MARCH 4, 2019

De-escalation approach for maintaining maximal efficacy while limiting toxicity

The HER2/neu gene is amplified or overexpressed in 20%-25% of breast cancers. The introduction of anti-HER2 antibody-based therapies has yielded remarkable improvements in long-term outcomes in patients with HER2-positive cancers, both in metastatic and early-stage settings. Currently, the standard of care for patients with stage II/III HER2-positive breast cancer is a multi-agent chemotherapy regimen in conjunction with HER2-targeted agents. Systemic chemotherapy usually consists of a few cycles of an anthracycline-containing regimen such as doxorubicin-cyclophosphamide (AC/ Adriamycin-®Cytoxan®) followed by a taxane such as paclitaxel (T/Taxol^®), with the latter administered concurrently with trastuzumab with or without pertuzumab.¹

This pilot study, Dr. Waks said, is “evaluating whether — in a subset of patients selected based on very good prognosis — it is acceptable to decrease the chemotherapy from 2 or 3 agents to one agent, given the toxicity and side effects associated with chemotherapy.”

There is a strong association between pCR, long-term outcomes in patients with HER2-positive breast cancer and regimens that incorporate HER2-directed antibody doublets such as the HP regimen, have yielded further improvements.^2,3 Singlet and multi-agent chemotherapy have not been compared head-to-head in this setting. In fact, Dr. Waks said that the favorable prognosis of patients who achieve pCR, an outcome profile associated with single-agent chemotherapy and HER2-targeted therapy in early stage HER2-positive breast cancer, form a convincing rationale for assessing the feasibility of de-escalation in this setting.

 “[The central question of this trial] is based on data showing that the additional chemotherapies are associated with adverse effects both in the short-term such as nausea, fatigue, and hair loss, and the long-term, such as the potential for heart damage,” Waks explained. Chemotherapy-associated toxicities can be common, with temporary reduction in quality of life or rare and life-threatening such as secondary leukemia. She also explained that even though "these therapies are associated with side effects," they are still "useful and even necessary in patients who can benefit from the additional chemotherapies." When alluding to the critical process of patient selection for this individualized approach, Dr. Waks said: “Of course, we want to utilize de-escalation only in patients who do not stand to benefit from getting the additional chemotherapy."

Personalized medicine for early-stage HER2-positive breast cancer

Patient selection and treatment individualization that is based on reliable measurements presents a great opportunity for delivering personalized medicine. Waks said that an aspect of this study that excites her is de-escalation or tailoring therapy for individual patients to minimize therapy-related toxicity, without compromising effectiveness. Dr. Waks added: “[De-escalation] is particularly important for patients with HER2-positive breast cancer, because many patients with this subtype do exceptionally well with the targeted agents and we would like to maintain that without having to expose all patients to highly toxic therapies.” 
 

Study design and endpoints

The study, which is entitled DAPHNe (study of De-escalation to Adjuvant Antibodies Post-pCR to Neoadjuvant THP [Paclitaxel/Trastuzumab/Pertuzumab] — a Pilot Study in HER2-positive Breast Cancer), is a single arm, open-label pilot trial enrolling patients with treatment-naïve anatomic stage II-III HER2-positive breast cancer with primary tumor size ≥1.5 cm, with any hormone receptor status. All patients will receive neoadjuvant THP (neoadjuvant taxane along with HP, for 12 weeks, prior to surgery) and the pathologic response will be assessed at surgery.  Patients with pCR will complete one year of HP in the adjuvant setting. For patients who do not achieve pCR, additional adjuvant chemotherapy plus adjuvant HP for 1 year are recommended. Furthermore, endocrine therapy (for hormone receptor-positive tumors) is also advised.

The study is currently enrolling at DFCI and BIDMC, with imminent enrollment at MGH and seven other DFCI satellite/collaborative sites, including DFCI at Milford, South Shore Hospital, St Elizabeth's, and Londonderry, along with Eastern Maine Medical Center, Lifespan Oncology, and Stamford, CT. In the three months since the trial opened, 16 patients have either been recruited or are in screening. “I think the quick accrual is indicative of the excitement of the patients and doctors for being able to figure out, based on good preliminary data, who is likely to do well with the single-agent chemotherapy regimen,” Dr. Waks said. 

Tissue samples will also be collected at registration and surgery for the purposes of assessing the immune microenvironment and level of antibody-dependent cell-mediated cytotoxicity before and after THP treatment. In reference to the the immune profile analysis, Wax said: “We are collaborating with Elizabeth Mittendorf, MD, PhD (BWH) to analyze the tissue specimens to get a detailed understanding of how the antibody-based agents are impacting the immune system and the differences in immune profiles between responders and non-responders.”

While outcomes data and immune profiling of the tissue samples are planned, Dr. Waks reported that the primary endpoint of interest in this pilot trial is the feasibility of this new approach for patients and their clinicians.

A pilot model to evaluate feasibility

Dr. Waks noted that this pilot trial will serve as a precursor to a larger national trial currently in the planning stages, with enrollment of a few thousand patients. She said that with this pilot trial, the goal is “to learn about the experiences of patients and clinicians with this approach not only at DFCI, but throughout the wider community to help its utilization more broadly in the future.”

She noted that feasibility data — in the form of questionnaires from patients and based on their doctor’s notes — will not only be used to assess whether patients and doctors adhere to the de-escalation to single-agent chemotherapy as specified, but also to understand physician-patient communication during the review of surgical outcomes and the clinical decision-making process. “We have been able to build in many smaller endpoints of interest, in collaboration with radiologists, pathologists, and QoL experts," Dr. Waks said. "And as a junior investigator, this collaborative approach has been exciting for me.”

—Written by Krithika Subramanian

References

1. Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN Guidelines Insights: Breast Cancer, Version 1.2017. J Natl Compr Cancer Netw JNCCN. 2017;15(4):433-451.
2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.Lancet Lond Engl. 2014;384(9938):164-172. doi:10.1016/S0140-6736(13)62422-8
3. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi:10.1056/NEJMoa1703643