The State of HER2+ Breast Cancer in the Curative Setting

Rashmi K. Murthy, MD

HER2-positive breast cancer accounts for 20% of all invasive breast cancers, and was, for several decades, the subtype of breast cancer with the poorest prognosis. With the options available today, a HER2-positive diagnosis can still mean a long and healthy future for a patient, according to Rashmi K. Murthy, MD.

The monoclonal antibody trastuzumab (Herceptin) has had a journey in the breast cancer space that has spanned several decades. The FDA approved the agent in 1998 for the treatment of patients with HER2-positive metastatic breast cancer, and then gained an indication for HER2-positive early-stage breast cancer in the adjuvant setting in 2006. The pivotal trials that established the agent as a standard option for early-stage HER2-positive breast cancer were HERA, NSABP B-31/NCCTG, BCIRG-006, FinHer, and PACS 04.

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Murthy, an assistant professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, discussed selecting therapy for patients with HER2-positive breast cancer in the curative setting.

Murthy detailed the roles of dual HER2-targeting, extended adjuvant therapy, targeting high-risk patients, shorter duration of trastuzumab, and less toxic regimens for patients with HER2-positive breast cancer.

Despite these advances in HER2-positive breast cancer treatment, about one-third of patients still have a recurrence, said Murthy.

“There has been a need to look at strategies, [such as in] the neoadjuvant setting. There were trials done around the same time that showed that patients who received neoadjuvant trastuzumab had higher rates of pathological complete response (pCR),” said Murthy. “A neoadjuvant approach is nice in that it has several unique advantages from downstaging the patient for surgery, earlier treatment of micrometastatic disease, and also serving as a tool for estimation of prognosis as well as selection of patients who are higher risk for clinical trials.”

Escalating Therapy

It has been discovered that patients who have residual disease following neoadjuvant trastuzumab plus chemotherapy are at a much higher risk of recurrence, added Murthy. This has caused investigators to develop strategies to escalate therapy and to develop additional drugs. Neoadjuvant and Adjuvant Dual HER2-Targeting

Patients who receive 2 HER2-targeted drugs in the neoadjuvant setting have better pCR compared with receiving a single HER2-targeting agent, according to Murthy. The first partner for trastuzumab in this space was lapatinib (Tykerb).

The NeoALTTO and ALTTO studies, in the neoadjuvant and adjuvant settings, respectively, evaluated the use of lapatinib and trastuzumab; neither trial showed a connection between pCR improvement and overall survival.

NeoALTTO specifically explored the combination of paclitaxel plus trastuzumab and lapatinib. Neoadjuvant therapy with dual HER2 inhibition significantly improved the odds of pCR in patients with early disease, though patients who received a single HER2-targeted agent had similar rates of pCR.¹

ALTTO evaluated adjuvant lapatinib plus trastuzumab; results showed that it did not produce a statistically significant advantage over single-agent trastuzumab.² Due to the toxicity of lapatinib and lack of improvement in long-term outcomes in ALTTO, this regimen was not approved in the adjuvant setting.

The next candidate for combination with trastuzumab was pertuzumab (Perjeta).

In September 2013, the FDA approved pertuzumab in combination with trastuzumab and chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer. This approval was based on phase II findings from the NeoSphere trial, which showed an improvement in pCR. Data from the phase II TRYPHAENA study and the phase III CLEOPATRA study were also considered in this approval.

In the adjuvant setting, findings from the phase III APHINITY trial of patients with HER2-positive early breast cancer at high risk for recurrence showed that the combination demonstrated a 3-year invasive disease-free survival (iDFS) rate of 94.1% versus 93.2% for those who received trastuzumab plus chemotherapy and placebo at 3 years, representing a 18% reduction in the risk of developing invasive disease or death (HR, 0.82; 95% CI, 0.67-1.00; P = .047).³ At 4 years, the iDFS rates was 92.3% for the combination. These results supported the FDA's decision to approve the combination for this adjuvant indication in December 2017.

“In the subset analysis, it was noted that patients who were node-positive appeared to have a higher absolute benefit, also patients who were hormone receptor (HR)-negative,” noted Murthy. “It is important to note that almost 80% of patients in both arms actually received anthracycline-based chemotherapy. This may be why the control arm performed better than expected.”

