Liquid biopsy developers take aim at colorectal cancer

Natera and Guardant are about to shake things up with indication-specific blood tests, but Exact is keeping faith with Cologuard – for now.

The first pan-cancer blood tests were approved by the FDA in 2020. Now several liquid biopsy companies are turning their attention to new settings specifically in colorectal cancer – screening and detecting cancer recurrence – and testing for this tumour type could soon change drastically.

Recent data from Natera have shown for the first time that its Signatera blood test can predict which post-surgical colorectal cancer patients will benefit from adjuvant chemotherapy. And Guardant Health will soon present data from a vast pivotal trial of its colorectal screen, Lunar-2, potentially threatening the current leader in non-invasive screening, Exact Sciences.

Natera has long been one of the leaders in so-called minimal residual disease detection – using circulating tumour DNA (ctDNA) to pick up malignant re-growth following surgical removal of tumours, a market SVB Leerink analysts put at $20bn. Now data from the Galaxy sub-study of the Circulate-Japan trial, which emerged at the Asco-GI meeting last month, have taken things a step further.

So what? 

Signatera and tests like it have been shown to effectively differentiate whose cancer will or will not recur, according to Alexey Aleshin, the company’s vice-president. “But the lingering question for the last few years has been, so what? Can we actually intervene based on ctDNA positivity or negativity and alter outcomes?,” he adds.

The Galaxy data show that the answer is yes, he says. Of patients with stage III cancer with a positive Signatera result, those who did not receive adjuvant chemotherapy had a greater than eightfold increase risk of recurrence versus those who did – a significant difference. This is the first definitive link that post-surgical treatment guided by Signatera can improve outcomes.

Signatera could also track which patients are benefiting from the chemo. Chemo-treated patients who cleared their ctDNA – going from having a positive Signatera result to a negative – did significantly better than those who remained positive, with a six-month disease-free survival of 100% and 58% respectively. 

Indeed, the patients who went from positive to negative did as well as patients who were ctDNA-negative to begin with.

Mr Aleshin says the group expects these data to increase interest in the test, though he declines to say exactly what it might mean for sales. 

Blood and guts

Also in colorectal cancer, but in the screening setting rather than recurrence, a battle is looming. The pivotal Eclipse trial of Guardant’s Lunar-2 liquid biopsy, a vast undertaking in 13,000 patients, will report this summer. 

The gold standard for colorectal cancer screening is colonoscopy, but compliance with this invasive and unpleasant procedure is low. The main non-invasive screen is Exact Sciences’ faecal test Cologuard, which has been tremendously successful since its launch in 2014. If Lunar-2 reaches market on the strength of the Eclipse readout – and a filing is pencilled in for the second half of this year – it could cut into Cologuard’s sales, particularly if people decide they prefer giving a blood sample to a faecal sample. 

Of course, Exact has its own liquid biopsy, a pan-cancer test obtained via its acquisition of Thrive Earlier Detection in 2020. It would be logical to assume that Exact would be putting Cologuard aside and throwing its efforts behind the blood test to try to compete with Guardant and the other liquid biopsy developers. It would also be wrong.

Instead the group is trumpeting Cologuard 2.0, a second-generation faecal test designed to have better efficacy. Data from a small trial, also presented at Asco-GI, showed the test to have sensitivity of 95% for colorectal cancer, 83% for high-grade dysplasia and 57% for all advanced precancerous lesions, all at a pre-set specificity of 92%.

Paul Limburg, Exact’s chief medical officer, believes Cologuard 2.0 has an advantage over Lunar-2, however, in that as well as picking up early malignancies it can also detect precancerous lesions.

“Biologically, precancerous lesions may not have the same potential to shed biomarkers into the bloodstream,” he says. Detecting them using a stool-based test is biologically and technically feasible, he says, but a liquid biopsy would not be able to match this. 

The next step for Exact is Blue-C, the pivotal trial of Cologuard 2.0. Dr Limburg says this will have to exceed what the first-gen test showed in its pivotal trial, which was 92% sensitivity and 87% specificity. Blue-C will report in 2024.

But a parallel trial suggests that Exact is keeping its options open when it comes to blood tests for colorectal cancer. Patients enrolled in Blue-C may also provide a blood sample. “Those specimens will be used to further explore blood-based biomarkers, compare performance to other existing assays – with the development of a blood based assay in mind,” Dr Limburg says. 

This is unlikely to form the basis of an approval application for a liquid biopsy to screen for colorectal cancer, however, so a blood test to rival Lunar-2 is not imminent. Exact will be dependent on first-generation Cologuard for some time yet. 

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