November 27, 2022

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How about the Clinical treatment status of hepatocellular carcinoma?

How about the Clinical treatment status of hepatocellular carcinoma?

How about the Clinical treatment status of hepatocellular carcinoma?  Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers.

Globally, liver cancer is the fourth leading cause of cancer-related deaths and sixth in the number of new cases. The 5-year survival rate of liver cancer is only 18%, which is the second most lethal tumor after pancreatic cancer.

In recent years, significant progress has been made in the clinical treatment of hepatocellular carcinoma. SHARP is the first clinical trial to lay the foundation for the use of multi-target receptor tyrosine kinase inhibitors (RTKI) for the treatment of liver cancer. Since SHARP, there have been five successful Phase 3 clinical trials.

How about the Clinical treatment status of hepatocellular carcinoma? 

In addition, the Phase 2 clinical trials of PD1 inhibitors nivolumab and pembrolizumab showed good prospects and led to accelerated approval by the FDA. The latest phase 3 clinical trials show that the anti-PD-L1 antibody Atezolizumab and the anti-VEGF antibody bevacizumab (atezo/bev) as a first-line combination therapy are stronger than sorafenib, with superior progression-free survival (PFS) and overall survival (OS), This is the first clinical trial to achieve this goal since SHARP. Therefore, Atezo/bev has now become the new standard for the first-line treatment of advanced HCC, and all upcoming clinical trials need to be tested according to this new benchmark.

First-line and second-line systemic treatment of advanced liver cancer

Several treatments are trying to follow in the footsteps of atezo/bev: cabozantinib combined with Atezolizumab (COSMIC-312; NCT03755791); lenvatinib combined with pembrolizumab (LEAP-002; NCT03713593); durvalumab combined with anti-CTLA-4 antibody tremelimumab (HIMALAYA; NCT03298451) ; Nivolumab combined with ipilimumab (CheckMate 9DW; NCT04039607); anti-PD-1 antibody camrelizumab (SHR-1210) combined with apatinib (NCT03764293) and anti-PD-1 antibody tislelizumab as a monotherapy (RATIONALE-301; NCT03412773).

How about the Clinical treatment status of hepatocellular carcinoma? 

These combinations are currently undergoing phase 3 clinical trials, using the same similar design: all trials are first-line treatment, including patients with unresectable HCC, that is, mid-stage patients (BCLC B), and advanced patients (BCLC C). The only exception here is CheckMate 9DW, which is limited to advanced HCC. As for the primary endpoint, COSMIC-312, LEAP-002, and camrelizumab+apatinib trials used PFS and OS according to RECIST 1.1, while HIMALAYA, CheckMate 9DW, and Rational-301 used OS only. It is worth mentioning that none of these phase 3 clinical trials currently use Atezo/bev as a control, but sorafenib or lenvatinib.

In addition, there are some combination therapies in the early stages of the clinic (Phase 1 or 2). It is worth noting that all trials include a checkpoint inhibitor. Two trials are evaluating the combination of regorafenib and nivolumab (NCT04170556 and NCT04310709). Regorafenib is also undergoing clinical trials of combination therapy with pembrolizumab (NCT03347292) and tislelizumab (NCT04183088), as well as cabozantinib and pembrolizumab (NCT04442581) and sitravatinib and tislelizumab (NCT03941873).

Systemic treatment of mid-stage liver cancer

The IMbrave 150 trial included patients with unresectable HCC, namely BCLC B and C stages, of which >80% of patients were in BCLC C stage. As the proportion of BCLC stage B patients is quite small (~15%), it is currently impossible to finalize the efficacy of atezo/bev in this type of patient group, especially with transcatheter arterial chemoembolization (TACE) treatment (current standard of care) Comparison.

ABC-HCC (NCT04803994) is a large-scale phase 3b clinical trial that compares atezo/bev and TACE initiated by researchers, and it will answer this question accurately. In addition, RENOTACE (NCT04777851) is another phase 3 clinical trial initiated by a large investigator, which will test the effect of regorafenib combined with nivolumab compared with TACE. These two clinical trials will pave the way for systemic treatment of BCLC stage B patients.

However, the challenge in designing such clinical trials is that they compare two different treatment modalities. Therefore, the ABC-HCC trial uses a new primary endpoint, which measures the time it takes for the investigator to stop treatment (atezo/bev or TACE) due to treatment failure. In contrast, RENOTACE is more conservative in this regard and uses PFS. In the next few years, other clinical trials comparing mid-stage liver cancer with TACE will definitely follow up.

