Addition of Ipilimumab Improves Nivolumab Response in PD-L1 Unselected Patients with Platinum-Pretreated Metastatic Urothelial Cancer

Although some patients with platinum-pretreated metastatic urothelial cancer (mUC) demonstrated good responses to nivolumab monotherapy, the response rate and survival were higher with combined nivolumab plus ipilimumb therapy, according to findings presented at the ESMO 2018 Congress in Munich, Germany. Dr. Jonathan E. Rosenberg of the Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York, United States of America, presented results from the  CheckMate 032 (NCT01928394) study on behalf of colleagues. 

CheckMate 032 was a multicentre, open-label study evaluating nivolomab monotherapy and 2 dose levels of combined nivolumab and ipilimumab. Patients with previously treated locally advanced or metastatic UC, RECIST v1.1 measurable disease, and ECOG performance status ≤1 were enrolled; most patients had been heavily pretreated. 

Seventy-eight patients were treated with nivolumab monotherapy at 3 mg/kg, 104 received nivolumab at 3 mg/kg plus 1 mg/kg  ipilumumab for up to 4 doses followed by nivolumab 3 mg/kg, and 92 patients received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab for up to 4 doses followed by nivolumab 3 mg/kg. 

The primary endpoint in the trial was investigator-assessed objective response rate (ORR) per RECIST v1.1 with duration of response (DoR). Secondary endpoints included investigator- assessed progression-free survival (PFS), overall survival (OS), and safety. 

Dr. Rosenberg noted an ORR of 26% had been previously reported for the nivolumab 3 mg/kg and nivolumab 3 mg/kg / ipilimumab 1 mg/kg cohorts, and a preliminary ORR of 38% for the nivolumab 1 mg/kg / ipilimumab 3 mg/kg cohort (n=26). 

Median PFS and OS were  longer with nivolumab 1 mg/kg plus ipilimumab  3 mg/kg 

The data presented at ESMO 2018 Congress were after a minimum follow-up of of 37.7 months for the nivolumab monotherapy, 38.8 months for the nivolumab 3 mg/kg / ipilimumab 1 mg/kg arms, and after a minimum of 7.9 months for the nivolumab 1 mg/kg / ipilimumab 3 mg/kg cohort. The ORR per investigator was 26% (95% confidence interval [CI], 16 - 37%), 27% (95% CI, 19 – 37%), and 38% (95% CI, 28 – 49%), respectively. The median DoR was 30.5 (95% CI, 8.3 – not estimable [NE]), 22.3 (95% CI, 12.8 - NE), and 22.9 (95% CI, 9.8 - NE) months, respectively. 

In the respective treatment arms, median PFS was 2.8 (95% CI, 1.5 – 5.3), 2.6 (95% CI, 1.4 – 3.9), and 4.9 (95% CI, 2.7 – 6.6) months, and median OS was 9.9 (95% CI, 7.3 – 21.1), 7.4 (95% CI, 5.6 – 11.0), and 15.3 (95% CI, 10.1 – 27.6) months. 

The highest nivolumab / ipilimumab response was seen in patients with tumour cell PD-L1 expression 

The response was highest in patients with tumour cell expression of PD-L1 ≥1%, especially at the nivolumab 1 mg/kg / ipilimumab 3 mg/kg dose. 

The ORR in patients with PD-L1 ≥1% was 27% (95% CI, 12 – 48%), 35% (95% CI, 19 – 55%), and 58% (95% CI, 39 – 76%) in the nivolumab 3 mg/kg, nivolumab 3 mg/kg / ipilimumab 1 mg/kg, and nivolumab 1 mg/kg / ipilimumab 3 mg/kg arms, respectively. 

By contrast, in patients with PD-L1 < 1%, the ORR was 26% (95% CI, 14 – 41%), 25% (95% CI, 14 – 38%), and 24% (95% CI, 12 – 40%) with the respective treatments.

In the overall patient population, grades 3/4 treatment-related adverse events (TRAEs) occurred in 27%, 31%, and 39% of patients in the respective treatment arms. Grade 5 TRAEs of pneumonitis were reported in one patient in the nivolumab monotherapy arm and one patient in the nivolumab 3 mg/kg / ipilimumab 1 mg/kg arm. 

Discussant Points

Dr Cora N. Sternberg, Chief of the Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy, who discussed the study findings said that CheckMate 032 is a multicentre, phase I/II study and not a randomized trial. It cannot compare across studies and cannot even compare investigator and BICR results. The findings reproduce previous results, but a phase III trial is needed and ongoing (CheckMate 901; NCT03036098). Selected toxicities are higher but don’t preclude treatment. The response rate of 38% is encouraging. Follow-up is not mature but long-term outcomes may be important. PD-L1 positive tumours may benefit the most but she questioned if PD-L1 is really a good biomarker. More detailed interrogation of tumours beyond just PD-L1 would be ideal.

Conclusions 

The authors reported that a trend toward a higher ORR and longer PFS and OS compared with  previous reports of PD-1/PD-L1 monotherapies was observed with the combination of nivolumab 1mg/kg / ipilumumab 3 mg/kg in this PD-L1 unselected population. Furthermore, the combination had a manageable safety profile. 

These results support the ongoing phase III CheckMate 901 (NCT03036098) trial of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg compared to standard chemotherapy in patients with previously untreated mUC.

Disclosure 

This trial was sponsored by Bristol-Myers Squibb and ONO Pharmaceutical Company Limited. 

Reference 

LBA32 – Rosenberg JE,Sharma P, de Braud FGM, 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.