Tumour Therapy: Better Off Not Labelling Off-Label

20. September 2016
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Treatments using off-label medications are controversial – in tumour medicine as well. A new study aims to prove that when it comes to medication it makes sense to pay less attention to tumour type but more to the metabolism of malignant cells.

Even more in America than in Europe one particular short presentation at the annual conference of the American Oncologists (ASCO) raised a lot of hype. In particular, American media reported the preliminary findings of a study that dealt with nothing other than the use of drugs outside the boundaries of their actual indication, as “off-label use”. Many saw in this report the first departure from the principle of treating a tumour according to its origin, but rather its histology. Are these preliminary findings of the so-called My Pathway study a sign of future predominance of molecular biology over previous established guidelines and restrictions relating to approval?

ASS: few patients, big impact

About four years ago the New England Journal published a study on the benefits of aspirin (ASS) in colon cancer. The painkiller at the time demonstrated a particularly strong effect when the tumour carries a mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphonate, 3-kinase), an enhancer of the ASS-binding partner Cox-2. This mutation occurs on average in 17 percent of all patient cases, the effect then increasing their chances of survival by more than 80 percent. In the absence of the relevant tumour mutation, the daily tablet is however probably ineffective. According to recent reports ASA appears to act not only on colon cancer but also to effectively tackle oesophageal carcinomas.

Her2 and BRAF: Success For Off-label

The idea that modern cancer therapies concern themselves less with the tumour type but rather more with the metabolism of malignant cells was also the basis of the multi-centre study which John Hainsworth from the Sarah Cannon Research Institute, in Nashville USA, initiated and launched in 2014. Hainsworth and colleagues looked for patients with advanced solid tumours, all of whom had an average of three unsuccessful tumour treatments behind them. All participants were accurately characterised in terms of molecular biology and had picked up alterations in the cancer key genes HER2, BRAF, Hedgehog and EGFR over the course of their disease.

The results of the grouping in molecular patterns then defined their therapy. Her2 patients received trastuzumab and pertuzumab, those with Braf-mutation vemurafenib. In this study vismodegib and erlotinib were used to take up the fight against tumours involving Hedgehog and EGFR mutations. None of these patients had been indicated the respective active agent on account of histological tumour characteristics until that point in time.

With 129 participants the interim results were compiled after three to eleven months of treatment. With 61 of those affected alterations – ie mutation, amplification or over-expression, of the Her2 gene were predominant. Twenty of these changes were part of an advanced colon cancer, eight were part of a bladder carcinoma and seven of a non-small cell lung cancer.

In this group, the researchers even achieved treatment successes which they had previously not expected. One-third of cancer patients responded to the targeted trastuzumab therapy with more than 30 percent reduction in the tumour; the same with three patients with bladder cancer and two of the lung cancer subjects. With the 33 BRAF tumours as well, on average a quarter of patients responded with a complete or partial remission. A total of 12 different types of tumours respond to treatment using an active agent which was not actually intended for them.

John D. Hainsworth, MD, presents LBA11511 during Precision Medicine: Making Progress for Patient Benefit

John Hainsworth is the initiator of My Pathway Study © ASCO / Rodney White 2016

Response: Good, but also good enough?

Viewed overall, the new approach to this oncological treatment achieved one complete remission, 28 partial remissions and at least 40 times a temporary cessation of the illness. The characterisation of the tumour according to its molecular genetic characteristics is not yet a panacea. This is because half the partial remission cases saw the tumour return after about half a year.

Nevertheless, the authors are happy with their results. “Our results indicate”, says John Hainsworth, “that targeted Her2 therapy for instance could be extended beyond the hitherto used indications for breast and stomach cancer”. He has in mind in particular colorectal cancer. The study should therefore continue into 2019 and in the end is supposed to include 500 participants. The plan is to also include new treatment options and to drop unsuccessful ones.

„Targeted-intervention“ databank

MyPathway, sponsored by the biotech firm Genentech, is not the only study that specialises in the treatment of cancer cells according to their “driver” mutations. With the TAPUR study researchers want to build a database where the use of targeted agents in oncology, regardless of the origin of the tumour, is employed. Solid tumours in advanced stages, multiple myeloma and non-Hodgkin B-cell lymphomas are in particular the focal point of researchers. An entire panel of pharmaceutical companies, among them the “big players” AstraZeneca, Bayer, BMS, Eli Lilly, Merck and Pfizer, want to offer their own active agents, and the respective knowledge about the application of these products, to the project. Signature-Study (Novartis) and the NCI-MATCH trial are operating similar research approaches.

Aiming at the “driver”

Alongside all the great publicity that My Pathway received at the ASCO meeting, there is also criticism. For instance in this “single-arm” study their is an absence of comparison with a control group in order to determine a “net effect” of the new approach. Already last year the French “SHIVA” study concluded: “The use of medications outside indication involving a target at the molecular level does not improve progression-free survival, compared with the method of choice of the attending physician”. Finally, data on tumours with BRAF mutation already indeed shows that the appropriate inhibitors seemed to have an effect in melanoma, but not with colorectal cancer involving the same mutation.

Which is the “driver”, which is only a “fellow traveller” in a fast-growing tumour? Investigations of this kind could bring answers to the question as to why some instances of targeted intervention leave the tumour unresponsive. Around 76 copy number mutations and at least 30 to 80 functional single base substitutions as occur in an average breast cancer cell come about on top of the thousands of somatic mutations which occur in humans over the course of life. Questions relating to whether in an ideal situation trastuzumab, erlontinib and the like encounter the driver of unlimited growth, or whether other changes keep the tumour from growing further, might be accurately answered by studies such as MyPathway in a few years. The current ongoing studies and their small participant numbers would be only the beginning.

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