Expert Insight: Professor Bengt Glimelius

Though metastatic colorectal cancer (mCRC) remains a devastating disease, promising progress has been made in the field of mCRC research. We interviewed Prof. Bengt Glimelius, from the University of Uppsala, Sweden, about the recent developments in mCRC treatment and insights on prognostic factors.

What do you see as the most important progresses in the field of mCRC during the last decade?

At the end of the 1990s and in the first decade of 2000, several important new drugs were registered that add clinical value to the long-standing usage of the fluoropyrimidine 5-fluorouracil. Little progress was made during the next decade. A few new compounds were registered but they added very limited value both in terms of responses and survival. Longer survival was recorded in several trials but a major reason for this was most probably better selection of patients, who tolerated the more intense treatments, and tumours. Since an EGFR-inhibitor was frequently part of the trials, only RAS and BRAF-wild type tumours were included. Triple chemotherapy combinations, sometimes also including a biologic agent, became more established and contributed to more responses, facilitating subsequent surgery in a conversion situation, and prolonged survival.
During the most recent years, several new drugs have been approved for use, however, all of them for use in rare subgroups. In tumours that are deficient in mismatch repair (dMMR or MSI-H), check-point inhibitors can sometimes have strikingly positive effects, initially in a second- or later line treatment (pembrolizumab and a combination of nivolumab and ipilimumab) and most recently also in the first-line treatment (pembrolizumab). In BRAF-V600E mutated tumours, a combination of a BRAF-inhibitor and an EGFR-inhibitor was compared with a control group (investigators´ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, 5-fluorouracil, and irionotecan)). The median overall survival was 8.4 months (95% CI, 7.5 to 11.0) in the doublet-therapy group and 5.4 months (95% CI, 4.8 to 6.6) in the control group. The risk of death was significantly lower in the doublet-group than in the control group (hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P<0.001).1

What is the new knowledge when it comes to RAS, BRAF and MSI status in the general cancer population (unselected) versus what is known from clinical trials?

In clinical trials, BRAF-V600E mutated tumours are reported in 4–8% of the patients and MSI-H (or dMMR) in 3–5%, with these two subgroups carrying the worst prognosis of all. When analysed in tumours of patients from defined populations, the frequencies of these molecular properties have been about twice as high.2–4 This has so far been best studied in populations from the Scandinavian or Nordic countries where population-based series are easier to collect and analyse than in many other countries. Drugs are presently also developed against the KRAS-G12C mutation, frequently seen in non-small cell lung cancer where one drug has been approved by FDA, but present also, e.g., in mCRC and pancreatic cancer. In mCRC, it has been reported from trial or hospital populations to carry a worse prognosis than other KRAS mutations. However, in a large population-based Nordic study it was present in 2% (n= 8/449) of the tumours (4% of those KRAS-mutated) and did not result in a poorer prognosis.4–5

When should clinicians do the testing of RAS, BRAF and MSI status? Is it done routinely?

For many years it has been required to exclude EGFR-inhibitors when treating a RAS-mutated tumour. Although not universally agreed upon, it has also been required to test for the presence of a BRAF-V600E mutation, since this mutation most probably also confers resistance to EGFR-inhibition. Thus, mutations in RAS and BRAF are routinely tested prior to initiation of systemic chemotherapy that can contain an EGFR-inhibitor. Since the drugs against MSI-H/dMMR tumours were not approved until recently, testing for this has usually not been done, although today this analysis is most probably done. Not infrequently, and particularly in tumours that turn out to be either BRAF-mutated or MSI-H/dMMR, the patients may have progressive symptoms and the wish to start treatment “more or less yesterday” can be pronounced. These tests usually take several days or a week, time that may not be present. To order the test as soon as the knowledge of mCRC is known can help, but the earlier the results are known the more advantageous they might be. This so-called reflex testing of all newly diagnosed CRCs will, besides being practical if metastases appear, also give other information of relevance in early-stage disease. Presence of MSI means most probably less effect of neo-adjuvant chemotherapy in a locally advanced colon cancer, if this is practised, and the risk of recurrence, at least in stage II, is only about half of that if the tumour is MSS (pMMR). Also, presence of a BRAF mutation may indicate less risk of recurrence. Further, knowledge about MMR status and BRAF-mutation status is important to detect hereditary disease. Personally, I see advantages in reflex testing. On the negative side are the costs for the tests for many more patients than there is a clear clinical need.

Which prognostic factors in mCRC are most important for clinicians to be aware of?