In Europe, the NeoSphere and TRYPHAENA data led to the 2015 approval of the combination of pertuzumab plus trastuzumab with chemotherapy as a neoadjuvant therapy for adult patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer who are at high risk of recurrence.

In June 2018, the European Commission approved pertuzumab in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk of recurrence. The decision was based on the phase III APHINITY findings.

ASCO recently updated their guidelines for adjuvant therapy in patients with HER2-positive breast cancer. For patients who have high-risk, early-stage disease, clinicians may add 1 year of adjuvant pertuzumab to a trastuzumab-based combination with chemotherapy. Murthy added that the panel favors the use of pertuzumab in node-positive patients.

Extended Adjuvant Therapy

Neratinib (Nerlynx) was approved in July 2017 for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative trastuzumab. This was based on findings from the ExteNET and CONTROL trials, and came following a 12 to 4 recommendation from the FDA's Oncologic Drugs Advisory Committee.

Since the approval, updated long-term data from ExteNET were published in Lancet Oncology.⁴ In a 5-year follow-up, extended adjuvant therapy with neratinib demonstrated a significant reduction in the proportion of clinically relevant breast cancer relapses without increasing the risk of long-term toxicity.

The risk of invasive disease recurrence or death was 27% with neratinib compared with placebo as extended adjuvant therapy for patients with HER2-positive early stage breast cancer following 12 months of trastuzumab. The iDFS rate with neratinib was 90.2% (95% CI, 88.3-91.8) compared with 87.7% (95% CI, 85.7-89.4) with placebo. Additionally, patients on neratinib had 116 invasive DFS events compared with 163 for those in the placebo group at a median follow-up of 5.2 years (HR, 0.73; 95% CI, 0.57-0.92; P = .0083).

One of the biggest concerns with neratinib is the diarrhea associated with treatment.

“The rate of grade 3 diarrhea was 40%, which is definitely something to recognize and discuss with our patients,” said Murthy. “There is an ongoing phase II study looking at diarrhea prophylaxis for these patients that we have opened at The University of Texas MD Anderson Cancer Center looking at the concept of incorporating diarrhea prophylaxis upfront to mitigate the toxicity. This may enable more patients to potentially benefit from this drug.”

For patients with HR-positive or node-positive early-stage disease, ASCO guidelines advise that the clinicians who use extended adjuvant therapy with neratinib following trastuzumab incorporate a diarrhea prophylactic.

Selectively Targeting High-Risk Patients

Murthy noted that the big challenge in this space is identifying the high-risk population.

“We know that patients who have residual disease following neoadjuvant therapy are at a higher risk for recurrence long term,” explained Murthy. “These results are anticipated, and might have the potential to change the standard of care for these patients in the future.”

The KATHERINE trial has enrolled patients with residual disease following standard neoadjuvant chemotherapy and randomized them to the standard at that time, which was trastuzumab every 3 weeks for a total of 1 year compared with the experimental arm of ado-trastuzumab emtansine (T-DM1; Kadcyla) every 3 weeks for a total of 1 year (NCT01772472).

Murthy explained that the remaining gaps in the understanding of escalation are that there are no overall survival data, and for patients who achieve a pCR, the role and benefit of pertuzumab maintenance, and the role and toxicity profile of neratinib in patients who received prior pertuzumab, need to be addressed.

De-Escalating Therapy

“We need to estimate risk of recurrence for each individual patient while calculating the absolute benefit of additive therapy and assessing the short- and long-term toxicity, as well as cost,” Murthy said. “It is important to engage in a shared decision making process with the patient, given the unanswered questions.” Shorter Duration of Trastuzumab

Trastuzumab escalation was previously studied in the HERA trial, which showed no difference between 1 and 2 years of trastuzumab in the adjuvant setting. Several trials since have looked at shortening this duration, especially for lower-risk patients.

The PHARE trial randomized patients with HER2-positive early breast cancer to receive 6 months of trastuzumab versus 1 year. The primary endpoint was a noninferior DFS. This trial did not demonstrate noninferiority, reported Murthy, so the standard of care remained unchanged. Short-HER and the SOLD trials also evaluated shorter duration of trastuzumab.

The trial that garnered the most attention for de-escalated trastuzumab was the PERSEPHONE trial, which was presented at the 2018 ASCO Annual Meeting.⁵ The randomized phase III noninferiority trial compared 6 months of adjuvant trastuzumab versus the standard 1 year in 4000 patients with HER2-positive early breast cancer.

