Nivolumab And Higher-dose Ipilimumab Improves Responses in Metastatic Urothelial Carcinoma

The latest results from the CheckMate 032 trial have found that the combination of nivolumab plushigher-dose ipilimumab improved the objective response rate in heavily pretreated patients with metastatic urothelial carcinoma compared with nivolumab monotherapy or a combined regimen with a lower dose ofipilimumab.

Padmanee Sharma, MD, PhD

The latest results from the CheckMate 032 trial have found that the combination of nivolumab (Opdivo) plushigher-dose ipilimumab (Yervoy) improved the objective response rate (ORR) in heavily pretreated patients with metastatic urothelial carcinoma (mUC) compared with nivolumab monotherapy or a combined regimen with a lower dose ofipilimumab.1

The regimen of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) induced an ORR of 38.0% (95% CI, 28.1%-48.8%). The monotherapy regimen of nivolumab 3 mg/kg (NIVO3) showed an ORR of 25.6% (95% CI, 16.4%-36.8%) and the regimen of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) hadan ORR of 26.9% (95% CI, 18.7%-36.5%).The median duration of response was more than 22 months across all 3 arms.

“In CheckMate 032, NIVO3 continues to provide antitumor benefit with durable responses and prolonged OS with longer follow-up. Our results show evidence of clinical activity with combined PD-1 and cytotoxic T-lymphocyte antigen-4 inhibition in mUC, as previously observed with nivolumab plus ipilimumab across several tumor types,” the authors, led byPadmanee Sharma, MD, PhD, ofThe University of Texas MD Anderson Cancer Center, wrote in theJournal of Clinical Oncology. “Especially promising efficacy was observed with the NIVO1+IPI3 combination, which resulted in the highest ORRs relative to the NIVO3 and NIVO3+IPI1 arms, although the study design precludes direct comparison.”

Patients in the mUC cohort of the multicenter, open-label, multi-arm, phase I/II CheckMate 032 trial were treated at 38 sites in 8 countries. Inclusion criteria included UC of the renal pelvis, ureter, bladder, or urethra; disease progression following previous platinum-based chemotherapy for metastatic or locally advanced unresectable disease; and recurrence within 1 year of completing platinum-based neoadjuvant or adjuvant treatment. All patients had an ECOG performance status of 0 or 1.

Exclusion criteria included brain metastases, autoimmune disease, systemic corticosteroid use, and prior treatment with experimental antitumor vaccines and T-cell or immune checkpoint modulators. Patients were randomly assigned among treatment arms that were open at the time of enrollment; since the NIVO1+IPI3 arm was later expanded, additional patients were enrolled in this arm after enrollment was closed for the other trial arms. Treatment in all arms continued until disease progression or unacceptable toxicity, and dose reductions were not permitted.

The primary endpoint was ORR, further characterized by the duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability.

The NIVO3 arm contained 78 patients, while the NIVO3+IPI1 arm had 104 patients. In the NIVO1+IPI3 arm, 86 of 92 treated patients were enrolled after the other 2 arms completed enrollment, thus leading to different follow-up lengths.More than 60% of patients in each arm received 2 or more prior treatment regimens.

The median PFS was 2.8 months (95% CI, 1.5-5.3) in the NIVO3 arm, 2.6 months (95% CI, 1.4-3.9) in the NIVO3+IPI1 arm, and 4.9 months (95% CI, 2.7-6.6) in the NIVO1+IPI3 arm. At 12 months, the PFS rates were 17.9%, 22.6%, and 25.9%, respectively.

In the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, the median OS was 9.9 months (95% CI, 7.3-21.1), 7.4 months (95% CI, 5.6-11.0), and 15.3 months (95% CI, 10.1-27.6), respectively. At 12 months, the rates of OS were 47.3%, 38.3%, and 56.9%.

The median DOR in the NIVO3 arm was 30.5 months (95% CI, 8.3 months to not estimable [NE]), 22.3 months (95% CI, 12.8 months—NE) in the NIVO3+IPI1 arm, and 22.9 months (95% CI, 9.8 months–NE) in the NIVO1+IPI3 arm. The median DOR in each arm was similar regardless of baseline tumor PD-L1 expression, the investigators found.

Sharma et al noted that their results are the highest ORR yet seen. “Previously, the highest ORR reported with immunotherapy in the platinum-pretreated population was 21.1% at median follow-up of 27.7 months in the KEYNOTE-045 trial of pembrolizumab versus investigator’s choice of chemotherapy,” the investigators wrote.2

A large majority of patients experienced treatment-related adverse events (TRAE), including 84.6% in the NIVO3 (n = 66) andNIVO3+IPI1 (n = 88) arms, and 80.4% in NIVO1+IPI3 arm (n = 74). There was a wider between-group difference in grade 3 and 4 TRAEs, with 21 patients (26.9%)in the NIVO3 group, 32 patients (30.8%) in theNIVO3+IPI1 group, and 36 patients (39.1%) in the NIVO1+IPI3 arm. One patient each in the NIVO3 and NIVO3+IPI1 arms died of treatment-related pneumonitis.

In the NIVO3 arm, 3 patients (3.8%) discontinued treatment as a result of grade ≥3 TRAEs, while 12 patients (11.5%) in the NIVO3+IPI1 and 10 patients (10.9%) in the NIVO1+IPI3 arms did. The most common TRAEs involved the endocrine and hepatic systems, skin, and the gastrointestinal tract.In all arms, investigators found that the majority of grade 3/4 treatment-related select AEs resolved with the use of immune-modulating medication.

The study’s limitations include the fact that it was not designed to directly compare outcomes among treatment arms, which each had a different length of follow-up, or with a standard current practice comparator. “However, the ongoing phase III CheckMate 901 trial will further evaluate the NIVO1+IPI3 combination versus chemotherapy in patients with previously untreated mUC,” the authors wrote. “The relatively small sample size in each arm of the current study could also be a limitation, especially in evaluating the effects of tumor PD-L1 expression on efficacy.”

Sharma et al concluded that, with longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. “NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile,” they wrote. “This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.”


  1. Sharma P, Siefker-Radtke A, de Braud F, et al. Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: CheckMate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results.J Clin Oncol. 2019;37(19):1608-1616.doi: 10.1200/JCO.19.00538.
  2. Bellmunt J, de Wit R, Vaughn DJ, et al. Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab (pembro) vs investigator’s choice (paclitaxel,docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC).J Clin Oncol. 2018;36(suppl; abstr 410).