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Rosenberg Reflects on Immunotherapy Developments in Urothelial Carcinoma

Angelica Welch
Published: Friday, Nov 09, 2018

Jonathan E. Rosenberg, MD

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).

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.

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

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.

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.

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

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. 

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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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