The NeoSphere and TRYPHAENA studies established the FDA accelerated approval of pertuzumab in combination with trastuzumab and chemotherapy for neoadjuvant therapy for patients with HER2+ locally advanced, inflammatory, or early-stage breast cancer with either ≥2-cm diameter tumor or node-positive disease because of the significant increase in pCR rate and the evolving understanding that pCR is a good biomarker for long-term outcome.

Additional work on adjuvant therapy has been established since those studies were first conducted, and in the last few years, other HER2-targeted therapies have been approved in the adjuvant setting. Neratinib was approved by the FDA in 2017 as extended adjuvant therapy for patients with HER2+ EBC following adjuvant trastuzumab-based therapy.⁸ In 2017, the combination of trastuzumab/pertuzumab was granted full FDA approval in the neoadjuvant setting and FDA approval for adjuvant treatment in combination with trastuzumab and chemotherapy for patients with HER2+ EBC at high risk of recurrence.^9-11 Most recently, in 2019, the HER2-targeted antibody–drug conjugate T-DM1 was approved by the FDA as adjuvant therapy for patients with HER2+ EBC and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.¹²

The APHINITY trial was an international, randomized, double-blind, placebo-controlled phase III trial that enrolled 4805 patients with HER2+ EBC and no previous invasive breast cancer or anticancer treatment or radiology.^11,13 Patients were allowed to enroll if their tumors were >1 cm in diameter and LN negative or if they were LN positive, with any tumor size. There was also a limited number of patients who enrolled on the trial with node-negative disease and tumors >0.5 to ≤1 cm with ≥1 of the following risk factors: histologic/nuclear grade 3, ER negative and PgR negative, and younger than 35 years of age. The number of patients with node-negative disease was capped after the first 3655 patients were randomized.

In this study, patients were randomized to receive standard anthracycline or nonanthracycline chemotherapy and trastuzumab with either pertuzumab or placebo, with a total of 1 year of the anti-HER2 therapy. The primary endpoint was invasive disease–free survival (IDFS), and the secondary endpoints included OS and disease-free survival. The results of this trial were first reported at 3 years, but recently, the 6-year follow-up was published. The results of the 6-year follow-up are worth looking at because the results have changed somewhat from where they were at 3 years.

For IDFS in the ITT population, there was <1% difference in the rate of IDFS for patients receiving pertuzumab and patients receiving the placebo at 3 years; however, at the 6-year follow-up, that difference had increased to 2.8%.¹⁴ This was statistically significant, with a 6-year IDFS rate of 90.6% with the addition of pertuzumab vs 87.8% with placebo(HR: 0.76; 95% CI: 0.64-0.91) or a 24% improvement in IDFS with the addition of pertuzumab at 6 years of follow-up.

For the ITT population, there was no difference in OS with the addition of pertuzumab vs the placebo group at the 6-year mark. The stratified HR was 0.85 (95% CI: 0.67-1.07), and for both groups, 94% to 95% of patients were alive at 6 years. This points out how well this population of patients can do with optimal therapy.

Patients in the APHINITY study were stratified by nodal status. Patients with node-positive disease had an approximately 2% improvement in the rate of IDFS with the addition of pertuzumab at 3 years (92.0% vs 90.2%) which increased to 4.5% at 6 years (87.9% vs 83.4%). Therefore, in this higher-risk patient population with node-positive disease, the benefit of pertuzumab is shown more strongly (HR: 0.72; 95% CI: 0.59-0.87). This contrasts with the data in patients with node-negative disease where there was no difference in the rate of IDFS at 3 years, and there is still no difference at the 6-year follow-up. These data suggest that the benefit of adding pertuzumab therapy to standard chemotherapy and trastuzumab is largely seen in patients with a higher risk of recurrence.

Over time, the role of the hormone receptor status of patients with HER2+ EBC has changed. In the APHINITY trial, patients with hormone receptor–negative disease had a slightly better rate of IDFS at 3 years with the addition of pertuzumab vs placebo (92.8% vs 91.2%), and the rate of IDFS continues to be better at 6 years, with a 2.5% improvement in the EFS rate with the addition of pertuzumab (89.5% vs 87%). At 3 years, patients with hormone receptor–positive disease initially did not seem to derive a benefit in terms of the rate of IDFS, but with longer follow-up, we now see a 3% improvement in the rate of IDFS for patients with hormone receptor–positive disease who received pertuzumab (91.2% vs 88.2%).

