Nivolumab Plus Cabozantinib Shows Early Promise in Advanced HCC

Aiwu Ruth He, MD, PhD

Treatment with nivolumab (Opdivo) and cabozantinib (Cabometyx) with or without ipilimumab (Yervoy) in patients with advanced hepatocellular carcinoma (HCC) showed preliminary antitumor activity and consistent safety in cohort 6 of the phase 1/2 CheckMate 040 study (NCT01658878).¹

In 71 patients with advanced HCC treated in the study, the doublet combination of nivolumab and cabozantinib achieved an objective response rate of 17% (95% CI, 6%-33%). The triplet combination of nivolumab, cabozantinib, and ipilimumab showed an ORR of 29% (95% CI, 15%-46%). The median duration of response (DOR) observed with the doublet and triplet combinations were 8.3 (6.9 months to not estimable) and not reached (0.0 months to not estimable), respectively. Both combinations also showed progression-free survival (PFS), and overall survival (OS) benefit.

CheckMate 040, a dose-escalation, open-label, non-comparative study, was conducted based on the need for new therapies to treat advanced HCC. The current standard-of-care (SOC) therapies include sorafenib (Nexavar) and lenvatinib (Lenvima), which each produced a median OS of 12.3 months and 13.6 months, respectively.6 But for some patients, the occurrence rate of treatment-related adverse events (TRAEs) from SOC therapies can be high. However, research shows that adding the combination of anti-PD-1 therapy and VEGF inhibition can improve both survival and responses.²

“It is interesting to note that the mOS for sorafenib or lenvatinib have increased over time, maybe as the result of better second line therapy, or improved supportive care provided to the patients. The most recent mOS for sorafenib was 13.8 months in HIMALAYA study, 15 months in COSMIC-312 study, for lenvatinib 19.0 months inLEAP-002 study, Aiwu Ruth He, MD , PhD, told Targeted Oncology™

In the study, patients were treated with nivolumab monotherapy, nivolumab in combination with ipilimumab, or nivolumab in combination with cabozantinib with or without ipilimumab across multiple cohorts. The primary end points in the study were safety/tolerability, investigator-assessed ORR, and DOR. The study’s secondary end points were time to response, time to progression, and PFS, and OS by blinded independent review committee.

Median follow-up in the study was 32.0 months (range, 28.5-36.2 months). Baseline characteristics showed that the majority of patients in the study were males (87%) with a median age of was 65.0 years (range, 23-87 years).

The median duration of treatment was 7.1 months (95% CI, 3.9-13.6 months) in the doublet arm and 7.8 months (95% CI, 3.3-11.5 months) in the triplet arm. In the doublet arm, treatment with nivolumab lasted for a median of 13.5 doses (range, 1-77 doses), and the median number doses of cabozantinib was 118.0 doses (range, 10-1,094 doses). In the triplet arm, patients received a median of 15.0 doses (range, 1-79 doses) of nivolumab, 5.0 doses (range, 1-26 doses) of ipilimumab, and 73.0 doses (range, 14-964 doses) of cabozantinib.

Of the responses, 17% of patients had a response to nivolumab plus cabozantinib and 3% had complete responses (CRs). Partial responses (PRs) were achieved in 14%, and 64% of patients had stable disease (SD). Progressive disease occurred in 17% of patients. The level of response was undetermined in 3% of patients in the doublet arm.

The disease control rate (DCR) in the doublet arm was 39%. The duration of disease control (DDC) in this group was 6.5 months (95% CI, 5.2-1.6 month). The median time to response (TTR) was 4.5 months (range, 2.7-6.9 months).

In the triplet arm, responses consisted of CRs in 3% of patients, PRs in 26%, SD in 54%, and PD in 11%. The level of response was undetermined in 6%.

The DCR observed with the combination of nivolumab, cabozantinib, and ipilimumab was 83%. The DDC in this group was 7.0 months (95% CI, 5.5-22.2 months). The median time to response 3.5 months (range, 1.3-9.9 months).

In terms of survival, nivolumab plus cabozantinib achieved a median PFS of 5.1 months (95% CI, 2.8-10.9 months). Nivolumab plus cabozantinib and ipilimumab showed a median PFS of 4.3 months (95% CI, 3.6-11.9 months).

The median OS observed with the doublet combination was 20.2 months (95% CI, 13.1-32.2). With the triplet combination, the median OS was 22.1 months (15.2 months to not evaluable).

Both combinations appeared to be safe and tolerable, according to the study investigators. Any-grade TRAEs were seen in 89% of the doublet arm and 94% of the triplet arm. With nivolumab plus cabozantinib, the most frequently reported grade 3-4 TRAEs were diarrhea, hypertension, and aspartate (AST) aminotransferase increase. In the triplet arm, AST increase, hypertension, and lipase increase were the most frequently reported TRAEs. Serious TRAEs were reported in 11% of the doublet arm and 34% of the triplet arm.

No deaths in the study were a result of treatment. The most common cause of death among patients in the study was disease progression.

“Tripler combination therapy with better safety profile and improved efficacy will be evaluated next,” said He.

_REFERENCES:

_{1. Yau T, Zagonel V, Santoro A, et al. Nivolumab plus cabozantinib with or without ipilimumab for advanced hepatocellular carcinoma: results from cohort 6 of the CheckMate 040 trial. J Clin Oncol. 2023;41(9). 1747-1757.}

_{2. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.}

_{3. Finn RS, Qin S, Ikeda K, et al. IMbrave150: Updated overall survival data from a global, randomized, open-label phase III study of atezolizumab 1 bevacizumab vs sorafenib in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2021; 39(suppl 3). doi:10.1200/JCO.2021.39.3_suppl.267}