On April 27, 2020 I-SPY 2 TRIAL reported that results on April 27 at the clinical trial plenary session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 annual meeting, which showed that adding the immune checkpoint inhibitor durvalumab and the PARP inhibitor olaparib to standard of care pre-operative (neoadjuvant) chemotherapy improved outcomes for women with stage II/III, high-risk, HER2-Negative Breast Cancer (Press release, I-SPY 2 TRIAL, APR 27, 2020, View Source [SID1234556605]). Patients who received durvalumab + olaparib + paclitaxel (DOP) followed by doxorubicin/cyclophosphamide (AC), achieved complete eradication of their cancer from the breast and axillary lymph nodes at the time of surgery (i.e pathologic complete response) at a greater rate than patients treated with chemotherapy alone (37% versus 20%). This degree of response met the threshold for graduation, meaning that there is a greater than 85% predicted probability of success if this combination was tested against standard chemotherapy in a phase 3 trial of 300 neoadjuvant patients.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. I-SPY 2 evaluates drugs (or combination of drugs) in parallel with the goal of determining which drugs work best in various types of breast cancer. I-SPY 2 patients are given chemotherapy before surgery so that response to treatment can be assessed. The primary endpoint of the study is pathologic complete response (pCR). Patients who participated in this study had tumors ≥ 2.5 cm, were HER2-negative, and if the cancer was hormone receptor positive (HR+) had to be classified as MammaPrint high risk status. Lead investigator of the study arm, Dr. Lajos Pusztai, Professor of Medicine and Director of Breast Cancer Translational Research at Yale Cancer Center, presented the efficacy and biomarker results which showed the predicted probability of pCR for the overall HER2-negative group, (22% vs 37%) and by subtypes, in HER2-negative/ER-positive (14% vs 28%) and triple negative (TNBC) (27% vs 47%) breast cancer subtypes.

The investigators also evaluated proposed potential markers that could identify the subgroup of patients who selectively benefited from the inclusion of immune enhancing agents such as durvalumab and DNA damage response targeting agents such as olaparib. Among the HR+/HER2- cohort, the MammaPrint ultra-high group was the primary beneficiary of the combined therapy (pCR rates 64% with the combination versus 22% with chemotherapy alone). Specific gene expression signatures thought to be associated with response were prospectively identified and the following were found to be associated with higher pCR in the experimental arm among TNBC: low CD3/CD8 ratio; high Macrophage/T cell-MHC class II ratio, and high proliferation. The safety signals were not unexpected. Adverse events were consistent with known side effects of these drugs. Overall 11% of patients in durvalumab + olaparib arm experienced immune-related grade 3 adverse events vs 1.3% in the control arm. According to Dr. Pusztai, chaperone for this arm in the I-SPY 2 TRIAL, "These results provide further evidence for the clinical value of immunotherapy in early stage breast cancer and suggest new avenues for how to exploit these drugs in HR+ breast cancers."

As noted by I-SPY 2 principal investigator, Dr. Laura Esserman of the University of California San Francisco, "There is a consistent signal of improved response from immuno-oncology and DNA damage response targeted agents in the adaptive I-SPY 2 platform trial as well as other trials, which gives us confidence that these types of agents will have a place in improving outcomes for women with highest risk early breast cancer. "

AACR has selected these findings as newsworthy and will be highlight during an AACR (Free AACR Whitepaper) webcast with the meeting program chair Dr. Antoni Ribas and AACR (Free AACR Whitepaper) President Dr. Elaine Mardis.