Adding pembrolizumab to neoadjuvant chemotherapy more than doubled the rate of pathologic complete response, compared with chemotherapy alone, in women with early-stage breast cancer enrolled in the phase 2 I-SPY2 trial.
Pathologic complete response (pCR) rates up to 60% were reported for patients with high-risk, stage II/III breast cancer who received pembrolizumab plus chemotherapy in I-SPY2, an ongoing platform trial designed to rapidly screen multiple agents and pinpoint those with a high probability of success.
The doubling of pCR rates was seen in all three biomarker signatures studied, including ERBB2(HER2)-negative, hormone receptor (HR)-positive/ERBB2-negative, or triple-negative breast cancer.
These results mean that pembrolizumab can “graduate” from I-SPY2 and suggest a greater than 99% predictive probability that the pembrolizumab-plus-chemotherapy approach will be superior to chemotherapy alone in a phase 3 trial, according toof the University of Chicago, and colleagues.
“Notably, pembrolizumab was the first agent of 10 studied to graduate in the HR-positive/ERBB2-negative signature since I-SPY2 opened in 2010,” Dr. Nanda and colleagues wrote in.
The I-SPY2 study has enrolled adult women with stage II/III breast cancer at high risk of recurrence. The control arm included 181 patients randomized to receive standard neoadjuvant paclitaxel followed by doxorubicin plus cyclophosphamide. The pembrolizumab arm included 69 patients who received the same chemotherapy regimen plus pembrolizumab given concurrently with paclitaxel.
In ERBB2-negative patients, the estimated pCR rates were 44% in the pembrolizumab arm and 17% in the control arm. In HR-positive/ERBB2-negative patients, the estimated pCR rates were 30% and 13%, respectively. In triple-negative patients, the estimated pCR rates were 60% and 22%, respectively.
Residual cancer burden classified as extensive was less often seen in the pembrolizumab-treated patients, the investigators noted.
Event-free survival was qualitatively similar between the pembrolizumab and control arms, although the investigators cautioned against drawing conclusions based on this exploratory analysis in a small number of patients.
“Patients who achieved pCR had excellent outcomes regardless of arm,” the investigators wrote.
Immune-related adverse events (irAEs) were seen in the pembrolizumab-treated patients, although most were grade 1 or 2 and managed with dose interruption or corticosteroid therapy.
The most common irAE was thyroid dysfunction in 13% of patients, which was on par with what was seen in previously published reports. By contrast, adrenal insufficiency was observed in about 9% of patients, which is higher than in published reports for reasons that are unclear.
“Future work to characterize the risk factors for developing irAEs is warranted to improve the therapeutic index of these agents,” Dr. Nanda and colleagues wrote.
Pembrolizumab plus standard neoadjuvant chemotherapy is being evaluated in two ongoing, randomized phase 3 trials – KEYNOTE 522, which is evaluating patients with triple-negative breast cancer, and KEYNOTE 756, which is focused on high-risk, HR-positive/ERBB2-negative breast cancer.
The ongoing I-SPY2 study is supported by a grant from the National Cancer Institute as well as funding from charitable organizations, pharmaceutical companies, and private individuals. The investigators disclosed relationships with a range of pharmaceutical companies.
SOURCE: Nanda R et al. JAMA Oncol. 2020 Feb 13. doi: .