I-SPY 2: Durvalumab plus Olaparib and Paclitaxel Triplet in High-Risk Breast Cancer “Graduates” to Phase 3 Study

June 2020, Vol 11, No 3

The combination of the checkpoint inhibitor durvalumab (Imfinzi), the poly ADP-ribose polymerase (PARP) inhibitor olaparib (Lynparza), and chemotherapy with paclitaxel used as neoadjuvant therapy improved the pathological complete response (pCR) of patients with high-risk HER2-negative stage II or III breast cancer compared with the physician’s choice of chemotherapy.

The triplet combination also improved pCR in patients with triple-negative breast cancer (TNBC). These results from the I-SPY 2 clinical trial were presented at the plenary session of the 2020 American Association for Cancer Research virtual annual meeting, and signal that the triplet regimen has “graduated” for further study in a phase 3 clinical trial.

“Previous phase 2 studies established the safety of durvalumab added to taxane,” said lead investigator Lajos Pusztai, MD, DPhil, Director, Breast Cancer Translational Research, Yale Cancer Center, New Haven, CT. “Olaparib has been shown to improve median progression-free survival and improve response rates. The idea behind the combination was to boost the immune response by adding an anti–PD-1 checkpoint inhibitor, since PARP inhibitors are known to increase the expression of the PD-L1 protein in the tumor. There is a biological and preclinical rationale to combine a PARP inhibitor and checkpoint inhibitor,” Dr Pusztai added.

Adaptive Study Design

The I-SPY studies are a series of multicenter phase 2 clinical trials that use a response-adaptive randomization within molecular subtypes, defined by receptor status and the MammaPrint diagnostic test to evaluate novel agents as neoadjuvant therapy for breast cancer, with the primary end point of pCR (ie, no residual cancer). In these studies, multiple concurrent arms are tested with a shared control arm. Regimens either “graduate” for further study or are dropped for futility if they have a low predictive probability of being superior to the control arm.

I-SPY 2 included patients with HER2-negative breast cancer and a tumor size of ≥2.5 cm. Patients with hormone receptor (HR)-positive disease were eligible for inclusion. Patients in the experimental arm (N = 73, including 21 patients with TNBC) received treatment with durvalumab 1500 mg every 4 weeks for 3 cycles, olaparib 100 mg twice daily in weeks 1 through 11, concurrent with paclitaxel 80 mg/m2 weekly for 12 cycles, followed by 4 cycles of doxorubicin plus cyclophosphamide. The control arm (N = 299) received paclitaxel weekly for 12 weeks followed by 4 cycles of doxorubicin plus cyclophosphamide.

The experimental arm had a higher rate of probability of future success in a phase 3 study than the control arm, including 81% for all HER2-negative cancers (estimated pCR rate from 22% in controls to 37% with the experimental arm), 80% for TNBC (estimated pCR rate of 27% in controls to 47%, respectively), and 74.5% for patients with HR-positive, HER2-negative disease (estimated pCR of 14% to 28%, respectively).

Biomarker Results

The MammaPrint ultra-high-risk subgroup accounted for most of the benefit of this experimental combination in patients with estrogen receptor (ER)-positive, HER2-negative breast cancer. The estimated pCR rate was 64% in the MammaPrint ultra-high-risk group compared with 22% in the MammaPrint high-risk subgroup for the experimental arm, and 9% versus 10%, respectively, for the control arm.

Among the TNBC subgroup, low CD3/CD8 gene signature ratio, high macrophage/T-cell-MHC class II ratio, and high-proliferation signature were associated with higher pCR in the experimental arm versus the controls.

Correlative studies of BRCA mutation status, tumor mutational burden, and PD-L1 expression will be presented at a later meeting.

Adverse events were reported in 43 patients who received the triple-drug regimen and in 251 patients in the control arm. The rate of grade 3 or 4 adverse events was 58% in the experimental arm versus 41% in the control arm. More febrile neutropenia, colitis, and elevated liver enzymes were reported in the experimental arm than in the controls. Grade 3 immune-related adverse events were reported in 19% of patients versus 1.6%, respectively.

Promising Results

“The subset analysis presented by Dr Pusztai shows more benefit for the triple combination in the ultra-high MammaPrint group than in the lower-risk group. This may allow us to select patients who may benefit from a checkpoint inhibitor plus PARP inhibitor, and not use chemotherapy,” said discussant Pamela N. Munster, MD, Leader, Experimental Therapeutics Program, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

“The combination studied in I-SPY 2 is promising, and the potential patient selection of patients with ER-positive, HER2-negative according to ultra-high MammaPrint status is important. Toxicity data are incomplete, and we need to consider financial toxicity. The contribution of PARP inhibitor to checkpoint inhibitor in early-stage breast cancer remains uncertain. We await the results of confirmatory trials stratified for PD-L1 expression and BRCA mutation and homologous repair deficiency status,” Dr Munster stated.

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