Addition of Cabozantinib to Ipi/Nivo Shows Promising Antitumor Activity in Advanced HCC

The triplet combination of cabozantinib, nivolumab, and ipilimumab induced higher response rates, progression-free survival, and overall survival compared with nivolumab plus cabozantinib in patients with advanced hepatocellular carcinoma.

Thomas Yau, MD

The triplet combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) induced higher response rates, progression-free survival (PFS), and overall survival (OS) compared with nivolumab plus cabozantinib in patients with advanced hepatocellular carcinoma (HCC).

However, the triplet was associated with a higher rate of treatment-emergent adverse events (TREAs), according to a subanalysis of the phase I/II CheckMate 040 study.

“Both combinations showed encouraging outcomes compared with single-agent nivolumab or cabozantinib,” said Thomas Yau, MD, lead investigator, who presented the data at the 2020 GI Cancers Symposium, held January 23-25, in San Francisco, California.

With a median follow-up of about 19 months in each arm, median PFS by investigator assessment was 5.4 months in the doublet arm (95% CI, 3.2-10/9) compared with 6.8 months in the triplet arm (95% CI, 4.0-14.3), while median OS was 21.5 months with the doublet (95% CI, 13.1 to not reached) and not reached with the triplet (95% CI, 15.1 to not reached), reported Yau, clinical associate professor, University of Hong Kong, China. The 15-month OS rates were 64% (95% CI, 45-78%) and 70% (95% CI, 51-83%), respectively.1

Previous studies showed that nivolumab in combination with ipilimumab demonstrated durable responses in patients with advanced HCC previously treated with sorafenib (Nexzvar), with an overall response rate (ORR) exceeding 30%.2 Moreover, a previous pivotal phase III study of cabozantinib in patients with advanced HCC showed a median OS of 10.2 months.3

Therefore, the investigators assessed the efficacy and safety of 2 cabozantinib combination regimens with nivolumab (with or without ipilumumab) in 71 patients who were enrolled in the CheckMate 040 study.

Patients with histologically confirmed advanced HCC who were either sorafenib-naïve or previously treated with sorafenib (and had disease progression or were intolerant to sorafenib) were randomized to the doublet of nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg/day), or the triplet of nivolumab (3 mg/kg), ipilimumab (1 mg/kg every 6 weeks), and cabozantinib (40 mg/day). Treatment continued until intolerable toxicity or disease progression.

Median age was 64.5 years in the 36 patients who constituted the doublet arm and 67.0 years in the 35 patients treated with the triplet. Some 77.8% randomized to the doublet and 85.7% randomized to the triplet had Barcelona Clinic Liver Cancer stage C disease; 94.4% and 100%, respectively had a Child-Pugh score of 5 or 6; and 38.9% and 42.9%, respectively; had vascular invasion. PD-L1 expression ≥1% was present in about 10% in both arms.

“More patients in the triplet arm had extrahepatic spread and also had higher exposure to sorafenib compared to the doublet arm,” said Yau. In total, 47.2% in the doublet arm and 65.7% in the triplet arm had extrahepatic spread, while 53% and 66%, respectively, had prior sorafenib exposure.

The median duration of therapy was 7.1 months in patients receiving the doublet and 7.8 months in those treated with the triplet. Nineteen percent in the doublet arm and 29% in the triplet arm have continued on treatment; disease progression was the reason for treatment discontinuation in 64% and 46%, respectively.

The primary efficacy endpoint was overall response rate by RECIST v1.1, which was higher in the triplet arm versus the doublet arm (29% vs. 19%, respectively). By investigator assessment, best overall response in the doublet arm was a partial response (PR) in 7 (19%) and 20 additional patients had stable disease (SD), for a disease control rate (DCR) of 75%. The median duration of response (DOR) was 8.3 months and the median time to response (TTR) was 4.8 months. In the triplet arm, 10 (29%) of patients had a PR and 19 (54%) had SD, for a DCR of 83%. The median DOR in the triplet arm was not reached and the median TTR was 3.5 months.

Overall, 68.6% in the doublet arm and 69.7% in the triplet arm experienced a decrease in target lesion size.

Grade 3-4 TRAEs were reported in 17 patients (47%) in the nivolumab plus cabozantinib arm and 25 patients (71%) in the triplet arm, and led to discontinuation in 4 (11%) and 7 (20%) patients, respectively. No new safety signals were observed in either arm. Discontinuation for immune-related AEs occurred in 2 patients (6%) in the doublet arm and 4 (11%) of the triplet arm.

“Investigation with longer duration of follow-up may be necessary to better assess the true benefit-risk ratio of both the doublet and triple combination in patients with advanced HCC,” said Yau.


  1. Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. Presented at GI Cancers Symposium; January 23-25, 2020; San Francisco, CA. Abstract 478.
  2. Yau T, Kang Y-K, Kim T-Y, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol. 2019;37 (suppl): Abstract 412.
  3. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.

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