Innovative plasmaMATCH Trial Displays Feasibility With ctDNA in Breast Cancer

Joyce A. O'Shaughnessy, MD

The utility of circulating tumor DNA (ctDNA) continues to unfold in breast cancer, explained Joyce A. O'Shaughnessy, MD—citing the first results of the plasmaMATCH trial as the most recent demonstration of precision medicine in the field.

In the trial, approximately 1000 patients with metastatic breast cancer underwent ctDNA testing. Patients were grouped into 1 of 4 treatment cohorts depending on their genomic profile. In cohort 1, patients with ESR1 mutations received high-dose fulvestrant (Faslodex); in cohort 2, patients with HER2 mutations received neratinib (Nerlynx) with or without fulvestrant. In cohort 3, patients with AKT1-mutant estrogen receptor (ER)—positive breast cancer were treated with capivasertib plus fulvestrant. Finally, in cohort 4, patients with AKT1—mutant ER-negative breast cancer or a PTEN-inactivating mutation were treated with capivasertib.

Among the first 16 evaluable patients in cohorts 1 through 4, the objective response rates (ORRs) were 8.1%, 25.0%, 22.2%, and 10.5%, respectively. The primary end point, which was ORR, was met in cohorts 2 and 3.

"The trial showed that we can serially sample our patients' plasma upon progression on various options to try to more rationally choose and recommend the next therapy for patients," said O’Shaughnessy.

In an interview with OncLive, O'Shaughnessy, chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Texas Oncology, and chair of The US Oncology Network, as well as a 2016 Giant of Cancer Care^® in Community Outreach, discussed the design and findings of the plasmaMATCH trial and ongoing research with targeted therapy in breast cancer.

OncLive: Could you provide some background on the plasmaMATCH trial?

O'Shaughnessy: At the 2019 San Antonio Breast Cancer Symposium, Nicholas Turner, MD, MHSc, of The Royal Marsden Hospital, presented the first set of data from the plasmaMATCH trial. This is a long-awaited and very innovative trial, where over 1000 women with metastatic breast cancer in the United Kingdom had serial assessment of ctDNA. The investigators were looking for actionable mutations. This was a proof-of-concept trial to see whether we can show the clinical utility [of ctDNA] in patients with metastatic breast cancer by finding a genomic alteration and then treating patients with a therapy that’s [theoretically] effective against that activating mutation. [The trial is a great example] of precision oncology.

The alterations that were evaluated included activating HER2 mutations, AKT mutations, and ESR1 mutations, the latter of which is the ER mutation. There are other alterations one can look for in metastatic breast cancer, such as NTRK fusions. One can also look for microsatellite instability and high tumor mutational burden. PIK3CA is also very important; we have a new FDA approval for the PI3-kinase inhibitor alpelisib (Piqray) for patients with a PIK3CA mutation. Several others have clinical utility, but in the plasmaMATCH trial, they looked at ESR1, AKT, and HER2.

What did the results of the trial show?

They found that ESR1 mutations are very common. About 45% of patients had an ESR1 mutation, and these patients were pretreated with endocrine therapy. They were tested with high-dose fulvestrant. It was only modestly active; about 8% of patients had an objective response. The median time to progression was just 2.2 months. Doubling the dose of fulvestrant wasn’t particularly effective [in that cohort].

However, this is a new subtype of metastatic breast cancer, and there's a large amount of drug development going on. Many companies have oral selective ER downregulators to destroy the mutated ER. For example, elacestrant is being evaluated in the ongoing phase III EMERALD trial. [The trial, which is sponsored by Radius Pharmaceuticals] is comparing elacestrant with physician's choice of endocrine therapy. There are several others that are in early studies that look quite effective against the wild-type ER and mutated ER. You can find those patients very readily with ctDNA.

The second hypothesis was to test capivasertib, which is an oral AKT inhibitor. About 5% of patients had an activating mutation in AKT. Oftentimes, it's an acquired mutation in the setting of endocrine therapy resistance. Most patients [in this cohort] had clinical benefit. They either had an objective response or a substantial reduction in tumor volume, which we’ve seen before with capivasertib.

There's another drug, ipatasertib, which is also being developed in that space. That drug is in randomized trials in women with metastatic ER-positive breast cancer.

Could you highlight other research with targeted therapy in the space?

The SUMMIT trial looked at the combination of fulvestrant and neratinib and showed very nice efficacy. Patients either achieved an objective response or reduction in tumor volume. Some responses were very durable with the combination of neratinib and fulvestrant, as well as with capivasertib in [patients with] AKT mutations. These are quite durable [responses we’re seeing by] going after the precise driving mutation.

For patients with HER2 mutations, there is another iteration of the SUMMIT protocol, which involves adding trastuzumab (Herceptin), which can be safely done with neratinib and fulvestrant. That may provide even greater efficacy.

These are some examples showing proof-of-concept [with ctDNA], which is feasible to find activating mutations in the plasma and that we can target these mutations and benefit patients. These are usually clonally dominant. These are real driving mutations that have a high fraction of mutant alleles in ctDNA. Hopefully, we'll be able to find an increasing number [of these mutations] and most importantly, agents that will be effective in the context of these mutations.

Turner N, Kingston B, Kilburn L, et al. Abstract GS3-06: results from the plasmaMATCH trial: a multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010). Cancer Research. 2020;80(4). doi: 10.1158/1538-7445.SABCS19-GS3-06