CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: August 10, 2020
Expiration: August 09, 2021
During the past 3 years, 3 new HER2-targeted agents have been approved for the adjuvant treatment of HER2-positive breast cancer.
Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) of HER2, was approved as extended adjuvant treatment for patients with HER2-positive breast cancer following adjuvant trastuzumab-based therapy.24
The combination of trastuzumab and pertuzumab was originally approved as a neoadjuvant treatment for HER2-positive EBC, and in 2017, the indication was expanded to include adjuvant treatment for patients at a high risk of recurrence, including those that were hormone receptor negative or node positive.25,26
Most recently, in 2019, T-DM1 was approved as adjuvant therapy for patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.15
Let’s evaluate the data that led to these approvals.
The combination of pertuzumab, trastuzumab, and chemotherapy was evaluated as adjuvant therapy for patients with HER2-positive EBC in the large phase III APHINITY trial (N = 4805).26
Patients enrolled in this trial were either node positive (any tumor size) or node negative (tumors > 1 cm) with high-risk features (grade 3, hormone receptor negative, or < 35 years old) and were within 8 weeks of definitive breast surgery by their first dose of chemotherapy. Patients were randomized to receive chemotherapy with trastuzumab and pertuzumab or chemotherapy with trastuzumab and placebo. HER2-targeted therapy began at the first cycle of taxane therapy and continued for a full year. Patients with hormone receptor–positive disease also received endocrine therapy starting at the end of chemotherapy. The primary endpoint was invasive DFS per the STEEP definition.27
Updated results with 6 years of follow-up were presented by Piccart and colleagues28 at the 2019 SABCS. By that point, the addition of pertuzumab to a standard regimen of chemotherapy plus trastuzumab resulted in a 2.8% absolute improvement in invasive DFS (HR: 0.76). In other words, adding pertuzumab to standard adjuvant therapy resulted in a 24% reduction in the risk of invasive recurrence.
In regards to OS, at a relatively early follow-up of 6 years, there was no significant OS difference, with an HR of 0.85 (P = .170). Based on the trial design, the P value would have to be lower than .0012 to be statistically significant. These data highlight that even at 6 years, 94.8% to 93.9% of patients remain alive with or without pertuzumab, respectively, with today’s standard treatment regimens.
Looking at subgroup analyses in APHINITY is particularly interesting. At 6 years, there was a 4.5% absolute improvement in invasive DFS in patients who were node positive, that is, higher-risk patients. By contrast, for patients with node-negative disease, both groups did extremely well and there was no additional benefit with the addition of pertuzumab in this lower-risk group of patients (HR: 1.02).
Looking at the subgroups by hormone receptor status, at 3 years there was no difference in invasive DFS rates with or without pertuzumab in the hormone receptor–positive cohort. However, now, with 6 years of follow-up, there is a difference, with an HR of 0.73 or 27% relative improvement in invasive DFS. This is important because patients with hormone receptor–positive tend to relapse later and with this longer follow-up, the absolute improvement in invasive DFS at 6 years was 3% in the hormone receptor–positive group.
In patients with hormone receptor–negative disease, the HR was 0.83 with an absolute improvement in invasive DFS of 2.5% at 6 years.
In APHINITY, it is very reassuring to see that dual anti-HER2 antibody therapy caused very little incremental toxicity. The primary cardiac endpoints, which included heart failure and careful evaluation of the left ventricular ejection fraction, showed an increase only from 0.3% to 0.8% with the addition of pertuzumab. Even a mildly symptomatic left ventricular ejection fraction (LVEF) drop was seen in only 2.8% of patients with or without pertuzumab.
The rate of grade ≥ 3 AEs was similar with or without pertuzumab, with the exception of diarrhea. This is the major nonhematologic toxicity associated with the addition of pertuzumab (particularly with a nonanthracycline chemotherapy regimen).
In my own practice, pertuzumab-associated diarrhea occurs most often with the commonly used regimen of carboplatin, docetaxel, pertuzumab, and trastuzumab. However, early detection and management of pertuzumab-associated diarrhea is key to help patients cope with this toxicity and stay on therapy.
Neratinib is a novel, small-molecule, oral, pan-HER TKI. Therefore, it has a different mechanism of action than pertuzumab and trastuzumab.29 First, it is an irreversible inhibitor, so its activity is different than the antibodies—trastuzumab and pertuzumab—which are reversible. The anti-HER2 antibodies trastuzumab and pertuzumab, the ADC T-DM1, and the TKIs lapatinib and neratinib bind to the HER2 receptor at different epitopes and inhibit signaling. Trastuzumab binds to extracellular subdomain IV of HER2 and blocks HER2 cleavage, induces antibody-dependent cell-mediated cytotoxicity, and inhibits ligand-independent, HER2-mediated signaling. Pertuzumab binds to extracellular subdomain II of HER2 to prevent the dimerization of HER2 and HER3 (and therefore inhibiting PI3K signaling) as well as inducing antibody-dependent cell-mediated cytotoxicity. The HER2-targeted TKIs, lapatinib and neratinib, bind intracellularly at the tyrosine kinase active site. Lapatinib is a reversible TKI that targets HER2 and EGFR, whereas neratinib irreversibly prevents phosphorylation and downstream signaling of several tyrosine kinases in the EGFR family, including EGFR, HER2, and HER4.