A huge number of factors are of relevance in mCRC. As already mentioned above, presence of a BRAF-V600E mutation and MSI-H/dMMR means poor prognosis. Presence of a RAS mutation also means worse prognosis compared to when the tumour is neither BRAF nor (K)RAS mutated (double wild-type) although this difference is not pronounced. Since BRAF-mutations and MSI-H7Dmmr are much more common in right-sided colon cancers than in left-sided or in rectal cancers, right-sided primaries do worse. It is a matter of debate if sidedness is prognostic beyond the molecular properties. Multiple other factors are as relevant as the mentioned molecular factors. Patient properties, e.g., age, general health, presence of co-morbidities are of major relevance for whether treatment is possible and what treatment is most appropriate. Performance status is a good marker of tumour burden and the possibilities to respond and survival.

Which new tools/actions will lead to improvements for patients with mCRC during the next 5–10 years according to you?

The use of local procedures, chiefly surgery but also several locally ablative procedures, are of great relevance for the outcome in many patients where the extent of the disease is not extensive. Although the use of “oncosurgery” has markedly increased during the past 2 decades, it is probably still not appropriately utilized. More qualified multidisciplinary team evaluations, possibly also centralized, are probably of great importance to maximise the chances of favourable outcomes but also to create equal opportunities for all patients wherever they live. It is repeatedly noted that only a limited proportion of eligible patients are included in clinical trials. Improving trial participation and also running pragmatic trials answering important strategic questions will, besides testing new promising compounds, contribute to improvements.

Is there anything additional that you would like to highlight regarding mCRC?

The discrepancies in outcome between what is reported in clinical trials and what is seen in the background population must be better recognized. It is no longer appropriate to state in reviews and guidelines that a newly diagnosed patient with mCRC can expect to live for at least 30 months.
The statement is true for some, but only for the fittest patients with a favourable molecular profile of their tumour.



ND/BRAF/02/22/0003 2022 March

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Uppdaterad: 12 september, 2022
Kort produktresumé för Braftovi® (enkorafenib) CRC

Braftovi® (enkorafenib) Rx, F, Farmakoterapeutisk grupp: Antineoplastiska medel, proteinkinashämmare, ATC-kod: L01EC03

▼ Detta läkemedel är föremål för utökad övervakning
Behandlingstid: Behandlingen ska pågå tills den inte längre har någon positiv effekt eller oacceptabel toxicitet uppträder.
Beredningsform: Kapslar á 50 mg eller 75 mg.

Behandling med enkorafenib ska inledas av och ske under översyn av läkare med erfarenhet av användning av cancerläkemedel.

Rekommenderad dos enkorafenib är 450 mg (sex 75 mg-kapslar) en gång dagligen, när det används i kombination med binimetinib.

Kolorektal cancer
Rekommenderad dos enkorafenib är 300 mg (fyra 75 mg-kapslar) en gång dagligen, när det används i kombination med cetuximab.

Verksamma beståndsdelar: enkorafenib.
Indikation: enkorafenib i kombination med binimetinib är avsett för behandling av vuxna patienter med icke-resektabelt eller metastaserat melanom med en BRAFV600-mutation; i kombination med cetuximab för behandling av vuxna patienter med metastaserad kolorektalcancer (mCRC) med en BRAFV600E-mutation, som tidigare har fått systemisk behandling. Innan patienterna tar enkorafenib måste ett validerat test utförts som bekräftar att tumören har en mutation i BRAFV600.

Varningar och försiktighet: För ingående beskrivning av varningar och försiktighet angående test av BRAF mutation, vänsterkammardysfunktion (LVD), blödning, ögonbiverkningar, QT-förlängning, nya primära maligniteter, avvikande levervärden, nedsatt leverfunktion, effekter av andra läkemedel på enkorafenib se Enkorafenib rekommenderas inte under graviditet eller till fertila kvinnor som inte använder preventivmedel.

Fullständig information om varningar och försiktighet finns i avsnitt 4.4 i produktresumén för enkorafenib.

Interaktioner med andra läkemedel och övriga interaktioner: Enkorafenib metaboliseras främst av CYP3A4. Samtidig administrering av enkorafenib och starka CYP3A4-hämmare ska därför undvikas, samt att måttliga CYP3A4-hämmare och CYP3A4-substrat ska administreras med försiktighet. Alternativa substanser med ingen eller minimal potential att inducera CYP3A ska övervägas. Fullständig information finns avsnitt 4.5 i produktresumén.

För fullständig förskrivarinformation och pris, se
Produktresuméns senaste översyn 25/7/2022.

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