Lancet Oncol: COSMIC-312 – The Mystery of Liver Cancer Immunotherapy

Highly heterogeneous liver cancer, insensitive to chemotherapy, targeted therapy drugs in the era of targeted therapy, only sorafenib, lenvatinib and other drugs have been approved

The journal The Lancet Oncology (IF: 59.

COSMIC-312 is the first phase III randomized controlled trial (RCT) designed to evaluate tyrosine kinase inhibitors combined with immunocheckpoint inhibitors for the systemic systemic treatment of first-line patients with advanced liver cancer, with carbotinib (with extensive inhibitory properties of VEGFR2, c-Met, AXL, and RET) plus altelizumab (anti-PD-L1 monoclonal antibody) and sorafenib

COSMIC-312

The results of the COSMIC-312 trial were published on NEJM and Lance oncology, see: Which is stronger in the first-line treatment of advanced liver cancer? The Lancet Oncology publishes clinical results

Background

method

The specific study design is as follows

outcome

During the data cut-off date (March 8, 2021), from December 7, 2018 to August 27, 2020, a total of 837 patients were included in the carbotinib plus atirizumab group (n=432), the sorafenib group (n=217), and the carbotitinib group (n=188).

mPFS was 6.

mOS (interim analysis) was 15.

The most common grade 3 or 4 adverse events were elevated alanine aminotransferases (38 [9%] of 429 patients in the combination therapy group, 6 [3%] of 207 patients in the sorafenib group, 12 [6%] of 188 patients in the single-agent cabotinib group, hypertension (37 [9%] vs 17 [8%] vs23 [12%], elevated aspartate aminotransferase (37[9%] vs.

The failure of the COSMIC-312 study forced us to think about why the IMbrave150 study was successful (altelizumab combined with bevacizumab).

Comparison of COSMIC-312 and IMbrave150 studies

Analysis of COSMIC-312 failure studies

Phase Ib jumps directly to the risk of a phase III HCC head bullish study

Cabozantinib targets multireceptor tyrosine kinases involved in tumor pathogenesis, including angiogenic growth factors VEGFR and MET, and TAM kinase families (tyrosine 3, AXL, MER), helping to lift the immunosuppressive environment in the tumor microenvironment

Cabozantinib targets pathways associated with tumor immunosuppression

Based on the above chain of evidence, cabozantinib opened a head-to-head three-arm test of bisorafinib - COSMIC-312

1.

I am more concerned with the stratification factors involved in the etiology than with the trial cohort design, and I have described the different immune benefits of HCC patients with different etiologies

Cancers: well-controlled viremia predicts hepatocellular carcinoma prognosis in patients with chronic viral hepatitis treated with sorafenib

Front Immunol: Investigation of hepatitis B vaccine immune response in patients with occult hepatitis B virus infection

Front Immunol: Correlation between HBV DNA and hepatitis B surface antigen levels and tumor efficacy, liver function, and immunological indicators in patients with HBV-infected liver cancer receiving PD-1 inhibitor combination therapy

In my rough opinion, why have many global studies failed, but the data in the Asian population, especially the Chinese subgroup, are significantly higher than those of other subgroups? China's HCC patients are mainly caused by hepatitis B virus infection, in China viral hepatitis B related liver cancer accounted for 75% to 90% of the total number of cases, in the disease process of viral hepatitis B related liver cancer disease process there is an immune dysregulation mechanism, of which PD-1 and CTLA-4 and other immunosuppressive factors overexpression caused by T cell inactivation, involved in the chronicity of viral infection, hepatitis self-limited development and liver cancer occurrence, development and many other processes

The same is true

Second, the follow-up treatment of the solafinib monotherapy group has a higher proportion of immunity than that of the combined group

Third, immune combined anti-vascular targeting drugs can not benefit from OS?

The revelation of the failure of the LEAP-007 lung cancer test (liver cancer) has mentioned that the effect of immune combination targeting in the early stage of tumor reduction is very obvious, but it may not be possible to achieve

Finally, summarize the small molecule anti-angiogenic drugs
that have been mainly marketed.

With the application of immunologic drugs in sequential therapy of sorafenib groups, the benefits of treatment varied in different subgroups of
patients.
The clinical trial design of liver cancer has gradually reached the stage
of competing for the real strength of the product.
However, between different trial designs, there can be no direct comparison, and there is currently a lack of detailed discussion of the mechanism, which also makes it difficult for latecomers to carry out large-scale phase III research in the field of heterogeneous liver cancer, but there is no doubt that immunotherapy has undoubtedly profoundly changed the treatment pattern of liver cancer, and in the future, it is expected that more benefit data can be published
.

References

1.
https://doi.
org/10.
1016/S1470-2045(22)00497-1

2.
Kelley RK, Yau T, Cheng A-L, et al.
 doi:10.
1016/j.
annonc.
2021.
10.
008

3CellMol Immunol,2016,13(3):267-276.
DOI:10.
1038/cmi.
2016.
3.
 

4.
IntJMol Sci, 2017, 18(7):1517.
DOI:10.
3390/ijms18071517.

5.
https://doi.
org/10.
1016/S1470-2045(22)00326-6.

6.
Kelley, Oliver, Hazra et al.
Future Oncol.
2020 Jul; 16(21):1525-1536.