Neoadjuvant Sacituzumab Govitecan Displays Activity in Muscle-Invasive Bladder Cancer, But Questions Remain

Following a protocol amendment consisting of a dose reduction and G-CSF prophylaxis, neoadjuvant treatment with sacituzumab govitecan-hziy (Trodelvy) demonstrated hypothesis-generating complete responses following surgery in patients with muscle-invasive bladder cancer (MIBC), according to findings from the phase 2 SURE-01 trial (NCT05226117) presented during the 2024 ASCO Annual Meeting.¹

"A few patients meeting rigorous criteria of clinical complete response [cCR] who elected to undergo a bladder-saving approach revealed a potential for cure," lead investigator Antonio Cigliola, MD, Medical Oncology Department, IRCCS San Raffaele Hospital, Milan, Italy, said during a presentation of the results. "Interim findings from SURE-01 trial provided us with useful information."

In the design of the study, patients were intended to receive 4 cycles of 10 mg/kg sacituzumab govitecan on days 1 and 8 every 3 weeks; however, after the initial 8 patients were enrolled in the study, the protocol was amended to address high rates of toxicity. Overall, in the first 8 patients, grade 3/4 neutropenia was observed in 75%, and 50% of patients also experienced grade 3/4 diarrhea. Additionally, there was 1 treatment-related death due to sepsis. With the amendment, the protocol was changed to a dose of 7.5 mg/kg for sacituzumab govitecan along with the introduction of G-CSF as primary prophylaxis starting on day 9 of the first cycle. Those with 3 or more risk factors for febrile neutropenia were excluded from the study.

Overall, there were 21 total patients enrolled in the study at a median age of 71 years. One-third of patients had cT3-4N0 disease at baseline and nearly half (47.6%) had mixed variant histology in addition to urothelial carcinoma. The primary end point was the rate of pathological complete response (ypT0N0). Secondary end points examined event-free survival (EFS), overall survival (OS), safety, and quality of life. UGT1A1 genetic testing was also completed.

Patients were screened at baseline using a pelvic MRI and were re-examined using MRI following neoadjuvant sacituzumab govitecan. Patients with a cCR or those who did not choose to undergo a radical cystectomy were allowed to choose transurethral resection of the bladder tumor (TURBT), which was followed by observation. Overall, 18 of the 21 enrolled patients completed neoadjuvant therapy with sacituzumab govitecan and moved on to surgery. Of these, 11 opted for radical cystectomy and 7 chose TURBT. Of those who refused cystectomy, the reason was a cCR for 6 and patient decision for 1. There was one patient who progressed/relapsed prior to surgery. The period between sacituzumab govitecan and surgery was 6.9 weeks (range, 4.3-9.9 weeks).

Of those who underwent radical cystectomy (n = 11), 4 had ypT0N0 (36.4% of patients; 95% CI, 14.9%-64.8%). A ypT≤1N0 outcome was observed in 5 patients (45.4%; 95% CI, 21.2%-72.0%). Across the entire intent-to-treat population (n = 21), there were 10 patients with a ypT0N0 outcome from surgery (47.6%; 95% CI, 28.3%-67.6%). One patient decided on TURBT despite evidence of residual disease following neoadjuvant sacituzumab govitecan and had an outcome of ypT2Nx and received subsequent chemotherapy plus radiation.

Of those who experienced a cCR with sacituzumab govitecan and opted for TURBT vs cystectomy, most continued to have a cCR following TURBT (6 of 7). Those who continued to respond had negative findings on cystoscopy and by circulating tumor DNA testing by Signatera. These individuals were currently under observation. One patient in the initial cCR group opted for TURBT and had a ypT2Nx outcome to surgery and tested positive by cystoscopy and ctDNA. This individual went on to receive chemotherapy plus radiation.

"Our biomarker analysis, although immature, showed that the patients with that pathological complete response were enriched in BRCA2 and ARID1A mutations, while those from patients who didn't achieve a pathological complete response were enriched in ERBB2 mutations," Cigliola noted.

Of the 21 enrolled patients, an adverse event (AE) of any grade was experienced by 81% of patients, with the most common being diarrhea (42.9%), anemia (42.8%), alopecia (38.1%), and neutropenia (33.3%). The most common grade 3/4 events were neutropenia, with a grade 3 rate of 9.5% and a grade 4 rate of 19.1%. Grade 3 diarrhea was experienced by 23.9% of patients.

Treatment-related AEs (TRAEs) leading to a dose interruption were experienced by 19.0%, which occurred exclusively in the patients treated with the 10 mg/kg dose. Those treated with the 7.5 mg/kg dose of sacituzumab govitecan and primary prophylaxis with G-CSF did not experience a dose interruption. There was 1 dose reduction in the 7.5 mg/kg arm related to grade 3 treatment-related neutropenia.

A correlation was observed between UGT1A1 polymorphisms and an increase in toxicity. Grade 3/4 TRAEs were seen in 62.5% of those with a homozygous or heterozygous UGT1A1 polymorphism compared with 20% of those with wild-type UGT1A1. "Patients who had the UGT1A1 polymorphism had the most toxicity, but our results are preliminary," said Cigliola. "We don't have a lot of data regarding UGT1A1 and the correlation with toxicities is not enough to recommend broad testing."

On May 30, Gilead, the developer of sacituzumab govitecan, announced that topline results from the confirmatory phase 3 TROPiCS-04 study showed that the agent failed to improve OS compared with single-agent chemotherapy for patients with metastatic urothelial carcinoma that had been previously treated with a platinum-based chemotherapy and PD-1 or PD-L1 inhibitor.² The company noted that a higher level of deaths were associated with AEs seen with sacituzumab govitecan, primarily those related to neutropenic complications and infection.

In addition to other indications, sacituzumab govitecan received an accelerated approval for patients with metastatic urothelial carcinoma who previously received a platinum-based chemotherapy and immune checkpoint inhibitor. This approval is based on tumor response and is contingent on findings from confirmatory studies, which included TROPiCS-04. Gilead noted it was continuing to analyze the data and would be discussing the findings and next steps with the FDA.

With the TROPiCS-04 announcement, the future of sacituzumab govitecan remained unclear among the audience at ASCO. A partner study of the SURE-01 study that was not presented, SURE-02 (NCT05535218), which is exploring sacituzumab govitecan as a neoadjuvant therapy in combination with pembrolizumab (Keytruda) followed by adjuvant pembrolizumab. This combination is where the greatest potential still lies, according to another presenter at the genitourinary session, Thomas Powles, MBBS, MRCP, MD.

"I wouldn't launch a randomized phase 3 off the data presented here [SURE_01]. We need to look very carefully at this toxicity signal, and we need to think about whether G-CSF should be mandatory," said Powles, professor of Genitourinary Oncology, director, Barts Cancer Centre at St. Bartholomew's Hospital. "I would quite like to see some data for that combination. From my perspective, I look at that combination as something that was worth looking at, not in the 1000 patients, but in a relatively modest number of patients."

References

1. Cigliola A, Moschini M, Tateo V, et al. Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (Pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results. J Clin Oncol. 2024;42(suppl 17):LBA4517. doi:10.1200/JCO.2024.42.17_suppl.LBA4517

2. Gilead provides update on phase 3 TROPiCS-04 Study. News release. Gilead Sciences. May 30, 2024. Accessed May June 1, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/5/gilead-provides-update-on-phase-3-tropics-04-study