Combinational Treatments Must Follow the Principle of Drug Combination-Feeling from the Treatments of Hepatocellular Carcinoma

Comment

Treatments for liver cancer have been generally divided into liver-directed and systemic therapies. Systemic treatments include chemotherapy, molecular targeted therapy, and immunotherapy. In the recent one decade, the treatment using targeted drugs for Hepatocellular Carcinoma (HCC) has been aggressive, such as Sorafenib as a hallmark [1-2], followed by Lenvatinib as the firstline treatment [3]. Regorafenib is recommended as the second-line therapy [4]. Trials with immunotherapy including anti-PD1 or anti-PD-L1 antibodies are ongoing. Although KEYNOTE-224 and KEYNOTE-240 failed to achieve positive results, overall survival of patients with checkpoint inhibitor seems better than the control group [5-6]. The effect of chemotherapy on HCC is still controversial for advanced HCC [7]. Despite the breakthroughs in drug therapy for HCC, it remains a systematic treatment but not a radical cure, with such a palliation to prolong the survival for a few months. It is mandated to explore more effective combination of novel drugs with other treatment modalities.

The use of combinational anti-cancer treatments for HCC should follow these principles: Firstly, the use of anti-cancer drugs alone is partially effective. Secondly, the combined use of a drug and other treatment modalities should be selected based on toxicity that does not overlap each other. Thirdly, different mechanisms of action with the combined treatments should be considered. We reviewed www.clinicaltrials.gov which is a database of privately and publicly funded clinical studies conducted around the world. The screening of the disease HCC included 1773 studies and consisted of 230 phase 3 studies. Among them, 65 studies were completed and 11 studies had available results. We selected the studies using anti-cancer drug combined with other treatment modalities, and 6 studies met the condition as listed in (Table 1). Unfortunately, all these clinical trials using combinational treatments including anti-cancer drug had either no results or negative results. We also reviewed 2019 ASCO annual meeting abstracts with phase 1 or 2 clinical trials on HCC testing combined anti-cancer drugs, as listed in Table 1. However, most of the trials presented with grade 3 or higher treatment-related adverse events ranged from 53% to 85%, with the toxicity beyond permissible limits (usually less than 35%). These combination therapies failed to follow the principle of drug combination, which was the main reason for the negative results. Some trials used the combinational therapy with the drugs such as Erlotinib, Avelumab, or Axitinib, which had been confirmed with no effect in HCC. Other trials combined more than one systemic therapy, but the toxicity of individual drug (molecular targeted drugs and/or checkpoint inhibitors) overlapped with each other. Surprisingly, a lot of phase 1 or 2 clinical trials were investigating the combinational systemic therapies, but none of them followed the principles of combination treatment. Fortunately, PACIFIC study was the most successful clinical trial on the combination therapies for non-small cell lung cancer. It did follow the three principles of combined therapies, including effective drug choice when used alone, space-time synergy, and no overlapped toxicity.

  

    
Phase 3 clinical trial on HCC using anti-cancer drug combination with    other treatment modalities
  
  

    
NCT No.
    
Treatment groups
    
n
    
results
    
P value
    
TRAEs
  
  

    
617981
    
Thermo Dox+RFA
    
354
    
mTTP:13.9
    

    

  
  

    
GS+RFA
    
347
    
mTTP:13.8
  
  

    
1829035
    
Sorafenib
    
169
    
mOS:10.8
    
0.29
    

  
  

    
Sorafenib + TACE
    
170
    
mOS:12.8
  
  

    
149565
    
resection
    
135
    
5y RFS:48.6
    
0.828
    

  
  

    
Resection+IFNα-2b
    
135
    
5y RFS:42.2
  
  

    
494299
    
TACE+Sorafenib
    
229
    
TTP:5.4
    
0.252
    

  
  

    
TACE+Placebo
    
229
    
TTP:3.7
  
  

    
901901
    
Sorafenib+ Erlotinib
    
362
    
mOS:9.5
    
0.2
    

  
  

    
Sorafenib+Placebo
    
358
    
mOS:8.5
  
  

    
692770
    
Resection+Sorafenib
    
556
    
mRFS:33.3
    
0.26
    

  
  

    
Resection+Placebo
    
558
    
mRFS:33.7
  
  

    
Studies on HCC testing combined anti-cancer drugs from 2019 ASCO    annual meeting
  
  

    
ASCO abstract No.
    
Treatment groups
    
n
    
results
    
P value
    
TRAEs
  
  

    
4012
    
Nivo 1+Ipilimu 3 Q3w×4
    
50
    
mOS 22.8m
    

    
III–IV53%
  
  

    
Nivo 3+Ipi 1 Q3w×4
    
49
    
mOS 12.5m
    
29%
  
  

    
Nivo 3 Q2w/Ipi 1 Q6w
    
49
    
mOS 12.7m
    
31%
  
  

    
e15630
    
Sorafenib+oxaliplatin+capecitabine
    
22
    
TTP: 3.2:2.8m, 
    
0.29
    

  
  

    
Sorafenib alone
    
24
  
  

    
TPS4152
    
Lenvatinib + pembro
    
30
    
mOS: 14.6m
    

    

  
  

    
Lenvatinib+Placebo
    
ORR: 26.9%
  
  

    

    
(Keynote 524)
  
  

    
4074
    
Camrelizumab +FOLFOX/GEMOX
    
34
    
ORR:9(26.5) 
    

    
III–IV 85.3%
  
  

    
4072
    
Avelumab+ Axitinib
    
22
    
1-year OS 54.5% ORR:13.6%
    

    
III 72.7%
  
  

    
e15601
    
TACE+Sorafenib
    
73
    
mOS:17.2:12.1m;
    
0.024
    

  
  

    
TACE only
    
60
    

    

  
  

    
TACE+Sorafenib
    
55
    
mOS:42.7:32.6m;
    
0.247
  
  

    
TACE only
    
72
    

    

  

Table 1: HCC clinical trials with combined anti-cancer drugs and other treatments
in both clinicaltrial.gov and 2019 ASCO abstracts.