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The Use of MKIs in Clinical Practice: Real-World Evidence

Speaker: Bruno Daniele MD, PhD (Italy)

SlotAJ-2 Daniele, B.

Director, Department of Oncology and Medical Oncology Unit
G. Rummo Hospital
Benevento, Italy
Professor, Department of Oncology
Postgraduate School of Federico II University of Naples
Naples, Italy


Good afternoon to everybody. Thank you Mark and thank you to Bayer for the invitation to discuss some real-world aspects of use of multikinase inhibitors in cancer.


As you have just heard from Dr Peck, multikinase inhibitors have been used in clinical practice for treatment of a number of cancers, including non-small cell lung cancer, kidney cancer, hepatocellular carcinoma.

Full transcription

Full transcription

Good afternoon to everybody. Thank you Mark and thank you to Bayer for the invitation to discuss some real-world aspects of use of multikinase inhibitors in cancer.


As you have just heard from Dr Peck, multikinase inhibitors have been used in clinical practice for treatment of a number of cancers, including non-small cell lung cancer, kidney cancer, hepatocellular carcinoma.  These, because of the results of a number of Phase 3 prospective placebo controlled trials that demonstrated the benefit in survival for most of these compounds.  However, as Dr Peck said, there are a number of open issues that we face in clinical practice and here there are some of them.  One is dosing – what is the appropriate dose to start with the treatment?  The time of initiation of treatment during the natural history of the disease and which are the predictive factors, if there are any, of treatment response?

Multiple Factors Play a Role in the Development of HCC

We believe that hepatocellular carcinoma is a good model to address these issues because it is a cancer characterised by an enhanced neovascular angiogenesis because we have data indicating that high blood levels of VEGF are associated with a poor prognosis and a higher incidence of relapse after treatment.

In addition to VEGF also PDGF and the MAP kinase pathway are involved in the promotion of new blood vessel growth. 

Sorafenib in HCC

Sorafenib acts in two ways: one on vascular endothelial growth factor receptor pathway and blocks the formation of new vessels induced by cancer cells, but there is also an interaction of Sorafenib with the RAF pathway interfering with the proliferation of the cancer cells itself.

Overall Survival in the SHARP and Asia-Pacific Studies

Sorafenib was tested in two prospective randomised placebo controlled trials in different populations: one in Western patients, the SHARP trial, and the other one in Asian patients, the Asia-Pacific trial.  Both trials demonstrated an equal effect on survival.  If you look at the hazard ratio it is 0.68 and 0.69, demonstrating that Sorafenib is effective irrespective of the etiology of the hepatocellular carcinoma and the race of the patients.

EASL-EORTC Guidelines

The results of these trials led to the inclusion of sorafenib as a treatment of advanced hepatocellular carcinoma in a number of guidelines.  Here you see the EASL-EORTC guidelines that are mainly mutated from the BCLC algorithm and they showed that in patients with advanced HCC, which is characterised by presence of a macrovascular invasion or a distant metastases or both, sorafenib is clearly recommended as the first-line treatment for these patients.

Pooled Analysis: Methodology

To try to understand if there are prognostic factors in patients with un-resectable hepatocellular carcinoma a possibly predictive factor that can anticipate a better response to sorafenib treatment, a pooled analysis of the two trials was performed in 827 patients, which is the sum of the patients randomised in both trials.  The first type was to try to identify prognostic factors using univariate and multivariate analysis and then by an interaction test using hazard ratio and median survival to understand if there are also predictive factors to treatment response.

Pooled Analysis: OS by Tumour-Related Variables

This table showed the impact of tumour related variables and overall survival. The first indication is that sorafenib is superior to placebo in terms of overall survival, whichever subgroup of patients you take in consideration from stage, amount of tumour, presence of vascular invasion, extrahepatic spread, number of target lesions.  In any case, sorafenib performs better than placebo in these patients. 

The other interesting indication is that a low tumour burden and the absence of an extrahepatic metastases are a predictive factor of even better activity of sorafenib.  In other words, if you start sorafenib in patients without a high volume of the disease, mainly if the disease is limited to the liver, you have a greater chance to obtain a better results.

