, these possible hindrances are mostly not insurmountable to overcome, they said.

The Phase III EV-302 trial is investigating Padcev in combination with Merck’s Keytruda (pembrolizumab) in 1L UC. However, EV-302’s trial design may not reflect the current standard of care (SOC) as it does not consider the use of Pfizer’s Bavencio (avelumab) as 1L maintenance therapy, they said. This means EV-302 should not only improve upon EV-302’s chemotherapy comparator, but also Bavencio’s 1L maintenance data, they explained.

However, Padcev/Keytruda has the potential to make Bavencio redundant as a maintenance therapy if EV-302 reports positive data, which is possible based on results from an earlier trial, some experts said. Additionally, EV-302 patients may receive Keytruda monotherapy after the use of Padcev/Keytruda to emulate the Bavencio maintenance therapy approach, others noted.

Although approvable, positive data from the Phase II EV-201 trial’s cohort 2, recruiting patients who have progressed from immunotherapy and are ineligible for cisplatin, may not apply in all real-world patients, investigators noted. These 2L patients are older and have significant comorbidities, making them harder to treat, which means Padcev’s efficacy and side-effect profile would need monitoring, they explained. Still, Padcev can still be beneficial in a notable chunk of 2L patients due to its positive efficacy and side-effect profile, some experts said.

At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, held online during 4–8 June, Seagen and Astellas announced updated Padcev results from EV-201 cohort 2 and the Phase I/II EV-103 trial in 1L UC patients. Padcev garnered FDA accelerated approval in December 2019 in third-line (3L) patients who previously received an immunotherapy and platinum-based chemotherapy. On 19 April, the companies announced they were seeking to convert this into a full approval, as well as expansion into the 2L patients recruited in EV-201 cohort 2. The FDA has an action date of 17 August. Investigators noted Padcev is likely to secure full approval in 3L due to the Phase III data solidifying its efficacy and safety profiles in this later-line setting.

Padcev has peak sales estimate of $4.56bn in 2026, according to GlobalData’s consensus forecast. Seagen has a $28.58bn market cap, while Astellas’ is $32.51bn.

1L trial design may be out of date without maintenance therapy element

Padcev plus Keytruda has showed promising data so far in patients who have not received any prior systemic therapy, said Phase I investigator Dr Srikala Sridhar, clinician investigator, Princess Margaret Cancer Centre , Toronto, Canada. In the Phase I/II EV-103 trial in 45 1L UC patients, the overall response rate was 73.3% with a median follow-up of 11.5 months, the trial’s primary endpoint (Rosenberg, J., et al., Journal of Clinical Oncology, 38(6_suppl), p. 441). At ASCO, the median duration of response was showed to be 25.6 months, a secondary endpoint (Abstract #4528).

However, one caveat to the trial design of the ongoing 760-patient Phase III EV-302 trial is the way it does not reflect the current standard in 1L, said Phase I investigator Dr Guillermo de Velasco, medical oncologist, Hospital Universitario 12 de Octubre , Madrid, Spain. EV-302 has a chemotherapy active comparator of gemcitabine plus cisplatin or carboplatin. However, since June 2020, Bavencio has been used as maintenance therapy in 1L patients who respond to chemotherapy, noted Phase III investigator Dr Guru Sonpavde, director, Bladder Cancer Program, Dana-Farber Cancer Institute , Boston, Massachusetts. The first patient in EV-302 was recruited in March 2020.

This means EV-302 needs to report dramatic data, Sonpavde and Velasco said. The magnitude of efficacy with Padcev/Keytruda should challenge Bavencio data as a maintenance therapy to offset EV-302’s design shortcoming, they added. In the Phase III Javelin Bladder 100 trial, Bavencio offered overall survival of one year in 71.3% of patients, compared to 58.4% in the control arm (p= 0.001) (Powles, T., et al., N Engl J Med, 383(13), pp. 1218–1230). EV-302 has progression-free survival (PFS) and overall survival (OS) coprimary endpoints.

Still, EV-302 does take into consideration data from the JAVELIN trial, Sridhar said. Once the Padcev/Keytruda treatment is completed, Keytruda alone may be administered for additional cycles, she added. While this may emulate the concept of maintenance therapy, patients’ response is not assessed after Padcev/Keytruda before Keytruda is used for further cycles, compared with how Bavencio is used, she noted.

If EV-302 reports positive data, it would offer a new approach and JAVELIN may become less relevant, said Phase III investigator Dr Daniel Petrylak, professor of medical oncology and of urology, Yale School of Medicine , New Haven, Connecticut. EV-302 would lead to earlier use of immunotherapy, compared to delaying it to a maintenance approach, he explained. Keytruda targets PD1, while Bavencio targets PDL1.

