Questions Remain About Optimal Treatment for HER2-Positive Breast Cancer

Questions Remain About Optimal Treatment for HER2-Positive Breast Cancer

“Optimizing Treatment of HER2-Positive Breast Cancer,” an Education Session held Tuesday, June 2, reviewed data on neoadjuvant and adjuvant therapy, targeted therapies for metastatic disease, and management of brain metastases.

Session chair Stephen Chia, MD, of the British Columbia Cancer Agency, University of British Columbia, Canada, presented recent trial results about neoadjuvant and adjuvant therapy. Standard therapy for stage I-III HER2-positive disease is adjuvant chemotherapy (taxane with or without anthracycline) plus trastuzumab for 12 months. The prognosis for treated cohorts with node-negative disease has been excellent, he said, and “warrants a shorter course of chemotherapy (four cycles) plus trastuzumab for 12 months. The preferable course is treatment free of anthracycline.”

Data have also indicated that there is a possible advantage to using taxane concurrently with trastuzumab, but “we lack validated predictive biomarkers … to select the type of chemotherapy regimen or duration of trastuzumab. Currently, only nodal status is a prognostic factor for residual risk of relapse,” Dr. Chia said.

Several clinical controversies remain, including the role of extended anti-HER2 inhibition following 1 year of adjuvant trastuzumab. The ExteNET trial, presented during the 2015 ASCO Annual Meeting (Abstract 508), included patients who had prior adjuvant trastuzumab and chemotherapy; lymph node–negative, lymph node–positive, or residual invasive disease after neoadjuvant therapy; and ER/PR­­–positive or ER/PR–negative disease. Patients were randomly selected to receive 240 mg per day of neratinib or placebo for 1 year. The primary endpoint was invasive disease-free survival (iDFS).

Nearly 47% of patients had one to three positive nodes, and 57.5% had HR–positive disease. The 2-year follow-up showed a 93.9% iDFS rate among treated patients compared with a 91.6% rate with placebo therapy (hazard ratio [HR] 0.67, CI 95% [0.50, 0.91]; p = 0.009). Diarrhea was a noteworthy adverse event among treated patients (95.4%). Dr. Chia noted that the benefit of neratinib appeared greater in ER-positive disease and centrally confirmed HER2-amplified breast cancers.

“Neratinib offers a potential additional risk reduction strategy following standard trastuzumab therapy,” he said.

A second controversy concerns the role of neoadjuvant pertuzumab in primary operable and locally advanced HER2-positive breast cancer. Recent research data indicate that pertuzumab neoadjuvant regimens have relatively high pathologic complete response (pCR) rates and that pertuzumab appears to add limited additional toxicity to docetaxel-based regimens. The benefit appears greatest in stage IIb-III disease and in the ER-negative cohort.

The third controversy is whether pCR correlates with long-term clinical outcomes or DFS. “My belief is that pCR does correlate with longer-term clinical outcomes in appropriately designed neoadjuvant trials and that the neoadjuvant model is still valid for drug development … and as a standard of care with appropriate multidisciplinary attention and approach,” Dr. Chia said.

Targeted Therapies

Sunil Verma, MD, of the University of Toronto and Sunnybrook Odette Cancer Centre, Canada, reviewed data related to first- and second-line therapies. The MARIANNE trial, presented during the 2015 ASCO Annual Meeting (Abstract 507), was a phase III study of ado-trastuzumab emtansine (T-DM1) with or without pertuzumab compared with taxane plus trastuzumab and no pertuzumab. In the trial, 364 patients were randomly assigned to taxane plus trastuzumab, 364 to T-DM1 plus pertuzumab, and 364 to T-DM1 plus placebo.

Dr. Sunil Verma

“The results showed that there is no additional benefit of adding in pertuzumab to T-DM1,” Dr. Verma said. “And there was no difference in outcomes in patients receiving T-DM1.”

Several unanswered questions remain, including whether pertuzumab and trastuzumab can be combined with other taxanes, chemotherapies, or biologics, given that T-DM1 did not result in significant improvement.

“How long should we be treating these patients when they respond? We still don’t have an answer. These are expensive medications,” said Dr. Verma. “We need to have better, innovative trials to see if we can provide therapy in a more standardized, individualized fashion for some of these patients who have a great response.”

In his review of trial designs related to second-line therapy and beyond, Dr. Verma said that “if there is going to be any benefit of continuing these agents beyond progression, as we have seen with trastuzumab, we don’t know. The standard practice should be that they not be used beyond progression because we have absolutely no evidence. But, of course, this is something we should consider for study designs.”

