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Assessing Treatment Effects of MKIs

Speaker: Rodolfo Sacco MD, PhD (Italy)

SlotAJ-4 Sacco, R.

Head, Hepatocellular Carcinoma Outpatient Section
Department of Gastroenterology
Cisanello Pisa University Hospital
Pisa, Italy


Thank you very much, Mark.  Good afternoon, let me thank the organisers so much for this kind invitation, it is, for me, an honour to be here today.  I will talk about assessing treatment effects of multikinase inhibitors. 


This is the summary of my presentation.  

Full transcription

Full transcription

Thank you very much, Mark.  Good afternoon, let me thank the organisers so much for this kind invitation, it is, for me, an honour to be here today.  I will talk about assessing treatment effects of multikinase inhibitors. 


This is the summary of my presentation. 

First of all, I will be considering emerging data in hepatocellular carcinoma, particularly current assessment of tumour response to treatment based on radiological evaluation in HCC and future directions in the development of assessment tools for treatment effect in HCC. 

The second part of my presentation will be regarding assessment of tumour growth rate in renal cell carcinoma and differentiated thyroid cancer. 

Current Assessment Criteria of HCC Response to Treatments

About current assessment criteria of HCC response to treatment, we have to consider that Response Evaluation Criteria in Solid Tumours, version 1.1, (RECIST) is currently considered as a standard method for the evaluation of tumour response in patients in clinical trials, and is considered to be a surrogate endpoint to predict survival outcomes in patients with solid tumours. 

We have to consider that the development of new treatment options in HCC has changed not only the way in which cancer is treated, but also in the assessment of tumour response.

Thus, the RECIST 1.1, mainly based on the evaluation of changes in tumour size, is considered to be insufficiently sensitive and unreliable for determining HCC progression, particularly when targeted therapies, such as sorafenib, are involved. 

Current Assessment Criteria of HCC Response to Treatments

To overcome these limitations of RECIST 1.1, when assessing HCC response to treatments, other evaluation methods were considered. 

We know about the European Association for the Study of the Liver (EASL) criteria and the modified RECIST, but we also have to consider that these methods are based on the evaluation of reduction of viable tumour, but they present differences regarding, in particular, measurable target lesions and the evaluation of the amount of viable tumour. 

Modified Response Criteria in HCC

In particular these differences are indicated in this cartoon, most of all regarding the partial response from EASL and mRECIST, and the progressive disease, as shown in these red circles.

Are EASL/mRECIST Satisfying to Evaluate HCC Response to Sorafenib Treatment?

The question is, are EASL and mRECIST satisfactory to evaluate HCC response to sorafenib treatment?  Maybe not, because as sorafenib does not shrink the tumour to meet partial response by RECIST/mRECIST/EASL, in many cases premature termination has often been observed. 

Although the label recommends that sorafenib is continued as long as the patients benefit, many patients discontinue sorafenib when they have progressive disease on radiological exam.

Furthermore, response by common Tumour Assessment Criteria may not be sensitive enough to indicate a signal of sorafenib efficacy. 

Progressive disease by RECIST/mRECIST/EASL may not mean no efficacy/benefit from sorafenib, and also we have to consider that the speed of growth often is not considered in decision making for continuation/discontinuation of treatment.

Investigations of New Clinical Response Measures to Targeted Therapies

For this reason recently there are investigations of new clinical response measures to target therapy. 

For example, the Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2015 by the Liver Cancer Study Group of Japan based on the 2009 version of RECICL, which was commonly used in Japan. 

Arizumi and other colleagues reported that of the three response criteria, RECIST 1.1, modified RECIST and RECICL, only categorisation using RECICL was found to be significantly correlated with overall survival.

We also have to consider that Choi et al showed that in patients with gastrointestinal stromal tumours treated with imatinib decrease in tumour volume is also not the optimal indicator to assess antitumour activity.  Their modified response criteria for gastrointestinal stromal tumour patients correlated better with time to progression than response according to RECIST.

