Scott T. Tagawa, MD, highlighted pivotal data for enfortumab vedotin and sacituzumab govitecan at the 38th Annual CFS meeting.
Antibody-drug conjugates (ADCs) are swiftly emerging in the bladder cancer armamentarium, Scott T. Tagawa, MD, explained in a presentation during the 38th Annual CFS meeting.1
In his discussion, Tagawa, a professor of Medicine and Urology at Weill Cornell Medicine, and an Attending Physician at NewYork-Presbyterian/Weill Cornell Medical Center, focused on the 2 ADCs furthest along in the bladder cancer paradigm, enfortumab vedotin-ejfv (Padcev) and sacituzumab govitecan-hziy (Trodelvy).
Enfortumab vedotin targets Nectin-4, a protein that is highly expressed in urothelial cancers. Pivotal data for the ADC came from the single-arm, phase 2 EV-201 trial, in which investigators administered enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer previously treated with a PD-1/PD-L1 inhibitor, including those who had also been treated with a platinum-containing chemotherapy (cohort 1) and those who had not received a platinum-containing chemotherapy and who were ineligible for cisplatin (cohort 2).
There were 125 evaluable patients in cohort 1. Seventy percent of the patients were male and the median age was 69 years (range, 40-84). Patients had received a median of 3 lines (range, 1-6) of prior systemic treatments in the locally advanced or metastatic setting but had not received treatment for ≥2 weeks prior to enrolling in the study. Moreover, the combined positive scores of PD-L1 expression were <10 in 65% of patients and ≥10 in 35%.
Data for cohort 1 shared during the 2020 ESMO Congress showed overall survival (OS) rates of 50.4% at 12 months and 34.2% at 18 months.2 At a median follow-up of 22.3 months, the median OS was 12.4 months.
Regarding cohort 2, Seagen and Astellas, the codevelopers of enfortumab vedotin, reported in a recent press release that the ADC led to an objective response rate (ORR) of 52% and a duration of response of 10.9 months in this less heavily pretreated subgroup.3 The companies plan to share the full data from cohort 2 at an upcoming medical meeting.
Based on initially reported data from cohort 1, the FDA granted an accelerated approval to enfortumab vedotin in December 2019 for the treatment of patients with locally advanced or metastatic urothelial cancer previously treated with a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy.
The preliminary EV-201 cohort 1 data on which the approval was based showed an ORR of 44%, comprising a 12% complete response (CR) rate and a 32% partial response (PR) rate.4 The median time to response was 1.8 months (range, 1.2-9.2), with 44% of responses ongoing at the data cutoff.
Regarding safety, the most common treatment-related adverse events (TRAEs) of any grade were fatigue (50%), alopecia (49%), and decreased appetite (44%), while TRAEs of interest included any case of rash (all grade, 48%; grade ≥3, 12%), any peripheral neuropathy (all grade, 50%; grade ≥3, 3%), and any hyperglycemia (all grade, 11%; grade ≥3, 6%).
FDA accelerated approvals are contingent on the results of a subsequent confirmatory trial. Seagen and Astellas recently reported summary data from the EV-301 confirmatory trial in a press release.5 The data showed that that enfortumab vedotin reduced the risk of death by 30% compared with chemotherapy in patients with locally advanced or metastatic urothelial cancer previously treated with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor (HR, 0.70; P = .001). The ADC also reduced the risk of disease progression or death by 39% (HR, 0.61; P <.00001).
The global, multicenter, open-label, phase 3 EV-301 trial randomized patients to enfortumab vedotin or physician's choice of either docetaxel, paclitaxel, or vinflunine. The target enrollment was approximately 600 patients. The companies plan to present additional data from EV-301 at an upcoming medical meeting.