Another possibility to treat mid-stage liver cancer is to add systemic therapy to TACE. There are currently three phase 3 trials in progress. LEAP-012 is testing the addition of lenvatinib and pembrolizumab to TACE (NCT04246177), the EMERALD-1 trial adds durvalumab or durvalumab plus bevacizumab (NCT03778957) to TACE, and the CheckMate 74W trial adds nivolumab or nivolumab plus ipilimumab to TACE (NCT04340193). All these tests are compared with TACE alone.

Adjuvant therapy

So far, no systemic treatment has been proven to be beneficial in the adjuvant treatment of therapeutic hepatectomy or ablation. The STORM trial failed to prove the benefits of sorafenib in this regard.

https://en.wikipedia.org/wiki/Hepatocellular_carcinoma

Four ongoing Phase 3 trials are exploring new methods: CheckMate 9DX trial is testing adjuvant therapy with nivolumab (NCT03383458); KEYNOTE-937 trial is testing adjuvant therapy with pembrolizumab (NCT03867084), IMbrave050 trial is testing atezolizumab and beva Adjuvant therapy with monoclonal antibodies (NCT04102098), and the EMERALD-2 trial tested adjuvant therapy with or without bevacizumab (NCT03847428).

Neoadjuvant therapy

There are currently no mature data to support the use of systemic drugs before surgery or local treatment. However, early clinical trials evaluating neoadjuvant therapies are ongoing. The NIVOLEP trial is evaluating the efficacy of nivolumab before and after electroporation ablation (NCT03630640); the CaboNivo trial is evaluating the safety of combining cabozantinib and nivolumab before locally advanced/borderly resectable HCC hepatectomy (NCT03299946).

How about the Clinical treatment status of hepatocellular carcinoma? 

There is also an upcoming test of the efficacy of pembrolizumab before and after therapeutic ablation or resection (NCT03337841); the PLENTY202001 trial is testing the efficacy of combined treatment of lenvatinib and pembrolizumab before liver transplantation (NCT04425226).

In short, neoadjuvant therapy is an unknown area of ​​systemic therapy, and it remains to be seen which of these new concepts will eventually be realized.

Cell therapy and gene therapy

Most of the cell and gene therapy of HCC are still in the preclinical or early clinical stage. Such immunotherapies include chimeric antigen receptor (CAR)-T cells, allogeneic NK cells, and oncolytic viruses.

How about the Clinical treatment status of hepatocellular carcinoma? 

Currently, there are six registered Phase 1 clinical studies of CAR-T cells targeting Glypican 3 (GPC3) (NCT04121273; NCT04506983; NCT03198546; NCT02905188; NCT03884751; NCT03980288). There is a phase 2 study comparing the effect of iNKT cell therapy plus TACE with TACE alone (NCT04011033).

Similarly, FT500 (an allogeneic NK cell line) and FATE-NK100 (a donor-derived NK cell) are undergoing phase 1 trials in various cancer indications including HCC (NCT03319459; NCT04106167; NCT03841110) . In the Phase 2b trial of TRAVERSE, the oncolytic virus pexastimogene devacirepvec (Pexa Vec) failed as a second-line monotherapy for advanced liver cancer. It is currently being combined with nivolumab for a Phase 1/2a trial (NCT03071094). However, PHOCUS’s Phase 3 trial (NCT02562755) studied the combination of PexaVec and sorafenib, which was terminated early due to the obvious lack of clinical benefit in the interim analysis. This also highlights the risks of new immunotherapy methods in the treatment of HCC.


Summary

In recent years, systemic treatment of liver cancer has made considerable progress. In the next few years, we will see a large amount of data from phase 3 clinical trials. These data are likely to bring profound changes to the clinical treatment of HCC.

So far, atezo/bev is the first and only immunotherapy with curative effect on liver cancer. And such drugs are no longer limited to advanced HCC, but include the early stages of the disease. In addition, other immunotherapy methods, such as CAR-T or CAR-NK cells, have now entered the clinical development stage, and may further expand the scope of treatment for HCC.

In short, the current prospects of tumor immunotherapy for HCC are very promising. Tumor immunotherapy now has a place in the treatment of liver cancer, and its coverage may continue to expand. In the next few years, clinical trials will provide a lot of exciting data, which is expected to provide better treatment options and improved prognosis for liver cancer patients.

How about the Clinical treatment status of hepatocellular carcinoma? 

(source:internet, reference only)


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