Results from the multicenter, multicohort, phase 2a plasmaMATCH platform trial revealed that circulating tumor DNA (ctDNA) testing provides sufficient accuracy for widespread adoption in routine clinical practice to identify patients with breast cancer who are suitable for licensed targeted therapies, with the potential of efficient and rapid screening for clinical trials as well.1
The study, published in Lancet Oncology, went on to suggest that ctDNA testing can be seen as a standard of care test for both common and rare genetic events for patients with breast cancer.
“The plasmaMATCH trial platform has allowed us to look at the activity of various different treatments at the same time,” Judith Bliss, MSc, professor of Clinical Trials at the Institute for Cancer Research (ICR) and director of its Cancer Research UK-funded Clinical Trials and Statistics Unit, said in a press release.2 “This efficient trial set-up has been a success and it is already starting to bring patients closer to new targeted treatments.”
The trial was conducted in 18 hospitals across the UK and included adult women with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0 to 2. Further, participants had completed at least 1 prior line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy.
Patients were recruited into 4 parallel treatment cohorts matched to mutations identified in ctDNA. Cohort A comprised patients with ESR1 mutations treated with 500 mg of intramuscular extended-dose fulvestrant; cohort B comprised patients with HER2 mutations treated with 240 mg of oral neratinib (Nerlynx), and if estrogen receptor-positive with intramuscular standard-dose fulvestrant (Faslodex); cohort C comprised patients with AKT1 mutations and estrogen receptor-positive cancer treated with 400 mg of oral capivasertib plus intramuscular standard-dose fulvestrant; and cohort D comprised patients with AKT1 mutations and estrogen receptor-negative cancer or PTEN mutation treated with 480 mg of oral capivasertib.
The primary end point for each cohort was confirmed objective response rate. Specifically for cohort A, 13 or more responses among 78 evaluable patients were required to infer activity; 3 or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete, though long-term follow-up remains ongoing.
Between December 21, 2016 and April 26, 2019, a total of 1051 patients registered for the study, with ctDNA results available for 1034 patients. In all cohorts, the combined median follow-up was 14.4 months (IQR 7.0-23.7).
Notably, agreement between ctDNA digital PCR and targeted sequencing was 96% to 99% (n = 800, kappa 0.89-0.93). Further, sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI, 83-98) overall and 98% (95% CI, 87-100) with contemporaneous biopsies.
Cohorts B and C met or exceeded the target number of responses, with 5 (25%; 95% CI, 9-49) of 20 patients in cohort B and 4 (22%; 95% CI, 6-48) of 18 patients in cohort C having a response. However, cohorts A and D did not reach the target number of responses, with 6 (8%; 95% CI, 3-17) of 74 in cohort A and 2 (11%; 95% CI, 1-33) of 19 patients in cohort D having a response.
Overall, the most common grade 3 to 4 adverse events (AEs) were raised gamma-glutamyltransferase (cohort A, 16%), diarrhea (cohort B, 25%), fatigue (cohort C, 22%), and rash (cohort D, 26%). Moreover, 17 serious AEs occurred in 11 patients, and there was 1 treatment-related death caused by grade 4 dyspnea in cohort C.
“Tests that detect tumor DNA in the blood have huge potential and could transform how doctors select targeted therapies for patients with advanced cancer,” Nick Turner, MD, professor of Molecular Oncology at the ICR and head of the Ralph Lauren Centre for Breast Cancer Research at The Royal Marsden, said in the release. “Our study shows that these liquid biopsies can pick up the mutations that drive a patient’s breast cancer and can successfully match patients with the best available precision medicine for their cancer.”
Moving forward, the researchers intend to take the targeted drugs that demonstrated initial promise in this study and carry out larger clinical trials to assess whether they are better than already existing treatments.
References:
1. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncology. doi: 10.11016/S1470-2045(20)30444-7
2. Major ‘plasmaMATCH’ trial uses blood test to match women with breast cancer to range of precision treatments [news release]. Published September 10, 2020. Accessed September 16, 2020. https://ift.tt/2FNe3HE
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