Findings Clarify Picture for HER2-Positive Breast Cancer

Adam M. Brufsky, MD, PhD

Major changes for patients with HER2- positive breast cancer are not on the horizon, but there are a number of new study findings that have amplified knowledge about how best to care for this population.

Dual-Targeted Neoadjuvant Therapy: Pertuzumab Plus Trastuzumab With Chemotherapy

That was the consensus of a panel of breast cancer oncologists who participated in an OncLive Peer Exchange^® discussion of research presented at the San Antonio Breast Cancer Symposium (SABCS), held December 5 to 9, 2017, in Texas. These experts reviewed key abstracts on HER2+ breast cancer and provided perspectives on how studies of systemic therapy in this setting may influence clinical practice. Despite many advancements in the past 2 decades, the HER2-positive subtype presents challenges. Metastatic HER2- positive breast cancer remains incurable and represents an unmet medical need.¹Adam M. Brufsky, MD, PhD, session moderator, began the discussion by observing that interesting abstracts at SABCS covered both early and late disease. Neoadjuvant therapy in HER2-positive breast cancer has been a tremendous success, he said, noting research on determining the optimal chemotherapy backbone for using neoadjuvant trastuzumab (Herceptin) plus pertuzumab (Perjeta).

Trastuzumab (H) and pertuzumab (P) is approved as a standard neoadjuvant therapy for stage II to III HER2-positive breast cancer. Francisco J. Esteva, MD, PhD, discussed a singlecenter, retrospective study that evaluated chemotherapy used with neoadjuvant pertuzumab- containing regimens in this setting.² The study evaluated rates of pathologic complete response (pCR) in 226 patients with stage II to III HER2-positive breast cancer who received neoadjuvant trastuzumab plus pertuzumab (PH) in combination with backbone chemotherapies that included a taxane (T), an anthracycline and cyclophosphamide (A), or carboplatin (C). Combination therapies included paclitaxel, trastuzumab, and pertuzumab (THP) and docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP).

The pCR rates were 65% for THP (n = 48), 50% for TCHP (n = 90, including 5 who received TCHP-A), and 58% for THP-A (n = 88); these differences were not statistically significant. Esteva said it was reassuring that THP did not result in a lower pCR rate than TCHP or THP followed by adjuvant chemotherapy.

“How those patients were selected, though, and why is the question,” he commented. “It’s something to keep in mind—that some patients may do very well with THP, like they did in the NeoSphere trial, which was the FDA registration trial for pertuzumab.” In the phase II NeoSphere trial (NCT00545688), patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned to neoadjuvant H plus docetaxel (HT), docetaxel plus HP (THP), HP, or P plus docetaxel (PT).³ After surgery, patients received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapy. The study showed that progression- free survival (PFS) rates were highest for the groups receiving THP or HT.

Patients who experienced pCR after any neoadjuvant combination had longer PFS. If patients experience pCR on neoadjuvant therapy, Esteva said, they might not need FEC after surgery. However, because patients received THP, then surgery, and then FEC, the pCR rates without adjuvant chemotherapy are unknown.

Hope S. Rugo, MD, pointed out that in the APHINITY trial (NCT01358877) of pertuzumab added to adjuvant trastuzumab and chemotherapy,⁴ as well as in the NeoSphere trial, the rates of grade 3 diarrhea are high. Using weekly paclitaxel plus trastuzumab plus pertuzumab is much better tolerated, Rugo said. “The idea is, less is more,” she continued. After induction therapy and response evaluation, additional therapy could be selected for patients based on tumor characteristics and tolerance. Rugo said that she thinks that weekly paclitaxel with THP is a better choice than docetaxel for older patients, and Komal Jhaveri, MD, noted that neutropenia is a serious adverse effect with docetaxel. Brufsky and Lee Schwartzberg, MD, said that they administer growth factors to all their patients with breast cancer because of the risk of neutropenia.

Schwartzberg expressed comfort with using docetaxel in older patients, although weekly paclitaxel is an option for patients with low-risk disease. Esteva administers weekly THP for 12 weeks, followed by dose-dense adjuvant chemotherapy before surgery, noting that some patients might not need it, but it’s difficult to tell. Because of toxicity, he said, he doesn’t like administering docetaxel or carboplatin.

Rugo says that her practice administers paclitaxel first, then 4 doses of pertuzumab, followed by dose-dense adjuvant chemotherapy. “But now, if somebody has a pCR essentially by exam and imaging after their THP, it’s hard to give them adjuvant chemotherapy, especially for older patients,” she added.

Trastuzumab Plus TKIs and Chemotherapy

Schwartzberg still administers anthracyclines; so does Jhaveri. “It’s hard to say a nonanthracycline regimen is better, but they’re probably comparable,” Schwartzberg said. “The thing that I worry about, actually, is tumor heterogeneity and whether we should be giving adjuvant chemotherapy for those patient populations that have variable HER2 in their tumor, particularly larger tumors where there’s more likelihood [of heterogeneity].”The use of tyrosine kinase inhibitors (TKIs) such as neratinib (Nerlynx) and lapatinib (Tyverb) as neoadjuvant therapy in HER2- positive breast cancer was presented at SABCS.⁵ The panelists said they would not use TKIs off-label for neoadjuvant therapy at this time. Not a lot of data support this use, Brufsky said, and despite a slightly increased pCR rate, no survival benefit has been demonstrated.