Pooled Analysis: OS by Etiology and Liver-Related Variables

The other factors taken into the analysis were the etiology and the liver related variables.  Even in these cases viral etiology, alcohol use, race, performance status, albumin and bilirubin for each subgroup sorafenib performs better than placebo always.  While the infection with hepatitis C predicts a better efficacy of sorafenib in these patients.

Pooled Analysis: Conclusion

In conclusion and with the caution that is clearly due when you commence exploratory subgroup analysis from prospective trials, the indications are that the stage of the disease, the tumour burden, the tumour size, the performance status, bilirubin and albumin in both arms, placebo and sorafenib, are prognostic for overall survival.

The benefit of sorafenib was consistent across all the subgroups and sorafenib seems to give an enhanced benefit to patients with hepatitis C with less tumour burden and without extrahepatic disease.

Real-World Evidence: The GIDEON Study

Going from the randomised trials to real practice, the GIDEON study, which is a prospective, non-randomised observational non-interventional study examined the real-world practice of patients with unresectable hepatocellular carcinoma treated with sorafenib.  The study involved 39 countries in five regions of the world and enrolled more than 3,300 patients.

GIDEON versus Randomised Controlled Trials: Initial Dose

I will focus on the starting dose of sorafenib, which is one of the open issues and we'll find that compared to the randomised trials where 100% of patients started with the full dosage, in real practice there is about 80% of patients that start with the full dosage with a difference in the various regions of the world with Latin America – I am sorry, this is the overall, which is a little less than 80%, Latin America, Europe and Asia Pacific tends to use the recommended dosage as starting dose, while Japan and the USA tend to use a lower dosage, mainly the 400mg dose to start.

Please get ready to vote

Now there is a question for you.  Do you think that initiating sorafenib therapy at lower doses reduces the incidence of adverse events?  If you believe that this is true vote 1; if you believe that this is false, please vote 2.


Interestingly there is about half of the audience believing that the lower doses led to a reduced incidence of adverse events while the remaining half believe that this is not true. 

GIDEON Study: European Population

The analysis of the European subgroup of patients in the GIDEON study, which is quite a large number of patients, which is about 1,100 patients, indicates that adverse events of all grades, grade 3, grade 4, drug related, serious adverse events, are not superior in terms of incidence and severity if you analysed the cohort treated with 400mg/day compared to the 800mg/day and in some cases the adverse events appeared even more frequently in the patients treated with 400mg compared to 800. 

This indicates that in clinical practice we should try to start the treatment with recommended and registered 800mg doses, which of course doesn’t mean that in the presence of adverse events you do not have to reduce the dosage according to the recommendation of the regulatory agencies.

Gaps in Intermediate-Stage HCC: EASL-EORTC Guidelines

There are gaps also in the use of multikinase inhibitors in intermediate stage HCC, where the guidelines recommend the use of TACE as first-line treatment.

Real-World Evidence: Gaps in Advanced-Stage HCC

Before talking of intermediate stage HCC, I would like to call your attention on the fact that even in the advanced stage where the proof of evidence is quite strong in favour of a systemic therapy with sorafenib, still there is a very high percentage of patients in the real practice – these are data from the BRIDGE study, that are treated with TACE.  Indeed, if you look at this graph it comes out that TACE is the actual first-line treatment for patients with advanced hepatocellular carcinoma.  We think that we should change our minds first of all in the setting of advanced patients, because there is really no evidence whatsoever to use TACE in this setting of patients.

If you look at the stage B that represents the intermediate stage patients, those with cancer limited to the liver, that are not eligible for resection you have, even in this case, a very high prevalence of TACE, which apparently is more justified based on the recommendations of the guidelines.

TACE Unsuitability

We will see that there is something that we should change, because we know that there are some contraindications to TACE – some of them are absolute contraindications, for example the compensated cirrhosis, impaired portal vein blood flow, extensive tumour involvement to both lobes of the liver and there are some relative contraindications such as high risk of bleeding from oesophageal varices, large tumours some biliary pathology where TACE should not be used.

Progression after TACE: Current Guidelines

Also the major guidelines we have the EASL-EORTC, the ESMO, the AASLD and the Japan guidelines all recommend to start sorafenib when you have evidence that TACE is not effective.