ExteNET was a large and important phase III trial comparing neratinib vs placebo after completing neoadjuvant/adjuvant chemotherapy and 1 year of trastuzumab in patients with HER2-positive EBC (N = 2840).30 Participants had stage I-IIIc breast cancer, had completed 1 year of adjuvant trastuzumab within the previous 2 years, had node-positive or node-negative disease, and had residual disease after neoadjuvant therapy was allowed. The primary endpoint was invasive DFS at 2 years. Of note, after the trial had started, the study was amended to restrict enrollment to patients with node-positive disease and who had completed trastuzumab within 1 year before randomization.
At 2 years, neratinib 240 mg/day was superior to placebo, with an invasive DFS rate of 93.9% vs 91.6% with the placebo arm (HR: 0.67; P = .0091). The benefit from neratinib persisted at 5 years, with an HR of 0.73, which is highly statistically significant (P = .0083).31 The invasive DFS rate was 90.2% with neratinib vs 87.7% with placebo, which was an absolute benefit of 2.5% for the entire group of randomized patients.
In a prespecified subgroup analysis of ExteNET, results showed that the hormone receptor–positive subgroup derived the most benefit from the addition of neratinib. In fact, as seen here, in this group there was a 4.4% absolute improvement in invasive DFS at 5 years when using neratinib as extended adjuvant HER2-targeted therapy compared with placebo, with an HR of 0.60. The 5-year invasive DFS rate was 91.2% with neratinib vs 86.8% with placebo in patients with hormone receptor–positive disease. By contrast, patients with hormone receptor–negative disease essentially derived no benefit from neratinib (HR: 0.95), which is a very interesting observation.
This was a heterogeneous group of patients due to a few protocol amendments to the study design, and some had a significant delay in starting treatment with neratinib after completing previous HER2-targeted therapy. As a result, an exploratory analysis assessed the efficacy of neratinib in patients who were hormone receptor positive and started the study treatment (neratinib or placebo) less than 1 year from the last dose of trastuzumab. This analysis showed a 5-year invasive DFS rate of 90.8% with neratinib vs 85.7% with placebo (HR: 0.58; P = .002) in this group of patients. In a real-world setting, most patients would typically start neratinib soon after completing trastuzumab, and these data showed a 5.1% improvement in this setting.
In the subgroup of patients with hormone receptor–positive disease who did not achieve a pCR after neoadjuvant therapy and who began neratinib less than 1 year from their last dose of trastuzumab, the invasive DFS benefit was even greater: 85.0% were disease free vs 77.6% at 5 years, representing a 7.4% improvement (HR: 0.60).
The AEs in ExteNET are shown here. The most common toxicity of neratinib is diarrhea, with 55% of patients experiencing grade 1/2 events and 40% experiencing grade 3 events in this trial with neratinib vs 34% and 2% of patients, respectively, with placebo. Other common AEs include other symptoms of gastrointestinal upset such as nausea, vomiting, and abdominal pain, as well as fatigue, headache, and rash.
We will discuss the management of these AEs later, but these side effects are generally manageable with proper prophylaxis and early mitigation if diarrhea occurs.
As mentioned earlier, T-DM1 is a HER2-targeted ADC linking trastuzumab with the cytotoxic payload emtansine (DM1), which is a potent tubulin destabilizer.16
The phase III KATHERINE trial compared standard adjuvant treatment with trastuzumab to T-DM1 for patients with HER2-positive EBC who had residual invasive disease following neoadjuvant chemotherapy.32,33 This large, open-label study enrolled patients who had received neoadjuvant chemotherapy along with standard HER2-targeted therapy, and had residual invasive disease in the breast or axillary lymph nodes at surgery (N = 1486). Within 12 weeks of surgery, patients were randomized to either T-DM1 3.6 mg/kg or trastuzumab 6 mg/kg, both given every 3 weeks for 14 cycles. The primary endpoint was invasive DFS and secondary endpoints included distant recurrence-free survival, OS, and safety. Of note, patients who discontinued T-DM1 due to toxicity could crossover to trastuzumab to complete 14 cycles.
Patients enrolled in KATHERINE received at least chemotherapy and trastuzumab in the preoperative setting, but additional HER2-targeted agents were also allowed. Eighty percent of patients received trastuzumab alone; the other 20% received trastuzumab with other HER2-targeted agents, most commonly pertuzumab.
