In the treatment of metastatic colorectal cancer, there were new results on subgroup analyses of the OPUS trial at this year’s ASCO GI in San Francisco. As previously shown in other studies, mutation status appears to be the critical component in determining who benefits most from treatment with cetuximab in the first-line setting. In an interview with InFo ONKOLOGIE & HÄMATOLOGIE, Prof. Dr. med. Carsten Bokemeyer, Clinic Director at the University Medical Center Hamburg-Eppendorf, gave an exclusive assessment of the new data from the OPUS study.
Prof. Bokemeyer, an extended analysis on mutational status from FIRE-3 demonstrated the superiority of cetuximab over bevacizumab in patients with RAS wild-type metastatic colorectal cancer (mCRC). The combined first-line therapy of the two agents with FOLFIRI was investigated. In a retrospective analysis of the PRIME trial, the impact of panitumumab plus FOLFOX compared with FOLFOX alone was analyzed based on RAS mutation status. Only patients with RAS wild type benefited from such antibody therapy. So what new insights did the RAS analysis of the OPUS study provide, and how do they relate to the existing data from the FIRE-3 and PRIME studies?
Prof. Bokemeyer:
Our analysis of the OPUS trial, which is also a first-line treatment with either chemotherapy FOLFOX4 alone or as combination therapy with cetuximab, we see absolutely concordant results to the other trials with respect to the RAS analyses. The finding that RAS wild-type patients benefit from the addition of the antibody is confirmed.
However, there are also some differences to the other studies: First, the OPUS study used a very sensitive detection method, which meant that the number of mutations detected was significantly higher. We found about 30% additional new mutations compared to the known KRAS mutations in exon 2. From the results, we conclude that it probably does not only depend on whether a new mutation is present or not, but also on how frequent this mutation is in the total number of tumor cells. So there are likely to be tumor samples in which there are two to three mutant cells per 1000 non-mutated cells and other samples in which the DNA consists of 30 mutant cells per 100 non-mutated cells. These differences may also explain why the results are not quite the same as in other studies.
Second, we also see in the OPUS study the already known effect that the addition of cetuximab to FOLFOX4 can even be potentially negative in patients who have mutations. This was not seen in the FIRE-3 study, for example. However, it must also be said here that the chemotherapy was not FOLFOX4, but FOLFIRI – so in the end, not only the choice of the antibody itself, but also the choice of the corresponding chemotherapy could be decisive.
Consequently, is the therapy decision by means of biomarkers already useful for the first line?
It definitely makes sense for several reasons: First, I ideally only give a therapy to the patient who will really benefit the most from it, and second, I avoid a therapy that can cause costs and side effects in patients who I know will definitely not benefit from it.
Another reason is the health care system as a whole: Even if a test costs 1000 EUR, but in return you know which therapy cannot be used and is also not eligible for second- or third-line treatment, in the end I actually save money.
Consideration of biomarkers in first-line therapy allows identification of a patient population that will maximally benefit from one form of therapy. I would then also like to send these to all suitable patients if possible. Furthermore, it is known that patients who are progressive after first-line treatment can get into such a bad condition that no second-line therapy is possible at all, which is the case in about one third of all patients. So you shouldn’t save the biologically best therapy for later.
Considering all the clinical data from a wide variety of studies, what impact do they have on your therapy algorithm in clinical practice?
First, that we test all patients with metastatic disease upfront to see if they have a RAS mutation. This is true for all RAS mutations, not just KRAS.
Second, that for patients with RAS wild-type, we are most likely to consider first-line therapy with chemotherapy plus EGFR antibody, but always considering overall health status and comorbidities.
Third, for patients with mutant carcinomas, combination therapy with bevacizumab, or triple chemotherapy combination FOLFOXIRI is more likely to be considered, also tending to bevacizumab.
After reviewing the latest data more generally on mCRC, does your standard of care that you choose for the RAS wild-type patient population change?
After all, since we are actively involved in producing this new data, our idea of the treatment algorithm is consolidated rather than actually changing. In principle, we have anticipated these results and our concrete approach in everyday life is not really different from before.
As you mentioned, the right choice of first-line therapy is very important, because second- and third-line therapies are often less effective or cannot be used at all. Do you consider potential skin reactions with cetuximab as first-line therapy in RAS wild-type patients a barrier to its use?
In principle, it is not an impediment. However, good education and prophylactic measures are needed to reduce skin toxicities as much as possible. This also includes adequately informing the patient about it. And there will always be individual cases where I think that cetuximab is biologically the best therapy for the patient, but the patient cannot tolerate this therapy clinically. Then you have to switch to another alternative.
It’s the same in principle with the choice of chemotherapy: if patients are prone to diarrhea, FOLFIRI is not necessarily optimal; on the other hand, if a patient has diabetes or polyneuropathy, FOLFOX is not my first choice. Ultimately, therefore, in addition to all molecular profiling, knowledge of the clinical feasibility of the therapy in the respective patient is a prerequisite for optimal treatment. This is actually what makes oncology so fascinating today: on the one hand, the knowledge of molecular mechanisms of action, but on the other hand also the transfer to the individual clinical situation.
In your opinion: Is personalized and individualized first-line treatment in mCRC now a reality? Or what is still missing here?
Of course, we have made a lot of progress along this path. However, at the end of the day, unfortunately, there is still no 100 percent personalized therapy. However, the full spectrum of tumor genomic alteration is not considered for any patient, but this is also not yet measurable. On the other hand, on the basis of the measurement results possible today, certain patient groups are formed for which special therapies are suitable. However, an individualized therapy concept, i.e., an individualized drug for an individualized tumor configuration, unfortunately does not yet exist.
On studies in the field of cancer treatment more generally. Many substances that initially looked very promising fail in large registration trials. However, retrospective analyses in particular sometimes show that substances are effective after all, or only for a certain proportion of patients. This effect is no longer detected across the cohort. In your opinion, is this an inherent problem of new substances and studies that simply cannot be solved, or do you see a conceptual opportunity for improvement here?
On the one hand, yes, there is the possibility of highlighting further findings of certain subgroups in particular from large randomized trials. However, all of this must always be interpreted very carefully and attention must be paid to the extent to which these groups are then at all representative of the entire collective being treated. This, of course, requires an enormous amount of methodological work. Of course, it is good to know as much as possible about tumor diseases and mechanisms of action of substances in advance so that the right patients can be included prospectively. However, despite knowing this, in many cases this will not succeed.
The example of cetuximab clearly shows this: Originally, it was thought that it was important that the receptor was present on the surface. For this reason, the inclusion criteria of the study, which we now interpret quite differently, were that the EGF receptor is expressed. Then, thanks to technological progress, the analysis of the exon 2 KRAS mutation became possible and it was seen that this was the crucial variable to separate the good from the bad. Now, one has currently gone even further into even finer subgroups, so to speak.
In my opinion, this path is relatively typical: First, the one big biological determinant must be found. If you look at the results of our data, you can see that the division that you make by exon 2 KRAS mutation separation into wild type and non wild type already makes the biggest difference. The new mutations that have now been added improve differentiation by another 10-15%, so to speak, but are no longer as fundamentally splitting as the discoveries at the beginning.
So actually a giant registry with any cancer patients and very many gene analyses and mutation differentiations would be the optimal thing?
There, too, we will end up with new techniques and findings based on existing data in which biosamples are available. The good thing is that you already know the end result. If this were not the case, each finding would have to be tracked prospectively, but this would take four to five years longer.
Interview: Lena Geltenbort
InFo ONCOLOGY & HEMATOLOGY 2014; 2(2): 25-27.