For example, the EASL-EORTC guidelines recommend that BCLC patients not responding to two or three cycles of TACE should be offered sorafenib.  The same is true for all the other guidelines.

Please get ready to vote

We have another question.   A patient with intermediate, unresectable hepatocellular carcinoma has received two TACE procedures, progressive disease was observed after both procedures.  According to the guidelines that I just showed you which treatment option should you recommend next?  If you believe that the patient should be treated again with TACE vote 1.  If you believe that it is appropriate to switch to another loco-regional treatment vote 2.  If you believe that the patient is an appropriate patient for systemic therapy please vote 3.


We have been quite effective in convincing you that systemic therapy is the way to go if TACE is not working after two, a maximum three sessions, although some still believe that TACE and another loco-regional treatment could be effective.

Retrospective Study Suggests Efficacy of Sorafenib versus Continued TACE in Patients Refractory to TACE

The reason not to use TACE again after failure, after two or three sessions, comes from a number of evidence.  One is there is evidence on a small number of patients, but still they are interesting data – 56 patients with intermediate hepatocellular carcinoma refractory to TACE, 20 of them switched to sorafenib while 36 continued to receive TACE.

In terms of median overall survival we have 25 months versus 11.5 and also in terms of time to advanced stage disease, time to disease progression, sorafenib performs much better than TACE.

One other thing that I would like to add is also mutated from other types of cancer, for example metastatic colorectal cancer, we know that the more treatment you are able to give to the patients the better is the prognosis and the outcome.  If this holds true also for hepatocellular carcinoma, keeping treating patients with TACE may impair the liver function and prevent these patients to receive a useful treatment like sorafenib.

OPTIMIS Study: Study Design

To describe how, in clinical practice, the physicians behave in terms of sequence of treatment, the OPTIMIS Study, whose PI is Dr Peck, registered in 1,650 patients classified as BCLC stage B, which means intermediate or higher, what happens when a decision to treat these patients with TACE was made?  Basically the patients will be divided into two cohorts: one patients that start sorafenib soon after the physician decides that TACE is not appropriate because it is no longer effective or because it is not appropriate, and cohort two were patients who will not start sorafenib early, either they will start sorafenib later or they will not start sorafenib at all.

OPTIMIS Study: First Interim Analysis

Baseline Demographics and Disease Characteristics

An interim analysis was performed after 500 patients were observed for more than six months and some interesting data came out. First of all, based only on the BCLC stage, we have about one in four patients treated with TACE that are not considered eligible in first place to receive TACE.

The deviation from guidelines is especially high in China while Japan seems more respectful of the guidelines, at least considering only the BCLC stage.

OPTIMIS Study: First Interim Analysis –

Conditions Not Indicated for TACE at Initial TACE

There are all differences in terms of etiology, but if you look at all the possible contraindications to TACE in BCLC B patients you will find that more than 55% of the patients are considered not eligible for this treatment in the first place.

Again, the highest deviation from the guidelines has been observed in China, while Asia, Europe and Canada are not respectful of the guidelines in more than 50% of the patients. 

These interim results revealed substantial regional differences and tell us that real-life practice with TACE deviates from current guidelines and so calls for a standardisation of procedures and especially indications for the use of the TACE in these patients.


In conclusion the Phase 3 trials demonstrated that sorafenib is effective in significantly improving overall survival in patients with unresectable hepatocellular carcinoma and this was the reason why it was registered in the US, in Europe and in the rest of the world and recommended by all the major guidelines.

The pooled analysis showed that the benefit of sorafenib in terms of overall survival was consistent in all the subgroups examined, but the presence of less tumour burden and infection with hepatitis C is predictive of an even better efficacy of sorafenib. The daily practice studies, such as GIDEON demonstrated that the results observed in Phase 3 trials can be transported in everyday practice – there are still a number of deviations from what the guidelines recommend and the actual behaviour of the physician managing patients with hepatocellular carcinoma.

We believe that, along with information and education activity also in approach and possibly a multidisciplinary approach to patients either before and during sorafenib treatment is the way to go to follow in the best way the recommendation of the guidelines.

Thank you for your attention.