Early-Stage Immunotherapy Use in HCC Produces High Response Rate

Arndt Vogel, MD

Immunotherapy-based combinations have been a game changer for the treatment of advanced hepatocellular carcinoma (HCC). However, the benefit of immunotherapy in earlier-stage disease remains unclear.¹

The ongoing IMMUTACE (NCT03572582) study evaluates the efficacy of nivolumab (Opdivo) in combination with transarterial chemoembolization (TACE) for the treatment of multinodular, intermediate-stage HCC as a first-line therapy. The study has an actual enrollment of 49 participants. The primary end point of the study is objective response rate. Secondary end points include progression-free survival (PFS), time to progression, overall survival, duration of response, objective response rate, time to failure of strategy, quality of life, and safety.²

During the study, treatment was divided into 4-week cycles from TACE start date. The second TACE is repeated on day 1 of cycle 3. Nivolumab treatment begins on day 2 to 3 after the first TACE session and is administered every 2 weeks until disease progression or up to 2 years.

Lead investigator Arndt Vogel, MD, the managing senior consultant and professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, discussed the use of immunotherapy in earlier-stage HCC and findings from the IMMUTACE in an interview with Targeted Oncology^TM.

TARGETED ONCOLOGY™: Can you discuss the use of immunotherapy combinations in a real-world setting? What therapies are available for these patients currently?

VOGEL: In the last 5 years, we have made tremendous progress with systemic therapies for hepatocellular carcinoma, and after the approval of a lot of tyrosine kinase inhibitors in the first and second setting, the IMbrave150 study [NCT03434379] was the first positive study with an immuno-onology [IO] combination, with atezolizumab [Tecentriq] and bevacizumab, with a clear and significant improvement in median overall survival for patients with advanced HCC. And given the activity of immunotherapy in patients with metastatic disease, the question is can we move immunotherapy to earlier stages, and this is what people are interested in the IMMUTACE study.

What do outcomes look like with these therapies right now in the real world? Would you say they're comparable with what was observed in the clinical trials of these agents? 

For the IO combinations in advanced disease, we have observed a median overall survival of almost 20 a month. It's pretty great. With tyrosine kinase inhibitors, we usually observe a median overall survival of 12 to 13 months. So, there was an almost six-month improvement. For local therapies, and local therapies are the standard of care for patients in intermediate stages. So, patients with the tumor confined to the liver, no vascular infiltration, no extra hepatic metastases, these patients we usually use TACE. And when we look at the outcome in the phase 3 studies using these, they have a median overall survival of around 20 to 35 months. So, there's a wide heterogeneity, which reflects the inclusion of patients in the different trials. In the real-world cohort median overall survival is much shorter, usually below 20 months, which is most likely a reflection of a broader indication for this therapy and probably patients that we would not treat within a clinical trial, have receive these in a real-world setting. So, I think we need to really distinguish a lot of clinical trial population and to real-world population. At the moment we're in a transition period very, very restrictive, but the local therapist and may use these IO based combinations more frequently in earlier stages.

What led to your study of TACE in combination with nivolumab for the treatment of intermediate-stage HCC?

We tried to combine basically the best of both treatment approaches, specifically in patients with liver limited disease. So, the idea was to use TACE to get control of the tumor, maybe also destroy the tumor a little bit, which should lead to an antigen release, which could prime the immune system to the checkpoint inhibitor, which we applied after the first TACE. Patients were allowed to receive that second TACE when it was considered reasonable by the investigator and then nivolumab was continued. The idea was really to combine immunotherapy with local therapies to get a better disease control. Since this was a proof of concept study, we used overall response rate as a primary endpoint. We assumed a response rate of more than 55% as clinically meaningful. In the end, we were able to achieve a response rate of over 70% indicating that the study met it primary endpoint, and based on the data we have seen so far, I think it looks like a very promising combination which should be perused in subsequent and phase 3 studies.

Can you explain the study design and the findings of this analysis?

We looked at 50 patients with intermediate stage HCC. It was a single arm study. patients received to first TACE. Then after 2 or 3 days, nivolumab was started. Patients were allowed to receive a second TACE. And then nivolumab was continued. One patient had progressive disease. This was the time point where we determined the first progression. Patients were then allowed to get another local therapy if it was feasible, and patients then could continue with nivolumab. After the second progression, failure strategy was reached. This was a secondary end point which we have not yet reported. The primary end point was overall response rate. We saw a response rate of more than 55% as a positive segment.

Wat are the implications of your results?

This was an early readout. The study met it primary end point. We observed a very high overall response rate of more than 50%. PFS and overall survival is still early. And specifically, patients were allowed to continue nivolumab after the first progression, I think we have to wait for more major data in respect to the very important secondary endpoints like overall survival. Although I think the combination looks very promising in respect to maybe some synergistic, at least additive activity. I think it's a promising signal for the currently ongoing and phase 3 studies which compare TACE alone to TACE with various combinations.

_REFERENCES:

_{1.Vogel A, Saborowski A, Hinrichs J, et al. IMMUTACE: A biomarker-orientated, multicenter phase II AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate stage hepatocellular carcinoma (HCC). Ann Oncol. 2021;32(5):S1312. doi: 10.1016/j.annonc.2021.08.2114}

_{2.Transarterial chemoembolization in combination with nivolumab performed for intermediate stage hepatocellular carcinoma (IMMUTACE). ClinicalTrials.gov. Accessed October 25, 2021. https://bit.ly/3mdmlvn.}