(UroToday.com) The 2022 GU ASCO Annual meeting included a urothelial carcinoma oral abstract session featuring a presentation by Dr. Guru Sonpavde discussing “TROPHY-U-01 Cohort 3: Sacituzumab govitecan in combination with pembrolizumab in patients with metastatic urothelial cancer who progressed after platinum-based regimens” presented by Dr. Petros Grivas, and “Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with MIBC who are cisplatin ineligible” presented by Dr. Daniel Petrylak.
Dr. Sonpavde started by highlighting the current landscape of urothelial carcinoma therapy for metastatic disease:
Furthermore, the current landscape of urothelial carcinoma therapy for perioperative disease is as follows:
Sacituzumab govitecan is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolysable linker. In the TROPHY-U-01 registration phase 2 trial, sacituzumab govitecan monotherapy demonstrated significant activity and manageable safety in patients with metastatic urothelial cancer who progressed after prior platinum-based chemotherapy and checkpoint inhibitors, with 27% objective response rate (ORR) and median overall survival of 11 months [1]. Additionally, 77% of patients had a change from baseline in tumor volume:
Dr. Sonpavde highlighted that the EV-103 cohort assessing enfortumab vedotin + pembrolizumab as first line therapy for cisplatin ineligible advanced urothelial carcinoma is comparable in trial design to the TROPHY-U-01 cohort 3 design. Updated results were presented at GU ASCO 2020, noting promising overall response rate of 73.3%, complete response rate of 15.6%, 12 month duration of response rate of 53.7%, median PFS of 12.3 months, and 12 month OS rate of 81.6%.
TROPHY-U-01 is a multicohort, open-label, global phase 2 trial. Eligible patients had measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and creatinine clearance ≥30 mL/min. The primary endpoint for TROPHY-U-01 cohort 3 was ORR by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The key secondary endpoints included investigator-assessed ORR, clinical benefit rate [complete response (CR) + partial response (PR) + stable disease], progression-free survival (PFS), and safety. At the time of data cutoff, 41 patients received at least a dose of sacituzumab govitecan at the RP2D (10 mg/kg). Of these 41 patients, the median age was 67 years (range: 46–86), 83% were men, 61% were ECOG performance status 1, 76% had ≥1 Bellmunt risk factor, and the median number of prior anticancer regimens was 1 (range: 1–3). At a median follow-up of 5.8 months, the investigator-assessed ORR was 34% (95% CI 20.1–50.6; 1 CR; 13 PR) – notably much lower than the 73.3% ORR reported in EV-103 (but in the first-line setting), clinical benefit rate was 61% (95% CI 44.5–75.8), median PFS was 5.5 months (95% CI 1.7-not reached), and median OS was not reached. The median time to response was 2.0 months (95% CI 1.3–2.8) and median duration of response was not reached (95% CI 2.8 – not reached).
Dr. Sonpavde notes that the treatment-emergent adverse events were as expected, with the most common being diarrhea (76%), nausea (59%), anemia (56%), neutropenia (44%), and asthenia (41%). Treatment-related grade ≥3 adverse events occurred in 59% of patients. Key grade ≥3 treatment-emergent adverse events of any cause included diarrhea (24%), anemia (20%), febrile neutropenia (10%), fatigue (7%), and asthenia (5%).
There are several important ongoing first-line phase 3 trials in advanced urothelial carcinoma, as highlighted in the following figure:
Sacituzumab govitecan is also being tested in several other combination trials including:
- Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan as first-line therapy for metastatic cisplatin-ineligible urothelial carcinoma
- Sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma progressing on prior therapy: The Double Antibody Drug conjugate (DAD) phase I trial
Trop2 expression is based on intrinsic subtypes of urothelial carcinoma. TROP2 mRNA/protein is highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtypes. Furthermore, TROP2 mRNA levels correlate with NECTIN4 mRNA. CRISPR/Cas9-knockdown of TROP2 reduces sensitivity, however after prolonged enfortumab vedotin exposure, cells can downregulate NECTIN4 leading to enfortumab vedotin resistance, but retain TROP2 expression and remain sensitive to sacituzumab govitecan. This suggests non-overlapping resistance mechanisms and provides the rationale for combination of sacituzumab govitecan and enfortumab vedotin in the phase I DAD trial.
Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled patients with cisplatin ineligible cT2-T4aN0M0 muscle-invasive bladder cancer who were eligible for radical cystectomy and pelvic lymph node dissection and had an ECOG of 0-2. Patients received 3 cycles of neoadjuvant enfortumab vedotin (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to radical cystectomy and pelvic lymph node dissection. The primary endpoint of the study was pathological complete response rate (ypT0N0) by central review. Key secondary endpoints included pathological downstaging rate (yp T0,Tis,Ta,T1,N0) and safety. The trial design for EV-103 cohort H is as follows.
There were 22 patients treated, of which 19 patients completed all three cycles of enfortumab vedotin and 21 underwent radical cystectomy and pelvic lymph node dissection. Overall, 36.4% (95% CI 17.2-59.3) of patients had a pathological complete response, and pathological downstaging was seen in 50.0% (95% CI 28.2-71.8) of patients.
The most common enfortumab vedotin treatment-related adverse events were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). There were 18.2% patients that had Grade ≥3 enfortumab vedotin treatment-related adverse events. No surgeries were delayed due to enfortumab vedotin administration. There were three patients that had Grade 5 adverse events while on study that was unrelated to enfortumab vedotin, and in two patients these adverse events occurred > 30 days after radical cystectomy and pelvic lymph node dissection (one cardiac arrest, one pulmonary embolism).
The ongoing phase III trials evaluating neoadjuvant therapy are as listed in the following table:
Enfortumab vedotin continues to move up in the disease space, considering that now it is being assessed in BCG-unresponsive NMIBC (NCT05014139).
Dr. Sonpavde concluded his discussion of the TROPHY-U-01 cohort 3 and EV-103 cohort H trials with the following thoughts as to how to continue developing antibody drug conjugates for urothelial carcinoma:
- Antibody drug conjugates are a huge step forward as they represent a smarter way of delivering chemotherapy
- Principles of precision medicine: most urothelial carcinoma expresses Nectin4/Trop2 proteins
- Several questions revolve around the concept of immunogenic cell death
- Is than an optimal antibody drug conjugate? The ORR with sacituzumab govitecan + pembrolizumab appeared lower than expected and seen in enfortumab vedotin + pembrolizumab
- Is an antibody drug combination with CTLA4 + PD1/PDL1 inhibition more likely to be successful?
- What is the optimal partner for combination?
- We need correlative studies before launching large trials assessing immunogenic cell death by sacituzumab govitecan vs enfortumab vedotin
- Is there an optimal setting for utilizing antibody drug conjugates?
- We need to develop tolerable and rational antibody drug conjugate combinations. Some rational combinations will require the NCI (cooperative groups, ETCTN) support since drugs may belong to different pharmaceutical companies (and companies need to collaborate better with each other)
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022
References:
- Tagawa ST, Balar AV, Petrylak DP, et al. Metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485.