Higher Dose of Ipilimumab Added to Nivolumab Effective in Bladder Cancer

Jonathan E. Rosenberg, MD

Extended follow-up data from the CheckMate-032 study showed a trend toward higher overall response (ORR) and longer progression-free survival (PFS) with the regimen of nivolumab (Opdivo) at 1 mg/kg plus ipilimumab at (Yervoy) 3 mg/kg (N1/I3) in patients with platinum-pretreated metastatic urothelial carcinoma. Lead author Jonathan E. Rosenberg, MD, presented the findings for this cohort at the 2018 ESMO Congress.

"ORR was numerically higher in patients with ≥1% tumor PD-L1 expression treated with N1/I3 at 58%, but efficacy was observed across PD-L1 expression levels in all treatment arms," said Rosenberg, a medical oncologist and chief of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center.

The multicenter phase I/II trial included 3 cohorts; nivolumab monotherapy at 3 mg/kg; nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3/I1); and N1/I3. Previously, an ORR of 26% was reported for nivolumab monotherapy and N3/I1. The preliminary ORR was 38% among the 26 patients treated with NI/I3.

Rosenberg said that the higher dosage of ipilimumab was linked to more activity with an acceptable toxicity profile. N1/I3 showed an approximately 12% higher response rate, and the duration of response (DoR) appeared longer.

Median PFS per investigator review 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).

"A trend toward higher response rate and longer median PFS and OS compared to previous reports of PD-1 and PD-L1 monotherapies was observed here in the N1/I3 cohort in the PD-L1 unselected patient population, most of which have received at least 2 prior lines of therapy," said Rosenberg.

The primary endpoints of the study (NCT01928394) are investigator-assessed confirmed ORR by RECIST v1.1 and duration of response. Secondary endpoints include PFS, OS, and safety. There is an exploratory endpoint of ORR by PD-L1 expression status. Tumors were assessed by CT or MRI every 6 weeks from first dose for the first 24 weeks, then every 12 weeks after that, Rosenberg explained.

Although the data on OS are still premature, if these data are confirmed in a phase III randomized trial (CheckMate 901; NCT03036098), Rosenberg said the regimen of N1/I3 would move the field of urothelial carcinoma forward.

Systemic immunotherapy has become the standard of care for most patients with previously-treated metastatic urothelial carcinoma, Rosenberg said. With extended follow-up, all 3 regimens demonstrated sustained efficacy in patients with previously treated metastatic urothelial carcinoma, giving validity to that claim.

No new safety signals were identified with longer follow-up. In the N1/I3 arm, 10% of patients had grade 3/4 diarrhea, compared to 5% in the N3/I1 group. Elevated AST and ALT were also observed more frequently in patients treated with the higher dosage of ipilimumab. Although, this was not that different between the 2 combination nivolumab plus ipilimumab cohorts, noted Rosenberg.

"In general, treatment was well tolerated with the expected immune-related adverse events (AEs). There were some events that were higher in the ipilimumab arm, which we might expect," Rosenberg explained.

Treatment-related AEs by organ system showed that patients treated with N1/I3 did have a higher rate of gastrointestinal events. Skin toxicities were not very different between the arms, Rosenberg reported, and hepatic toxicities were more frequent in patients treated with N1/I3. Grade 3 or 4 treatment-related AEs occurred in 32 (31%) patients treated with N3/I1, and 36 (39%) patients treated with N1/31. In the nivolumab monotherapy arm, as well as in the N3/I1 arm, 1 patient each experienced grade 5 pneumonitis.

"In summary, with extended follow-up, nivolumab, N3/I1, and N1/I3, demonstrated sustained efficacy in patients with previously-treated metastatic disease," concluded Rosenberg.

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.

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