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Neoadjuvant therapy provides opportunity to discover new treatment strategies
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Editor’s Note: In this guest commentary, Douglas Yee, MD, discusses results from several trials presented at this year’s ASCO Annual Meeting that evaluated neoadjuvant therapy for breast cancer.
Adjuvant breast cancer therapies historically have been performed as postsurgical treatment.
Similarly, in clinical trials, adjuvant systemic therapy is applied after surgical removal of the tumor.
Although advances have been made using this approach, it can take thousands of patients and years to determine if a new treatment strategy is superior to the standard of care. As molecular and clinical subtypes of breast cancer become predictive of response to certain therapies, a large phase 3 trial may be difficult to complete due to the number of patients needed.
It has long been known therapy responses can be determined in the neoadjuvant treatment of patients with breast cancer. Virtually every trial has shown patients who achieve a pathologic complete response (pCR) — usually defined as no invasive cancer in the breast or lymph nodes — achieve better outcomes than patients with residual disease.
Residual cancer burden
W. Fraser Symmans, MD, has created a formal scoring system to determine response to neoadjuvant therapy called residual cancer burden (RCB).
This scoring system classifies the tumor remaining after neoadjuvant therapy. Although the scoring system is continuous, it includes four discrete classes (0 to 3) to demonstrate prognostic significance.
At San Antonio Breast Cancer Symposium in 2017, investigators in I-SPY2 — a phase 2 basket trial involving multiple agents — demonstrated a highly significant correlation between pCR (RCB 0) and EFS and distant RFS. Three-year EFS was 94% and 3-year distant RFS was 95%.
In the trial, all patients with locally advanced breast cancer — with the exception of hormone receptor-positive, MammaPrint (Agendia)-low tumors — were treated. Researchers observed the favorable results for EFS and distant RFS for all patients who achieved pCR, regardless of tumor subtype or assigned treatment. These data suggested pCR is an excellent surrogate for long-term outcomes.
At this year’s ASCO Annual Meeting, Symmans presented data for patients who achieved an excellent response but who did not have complete eradication of tumor — RCB-1.
When patients on I-SPY2 were grouped as RCB-0/RCB-1 vs. RCB-2/RCB-3, researchers saw a similar favorable HR. Patients with RCB-0 had a 94% 3-year EFS rate, whereas patients with RCB-1 had an 87% 3-year EFS.
When examined by subgroup, patients with hormone receptor-positive tumors had excellent outcomes if they achieved RCB-0/RCB-1. EFS appeared slightly worse for RCB-1 among hormone receptor-negative patients.
These data suggested excellent responses to neoadjuvant therapy — RCB-0 or RCB-1 — could be used to evaluate benefit for new regimens in the neoadjuvant setting. Improvements in pCR can serve as a pathway to FDA-accelerated approval of new drugs for neoadjuvant breast cancer therapy.
Checkpoint inhibitors
At ASCO, Sibylle Loibl, MD, PhD — on behalf of the German Breast Cancer Group and German Gynecological Oncology Working Group-Breast — presented results of GeparNuevo. The trial evaluated the addition of durvalumab (Imfinzi, AstraZeneca), an anti-PDL1 antibody, to an anthracycline- and taxane-based regimen in triple-negative breast cancer.
Notably, the 117 patients received a 2-week pretreatment of either durvalumab or placebo before chemotherapy (nab-paclitaxel followed by epirubicin/cyclophosphamide), but the independent data monitoring committee closed this “window of opportunity” arm.
In this trial, patients assigned durvalumab received the drug for the duration of chemotherapy.
Researchers reported pCR rates of 53.4% for the durvalumab group and 44.2% for the control group.
Of note, the patients who were pretreated with durvalumab for 2 weeks prior to chemotherapy had a 61% pCR rate, whereas patients who did not have the 2-week exposure had a pCR rate of 37.9%. Although the trial was not designed to test the clinical benefit of a 2-week pretreatment period with durvalumab prior to chemotherapy, the results are intriguing and hypothesis-generating.
Patients aged younger than 40 years also had increased benefit.
However, researchers noted hypo- and hyperthyroidism increased among durvalumab-treated patients.
These results were similar to those of a single-arm trial presented by Lajos Pusztai, MD, DPhil. This trial — which used durvalumab, nab-paclitaxel and dose-dense cyclophosphamide — resulted in a 60% pCR rate in triple-negative breast cancer.
Previously, the I-SPY2 group reported a 60% pCR rate in triple-negative breast cancer when the anti-PD-1 agent pembrolizumab (Keytruda, Merck) was added to weekly paclitaxel followed by cyclophosphamide. Of note, I-SPY2 researchers only administered pembrolizumab during the first 12 weeks of paclitaxel therapy.
Taken together, these reports suggest checkpoint inhibitors and enhancement of immune responses will play an important part in the neoadjuvant and adjuvant therapy of breast cancer.
PARP inhibitors
As molecular profiling of breast cancer becomes common, it is increasingly clear some breast cancers are driven by deficiencies in DNA repair pathways.
The most obvious are those caused by BRCA germline deficiency. In these tumors, deficiencies in the homologous recombination DNA repair pathway led to the development of synthetic lethal strategies to treat these tumors.
The first of these drugs were PARP inhibitors, which block single-stranded DNA repair, and several of these drugs received approval in ovarian cancer.
Jennifer Keating Litton, MD, presented data about use of talazoparib (BMN-673, Pfizer) — one of the most potent PARP inhibitors — for the neoadjuvant treatment of breast cancer.
In this trial, patients with germline BRCA mutations received oral talazoparib for 6 months.
Researchers obtained a biopsy after 2 months of once-daily talazoparib. If residual disease was present, patients could receive conventional anthracycline- and taxane-based chemotherapy.
Litton reported data on 19 patients who received talazoparib therapy alone; 53% achieved pCR and 63% achieved RCB-0/RCB-1. Notably, even hormone receptor-positive patients with BRCA deficiency achieved pCR on this therapy.
Further, the therapy was well tolerated except for grade 3 and grade 4 hematologic toxicity, including red cell transfusion. All dose reductions were due to hematologic toxicity.
Most other nonhematologic toxicities — including alopecia, nausea and fatigue — were grade 1.
Thus, high pCR rates can be obtained using a single-agent targeted therapy for patients with BRCA germline mutations. Given the findings associating pCR with RFS, the possibility of therapy de-escalation needs to be tested. If patients achieve pCR on talazoparib alone, then perhaps additional chemotherapy is not necessary.
Taken together, these three reports suggest the potential role of testing new therapies in the neoadjuvant setting using pCR and RCB-1 as surrogate endpoints for efficacy.
Because continuing to perform randomized phase 3 trials may not be possible in certain situations, such as germline BRCA-mutant tumors, the strength of the data from neoadjuvant trials and careful attention to pathologic response may be sufficient to bring new drugs to breast cancer therapy.
References:
Cortazar P, et al. Lancet. 20154;doi:10.1016/S0140-6736(13)62422-8.
Symmans WF, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2015.63.1010.
The following were presented at ASCO Annual Meeting; June 1-5, 2018; Chicago:
Litton JK, et al. Abstract 508.
Loibl S, et al. Abstract 3062.
Pusztai L, et al. Abstract 586.
Symmans WF, et al. Abstract 520.
For more information:
Douglas Yee, MD, is professor of medicine and pharmacology in the division of hematology, oncology and transplantation at University of Minnesota, as well as director of Masonic Cancer Center. He also is a HemOnc Today Editorial Board Member. He can be reached at yeexx006@umn.edu.
Disclosure: Yee reports no relevant financial disclosures.