It’s worth noting that the patients in KATHERINE represent, in general, a high-risk population. Approximately 25% of patients in both arms of KATHERINE were considered inoperable, based on a definition of T4 clinical lesions or clinical N2-3 disease. Also, approximately 72% had hormone receptor–positive disease, and adjuvant endocrine therapy was allowed per the trial protocol and recommended for these patients.
At 3 years, the invasive DFS rate was 88.3% with T-DM1 vs 77.0% with trastuzumab, representing an absolute benefit of 11.3%. The HR was 0.50, representing a 50% improvement in invasive DFS (P < .001).
This table shows that the first invasive DFS event was more likely to be a distant or locoregional recurrence with trastuzumab than T-DM1: 15.9% vs 10.5% and 4.6% vs 1.1%, respectively. Likewise, rates of contralateral breast cancer were notably lower with T-DM1: 0.4% vs 1.3% with trastuzumab.
The benefit from T-DM1 was seen across all subgroups in KATHERINE. Of note, there was a similar benefit with T-DM1 for hormone receptor–positive vs hormone receptor–negative patients (HR: 0.50 vs 0.48, respectively), and with vs without positive nodes (HR: 0.52 vs 0.44, respectively). Of importance, the benefit seen with T-DM1 was also similar for patients receiving trastuzumab as the only HER2-targeted agent for neoadjuvant therapy or for patients who received dual HER2-targeted therapy with trastuzumab and other HER2-targeted agents (HR: 0.49 vs 0.54, respectively). This is notable because patients should typically receive trastuzumab plus pertuzumab as the standard of care with chemotherapy in the neoadjuvant setting.
Secondary endpoints in KATHERINE included distant recurrence, where there was a 6.7% absolute benefit in reduction of distant recurrence for T-DM1 compared with trastuzumab (89.7% vs 83.0%; HR: 0.60).
The OS data from KATHERINE are not yet mature, and the number of events remains small. There is no statistically significant OS difference to date (HR: 0.70), but patients will continue to be followed over the long term until the number of events are reached for a final OS analysis.
The AEs in KATHERINE are shown here. There was more toxicity from T-DM1 than from trastuzumab, although it was mostly grade 1/2, with the most common AEs being fatigue, nausea, decreased platelet count, increased liver enzymes, particularly aspartate aminotransferase, and headache. There was also more neuropathy, constipation, and epistaxis for patients who received T-DM1 compared with trastuzumab. In addition, the discontinuation rate due to AEs was higher with T-DM1 at 18% vs only 2.1% with trastuzumab.
KAITLIN was an international, randomized, open-label phase III trial comparing adjuvant HER2-targeted regimens in patients with high-risk EBC (N = 1846).34 The trial was designed to determine whether T-DM1 can be used as a substitute for trastuzumab plus taxane in this setting. High-risk was defined as either node positive or node negative and hormone receptor negative with a tumor at least 2 cm in size (stage IIa). All patients received 3 or 4 cycles of anthracyclines followed by either T-DM1 plus pertuzumab for up to 18 cycles (1 year) or trastuzumab plus pertuzumab for 18 cycles (1 year) plus taxanes for 3 or 4 cycles or 12 weeks.
The coprimary endpoints were invasive DFS in the node-positive and intention-to-treat populations. Secondary endpoints included OS, secondary malignancies, DFS, recurrence-free survival, safety, and patient-reported outcomes.
At ASCO 2020, Harbeck and colleagues34 presented the primary analysis of KAITLIN, which was negative. Unfortunately, the use of T-DM1 plus pertuzumab after anthracyclines did not significantly reduce the risk of invasive DFS vs the standard of anthracycline-based therapy followed by a taxane, pertuzumab, and trastuzumab. Numerically, the invasive DFS rate slightly favored the control arm, at 94.2% vs 93.1% with T-DM1 plus pertuzumab, but this was not statistically significant, with HRs approaching 1.00 in both the node-positive and intent-to-treat populations. However, there was a lower risk of deterioration in quality of life with T-DM1 and pertuzumab; this was likely driven by the toxicity of taxane chemotherapy.
Although I would not consider T-DM1 therapy in this context, I would consider using T-DM1 for some select patients in the neoadjuvant setting. For example, I have a patient with low clinical stage HER2-positive EBC who absolutely refused to be treated with taxane (paclitaxel) plus trastuzumab and pertuzumab as neoadjuvant treatment. She was willing to be treated with T-DM1 because she wouldn’t lose her hair or experience other usual toxicities of chemotherapy, so we began therapy with T-DM1 instead. I would also consider it for elderly patients or those with preexisting neuropathy who are at higher risk for AEs with standard therapy.
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