Nivolumab Triplet Elicits Clinically Meaningful Responses in Advanced HCC

Thomas Yau, MD

The triplet regimen of nivolumab (Opdivo), ipilimumab (Yervoy), and cabozantinib (Cabometyx) achieved clinically meaningful responses in patients with advanced hepatocellular carcinoma (HCC) who were either sorafenib (Nexavar)-naïve, or resistant to or intolerant of sorafenib, according to cohort data from the phase I/II CheckMate-040 study that were presented during the 2020 Gastrointestinal Cancers Symposium.^1,2

“For patients with advanced HCC, we hope that, in the future, we can test the triplet combination in a randomized trial setting,” said lead study author Thomas Yau, MD. “Maybe this kind of triplet combination can be suitable for patients with aggressive disease upon presentation.”

Combining nivolumab with ipilimumab previously demonstrated clinical activity in HCC. In 2019, results showed that nivolumab plus ipilimumab yielded an objective response rate (ORR) >30% across 3 different dosing regimens of the PD-1 and CTLA-4 inhibitors in another cohort of CheckMate-040, which included sorafenib-treated patients with advanced HCC.³

In the exploratory cohort data presented at the 2020 Gastrointestinal Cancer Symposium, nivolumab/ipilimumab/cabozantinib elicited an investigator-assessed objective response rate (ORR) of 29% with a disease control rate (DCR) of 83% in patients who were treatment-naïve, had progressed on, or were intolerant to prior sorafenib. The investigator-assessed median progression-free survival (PFS) and median overall survival (OS) were 6.8 months and was not reached, respectively.

For patients with advanced HCC who received a doublet therapy of nivolumab plus cabozantinib, the investigator-assessed ORR was 19% and the DCR rate was 75%; the median PFS was 5.4 months and the median OS was 21.5 months, respectively.

Based on these results, Yau said that the triplet regimen has the potential to serve an unmet need for this patient population that has aggressive disease.

In an interview with OncLive during the 2020 Gastrointestinal Cancers Symposium, Yau, an clinical associate professor at the University of Hong Kong, discussed the early results of this triplet in patients with advanced HCC, and what next steps should be taken to bring the combination into clinical practice in the future.

OncLive: Could you provide an overview of the CheckMate-040 trial?

Yau: This is a phase I/II study investigating nivolumab combined with ipilimumab and cabozantinib in patients with advanced HCC; that is cohort 6 from CheckMate-040.

We all know that nivolumab has activity and safety data in patients with HCC. The addition of ipilimumab boosted the response rate to around 30% in advanced HCC. Also, cabozantinib is one of the options for these patients. We wanted to investigate whether we can safely and effectively use the combination in the advanced HCC population.

What was the study design?

In the phase I/II study, we enrolled patients who were sorafenib-naïve or were resistant or intolerant to sorafenib. Half of the patients were randomized to receive nivolumab plus cabozantinib; the other half of the patients were randomized to nivolumab/ipilimumab/cabozantinib and continued treatment until disease progression or unbearable toxicity.

The primary endpoint was safety and efficacy, similar to other phase II studies. There were a lot of secondary endpoints, including OS, PFS, and time to progression.

What results were presented at the 2020 Gastrointestinal Cancers Symposium?

We presented the mature results of a cohort from the CheckMate-040 trial. The efficacy shows that in the doublet arm, the ORR was about 20%. In the triplet arm, the ORR was about 29%. Based on whether you assess the patient depends on the investigator's assessment or the central review.

We have mature data on the responding patients, and they actually have partial responses. We had a few patients who achieved a complete response (CR). Some of the patients received the doublet, but more patients [who had a CR] received the triplet. What is more impressive is the DCR in the doublet arm; it was 75% in the doublet arm. In the triplet arm, the DCR was up to 83%.

The PFS, according to the investigator assessment, was about 5.4 months for the doublet arm and was about 6.8 months for the triplet arm. Finally, after almost 2 years of follow-up, the median OS for the doublet arm was [21.5] months and is still not reached in the triplet arm.

Concerning the treatment-related adverse events (TRAEs), the most common TRAEs in both arms were diarrhea, skin reactions, and hypertension. The rate of grade 3/4 AEs was [47%] in the doublet arm compared with 71% in the triplet arm. The majority of these grade 3/4 AEs were actually of grade 3; only 14% of the patients developed grade 4 TRAEs. There were no treatment-related deaths in either arm.

What is the key takeaway from this research?

We demonstrated promising early efficacy of using nivolumab plus ipilimumab plus cabozantinib in advanced HCC. This triplet therapy is the first of its kind in patients with HCC, even though the treatment may result in a higher incidence of TRAEs.

Where do you see this combination fitting into the treatment landscape for advanced HCC?

For patients with advanced HCC, we hope that, in the future, we can test the triplet combination in a randomized trial setting. Perhaps this kind of triplet combination can be suitable for patients with aggressive disease upon presentation.

There are a lot of immunotherapy/TKI combinations or immunotherapy/immunotherapy combinations, but this is the first that people have done an immunotherapy and immunotherapy plus a TKI.

References

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. J Clin Oncol. 2020;38(suppl; abstr 478).
2. Exelixis announces results for combination of cabozantinib and nivolumab with or without ipilimumab in advanced hepatocellular carcinoma [news release]. Alameda, CA: Exelixis, Inc; January 24, 2020. bit.ly/2tR2Z6K. Accessed January 25, 2020.
3. 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; abstr 4012). doi: 10.1200/JCO.2019.37.15_suppl.4012.

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