Response Evaluation Criteria in Solid Tumors (RECIST) vs modified RECIST response durability in advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab

Lead Investigator: Jeroen Dekervel, Universitaire Ziekenhuizen Leuven
Title of Proposal Research: Response Evaluation Criteria in Solid Tumors (RECIST) vs modified RECIST response durability in advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab
Vivli Data Request: 8324
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:
Every year, more than 900 000 people are diagnosed with liver cancer globally, with the most common form being hepatocellular carcinoma. This cancer type is the third leading cause of cancer deaths worldwide, with a relative 5-year survival rate of approximately 18%.

To evaluate the effect of treatment efficacy in hepatocellular carcinoma, usually, a computerized tomography (CT) or magnetic resonance imaging (MRI) scan is used. Two validated criteria are used to define whether a treatment has an effect on the visualized tumour lesion(s). Historically, the Response Evaluation Criteria in Solid Tumours (RECIST) criteria have been used (as in all other solid tumor types). This system takes into account the change of size of the tumour lesions as a response to the treatment. When shrinkage of tumour lesion(s) is observed beyond a certain cut-off (ie. 30% of initial diameter), this is called a response. Responses can be either partial or complete. When the lesion has increased in size > 20% of the smallest diameter measured, this is progressive disease. All changes between those margins indicate a stable disease.

Specifically for hepatocellular carcinoma, alternative methods to define a treatment effect have been developed; the so-called modified RECIST or mRECIST criteria. These criteria also take into account the intralesional necrosis as response to treatment. Necrosis is the death of body tissue. It occurs when too little blood flows to the tissue. Intralesional necrosis is the death of tissue inside a lesion (a region in an organ or tissue which has suffered damage through injury or disease). The rationale behind these adapted criteria is the fact that certain treatments for HCC (such as treatments with anti-angiogenic properties, e.g. a drug or substance that keeps new blood vessels from forming. In cancer treatment, anti-angiogenesis agents may prevent the growth of new blood vessels that tumors need to grow) induce necrosis of lesions, rather than real tumor shrinkage. Thus, if a tumour lesion does not shrink upon treatment but shows significant intralesional necrosis, this is called an mRECIST response.

We have obtained tissue biopsies prior to treatment with atezolizumab/bevacizumab for molecular analysis and in preliminary findings, we see differences in cancer biology in RECIST vs mRECIST responders. To further explore the differences between the two types of clinical responses, we aim to investigate whether patients that obtain a RECIST response (real tumor shrinkage) have a more durable effect from atezolizumab/bevacizumab compared to patients with an mRECIST response but no RECIST response (pure necrosis without shrinkage).

Statistical Analysis Plan:
With this study, we aim to compare the durability of two types of response seen with systemic treatment in HCC:
– tumor necrosis without lesion shrinkage (ie. a mRECIST response but no RECIST response) – GROUP 1
– tumor shrinkage with or without necrosis (ie. a RECIST response) – GROUP 2
In the IMbrave 150 study, both response criteria were used to assess the efficacy of treatments in both arms: atezolizumab/bevacizumab and sorafenib. As this analysis focuses on immunotherapy, we will only use the data of patients in the experimental atezolizumab/bevacizumab arm:
– in this treatment arm, 89 patients had a RECIST response and 108 patients had an mRECIST response.
– as all patients with a RECIST response, by definition, also have an mRECIST response, GROUP 1 will consist of 19 patients (mRECIST response but no RECIST response) whereas GROUP 2 will consist of 89 patients

The median duration of response will be calculated both for GROUP 1 and GROUP 2 using the Kaplan-Meier method. The log rank test will be used to assess between group differences. Duration of response (DoR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response.

Overall survival will also be calculated for both groups using the same approach.

This is a small exploratory subanalysis of the IMbrave trial without formal power analysis. No other sources will be used. No multivariate analyses will be performed given the relative low number of patients in each group. Missing data is not expected to be a significant problem in this data set from a global registrational trial. Response data will be available for the above mentioned patient numbers. Patients with missing values will be excluded from the analysis.

Requested Studies:
A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma
Data Contributor: Roche
Study ID: NCT03434379
Sponsor ID: YO40245

Summary of Results:
Evaluation of treatment efficacy in hepatocellular carcinoma (HCC) typically relies on computerized
tomography (CT) or magnetic resonance imaging (MRI) scans. Similar to other solid tumor types, the Response Evaluation Criteria in Solid Tumors (RECIST) criteria have been traditionally used to assess changes in tumor size as an indicator of treatment response in HCC.

However, in HCC, alternative methods for defining treatment effects have been developed, known as the modified RECIST (mRECIST) criteria. These criteria take into account intralesional necrosis as a response to treatment. In cancer therapy, anti-angiogenesis agents can hinder the growth of new blood vessels that tumors need, leading to necrosis of lesions rather than actual tumor shrinkage.

Preliminary molecular analyses of tissue biopsies from hepatocellular carcinoma have revealed
differences in the underlying cancer biology between RECIST and mRECIST responders. Further
exploration was needed using large datasets with clinical information on patient responses to

A Kaplan-Meier analysis of survival in the IMbrave 150 trial comparing RECIST and mRECIST
responders showed significantly longer overall survival for patients who responded according to both RECIST and mRECIST criteria compared to those who only responded according to mRECIST. Patients treated with sorafenib were excluded from this analysis. This finding supports the hypothesis that RECIST response and mRECIST response are driven by different underlying biological mechanisms.

In the future, investigating the gene expression signatures associated with different response types
would be an intriguing next step.