Rosenberg Reflects on Immunotherapy Developments in Urothelial Carcinoma

Jonathan E. Rosenberg, MD

As immunotherapy continues to move its way through the treatment landscape of urothelial carcinoma, the optimal dosing of combination regimens continues to be investigated.

The regimen of nivolumab (Opdivo) at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg (N1/I3) has demonstrated a longer progression-free survival (PFS) and higher overall response rate (ORR) in patients with platinum-pretreated metastatic urothelial carcinoma (mUC). These findings come from extended follow-up of the CheckMate-032 study, which was presented at the 2018 ESMO Congress by Jonathan E. Rosenberg, MD.

In addition to the N1/I3 cohort, this trial included an arm of nivolumab monotherapy at 3 mg/kg (N3), and nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3/I1). Earlier data showed an ORR of 26% for N3 and N3/I1, while patients treated with N1/I3 showed an ORR of 38%.

Per investigator review, the median PFS for N1/I3 (n = 92) was 4.9 months (95% CI, 2.7-6.6). This is compared with a median PFS of 2.6 months (95% CI, 1.4-3.9) for N3/I1 (n = 104). Median overall survival (OS) for N1/I3 was 15.3 months (CI 95%, 10.1-27.6) compared with 7.4 months for N3/I1 (CI 95%, 5.6-11.0).

OncLive: Could you provide some background on the CheckMate-032 trial?

In an interview with OncLive, Rosenberg, medical oncologist, chief of the Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center, discussed these findings, as well as the future of immunotherapy in urothelial carcinoma.Rosenberg: CheckMate-032 is a multicohort study of patients with different disease types treated with either nivolumab alone or nivolumab in combination with ipilimumab. In bladder cancer, the trial enrolled patients who were previously treated with at least 1 regimen of platinum chemotherapy, then progressed and enrolled on either N3, N3/I1 for 4 cycles followed by nivolumab maintenance, or N1/I3 for 4 cycles followed by nivolumab maintenance.

Previously, data from the N3 and N3/I1 cohorts were presented, as well as a small cohort of patients treated with N1/I3. That small cohort showed a response rate that was about 38% compared with about 26% for the nivolumab and the lower-dose ipilimumab regimen. Based on those early data, they expanded this cohort to include 92 patients rather than 26. In the 92 patients, the ORR was 38%, which mimicked the small cohort.

The toxicities were not that different than N1/I3 or N3; there was a bit of excess of gastrointestinal toxicity, which you might expect, but was otherwise manageable. The rates were not sky-high but definitely were increased. The OS and PFS were numerically longer with N1/I3 than N3 or N3/I1. The combination with the higher-dose ipilimumab looks like it has a higher response rate, and a numerically longer OS and PFS.

These are not randomized cohorts; they are sequentially enrolled, so it is a little difficult to make the comparisons across them. However, they give us some idea of the trends that you might expect to see. We hope in the future that we may be seeing immunotherapy as first-line therapy for more patients.

How will these findings impact the treatment of these patients moving forward?

What was interesting in the CheckMate-032 trial is that the patients who had high levels of PD-L1 staining had a much higher response rate in the N1/I3 cohort with a response rate of 58% compared with approximately 25% in low levels of PD-L1 expression. This suggests that PD-L1 staining might matter even in combination with ipilimumab, not just with first-line therapy with pembrolizumab (Keytruda) or atezolizumab (Tecentriq) in bladder cancer.The data supporting the higher dose of ipilimumab is leading to more activity with an acceptable toxicity profile. A higher dosing has about a 12% higher response rate, the duration of responses appears longer, and the OS—although the data are still premature—is about 15 months compared with about 8 or 9 months for patients treated with the other 2 regimens. It is a similar range for patients treated with atezolizumab or pembrolizumab in the second-line setting.

What is your take-home message from the presentation of these results?

In the treatment of patients with metastatic urothelial carcinoma, what unmet needs still exist?

Preliminarily, it looks quite good. If we see these things confirmed in the randomized phase III studies, it will move the field forward. The take-home message is that patients who respond to checkpoint inhibition with nivolumab tend to have durable responses. The follow-up of the original N3 cohort and N3/I1 cohort is almost 3 years out now. We have very mature data showing that a percentage of those patients continue to do very well. The most important and interesting thing is that this new I3/N1 combination data suggest that this may be the future first-line therapy. This is similar but different to renal cell carcinoma, where nivolumab and ipilimumab has supplanted tyrosine kinase inhibitors for many patients. In urothelial cancer, this combination, or other combinations like this, might lead to new first-line options for patients. The one group of patients who remain a challenge are those with low levels of PD-L1 expression in the first-line setting. The combination therapy might help those patients, although the CheckMate-032 data call that into question because the response rate was so much higher in the PD-L1—positive cohort. However, the PD-L1–low cohort did just as well as everyone else who got a checkpoint inhibitor. Perhaps, those patients are getting a benefit, as well.

We know that there is a large proportion of patients who still do not respond, so the mechanisms of resistance—either intrinsic or required—remain a big open question in bladder cancer. Over the next several years, I hope we see real insight on some biomarkers from these trials as they are analyzed, and see what the determinants of resistance are. This would give us new avenues of attack.

We do see that there are some exciting new drugs targeting FGFR3, and an antibody-drug conjugate called enfortumab vedotin, which are all active agents in platinum- and immunotherapy-refractory tumors. Hopefully in the next several years, we will have agents that are helpful in these patients. The question is, “Will they provide added benefit in patients in combination with immunotherapy?” Those questions are currently being investigated.

Rosenberg JE, Sharma P, de Braud F, et al. Nivolumab (N) alone or in combination with ipilimumab (i) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (muc), including the nivolumab 1 mg/kg + ipilimumab 3 mg/kg expansion from CheckMate-032. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA32.