Vantage point – NCI initiative could see drugs for mutations, not tumour types

Targeted drugs have revolutionised oncology over the past decade or so. But with big pharma understandably focusing on the biggest indications, perhaps these powerful drugs are not reaching all the patients they could benefit. With this in mind, the National Cancer Institute has begun a trial that could bring targeted therapies to patients with much rarer cancers.

The NCI-Match study will treat patients based on their genetic profile irrespective of the anatomic location of their tumours. But beyond potentially expanding the labels of drugs from the trial’s collaborators – which include Novartis, Pfizer and AstraZeneca – the trial could have much more far-reaching effects. In the long term, the investigators say, targeted drugs might be approved for mutations, rather than diseases.

“Not only will we look at response rates to these different targeted agents, we’re hoping to find new leads, particularly in the rarer tumours,” Robert Comis, co-chair of the organisation running the trial, ECOG-ACRIN Cancer Research Group, tells EP Vantage.

Mutations vs locations

Starting next month, the Match trial will enrol 1,000 patients with solid tumours or lymphomas who have advanced following treatment with standard therapy and who have biopsy-confirmed mutations. The plan is that at least 25% of these patients will have rare cancers.

They will be placed into 10 study arms as summarised in the table below, with each arm recruiting up to 35 patients. This will be determined by their genetic status; patients with cKIT mutations will go into the Sutent arm, for instance, regardless of what type of cancer they have.

The primary endpoints of the trial are overall response rate – defined as tumour shrinkage of 30% or more – and progression-free survival at six months. Treatments will be considered promising if 16-25% of the patients in an arm see their tumours shrink.

The first 10 arms of NCI-Match
Agent Collaborating company Status Molecular target Estimated mutation prevalence
Xalkori Pfizer Marketed ALK rearrangement 4%
Xalkori Pfizer Marketed ROS1 translocations 5%
Mekinist and Tafinlar Novartis Marketed BRAF V600E or V600K mutations 7%
Mekinist  Novartis Marketed BRAF fusions/non-V600E/non-V600K BRAF mutations 3%
Gilotrif Boehringer Ingelheim Marketed EGFR activating mutations 1-4%
Gilotrif Boehringer Ingelheim Marketed HER2 activating mutations 2-5%
Kadcyla Roche Marketed HER2 amplification 5%
Sutent Pfizer Marketed cKIT mutations 4%
AZD9291 AstraZeneca Phase III EGFR T790M mutations and rare EGFR activating mutations 1-2%
VS-6063 Verastem Phase II NF2 loss 2%
Source: NCI, ECOG-ACRIN and EvaluatePharma

To keep the focus on entirely new research, those drugs that are already on sale will not be tested in their approved indication. They will instead be used in patients with other cancers.

And the Match trial could help the collaborating companies expand their drugs’  labels – eventually.

The study provides a way for pharma companies to collect data on rare tumours far more cheaply and easily than if they were to run a trial in a single cancer type themselves. That said, with such small study arms, the trial is unlikely to provide concrete evidence of applicability of a drug to an entirely new tumour type, even if it is very unusual.

“Any results from this study will be difficult to take to the FDA for approval – there will have to be subsequent studies,” NCI medical officer Alice Chen tells EP Vantage. But the findings ought to give Match’s pharmaceutical partners an idea of where to spend their research dollars, she says.

Match point

If this strategy is successful it might lure both new patients and new pharma companies to the study. The investigators plan to add another 10 cohorts by this autumn, and are in discussions with GlaxoSmithKline, Genentech (Roche), Takeda and Bristol-Myers Squibb.

The study is expected to run for seven years with most arms enrolled within three years – as some mutations are more common than others, patients will accrue at different rates. But first signs of whether the trial can provide useful data could arrive much sooner than that.

“I would expect that by next year we might have a signal somewhere,” Dr Comis says. “It could take longer – it could take a couple of years – but I would hope we pick up some hit early.”

The trial depends on large part on the test used to assign the patients to their treatments. A single diagnostic device, based on Thermo Fisher Scientific’s Ion Torrent sequencing technology, will be used to perform all the genetic analyses for the study.

This will allow greater concordance than using the recognised companion diagnostics for the drugs, which are made by different manufacturers and use different sequencing technologies. It will also permit customisation, Dr Chen says – as more information on new mutations or abnormalities becomes available, and new drugs are added to the trial, the assay will be revised.

This ties in with a growing awareness among those who work in personalised medicine that separate companion diagnostics for the same drug – Roche, Qiagen and Dako all make companion diagnostics for Erbitux, for instance – might have different levels of accuracy.

Both the NCI’s Dr Chen and Dr Comis of ECOG-ACRIN believe that Match might provide a blueprint for future studies of targeted agents, with the anatomical location of the cancer taking a back seat to genetic makeup when it comes to patient recruitment.

And following this thought a little further, might the FDA and other regulators begin to approve drugs on the same basis – for a particular mutation, not a tumour type?

“Oh, I think that’s going to happen – it’s going to have to happen,” Dr Comis says.

It is not a simple task, of course. Herceptin works in both breast cancer and gastric cancer provided patients express the HER2 antigen, but BRAF inhibitors have been found to work in melanoma but not in patients with colon cancer, even though the tumours express the same mutation.

Study Trial ID
NCI-Match NCT02465060

To contact the writer of this story email Elizabeth Cairns in London at or follow @LizEPVantage on Twitter

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