Findings showed that a shorter 6-month course of adjuvant trastuzumab was noninferior for DFS compared with the standard 12-month schedule for this population of patients. At a 5-year follow-up, the 4-year DFS rate was 89.8% with 12 months of trastuzumab compared with 89.4% with the 6-month course, which met the criteria for noninferiority (HR, 1.07; 90% CI, 0.93-1.24; P = .01). Additionally, there was an almost 50% reduction in the number of patients who had to stop treatment due to cardiac toxicity.

“Now, the question is, should we change our practice based on this trial?” said Murthy. “We have only heard about this is an oral presentation, so it is important that we get the details from the manuscript that should hopefully be published relatively soon. It is also important to look at these results in the context of all of the other trials that have been published or presented.”

Murthy added that it is important to look at the patient population in the PERSEPHONE trial because those patients received trastuzumab not only in a different fashion then it is given now, but also without the newer agents like pertuzumab. This means that patients on PERSEPHONE may have received pertuzumab sequentially rather than concurrently. This could potentially have some bias, suggested Murthy.

Continuing the effort toward de-escalation, the BOLD-1 study is evaluating adjuvant trastuzumab and pertuzumab plus docetaxel in HER2-positive breast cancer (NCT02625441). The 2 arms are pertuzumab plus trastuzumab and docetaxel for 3 cycles plus 3 cycles of chemotherapy, and trastuzumab plus docetaxel for 3 cycles plus 3 cycles of chemotherapy and trastuzumab for 1 year. The primary endpoint is iDFS, and it is currently enrolling.

Less Toxic Regimens

Patients with small HER2-positive breast cancers are at higher risk for recurrence. Historically, these patients have been recommended for adjuvant treatment with chemotherapy in combination with trastuzumab.

The first study to change the standard of care for the de-escalation of these patients was the APT trial, stated Murthy.

“The updated results of 7-year follow-up show that patients who are treated who are node-negative with a tumor size under 3 cm do really well with treatment of a taxane alone in combination with trastuzumab with continuation of maintenance trastuzumab for a whole year,” she explained.

In the study, adjuvant paclitaxel plus trastuzumab for 12 weeks followed by weekly trastuzumab for 39 weeks led to a DFS rate of 93.3% and incidences of distant and local or regional recurrences of 1.0% and 1.2%.⁶

Other de-escalation strategies have been initiated in the ATEMPT, KRISTINE, and RESPECT trials.

ATEMPT is evaluating T-DM1 versus paclitaxel plus trastuzumab in patients with stage I HER2-positive disease. Lastly, RESPECT is evaluating trastuzumab alone versus trastuzumab plus chemotherapy in elderly patients with HER2-positive breast cancer (NCT01104935). Trastuzumab monotherapy can be an option for select patients, such as those who are frail or have multiple comorbidities, Murthy said.

In summation, 1 year of adjuvant trastuzumab remains the standard of care, with a possibility of a 6-month regimen for some patients. This provides reassurance that if patients cannot receive 1 year of therapy due to toxicities, they may not be at a significant risk for recurrence, Murthy said. She added that less toxic regimens are standard practice for node-negative patients, and further study is needed to better identify patients who may benefit from chemotherapy-free regimens and evaluate biomarkers like hormone receptor status.

“A review of the risk and benefits, and shared decision-making with patients, is key,” concluded Murthy. “Ultimately, we need further investigation and identification of biomarkers to select patients more accurately and to identify those who will really benefit or need additional interventions.”

References

1. de Azambuja E, Holmes AP, Piccart-Gebhart, M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014;15(10):1137-1146. doi: 10.1016/S1470-2045(14)70320-1.
2. Moreno-Aspitia A, Holmes EM, Jackisch C, et al. Updated results from the phase III ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L) or their combination (L+T) in the adjuvant treatment of HER2-positive early breast cancer [ASCO abstract 502]. J Clin Oncol. 2017;35(suppl). abstracts.asco.org/199/AbstView_199_191859.html.
3. von Minckwitz G, Procter MJ, De Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017; 377:122-131. doi: 10.1056/NEJMoa1703643.
4. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688-700. doi: 10.1016/S1470-2045(17)30717-9.
5. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2017;36 (suppl; abstr 506).
6. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) follow-up of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017;35(suppl 15):511. doi: 10.1200/JCO.2017.35.15_suppl.511.