TACE and immunotherapy for intermediate-stage HCC

"TIME" for combination trials?

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Liver cancer is the third-leading cause of cancer death worldwide, of which hepatocellular carcinoma (HCC) represents 75–85% of cases.1 Treatment algorithms for HCC have remained fairly aligned to disease stage for the last 10 years. For example, Barcelona clinic liver cancer (BCLC) stages 0 or A typically receive surgical or ablative therapy, stage B patients typically receive imaged-guided locoregional therapy like transarterial chemoembolization (TACE) or selective internal radiotherapy (SIRT), and stage C patients typically receive systemic treatment.2 In advanced-stage HCC patients (characterized by vascular invasion, lymphatic involvement or extrahepatic metastasis), tyrosine kinase inhibitors (TKIs) have been the mainstay of treatment since the 2008 SHARP trial over a decade ago. The SHARP (Sorafenib HCC Assessment Randomized Protocol) trial investigated 297 predominantly BCLC stage C HCC patients. It demonstrated that sorafenib produced a 31% reduction in risk of death and a 3-month increase in overall survival compared to placebo.3 Since then, other single-agent TKIs (levantinib) and immunotherapies (nivolumab) have failed to show superiority.

The rise of combination therapy

However, in 2018, investigators in the IMbrave 150 trial proposed that a combination therapy (immunotherapy paired with an antiangiogenic) might improve the overall survival for advanced-stage HCC patients compared to sorafenib. Indeed, IMbrave 150 showed that combination of atezolizumab (anti PD-L1) and bevacizumab (antiangiogenic) had better overall survival than sorafenib alone, with a 67.2% vs 54.6% survival rate at 12 months.4 Perhaps more importantly, the estimated percentage of patients with duration of response longer than 6 months was 87.6% in the atezo-bev group and 59.1% in the sorafenib group. The immunotherapy revolution, which has captivated patients’ hopes of longer survival through drugs that enhance their immune system, was finally underway in advanced-stage HCC. Other combination trials testing dual-agent immunotherapy (like the Himalaya trial) are currently underway in advanced-stage HCC.

During the same time period that the combination of immunotherapy and antiangiogenics was demonstrating benefits in advanced-stage HCC, interventional radiology studies began to examine the potential of combining locoregional therapies like TACE with systemic therapies in intermediate-stage HCC. In the TACE 2 trial,5 313 patients with intermediate-stage HCC were randomized to drug-eluting bead transarterial chemoembolization (DEB-TACE) with sorafenib or DEB-TACE with placebo. The results of TACE 2 showed no improvement in time to progression for sorafenib and DEB-TACE compared to DEB-TACE alone. In addition, a phase II randomized controlled trial was performed comparing conventional TACE to TACE plus bevacizumab in 32 predominantly intermediate-stage HCC patients.6 Median survival was worse in the study arm with bevacizumab (5.3 vs 13.7 months). No improvement in radiologic tumor response or overall survival was observed in patients in either group at 3, 6 or 12 months.

With the failure of enhanced overall survival in intermediate stage HCC patients with the combination TACE with TKIs or antiangiogenics, a lingering question remains: Can the overall survival of TACE be improved by adding immunotherapy? Studies conducted in the post-TACE tumor immune microenvironment (TIME) can shed some light on the subject. In the pre- and post-TACE tumor microenvironment, immune modulating cytokines are present. One study of 142 HCC patients treated with TACE7 looked at pre/post serum levels of the T cell cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ and TNF-α). Results revealed that patients with undetectable levels of IL-6 and high levels of IL-22 pre TACE had better overall survival than the converse. Likewise, patients with increased IFN/IL 10 ratio post-TACE demonstrated increased survival compared to those with a decreased ratio. Another study in 51 intermediate-stage patients with HCC showed that high levels of circulating Th-17 T cells 30 days post TACE was associated with improved overall survival compared to those with low levels.8 Thus, if locoregional therapies like TACE can affect the tumor immune microenvironment, TACE and immunotherapy could potentially improve survival by at least two mechanisms. At best, the necrosis caused by locoregional therapy could provide antigens and cytokines favorable for the function of immunotherapeutic drugs. At worst, debulking tumors with locoregional therapy could result in a lower tumor burden, potentially making the immunotherapy more effective.

Doublet and triplet combinations

Given what we know from combination medical therapies in advanced-stage HCC, it would be vital for IRs to test the effects of “doublet” and even “triplet” combinations of TACE and immunotherapy, TKIs and antiangiogenics. Agents being considered for study include durvalumab (anti PD-1), pembrolizumab (anti PD-1), nivolumab (anti PD-1), ipilimumab (anti CTLA-4), lenvatinib (TKI) and bevacizumab (anti-angiogenic). In fact, four new trials are currently underway, exploring combinations of TACE and immunotherapy in intermediate-stage HCC patients.

The Emerald-1 trial (NCT03778957) is a three-arm study of 710 patients randomized to TACE combined with durvalumab and bevacizumab vs. TACE and durvalumab vs. TACE alone.

Leap-012 (NCT04246177) is another study looking at 950 patients randomized to two groups: TACE with pembrolizumab and lenvatinib vs. TACE alone.

Checkmate-74W (NCT04340193) studies 765 patients randomized to TACE with nivolumab and ipilimumab vs. TACE and nivolumab vs. TACE alone.

Lastly the TACE-3 study (NCT04268888) involves 522 patients stratified to TACE and nivolumab vs. TACE alone.

Primary endpoints for all these trials include overall survival.

Conclusion

Just as immunotherapy’s combination with targeted therapy has radically changed the treatment paradigm in patients with advanced stage HCC, positive results of any one of the four combination trials of TACE and immunotherapy could shift the paradigm for treatment of intermediate-stage HCC patients.

Practicing interventional radiologists must heed the call to recruit, enroll and treat patients in immunotherapy trials to answer the question of TACE and immunotherapy for intermediate-stage HCC. If not, investigators in other disciplines may ask, “Are locoregional therapies like TACE or SIRT really needed at all in intermediate-stage HCC, or can advanced-stage treatments like immunotherapy and antiangiogenics/TKIs be more successful than TACE or SIRT alone in intermediate-stage HCC patients?”

The results of these trials and the answer to these questions remains unknown, but one thing is clear: Breakthroughs in the understanding of how locoregional therapies affect the TIME will shape future trials that define systemic, locoregional and combination therapies for intermediate-stage HCC patients for years to come. 

References:

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  2. Galle, PR et al,. EASL Clinical practice guidelines: Management of hepatocellular carcinoma. Jour Hep. 2018;69(1)182–236.
  3. Llovet, J and the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378–90.
  4. Finn, RS et al and the IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020 May 14;382(20):1894–1905.
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  6. Pinter M et al. Hepatocellular carcinoma: A phase II randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo. Radiology. 2015 Dec;277(3):903–12.
  7. Lee, HL et al. Inflammatory cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular carcinoma in patients treated with transarterial chemoembolization. Sci Rep 2019;9:3260.
  8. Liao Y, et al. Increased circulating Th17 cells after transarterial chemoembolization correlate with improved survival in Stage III hepatocellular carcinoma: A prospective study. PLoS ONE 2013;8(4): e60444.