Second-line and beyond in mCRC: Optimising the benefit and reducing the risk

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Published: 9 May 2019
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Prof Mohamed Salem - Georgetown University Hospital, Washington D.C., USA

Prof Mohamed Salem speaks to ecancer at the 2019 International Gastrointestinal, Liver and Uro-Oncology Conference (IGILUC) in Cairo about the
recent advances in the treatment of metastatic colon cancer in the second-line setting and beyond.

Despite numerous clinical trials in the past, Prof Salem acknowledges the fact these trials have not shown any clinical benefit thus far.

However, he discusses the positive results achieved from several clinical trials, including the addition of regorafenib to oxaliplatin or irinotecan and the use of TAS-102 in this setting.

Prof Salem also notes the increased understanding of the biology of colorectal cancer as a recent major advancement - as oncologists can now differentiate between different types of the disease.

He believes that this field is moving towards precision medicine, with the help of recent advances in genetic testing.

Currently we have about in the US 150,000 patients get diagnosed every year with colorectal cancer and 50,000 die from that disease. Until very recently we only had limited options for treatment; very much for first line what we used to use is FOLFOX, FOLFIRI plus biological agents and some patients also got FOLFOXIRI which very much was all the chemotherapy we have available. But when they progressed on either FOLFOX or FOLFIRI or FOLFOXIRI then until recently we didn’t have much option to give them. This is not because of the lack of effort, we tried very hard and many clinical trials have been conducted in that setting, unfortunately it did not show benefit. So, colorectal cancer is a little bit of a stubborn disease.

Back in 2013 regorafenib came along and was approved in the US back then based on the colorectal study. The colorectal study was a phase III trial that randomised metastatic refractory colorectal cancer patients, so very much the patients who received FOLFOX or FOLFIRI, and they were randomised to get regorafenib which was, back then, the experimental arm versus placebo because we didn’t have a standard of care. The study endpoint was overall survival and actually the study was positive with the patients who got regorafenib the median overall survival was about 6.4 months versus the placebo arm was 5 months. So on average it was an improvement in median overall survival of 1.4 months.

Based on that study the drug was FDA approved and became available. Along the same time, a few years later after that, another drug called Lonsurf, TAS-102 which is tipiracil plus trifluridine, was also tested in the same setting with a very much similar design. It was a study called the RECOURSE study. That study randomised metastatic refractory colorectal cancer again to either Lonsurf or placebo. The reason that placebo was acceptable was because at the time of the study concept we actually didn’t have regorafenib available yet. The study endpoint was overall survival and in fact the study was positive. Patients who received Lonsurf had an improvement in overall survival on average about 1.7 months improvement. That was updated, actually, a year after that publication and the absolute benefits were about 2 months. Because of the survival benefit the drug was approved and currently available in the US and I think also around the globe.

So now we have two agents approved in the refractory setting, regorafenib and Lonsurf. The obvious question is how we choose, which one we should put patients on. It comes very much to the adverse event profiles because the drugs although they seem very close in efficacy the side effect profile is different. So it very much comes to individual choice and the judgement of the treating oncologist which one makes sense for a patient.

But over the last few years one of the major advancements in colorectal cancer perhaps was not just more drugs available, was a better understanding of the biology of the disease. So we start to understand now that colorectal cancer is actually not one disease. I always tell my patients in the clinic colorectal cancer is a family name and each one of you have your own individual features. So, for instance, we know now colorectal cancer that starts on the right side of the colon behaves differently and responds differently to therapy compared to a tumour that started in the left side of the colon. Also with advancements in technology and wide utilisation of profiling and next gen sequencing we start to learn more about the microenvironment and mutation and fusion and so on and so forth. We are moving towards precision medicine and moving away from one size fits all. So, for instance, patients with refractory colon cancer, some of them have HER2 amplification or some of them have HER2 amplified tumours. We know for those patients using anti-HER2 therapy actually is very effective. Two trials were conducted in that setting, one, the HERCULES study that used HER2.  One trial, that was the HERCULES study, that presented at ASCO two years ago and was published in Lancet Oncology 2016, using anti-HER2 therapy showed about disease control in 60% almost which in that setting is very impressive.

Another study that just got published recently, it’s called My Pathway that was also published in Lancet Oncology, using trastuzumab and pertuzumab showed a response rate of 32% and, again, a disease control rate of 44%. That’s very impressive in that setting and it speaks to the fact that if we can target that particular actionable mutation in the tumour we can end up with a good result and also minimise the toxicity because if the drug doesn’t work for everyone then you expose everyone to the side effects.

Another problem we have in colorectal cancer is BRAF mutant colorectal cancer. The reason is because those tumours usually are aggressive and have a worse biology. We try to use a BRAF inhibitor like our colleagues in melanoma but the BRAF inhibitor really didn’t have much efficacy in BRAF mutant colorectal cancer. Now we are learning that a PIK3CA regimen, which is a MEK inhibitor plus a BRAF inhibitor plus anti-EGFR, the safety run in that including 30 patients actually showed a very impressive response. This now is moving to a phase III trial trying to see if this regimen can be really utilised as a standard of care. In fact, NCCN guidelines were updated recently to allow us to use such a regimen.

Obviously NTRK fusion was a very hot topic recently everybody was talking about and some colorectal cancer patients actually have those Trk fusions and there is a drug that can target this now. So we’re learning more and more about colorectal cancer and, as I mentioned before, we’re moving from just one drug or second line to really try to understand the biology and the targets those patients have and hopefully we’re using the right drug for them to minimise the toxicity and maximise efficacy.