These data are not surprising given that the natural history of hormone receptor–positive breast cancer, whether HER2 positive or HER2 negative, is one of later relapses. Therefore, it often requires longer follow-up to see a clear picture of what the outcome will be in this patient population. At 6 years of follow-up, we can now say that the benefit of adding pertuzumab to adjuvant chemotherapy and trastuzumab seems to be similar in both patients with hormone receptor–negative and hormone receptor–positive disease. This is in contrast to LN positivity where adding pertuzumab benefited patients with node-positive disease, who are at higher risk for disease recurrence.

Safety is an important consideration when adding another anti-HER2 agent to a standard treatment regimen. We need to make sure that there are no incremental long-term safety concerns. At 6 years of follow-up in the APHINITY trial, there were no notable differences in primary cardiac events, secondary cardiac events, or fatal AEs when comparing chemotherapy plus trastuzumab and pertuzumab vs chemotherapy plus trastuzumab and placebo. Fatal AEs occurred in 0.9% to 1.2% of patients. Primary cardiac events occurred in 0.3% to 0.8% of patients, and secondary cardiac events occurred in 2.7% to 2.8% of patients. Cardiac AEs identified via left ventricular ejection fraction (LVEF) assessment did not appear to differ with the addition of pertuzumab compared with placebo (2.1% vs 2.0%).

Based on these data, it does not appear that pertuzumab is adding any additional cardiac toxicity in the long term, which is reassuring.

Neratinib is a small molecule anti-HER2–targeted therapy that is administered orally.¹⁵ It is a pan-HER tyrosine kinase inhibitor, which means it works to inhibit all the members of the HER family, including EGFR (also known as HER1), HER3, and HER4. Neratinib inhibition is irreversible, which differs from the first-generation tyrosine kinase inhibitor lapatinib, which was reversible.

Neratinib works by targeting the tyrosine kinase domain on the intracellular portion of the HER molecules and has a different mechanism of action than that of trastuzumab and pertuzumab, which bind to parts of the HER2 extracellular domain and interfere dimerization. Dimerization of HER2 is necessary to trigger signaling through the tyrosine kinase domain intracellularly.

The pivotal randomized, double-blind, placebo-controlled phase III ExteNET trial compared neratinib vs placebo as extended adjuvant therapy after completion of 1 year of trastuzumab therapy in patients with HER2+ EBC.^16,17 Initially, this study included patients (N = 2840) who had stage I-III disease, either LN positive or negative, or had residual disease after neoadjuvant therapy and had completed adjuvant trastuzumab within 2 years of randomization. The study was amended midway through the trial to restrict enrollment to patients with node-positive disease who completed trastuzumab therapy less than 1 year before randomization. This means that some of the patients could have not started their neratinib until 2 years after they had completed their initial adjuvant therapy, and even after the amendment, they could have started up to 1 year after their adjuvant trastuzumab.

The primary endpoint was IDFS, which was evaluated at Year 2, but the study was amended to look at longer follow-up as well. In the primary analysis, the 2-year IDFS rate for neratinib was 93.9% compared with 91.6% for placebo (HR: 0.67; 96% CI: 0.5-0.91; P = .0091). We will now look at longer-term data.

At 5 years of follow-up, there was a 2.5% increase in IDFS with neratinib compared with placebo and a 27% relative benefit for neratinib (HR: 0.73; 95% CI: 0.57-0.92), which was statistically significant (P = .0083).¹⁷ The difference in IDFS was consistent throughout the 5-year time period and was true for those enrolled before and after the amendment.

When assessing the efficacy of neratinib by hormone receptor status, there was approximately a 5% increase in the IDFS rate with neratinib in patients with hormone receptor–positive disease (HR: 0.60; 95% CI: 0.43-0.83). However, the rate of IDFS was similar (approximately 89% with neratinib and placebo) for patients with hormone receptor–negative disease.

More recent analyses published on ExteNET assessed the patient population that started neratinib less than 1 year after their last dose of trastuzumab, which is much closer to the reality of the way we treat patients today.¹⁸ The best time to start extended adjuvant therapy would be immediately after finishing primary adjuvant therapy—in this case, after finishing 1 year of anti-HER2 therapy, whether that was trastuzumab or trastuzumab/pertuzumab.

