MoST study shows promise of precision medicine – Professor David Thomas

Prof David Thomas

Thousands of Australian cancer patients are accessing genome-directed therapies via a national precision oncology program, with many seeing positive results, Garvan Institute of Medical Research Kinghorn Cancer Centre Director Professor David Thomas told the COSA 2021 Annual Scientific Meeting.

The Molecular Screening and Therapeutics (MoST) study, run through Professor Thomas’ company Omico, aims to improve advanced-stage cancer patients’ access to targeted, efficacious treatments and outcomes via genomic profiling and clinical information.

It features several clinical trials operating under the biomarker-dependent Pan cancer subprogram for adolescents and adults with advanced or metastatic solid tumours, ASPiRATION for adults with newly-diagnosed metastatic non-squamous non-small cell lung cancer (mNSCLC) and MoST-LLY for patients with advanced blood cancers without an established therapeutic option, Omico’s website read.

To date, over 4,200 patients have enrolled across 22 centres in Australia and a 23rd in New Zealand, Professor Thomas told the COSA virtual meeting.

Having started with just eight centres (one per state or territory) less than three years ago, Professor Thomas said the program’s rapid expansion “speaks to demand, an unmet need in the community and the referral from more than 400 clinicians across more than 100 institutions”.

Latest outcomes

Already, MoST has shown promising results, with 461 of ~2,000 or one-in-seven patients on the program for 12+ months being treated with a matched therapy following molecular screening, he said.

The treatments extended median overall survival from 11 months in patients on unmatched therapies to 16 or 17 months, according to MoST’s C1 studies and other clinical trials.

This “is a highly significant difference in outcome”, but it’s “clearly not randomised and although they mimic the data . . . from international studies, this needs to be taken into account,” Professor Thomas said.

While wary of interpreting results on individual cases, he did highlight some examples of “good responses” to matched therapy.

One 66-year-old male on the MoST program saw a “dramatic” reduction in chromogranin A and metastatic disease within 12 weeks of receiving a RET inhibitor. He had pain in the right upper quadrant, nodular lesions in the adrenal bed, multiple liver lesions and pulmonary nodules on computed tomography and elevated chromogranin A (peak: 33,710 µg/L [normal: <102 µg/L]). He also had a right adrenalectomy for pheochromocytoma eight years earlier, according to the case study. MoST screening on TSO500 revealed an “unexpected” RET:SEPTIN9 fusion gene.

“Now, RET is druggable, but this would never have been tested in standard of care testing,” Professor Thomas said.

“For this patient at least, as for many others, the access to the program for this patient with a rare cancer has been absolutely transformative — reminding us that we shouldn’t assume that because a patient has a metastatic pheochromocytoma or any other cancer, who’s run out of conventional options that there isn’t something that we could learn if we can find the right target and if we have access to drugs through clinical trials or through access to therapies in some other form.”

He noted that Garvan Senior Research Officer Dr Frank Lin’s TOPOGRAPH (Therapy-Oriented Precision Oncology Guidelines for Recommending Anti-cancer Pharmaceuticals) database, which maps patient data against all current biomarker-dependent trials in the country could be key to improving patient access to targeted therapies.

Study impacts: beyond the patients

The program could also affect patients’ relatives as more cancer-related germline mutations come to light, Professor Thomas said.

So far, his team has identified 92 germline mutations (not including p53 mutations) in 90 individuals “who did not meet conventional testing criteria but were tested as a result of taking part in this program, of whom, the majority were only identified because of the [MoST] study.”

“That’s a very important result in my view because of what it says; first of all, that germline results are latent within the tumour profile and that’s something I think we need to understand as clinicians”.

And second, “as this technology is driven into the clinic . . . we’re going to need to consider all the downstream ramifications of performing assessments — not just in terms of the trials and access to drugs and monitoring outcomes and making sure that we’re doing the right thing — but also . . . how we manage our duty of care when we identify things that may be relevant to detecting cancers earlier in relatives of individuals who do carry these germline variants”.

What’s next for MoST?

Professor Thomas and his team are set to share results with the Netherlands’ Drug Rediscovery Protocol (DRUP) study which “is very similar to [MoST] in the sense of having a basket of trials based around genomic screening” in order to “put the maximum amount of information before our clinical community so they can evaluate the potential of these biomarker-dependent drugs as they’re applied across cancer populations”.

They’re also looking to extend MoST to 20,000 more Australian cancer patients through a program called PrOSPeCT.

They also hope to make MoST sustainable long-term through partnerships with local and international pharmaceutical and academic sectors, he said, adding that the national platform they’ve created “gives Australia a competitive advantage which it didn’t have previously in terms of being a destination for biomarker-dependent drug development”.

Looking further into the future, Professor Thomas predicted that whole exome sequencing and whole genome sequencing will yield even further opportunities, assuming the costs drop and the complexities of analysis can be dealt with.

There would be opportunities “particularly in the area of mutational signatures that might predict response to therapy, but also potentially other biomarkers that we don’t yet know about such as telomere lengths that we’re not capturing as part of our current panels,” he said.

Professor Thomas also cautioned that while there was great interest in moves to using liquid biopsies they were still not standard of care.

“They may have a particular role in tracking resistance mutations,  as we get people with serial targeted therapies over time,” he said.

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