Padcev/Keytruda avoids the use of chemotherapy in 1L, which has a significant side-effect burden, said Phase III investigator Dr Thomas Powles, professor of Genitourinary Oncology, Barts Cancer Center, London, UK. There are 1L patients who may perform poorly with cisplatin or carboplatin, and so would be ideal for the Padcev/Keytruda combination, Sridhar said, but added this may only constitute 10% of 1L patients. Bavencio is approved after cisplatin or carboplatin use in 1L.

To solidify future EV-302 data versus JAVELIN, patient data should be stratified according to how fit the patients are in order to determine which ones experience the best efficacy with Padcev/Keytruda, noted Phase II investigator Dr Jens Bedke, professor, Department of Urology, Universitätsklinikum Tübingen, Germany. In UC, patient fitness can be classified according to their Eastern Cooperative Oncology Group (ECOG) performance, creatine clearance, neuropathy and/or heart failure risk. EV-302 patients could also be divided according to programmed cell death-1 (PD-1) expression, Bedke added.

Padcev approvable in post-immunotherapy slot with uptake caveats

Based on Padcev monotherapy data, it has a positive shot at extending its FDA approval in patients previously treated with a PD-1 or programmed death-ligand 1 (PD-L1) and are ineligible for cisplatin, Sridhar said. In the Phase II EV-201 trial’s cohort 2, in 89 patients, the confirmed ORR was 52%, the trial’s primary endpoint (Yu, E., Lancet Oncol, 22(6), pp. 872–882). At ASCO, this was updated to 51% with a median follow up of 16 months (Abstract #4524).

Padcev has the potential to be the SOC in these patients, Sonpavde said. At present, these patients are given gemcitabine plus carboplatin and their OS does not exceed one year, he added. Padcev has a median OS of 14.6 months in EV-201’s secondary endpoint. Following PD-1 or PD-L1 therapy, tolerable and efficacious treatment options are limited, a Seagen spokesperson said.

Padcev’s EV-201 data may not apply to all real-world patients since most are not as susceptible to treatment, Bedke said. Such 2L patients are frail and have received many prior therapies, he explained. Padcev would ideally be used as early as possible, such as in 1L, as UC patients progress more quickly than other cancer indications, he noted.

Patient fitness status is critical in UC because patients have many comorbidities, Sonpavde said. One side effect of Pacdev is hyperglycemia, which should be monitored because many patients have pre-existing diabetes, he added. Peripheral neuropathy is another common side effect with Pacdev, so any patient who already has it will be precluded for its use, he noted, adding there are not many of these patients. However, Pacdev has a better side-effect profile than cisplatin, Sridhar said. Pacdev can be given to patients who have compromised renal function, which is common in UC patients as they are older and typically have a smoking history, she explained. Only 20–30% of all 2L patients are fit enough for cisplatin, Velasco added.

In the US, once Padcev is approved in this 2L setting, it could have a negative ripple effect in 3L therapies, Sonpavde said. Other 3L therapies like Gilead Sciences’ Todelvy (Sacituzumab govitecan) are approved for use in patients who have previously received a platinum-containing chemotherapy. But the use of Pacdev in the 2L means the patient would not have received such a chemotherapy approach, Sonpavde explained. Todelvy was granted accelerated approval in this setting on 13 April.

Australia and Canada will evaluate EV-201 for Padcev’s initial registrations, according to a 19 April media release. Even if approved outside the US, the data from EV-201 may not be relevant in many countries where PD-1 or PD-L1 are not used in 1L, Sridhar said. In territories like Canada, chemotherapy is used in 1L, so Padcev would be competing against Keytruda monotherapy in 2L, she added. Even if Padcev and Keytruda may have comparable data, Pacdev may have some edge as it may offer a quicker response, she noted.

Padcev is likely to convert its FDA accelerated approval to full approval in 3L patients who previously received platinum-containing chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor, Sonpavde said. This is based on positive Phase III EV-301 trial data, which solidified its efficacy profile, he explained. In Europe, where Padcev is yet to be approved at all, EV-301 supports its approval in this setting, noted Bedke and Powles. The Seagen spokesperson noted the EMA accepted the companies’ marketing authorisation application for Pacdev in this setting in March.

In EV-301, OS was longer with Padcev (12.88 months) versus chemotherapy (8.97 months), the trial’s primary endpoint (Powles, T., et al., N Engl J Med, 384, pp. 1125–1135). While it will not impede Padcev’s approval prospects, its quality-of-life data is not dramatically different with chemotherapy, which is notable due to the typical profile of a UC patient, Bedke said.

Reynald Castaneda is an Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.