Bruno Sangro, MD, PhD, discusses the efficacy and safety findings from a study of combination durvalumab and tremelimumab, as well as the clinical need for alternative combination regimens in advanced hepatcellular carcinoma.
Although the introduction of novel combinations has greatly enhanced the frontline treatment landscape of advanced hepatocellular carcinoma (HCC), the field is in need of additional active regimens, said Bruno Sangro, MD, PhD, who cited the combination of durvalumab (Imfinzi) and tremelimumab as one worthy of further investigation.
As part of the 2020 ESMO World Congress on Gastrointestinal (GI) Cancer, findings from part 3 of the phase 2 Study 22 revealed that a single dose of 300 mg of tremelimumab in combination with 1500 mg of durvalumab administered every 4 weeks elicited significant clinical activity with a manageable safety profile in patients with unresected HCC who progressed on, were intolerant of, or refused sorafenib (Nexavar).
In part 3 of the trial, patients were randomized to 1 of 4 arms: 300 mg of tremelimumab and durvalumab, 75 mg of tremelimumab and durvalumab, durvalumab alone, or tremelimumab alone.
Regarding efficacy, the median overall survival (OS) was 18.7 months with the high-dose tremelimumab combination, 13.6 months with durvalumab monotherapy, 15.1 months with tremelimumab monotherapy, and 11.3 months with the low-dose tremelimumab combination.
The objective response rates (ORRs) were 24.0%, 10.6%, 7.2%, and 9.5%, respectively. The median duration of response was not reached in the high-dose tremelimumab arm compared with 11.17 months with single-agent durvalumab, 23.95 months with single-agent tremelimumab, and 13.21 months with low-dose tremelimumab.
Regarding safety, treatment-related serious adverse events (AEs) including death occurred in 16.2% of patients treated with high-dose tremelimumab versus 10.9%, 24.6%, and 14.6% of patients in the durvalumab, tremelimumab, and low-dose tremelimumab arms, respectively.
“We believe that this combination has a clear antitumor effect with a tolerable safety profile,” said Sangro. “The more combinations we have, the better. We will be able to adapt our treatments to the needs of our patients in terms of comorbidities and [extenuating] circumstances. [Having more combinations] can allow us to tailor our choice of treatment to the profile of the patient.”
In an interview with OncLive, Sangro, director of the Liver Unit at Clínica Universidad de Navarra and a professor of medicine at the Clínica Universidad de Navarra School of Medicine in Pamplona, Spain, discussed the efficacy and safety findings from this study, as well as the clinical need for alternative combination regimens in advanced HCC.
OncLive: What was the rationale for evaluating this regimen in patients with unresectable, advanced HCC?
Sangro: Despite the activity of TKIs like sorafenib or lenvatinib (Lenvima), or the improved efficacy of some immunotherapy combinations with antiangiogenic [agents], there is an unmet need to have more potent and well-tolerated therapies in HCC.
Building on an old observation by our group and other groups, [we discovered that] HCC is sensitive to CTLA-4 blockade––we showed that in a pilot trial over 5 years ago. We believe that adding tremelimumab, which is a CTLA-4 inhibitor, to durvalumab, which is a PD-L1 inhibitor, could lead to enhanced activity. This was the rationale for this study.
The trial included different parts. Part 1 was a typical [dose]-escalation phase, for which results have already been presented.
At the 2020 ESMO World Congress on GI Cancer, we presented the results from parts 2 and 3 of the study. Part 2 compared 3 arms: single-agent tremelimumab at a high dose, single-agent durvalumab at a standard dose, and a combination of that standard-dose durvalumab with a low dose of tremelimumab.
Substantial evidence indicated that early administration of CTLA-4–blocking agents in combination with anti–PD-1/PD-L1 agents could produce not only more potent activity in terms of response rate, but also, a burst in proliferating effector T cells in the peripheral blood. Moreover, there was a hint of increased activity and a hint of mechanistic explanation for that increased activity.
Based on that, a fourth arm was incorporated into the study, consisting of a single high dose of tremelimumab in combination with a standard dose of durvalumab. This new cohort with this priming dose of tremelimumab was first tested for safety and then incorporated into part 3 of the study. We are now presenting the results patients treated in all 4 cohorts.
What were the findings of the study?
Patients treated with a single priming dose of tremelimumab in combination with the usual dose of durvalumab had the highest ORR at around 30% and prolonged OS at 22 months.
As a reminder, this is a mix of patients. Around 20% of patients across arms were naïve to sorafenib, and [the remaining] population had progressed on or were intolerant to sorafenib.
The results are very encouraging. When we compared the results with the other 4 cohorts, we observed that the aforementioned combination [performed] better than [the other 3 cohorts] regarding survival and response rate.
In the single-agent tremelimumab cohort, toxicity was slightly higher [which is likely due] to the higher dose of the agent. However, this toxicity was still fairly acceptable. The number of
patients with grade 3 or higher treatment-related AEs, those leading to the need for sorafenib, or those leading to treatment discontinuation remained at acceptable levels.
This is the combination being tested in the phase 3 HIMALAYA trial that has recruited patients with advanced HCC who are naïve to systemic therapy.
What did the pharmacodynamic biomarker analysis reveal in this study?
We interrogated peripheral lymphocytes obtained on day 15 after the initiation of therapy, and we checked the composition of those lymphocyte populations. The pharmacodynamic analysis showed that patients treated with a single dose of tremelimumab plus durvalumab had a significant burst in proliferating Ki-67–positive and CD8-positive T cells. These are activated T cells that [settle] in the peripheral blood compartment early on. They provide a mechanistic explanation to the improved activity observed with this particular combination.
How could positive results from the HIMALAYA study impact the treatment paradigm of advanced HCC?
We know that the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is better than sorafenib in terms of prolonging survival in patients with advanced HCC who are naïve to systemic therapies. However, there is still room for improvement.
With the activity that we observed with this combination, a 30% response rate and prolonged survival in the cohort of patients treated, I think it compares well with the preliminary activity we saw with atezolizumab and bevacizumab.
If the HIMALAYA trial is positive, this may provide an alternative regimen without an antiangiogenic agent. We need different active combinations in HCC, so I don’t believe we should neglect the activity of any combinations that are being testing in ongoing phase 3 trials, including the combination of tremelimumab and durvalumab. Also, this includes combinations with TKIs, such as the combination of lenvatinib and pembrolizumab (Keytruda).
What is your take-home message to your colleagues regarding this study?
We are witnessing a change in the treatment paradigm of HCC. It is clear the immunotherapy is in the HCC arena and that we have to build on the activity of PD-1/PD-L1 inhibitors to increase treatment efficacy while preserving safety. This will allow us to provide a spectrum of different active combination therapies.
I don’t want to neglect the possibility that patients may still benefit from single-agent immunotherapy. We should not forget that our patients are often elderly and have different comorbidities. The wider the spectrum of choices, the better we will be able to treat our patients.
Kelley RK, Kudo M, Harris W, et al. The novel regimen of tremelimumab in combination with durvalumab provides a favorable safety profile and clinical activity for patients with advanced hepatocellular carcinoma (aHCC). Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. Abstract O-6.