Future Directions in Development for Sorafenib Effect in HCC

What are the future directions in development for sorafenib effect in HCC? 

We have to address some challenges and to address these challenges there has been clinical investigation to identify signals of benefit from sorafenib. 

We can consider tumour volume, changes in vascularity, growth rate, decrease in alpha-fetoprotein, response seen through sonography and change on CT.

Identification of Responders to Sorafenib in Hepatocellular Carcinoma: Is Tumor Volume Measurement the Way Forward?

To address the challenge a study from our group evaluated the response to sorafenib in hepatocellular carcinoma, considering the variation of volume measurement during sorafenib therapy. 

We considered the baseline evaluation of volume and after two months.  We tried to identify, using ROC curve analysis, volume ratio cut-off, that was data measured as 1.1 and we tried to correlate these volume ratio cut-offs to survival, so that when considering survival curve rate patients who had a volume ratio minimal than 1.1 had 90% of cumulative survival at 12 months.  While patients with the volume ratio measured than 1.1 had cumulative survival of 45% at 12 months. 

Perfusion CT

Another method to address the challenge was in these studies by our workgroup and we used perfusion computed tomography to evaluate the response to sorafenib in HCC.  Perfusion computed tomography is a dynamic CT scan to evaluate the vascularisation into the liver in the hypervascularised liver. 

Particularly in this method we can consider different parameters, but the most important we considered was the mean transit time.  At the baseline the mean transit time obviously was low because the liver is hypervascularised and so the speed of a blow was very fast.  It is interesting to note that after three months the mean transit time increased because of the effect of sorafenib, vascularisation reduced, for this reason the mean transit time increased.  It is interesting to note that the increasing of the mean transit time correlated with survival of the patients.  Another interesting point was that the increase of mean transit time correlated with decrease of alpha-fetoprotein.

Other Modalities of Measuring Sorafenib Response

Obviously there are also other modalities to measure sorafenib response, you can see here many other methods were considered, such as duplex doppler ultrasonography, dynamic contrast enhanced ultrasound, decreased blood flow, volumetric assessment –

Other Modalities of Measuring Sorafenib Response

– or , for example, considering the value of alpha-fetoprotein, the decrease of tumour stain on contrast CT, duration of stable disease and early change in apparent diffusion coefficient. 

Sorafenib and Tumor Growth Rate in RCC and DTC

Now we consider the sorafenib and tumour growth rate – a very interesting method to evaluate response from sorafenib in renal cell carcinoma and differentiated thyroid cancer.

Tumor Growth Rate (TGR)

The tumour growth rate estimates the increase of the tumour volume over time.  It incorporates the time between the imaging examinations, allowing for a quantitative and dynamic evaluation of the tumour response. 

This is a representation of tumour growth rate across a specific treatment period.  We can see the tumour growth rate before the use of the drug, in a short period, under the treatment, at progression and after discontinuation, and at washout. 

Tumor Growth Rate and Sorafenib Therapy

To date, two studies have been analysed for tumour growth rate and sorafenib therapy, particularly the randomized Phase III TARGET trial in metastatic renal cell carcinoma and in randomized Phase III DECISION trial in differentiated thyroid cancer. 

TARGET: Phase 3 Trial in Advanced RCC

About the Phase III trial of renal cell carcinoma, this is the study.  Patients were randomized to receive sorafenib or placebo, and some of these patients were switched to sorafenib, with overall survival as the primary endpoint. 

Pairwise Comparisons of Tumor Growth Rate (TGR) at Clinically Relevant Treatment Periods in Sorafenib-treated Patients

It is important to note the pairwise comparison that was performed on tumour growth rate at clinically relevant treatment periods in sorafenib-treated patients. 

In the first part of the slide you can clearly see that tumour growth rate reduced under sorafenib treatment compared to a short period. 

