Abstract CT011: Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL

Abstract

Background: 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. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2. Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches > 85%. Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 - June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with > 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis). Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets. Citation Format: Lajos Pusztai, Hyo S. Han, Christina Yau, Denise Wolf, Anne M. Wallace, Rebecca Shatsky, Teresa Helsten, Judy C. Boughey, Tufia Haddad, Erica Stringer-Reasor, Carla Falkson, A. Jo Chien, Rita Mukhtar, Anthony Elias, Borges Virginia, Rita Nanda, Douglas Yee, Kevin Kalinsky, Kathy S. Albain, Aixa Soyano Muller, Kathleen Kemmer, Amy S. Clark, Claudine Isaacs, Alexandra Thomas, Nola Hylton, W. Fraser Symmans, Jane Perlmutter, Michelle Melisko, Hope S. Rugo, Richard Schwab, Amy Wilson, Amy Wilson, Ruby Singhrao, Smita Asare, Laura J. van't Veer, Angela M. DeMichele, Ashish Sanil, Donald A. Berry, Laura J. Esserman, Trial Consortium I-SPY 2. Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT011.

Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer

“…The GeparNuevo trial in TNBC demonstrated a numerical but not statistically significant increase in pCR rate (53% vs. 44%, p = 0.287) when durvalumab (1500 mg every 4 weeks) was included with weekly nab-paclitaxel (125 mg/ m 2 ) and epirubicin/cyclophosphamide 16 . The Bayesian randomized I-SPY2 trial evaluated the combination of 1500 mg durvalumab every 4 weeks and olaparib 100 mg twice a day concurrent with weekly paclitaxel (80 mg/kg) followed by AC without durvalumab or olaparib vs. the same chemotherapy regimen alone and reported an increase in pCR rate from 27 to 47% in the TNBC population of the trial with a 98% probability that the experimental arm is superior to the control 17 . The 95% confidence interval of the pCR point estimate in our trial includes the pCR rates seen in the immunotherapy arms of both these randomized trials and therefore the results are consistent with an improvement in pCR rate with the inclusion of durvalumab.…”

Recent advances in neoadjuvant therapy for breast cancer

“…Further supporting a role for immune checkpoint neoadjuvant therapy in high-risk ER-positive/HER2-negative breast cancer was the graduation of the PD-L1 inhibitor antibody durvalumab and the PARP inhibitor olaparib in combination with paclitaxel in the ER-positive/HER2-negative signature, driven by the MammaPrint ultrahigh (MP2) subgroup. In the MP2 subgroup, durvalumab/olaparib/paclitaxel combination exhibited a pCR of 64% versus 22% for the control chemotherapy arm 50 .…”

“…Indeed, pembrolizumab was the first agent of the initial nine tested that showed an improvement of pCR rates in the ER-positive/HER2-negative signature. This result was recently followed by the graduation of the PD-L1 antibody durvalumab in combination with olaparib and paclitaxel in the MammaPrint ultrahigh (MP2) ER-positive/HER2-negative signature, where a pCR rate of 64% was observed relative to 22% for control 50 . In TNBC, targeting the PD-1/PD-L1 checkpoint with pembrolizumab increased pCR rates from 22 to 60% 44 and with durvalumab/olaparib/paclitaxel from 27 to 47% 50 .…”

“…This result was recently followed by the graduation of the PD-L1 antibody durvalumab in combination with olaparib and paclitaxel in the MammaPrint ultrahigh (MP2) ER-positive/HER2-negative signature, where a pCR rate of 64% was observed relative to 22% for control 50 . In TNBC, targeting the PD-1/PD-L1 checkpoint with pembrolizumab increased pCR rates from 22 to 60% 44 and with durvalumab/olaparib/paclitaxel from 27 to 47% 50 . Notably, PD-1 is a marker of effector T-cell exhaustion 98 , and the I-SPY 2 trial results suggest that targeting T-cell exhaustion markers may be a very productive approach in hormone receptor–positive/HER2-negative breast cancer and TNBC.…”

“…The KEYNOTE-522 trial provided phase 3 confirmation of neoadjuvant efficacy of pembrolizumab in the TNBC signature, predicted by I-SPY 2 49 . The combination of durvalumab/olaparib/paclitaxel also recently graduated from I-SPY 2 in the ER-positive/HER2-negative (MammaPrint ultrahigh-MP2) and TNBC subtypes 50 .…”