However, Rugo said that in estrogen receptor (ER)—positive disease, if patients have received a year of pertuzumab and have gastrointestinal distress, neratinib might be an option. The randomized phase III ExteNET trial (NCT00878709) compared 1 year of neratinib, a pan-HER TKI, with placebo after neoadjuvant and adjuvant chemotherapy plus trastuzumab in 2840 women with nonmetastatic, operable HER2-positive breast cancer.⁶ At 5 years of follow-up, extended adjuvant therapy with neratinib significantly reduced clinically relevant relapses versus placebo.

Adjuvant HER2-Targeted Therapy

Treatment of neratinib-associated diarrhea was the subject of another abstract presented at SABCS, which showed that loperamide reduced the incidence, severity, and duration of neratinib-associated diarrhea and that adding budesonide or colestipol (Colestid, Cholestabyl) further reduced duration and number of episodes (CONTROL study, NCT02400476).⁷Duration of Adjuvant Trastuzumab

The issue of de-escalation of treatment in HER2+ early breast cancer was examined in the Synergism Or Long Duration (SOLD) study (NCT00593697), a follow-up of the FinHer trial in which 3 weekly doses of docetaxel were administered in place of weekly paclitaxel, FEC was administered in place of AC, and trastuzumab was administered continuously with docetaxel for 9 weeks.^8,9 Determining whether 9 weeks of trastuzumab could be used rather than the standard 12 months was an important question, Rugo said, because the optimal duration of trastuzumab is not known and because of its cost. “Most people in the world can’t afford trastuzumab,” she said. “Now, with the advent of biosimilars, we hope that that will change, but we have yet to see what the cost differentials will be and what the impact will be.”

Rugo characterized 9 weeks as a “funny choice,” however—9 weeks of trastuzumab did not meet noninferiority to 12 months. In a subgroup analysis, patients who received 100 mg/m² of docetaxel, which she called a toxic dose, did as well with 9 weeks of trastuzumab, as did patients with lowerrisk disease. “I think we’re a little encouraged by the fact that shorter may be enough for some patients, and that some trastuzumab is better than none. But our gold standard is still 12 months. Now, how long should you get pertuzumab for? We don’t know,” she said.

Trastuzumab Plus Adjuvant Chemotherapy in Low HER2 Expression

Novel Approaches

Schwartzberg said that risk must be weighed against benefit, and for trastuzumab, toxicity outweighs the benefit of extended therapy. There is room for de-escalation, Jhaveri said, and that should be the focus of biomarker studies. Rugo said that it will be important to determine which patients will require more therapy based on tumor response. Schwartzberg responded, “pCR is such a good biomarker in HER2-positive [breast cancer], so why not use it to either de-escalate or escalate?”In the NSABP B-31 trial, Brufsky said, an unplanned subset analysis showed that patients with tumors that had low expression levels of HER2 still benefited from trastuzumab. At SABCS, investigators presented results of a phase III study, NSABP B-47, that looked prospectively at adjuvant trastuzumab for 3270 women with low-level HER2-expressing invasive breast cancer.¹⁰ Adding trastuzumab did not provide a benefit in patients with HER2- nonoverexpressing breast cancer. Schwartzberg commented that the trial results confirm that HER2 is a target for trastuzumab therapy. The 5-year disease-free survival rate was 90% and could be attributed in part to the high percentage of women in the trial with ER-positive disease who, Brufsky said, would do well no matter what therapy they received. The panelists all follow American Society of Clinical Oncology/College of American Pathologists guidelines¹¹ for determining HER2 expression.Pembrolizumab Plus Trastuzumab

Immunotherapies are being tested in breast cancer. Rugo pointed out that although breast cancer is not very immunogenic, it increasingly affects the host immune system as it progresses. SABCS also saw results of the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) phase Ib/II study (NCT02129556), which evaluated the safety and efficacy of pembrolizumab, an anti—PD-1 immune checkpoint inhibitor, in combination with trastuzumab in patients with trastuzumab-resistant, metastatic, HER2- positive breast cancer.¹² The disease control rate was 24% in PD-L1—positive disease. In this early trial in 58 patients, tumor-infiltrating lymphocytes were low, which is expected as cancer progresses, and were identified as a potential predictive marker of response. Rugo suggested that adding agents to immunotherapy that would boost host response could help, but this would need to be done early in the disease course.

Trastuzumab Deruxtecan

Schwartzberg pointed out that PD-L1 is expressed at lower levels than in other tumor types, calling the data for pembrolizumab in the neoadjuvant I-SPY 2 trial¹³ “very impressive.” This study identified gene expression signatures associated with response to pembrolizumab and higher pCR rates.Also at SABCS, results of a phase I study of an antibody—drug conjugate targeting HER2 expression were reported.¹⁴ The agent, trastuzumab deruxtecan (DS-8201), a humanized HER2 antibody attached to a novel topoisomerase I inhibitor, was administered to several cohorts of patients, including those with HER2-positive breast cancer who had previously received ado-trastuzumab emtansine (T-DM1; Kadcyla) and patients with breast cancer expressing low levels of HER2. The overall response rate in the HER2-positive patients was 61%; it was 30% in the HER2—low expression group, which included patients with ER-positive, HER2-negative, and triple-negative disease. Jhaveri commented that the duration of response was impressive. Trastuzumab deruxtecan has been designated a breakthrough therapy by the FDA.

References

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