Further, it is also interesting to note that when considering progression compared to a short period most of these patients, at progression, still exhibited reduction of tumour growth rate, because sorafenib has still exerted certain tumoural effects during progression. 

Finally, it is also interesting to note that comparing progression versus washout period most of these patients show an increase of tumour growth rate only after discontinuation of sorafenib.

TGR is Associated with OS and PFS Independent of the Treatment Arm (Sorafenib or Placebo) and the Motzer Score in the TARGET Phase 3 Trial

Another important point to add is that tumour growth rate is associated with overall survival and progression-free survival independent of treatment arm and the Motzer score, which is the prognostic score for renal cell carcinoma in this trial.  We have to consider that in this landmark analysis hazard ratios were calculated for a 10% increase in tumour growth rate. 

As you can see, tumour growth rate is associated both to progression-free survival, death to overall survival, even after adjustment to Motzer score in the placebo cohort.  In the same way, also in the patients treated with sorafenib, we have the same things, that means the tumour growth rate is associated with progression-free survival and overall survival, even after the adjustment to the Motzer score. 


About the conclusions of this study, dynamic tumour growth rate measures may be more informative than static definitions.  Translating the tumour growth rate into clinical use could substantially change the decision making for metastatic renal cell carcinoma in several ways. 

The very important point is that progression is different from treatment failure. 

These findings from the analysis of tumour growth rate in TARGET support the practice of continuing a tyrosine kinase inhibitor upon RECIST progression.

Phase 3 DECISION Trial: Sorafenib vs Placebo in Locally Advanced/Metastatic RAI-refractory DTC

We now move to the trial about differentiated thyroid cancer, already Professor Brose has spoken about this study design.  Patients after randomization received sorafenib or placebo.  At progression, at the investigator’s discretion, were switched to continue on sorafenib in open-label phase, or from placebo to sorafenib in open-label phase. 


About the methodology, the target lesions were assessed by central radiological review every eight weeks, based on RECIST. 

Tumour growth rate was defined as mean percentage change per month of sum of target lesion diameters on sorafenib.  The tumour growth rate was also approximated by a parabola-like three-parameter model on sorafenib, the purple line.  Both for the double-blind phase, for the open-label phase, early tumour growth rate at baseline and late tumour growth rate at progression were derived, as you can see, with the grey line. 

Patient Disposition

This was the final disposition of the patients and you can see how many patients at progression received sorafenib in the open-label phase, either they were randomized to sorafenib or to placebo. 

Results: TGR for All Evaluable Patients

About the results – it is interesting to note that the tumour shrunk when the patient first received sorafenib, with this negative value of early tumour growth rate.  After that the tumour increased in size at the time of progression on sorafenib.  The tumour increased overall for patients receiving placebo.  Tumour growth was lower with sorafenib than with placebo at progression.

Tumor Growth Rates: Placebo-Sorafenib Patients

About placebo-sorafenib patients, early tumour growth rate was negative during open-label sorafenib, so it decreased over the tumour growth rate.  The late tumour growth rate was lower with sorafenib compared to growth during double-blind placebo treatment. 

Tumor Growth Rates: Sorafenib-Sorafenib Patients

About sorafenib-sorafenib patients, late tumour growth rate was similar during double-blind and open-label sorafenib treatment.


In conclusion, the traditional radiological methods, mainly based on changes in tumour size, are considered to be insufficiently sensitive and unreliable for determining no benefit from target therapies.  It is very important that from data we know that progression is different from treatment failure for sorafenib. 

Tumour growth rate is a new parameter observed in clinical practice and is under evaluation with available datasets.  Slow tumour growth rate may indicate patients benefit with a treatment.

Finally, careful evaluation with radiological exam is important for optional decision making to continue/discontinue on the target therapies.  In fact, comprehensive assessment taking clinical conditions, such as symptomatic progression, into consideration is critical.

Thank you

Thank you very much for your attention.