The next step with enfortumab vedotin in bladder cancer may involve combination approaches with immunotherapy, noted Tagawa. Phase 1b/2 data from the EV-103 trial (NCT03288545) shared during the 2020 Genitourinary Cancers Symposium showed that combining enfortumab with the PD-1 inhibitor pembrolizumab (Keytruda) led to an ORR of 73% in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy.6 The results, which included data from 45 patients, showed that the ORR comprised a 15.6% CR rate and a 57.8% PR rate.
Sacituzumab govitecan consists of the active metabolite of irinotecan, SN-38, linked with a humanized IgG antibody targeted against TROP-2, a cell-surface glycoprotein widely expressed in urothelial carcinomas.
Data from cohort 1 of the phase 2 TROPHY-U-01 trial presented during the 2020 ESMO Congress showed that sacituzumab govitecan induced an ORR of 27% in heavily pretreated patients with metastatic urothelial carcinoma following the failure of both platinum-based chemotherapy and checkpoint inhibition.7 There were 31 responders, including 6 (5%) CRs and 25 (22%) PRs. The median response duration with the ADC was 5.9 months.
The open-label, global phase 2 TROPHY-U-01 trial evaluated sacituzumab govitecan in 3 cohorts: patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and checkpoint inhibition (cohort 1); those who were ineligible for platinum-based chemotherapy and progressed following checkpoint inhibition (cohort 2); and those who never received checkpoint inhibitors but had progressed on platinum-based therapy (cohort 3).
The findings shared at ESMO were from cohort 1, which included 113 evaluable patients. The median age was 66 years, with 23% of patients 75 years of age or older and 78% male. Moreover, the majority of patients were white, at 74%. Twenty-eight percent of patients had an ECOG performance status of 0, while 72% had a status of 1. Overall, 62% of patients had visceral metastases; 40% had lung metastases, 28% had liver metastases, and 12% had other. The median number of prior anticancer regimens received was 3.
Grade 3 diarrhea occurred in 9% of patients, with only 1% experiencing grade 4. Forty-six percent of patients experienced neutropenia, with 22% having a grade 3 effect and 12% reporting a grade 4 effect. There was 1 treatment-related death reported, with a patient presenting with sepsis due to febrile neutropenia.
Summarizing his insight on sacituzumab govitecan, Tagawa said, “This drug has received Fast Track designation from the FDA, which could lead to an accelerated approval at some time over the next 1 to 2 years.”
He added that beyond enfortumab vedotin and sacituzumab govitecan, “There are a number of other ADCs being investigated [in bladder cancer], including several different anti-HER2 ADCs that look interesting, as well as the anti-EpCAM ADC oportuzumab monatox.
1. Tagawa ST. Role of antibody-drug conjugates in advanced bladder cancer. Presented at: 38th Annual CFS. November 4-6, 2020.
2. O’Donnell MD, Galsky JE, Petrylak DP, et al. EV-201: Long-term results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial caner previously treated with platinum and PD-1/PD-L1 inhibitors. Poster presented at: European Society of Medical Oncology Virtual Congress 2020; September 17-20, 2020. Abstract 746P.
3. Seagen and Astellas Announce Positive Topline Results from Second Cohort of Patients in Phase 2 Pivotal Trial of PADCEV® (enfortumab vedotin-ejfv) in Advanced Urothelial Cancer. Posted October 12, 2020. Accessed October 12, 2020. https://bit.ly/3iLKeoQ.
4. Petrylak DP, Balar AV, O'Donnell PH, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37(suppl; abstr LBA4505). doi: 10.1200/JCO.2019.37.18_suppl.LBA4505
5. Seattle Genetics and Astellas Announce PADCEV® (enfortumab vedotin-ejfv) Significantly Improved Overall Survival in Phase 3 Trial in Previously Treated Locally Advanced or Metastatic Urothelial Cancer [news release]. Bothell, Washington and Tokyo. Published September 18, 2020. https://bwnews.pr/3343rxD. Accessed November 11, 2020.
6. Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2020;38(suppl; abstr 441).
7. Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based regimens and checkpoint inhibitors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA24.