Also not yet known is why patients become resistant to pertuzumab, T-DM1, and/or lapatinib. “If we don’t know, how are we to develop the next generation of targeted agents?” said Dr. Verma. “There is an urgent need to try to understand the biological principles on how patients progress, why they progress, and why cancer progresses on these agents.”

The role of PI3K inhibitors is also unclear, along with which population of patients will derive benefit, which patients are most suited for dual targeted treatment alone, and what the next generation of anti-HER2 drugs will be. Many trials are ongoing with agents that could comprise the next generation, including EGFR-targeted small molecules (neratinib), androgen receptor inhibitors (enzalutamide), antibodies (panitumumab and margetuximab), antibody-drug conjugates (MM-302), HER2 vaccines (nelipepimut-S), biosimilars, Pi3K agents, CDK4/6 inhibitors, and immunotherapy.

Dr. Verma commented on several recommendations in the ASCO Clinical Practice Guidelines for first-line therapy. One states that clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment unless the patient has a contraindication to taxanes.

“It is important to acknowledge that most of the data [from the CLEOPATRA trial] was derived from a de novo patient population, and only 10% of the patients had adjuvant pertuzumab,” Dr. Verma said.

Another recommendation states that T-DM1 should be recommended as second-line treatment if a patient’s HER2-positive advanced disease has progressed during or after first-line HER2-targeted therapy. Dr. Verma said that very few patients on the CLEOPATRA trial actually received T-DM1 upon progression, and very few patients in the EMILIA trial had prior pertuzumab.

“We need long-term registry data to see the long-term efficacy of T-DM1 after patients have received trastuzumab in the first-line setting,” he said.

Another contentious topic is whether to offer pertuzumab if a patient’s HER2-positive disease has progressed during or after second-line or greater HER2-targeted therapy without pertuzumab. “We have absolutely no evidence so far that we can offer pertuzumab in the second- or third-line setting,” Dr. Verma said.

Management of Brain Metastases

Michelle E. Melisko, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, discussed management of brain metastases. Overexpression or amplification of HER2 is associated with a high risk of brain metastasis, with several trials showing the incidence rate ranging from 31%­-43%. Although many patients with HER2-positive disease develop brain metastases, “their survival is actually favorable compared to other patients with other tumor types, such as triple-negative breast cancer,” Dr. Melisko said. Survival for some patients with HER2-positive disease can extend more than 2 years.

Dr. Michelle E. Melisko

Radiation is still the foundation of treatment. The National Comprehensive Cancer Network guidelines state that surgery or stereotactic radiosurgery (SRS) should be offered for a patient with one to three metastases and that whole-brain radiation therapy (WBRT) should be considered as an addition. Dr. Melisko cited a controversy about the utility of adding WBRT to localized therapy, such as SRS and surgery. If a patient has advanced therapy, physicians should consider whether WBRT is the appropriate option. For patients with more than three metastases, WBRT or SRS in select cases can be considered.

The data about adding WBRT varies among trials. The JROSG 99-1 trial, which included all types of tumors, demonstrated that the addition of WBRT improved local control and that there was a longer time to neurocognitive deterioration for patients treated with WBRT. Dr. Melisko said the trial raises the question that people who have longer expected survival might benefit from better local control.

In contrast, the EORTC 22952-26001 trial evaluated patients with one to three metastases, including a mixture of tumor types. The addition of WBRT resulted in improved local control but no benefit in survival. The Columbia University Medical Center experience, published this year in Journal of Neuro-Oncology, included 528 patients with brain metastases, with 102 having breast cancer. That study found that the addition of WBRT extended survival compared with SRS.

Neratinib is being investigated in several trials for patients with HER2-positive disease and brain metastases. One trial with 40 patients—78% having been previously treated with WBRT—showed median progression-free survival of 1.9 months with the agent. The most common grade 3 adverse event was diarrhea, which decreased with loperamide prophylaxis.

In the question and answer session, one attendee asked how often screening for brain metastases should occur. Dr. Melisko said that the only prospective trial that looked at screening did not find an improved outcome with screening.

“That being said, I have a very low threshold to order a baseline MRI for patients with HER2-positive metastatic breast cancer,” Dr. Melisko said. “But I don’t necessarily do that for ER-positive HER2-negative [disease], but that’s not an evidence-based practice at all.”

She said she does not put patients on a screening schedule, but that when they are diagnosed with brain metastases and are treated with SRS, they end up getting follow-up screening frequently—sometimes as often as every 3 months.

Watch the session: Visit the ASCO Virtual Meeting website.