Durvalumab regimen improves pathologic complete response in HER2-negative breast cancer
Durvalumab and olaparib in combination with paclitaxel significantly improved pathologic complete response compared with chemotherapy alone among women with stage II or stage III high-risk, HER2-negative breast cancer, according to results of the randomized phase 2 I-SPY 2 study presented at the virtual American Association for Cancer Research Annual Meeting.
Researchers observed improvement among subsets of women with hormone receptor-positive and triple-negative disease.
“Sequencing and combination of the experimental drugs was driven by pragmatic considerations,” Lajos Pusztai, MD, professor of medicine and director of breast cancer translational research at Yale University and co-director of the Yale Cancer Center Genomics, Genetics and Epigenetics Program, said during the presentation. “This is a relatively nontoxic chemotherapy regimen that requires minimal immunosuppression with a low-dose of Decadron [dexamethasone, Merck] that can even be omitted in some cases.”
The I-SPY 2 trial evaluated novel agents as neoadjuvant therapy for breast cancer using response-adaptive randomization within molecular subtypes defined by receptor status and risk as determined by the MammaPrint (Agendia) 70-gene signature assay.
Researchers tested a combination of the anti-PD-L1 therapy durvalumab (Imfinzi, AstraZeneca), the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) and paclitaxel based on the rationale that DNA repair deficiency in cancer cells can result in immunogenic neoantigens and activation of the sting pathway, as well as the understanding that PARP inhibition can upregulate PD-L1 expression.
The study included women with HER2-negative breast cancer and tumors of 2.5 cm or less, and those with hormone receptor-positive disease had to have a MammaPrint high molecular profile.
Seventy-three women received the combination regimen of durvalumab dosed at 1,500 mg every 4 weeks for three cycles, olaparib dosed at 100 mg twice daily for 11 weeks, and paclitaxel dosed at 80 mg/m2 weekly for 12 weeks, followed by four cycles of doxorubicin and cyclophosphamide. Women in the control group (n = 299) received the weekly paclitaxel and doxorubicin/cyclophosphamide regimen.
The combination group included 21 women with hormone receptor-negative tumors and 52 women with hormone receptor-positive tumors.
Pathologic complete response served as the primary endpoint.
Researchers estimated — and continually updated — the predicted pathologic complete response rate based on serial MRI imaging and imaging response at weeks 3 and 12, combined with accumulating pathologic complete response data. “Graduation” occurred when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups exceeded 85%.
Results showed the combination group graduated 13 months after enrollment, with at least 85% predictive probabilities of success for all HER2-negative and the hormone receptor-positive/HER2-negative cohorts.
Seventy-two women completed surgery and were evaluable for pathologic complete response. Final predicted probabilities of success in a future phase 3 trial were 81% for all HER2-negative cancers (estimated pathologic complete response rate, 37%), 80% for the triple-negative subset (estimated pathologic complete response rate, 47%) and 74.5% for patients with hormone receptor-positive/HER2-negative disease (estimated pathologic complete response rate, 28%).
Researchers observed no unexpected toxicities.
“Follow-up is too short to report on PFS or OS in these patients, but that is something we will look at once the data mature,” Pusztai said. – by John DeRosier
Reference:
Pusztai L, et al. Abstract CT011. Presented at: AACR Annual Meeting; April 27-28, 2020.
Perspective
Back to TopSeveral individual and composite studies suggest pathologic complete response rate — defined as complete eradication of tumors in breasts and lymph nodes with preoperative therapy — is associated with better long-term survival. In 2014, the FDA supported use of pathologic complete response as a surrogate endpoint for accelerated drug approval.
The association of pathologic complete response and degree of residual tumor burden is clearly established for triple-negative and HER2-overexpressing breast cancer. However, this may be less so in hormone-sensitive tumors, particularly less aggressive hormone-sensitive tumors.
With the approval of checkpoint inhibitors in combination with chemotherapy in triple-negative metastatic breast cancer, much emphasis has been placed on integrating checkpoint inhibitors in early-stage breast cancer. The possibility of this integration, or replacing chemotherapy altogether in the preoperative setting, has created much excitement.
The most important questions discussed in this presentation are the benefit of combining PARP inhibitors and immune checkpoint inhibitors in early-stage breast cancer and the relevance of such combinations in tumor BRCA mutations and homologous recombinant deficiency (HRD)-unselected patients. The rationale for immunotherapy and PARP inhibitors has been discussed in many preclinical studies. However, clinically the enthusiasm has been somewhat dampened because the responsiveness of atezolizumab (Tecentriq, Genentech) has been linked to PD-L1 expression and not to BRCA mutation status.
So, what is the contribution of olaparib to durvalumab, with the caveat of BRCA mutation status not being presented? With the understanding that cross-comparisons between trials are fraught with uncertainties, it appears that among patients with HER2-negative tumors — either hormone-positive or triple-negative — the difference in pathologic complete response is fairly similar with veliparib (ABT-888, AbbVie) alone or pembrolizumab (Keytruda, Merck) alone in previous I-SPY trials. Thus, the contribution of olaparib will need to be studied with a specified patient population.
Lastly, regarding the toxicity of adding durvalumab and olaparib to the standard-of-care neoadjuvant regimen, there appears to be a 10% excess of grade 3 and higher immune toxicity, which is similar to other studies. However, the data may be incomplete. Other studies with PARP inhibitors have shown excess anemia, with many patients requiring transfusions. In this study, anemia and fatigue rates are lower than with paclitaxel alone.
In the absence of a clear delineation of the contribution of olaparib, some weight should be given to the financial burden of adding both durvalumab and olaparib to a preoperative regimen.
Is combined immune checkpoint and PARP inhibition in early-stage breast cancer ready for use? What we know so far in preoperative therapy for breast cancer is that pathologic complete response is associated with better outcomes. There likely are additional benefits of carboplatin, particularly in tumors with HRD-deficiency.
The promising activity of olaparib and durvalumab in addition to paclitaxel may be of particular interest to a subgroup of women with tumors expressing ultra-high MammaPrint risk.
Overall, the contribution of PARP inhibitors to immunotherapy in early-stage breast cancer remains uncertain. Thus, we should wait for confirmatory randomized studies that are stratified for PD-L1 expression and BRCA mutation HRD status before using combined therapies in these patients.
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