QOL Benefits With Nivolumab, Challenges with Sacituzumab Govitecan Characterize Bladder Cancer Management Updates

Guru Sonpavde, MD

In an interview with OncLive^®, Guru Sonpavde, MD, discussed topline data from an exploratory analysis of quality of life (QOL) outcomes in the phase 3 CheckMate 901 trial (NCT03036098) and a phase 1/2 trial (NCT04863885) investigating sacituzumab govitecan-hziy (Trodelvy) plus ipilimumab (Yervoy) and nivolumab (Opdivo) in metastatic urothelial cancer, both of which were presented at the 2024 ESMO Congress.

According to the primary patient-reported outcome analysis of CheckMate-901, nivolumab plus chemotherapy showed noninferiority on all key health-related QOL measures vs chemotherapy alone. At week 16, the percentage of patients who experienced a clinically meaningful improvement (29% with nivolumab plus chemotherapy vs 23% with chemotherapy alone) or deterioration (28% vs 30%) in global health status was comparable between arms. Moreover, a trend toward improvement across visits was observed with the nivolumab regimen.¹

“These results consolidate the role of this regimen by showing that it does not lead to any declining QOL, and it does improve outcomes,” said Sonpavde, who is the assistant director of the Clinical Research Unit and the Christopher K. Glanz Chair of Bladder Cancer Research at AdventHealth Cancer Institute in Orlando, Florida.

Initial findings from the phase 1/2 trial evaluating sacituzumab govitecan plus ipilimumab and nivolumab showed that the recommended phase 2 dose (RP2D) of 8mg/kg of sacituzumab govitecan was active in patients with cisplatin-ineligible metastatic urothelial cancer (n = 25). The overall response rate (ORR) in evaluable patients (n = 178) who received this dose was 83.3%; the median duration of response was 8.04 months at a median follow-up of 21.57 months. However, the trial was terminated early due to 2 higher-than-anticipated grade 5 myocarditis events in phase 2 (n = 16) that were attributed to ipilimumab plus nivolumab.²

“[Ultimately,] the presentation showed that the combination of an antibody-drug conjugate [ADC] plus immune checkpoint inhibition remains an exciting combination for many malignancies,” Sonpavde added, emphasizing that, “we have to proceed carefully to [prevent] associated toxicities and make sure the therapeutic index is reasonable.”

OncLive: What did previously reported data from CheckMate 901 reveal about the efficacy of cisplatin/gemcitabine plus nivolumab in first-line urothelial cancer?

Sonpavde: CheckMate 901 was a randomized phase 3 trial, [findings from which were] initially presented at the 2023 ESMO Congress. This is a trial in which cisplatin/gemcitabine was compared with cisplatin/gemcitabine and nivolumab in patients who were cisplatin eligible. The trial was positive; there was an improvement in overall survival with an HR of 0.78 and an improvement in progression-free survival with an HR of 0.72. The key finding in this trial was that the complete response [CR] rate, which nearly doubled from 11.8% [with standard chemotherapy] to 21.7% [with nivolumab plus chemotherapy], was highly durable. The median duration of CR was 37.1 months [with nivolumab plus chemotherapy].

At the 2024 ASCO Annual Meeting, it was reported that patients with lymph node–only disease were enriched for CR. The CR rate in patients [in the nivolumab arm] with lymph node–only disease, which was 18% of all patients [in that arm], was 63%. This is a high CR rate in this group, [indicating] that cisplatin/gemcitabine plus nivolumab deserves serious consideration [for this population], in the context that we have enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda] approved for all-comers in the first-line setting.

How did the addition of nivolumab to standard gemcitabine/cisplatin impact QOL outcomes based on findings presented at this year’s ESMO Congress?

At the 2024 ESMO Congress, we [presented] QOL data [with] cisplatin/gemcitabine vs cisplatin/gemcitabine plus nivolumab [in CheckMate 901]. QOL was measured intermittently in both those groups up to the end of chemotherapy and thereafter in patients in the experimental group who received nivolumab maintenance alone. [Results showed that] QOL was maintained with cisplatin/gemcitabine plus nivolumab when compared with cisplatin/gemcitabine, so there was no detriment to QOL by adding nivolumab to [this standard regimen]. These data support [the use of] this regimen in this patient population.

What were the key efficacy and safety data from the phase 1/2 investigator-initiated trial of sacituzumab govitecan plus ipilimumab and nivolumab in urothelial carcinoma? Why was the trial prematurely terminated?

In this investigator-initiated trial, we combined the TROP-2–targeted ADC sacituzumab govitecan with ipilimumab plus nivolumab. In the phase 1 component, we found that it was feasible to combine these agents. The RP2D was identified as 8 mg/kg of sacituzumab govitecan on day 1 and day 8, combined with the higher 3-mg dose of ipilimumab and the lower 1-mg dose of nivolumab. That’s how [the regimen has] been developed in urothelial carcinoma. We took this dose forward to a phase 2 component.

During the phase 2 component, we unfortunately saw some unexpected toxicity. We saw 2 instances of immune myocarditis that were both serious events, and accordingly stopped the trial early when we had accrued 25 patients overall. Despite the 2 immune myocarditis events, we noticed that [the combination is] an active regimen. In the 18 efficacy-available patients, the response rate was 83.3%.

What still needs to be learned about this combination? Are any further investigations planned to address these knowledge gaps?

We’re still trying to conduct correlative studies to see whether we can predict which patients [might experience] immune myocarditis. Could these [events occur in] patients who have the UGT1A1 polymorphism that leads to increased toxicity from the sacituzumab govitecan payload? Could the combination of single nucleotide polymorphisms with UGT1A1 polymorphisms lead to immune adverse effects causing these grade 5 events? We are investigating this as we speak.

References

1. Bedke J, Liao W, Shi L, Blum SI, Patel M, Powles TB. Health-related quality of life from the CheckMate 901 trial of nivolumab as first-line therapy for unresectable or metastatic urothelial carcinoma. Ann Oncol. 2024;35(suppl 2):S1135-S1169. doi:10.1016/annonc/annonc1616
2. Jain RK, Chatwal M, Chadha J, et al. Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma. Ann Oncol. 2024;35(suppl 2):S1135-S1169. doi:10.1016/annonc/annonc1616