In the phase IIa plasmaMATCH platform trial reported in The Lancet Oncology, Nicholas C. Turner, MD, and colleagues found that circulating tumor DNA (ctDNA) provided accurate genotyping that permitted selection of directed therapies in patients with advanced breast cancer.
Nicholas C. Turner, MD
Study Details
The multicenter study involved ctDNA testing in patients who had completed at least one previous line of treatment for advanced breast cancer or who had experience disease relapse within 12 months of neoadjuvant or adjuvant chemotherapy.
Patients were recruited into four treatment cohorts matched to mutations identified in ctDNA, with each cohort having a primary endpoint of confirmed objective response rate.
- Cohort A consisted of patients with ESR1 mutations treated with intramuscular extended-dose fulvestrant at 500 mg.
- Cohort B consisted of patients with HER2 mutations treated with oral neratinib 240 mg; if patients were estrogen receptor–positive, they also received intramuscular standard-dose fulvestrant.
- Cohort C consisted of patients with AKT1 mutations and estrogen receptor–positive cancer treated with oral capivasertib at 400 mg plus intramuscular standard-dose fulvestrant.
- Cohort D consisted of patients with AKT1 mutations and estrogen receptor–negative cancer or PTEN mutations treated with oral capivasertib at 480 mg.
For cohort A, ≥ 13 responses among 78 evaluable patients were required to infer activity; ≥ 3 responses among 16 evaluable patients were required for each of cohorts B, C, and D.
Key Findings
In all cohorts, combined median follow-up was 14.4 months.
In cohort A, the target number of responses was not reached, with confirmed responses (all partial responses) observed in 6 (8%) of 74 patients. Median duration of response was 7.0 months, with four patients continuing on treatment at data cutoff. The clinical benefit rate was 16%. Median progression-free survival was 2.2 months.
In cohort B, the target number of responses was met, with confirmed responses in 5 (25%) of 20 patients, including complete response in 1 (ongoing at 29 months). An additional three patients had unconfirmed partial responses. Median duration of response was 5.7 months, with three patients continuing on treatment at data cutoff. The clinical benefit rate was 45%. Median progression-free survival was 5.4 months.
In cohort C, the target number of responses was met, with confirmed responses (all partial responses) in 4 (22%) of 18 patients. An additional four patients had unconfirmed partial responses. Median duration of response was 7.5 months, with four patients continuing on treatment at data cutoff. The clinical benefit rate was 39%. Median progression-free survival was 10.2 months.
In cohort D, the target number of responses was not reached, with confirmed responses (all partial responses) observed in 2 (11%) of 19 patients. An additional two patients had unconfirmed partial responses. Median duration of response was 3.9 months, with one patient continuing on treatment at data cutoff. The clinical benefit rate was 11%. Median progression-free survival was 3.4 months.
The most common grade ≥ 3 adverse events were increased gamma-glutamyltransferase (16%) in cohort A, diarrhea (25%) in cohort B, fatigue (22%) in cohort C, and rash (26%) in cohort D. A total of seven patients had serious adverse events. One patient in cohort C died from treatment-related dyspnea.
The investigators concluded, “ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment.”
Dr. Turner, of the Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK, AstraZeneca, and Puma Biotechnology. For full disclosures of the study authors, visit thelancet.com.