In a subgroup analysis of patients with hormone receptor–positive disease who began neratinib less than 1 year after finishing trastuzumab therapy, the rate of IDFS improved by 5.1% in patients receiving neratinib when compared with the placebo group (5-year IDFS rate: 90.8% vs 85.7%, respectively; HR: 0.58; 95% CI: 0.41-0.82).

The ExteNET trial also allowed patients to enroll who had received either neoadjuvant and adjuvant therapy or adjuvant therapy alone. In a subgroup analysis of patients with hormone receptor–positive disease who began neratinib less than 1 year after finishing trastuzumab therapy, there was a group of approximately 300 patients who received neoadjuvant therapy and did not achieve a pCR. In this scenario, one would expect a worse overall outcome for these patients, and that was true in ExteNET as well. The group of patients with residual disease after neoadjuvant therapy and no extended adjuvant therapy did not fare well, with a 5-year IDFS rate of 77.6%. The rate of IDFS was improved by 7.4% (to 85.0%) with the addition of neratinib less than 1 year after cessation of trastuzumab in this patient subgroup.

These are exploratory analyses, but they suggest that more intensive therapy for patients who do not achieve a pCR can make a difference. 

Similar to APHINITY, there was no OS benefit in ExteNET, even at 8 years of follow-up.¹⁹ At this time point, there was <1% difference in the rate of OS at 8 years between the group of patients receiving neratinib and the group receiving the placebo (HR: 0.95; 95% CI: 0.75-1.21; P = .6914). As expected, these patients tend to do well even if they do have an invasive recurrence, and the majority of these patients (90%) are doing well at this point in follow-up.

In the subgroup analysis of patients with hormone receptor–positive disease who received neratinib less than 1 year from trastuzumab cessation, there was a 2% benefit in the 8-year OS rate for neratinib compared with placebo (HR: 0.79; 95% CI: 0.55-1.15; P = .203).¹⁸

In the patient population that received the neoadjuvant therapy and did not achieve a pCR, the 8-year OS rate was 9% better with neratinib treatment. This again demonstrates the benefit of pCR after neoadjuvant therapy for telling us what the patient outcomes will be and also the potential for interventions that we might consider for this population that has a historically worse outcome.

In the group of patients with hormone receptor–positive disease who began therapy with neratinib less than 1 year from the end of trastuzumab, there was a 5% benefit in the rate of distant disease–free survival compared with the placebo group (HR: 0.57; 95% CI: 0.39-0.83; P = .003). For the subgroup of patients who did not achieve a pCR after neoadjuvant therapy, there was a 7% benefit in the rate of distant disease–free survival with neratinib treatment (HR: 0.61; 95% CI: 0.32-1.11; P = 0.112). 

In the ExteNET trial, investigators also captured the incidence of central nervous system (CNS) recurrences as the first site of metastases at 5 years. In general, many patients with HER2+ EBC are destined to relapse, and one of the common first sites of relapse includes the CNS. Anti-HER2 antibodies and standard chemotherapy do not penetrate the blood–brain barrier well, but neratinib has been shown to penetrate the blood–brain barrier and reduce the number of CNS events and time to intervention for CNS events in the metastatic setting.²⁰

In ExteNET, the number of CNS as the first site of metastases events in the neratinib arm was numerically less in every subgroup (hormone receptor positive/≤1 year, LN status, previous trastuzumab regimen, adjuvant or neoadjuvant therapy, or pCR status after neoadjuvant therapy) than in the placebo arm. The overall incidence of CNS recurrences at 5 years tends to be approximately 2-fold to 3-fold higher in the placebo group. 

If we look at the CNS disease-free survival at 5 years in the subgroup of patients with hormone receptor–positive disease and who started extended adjuvant therapy less than 1 year from completing trastuzumab, there is not only a benefit with neratinib treatment in terms of the number of CNS events compared with the placebo arm, but the 5-year CNS disease-free survival estimates are also improved. Overall, the 5-year estimate for this subgroup of patients was 98.4% with neratinib vs 95.7% with placebo (HR: 0.41; 95% CI: 0.18-0.85), with similar trends in subset of patients regardless of nodal status, whether a patient received adjuvant or neoadjuvant therapy and whether she achieved pCR. 

T-DM1 is an antibody–drug conjugate that includes the anti-HER2–targeted antibody trastuzumab and a stable linker molecule that covalently links the cytotoxic agent.²¹ The cytotoxic agent is emtansine (also called DM1), a highly potent tubulin destabilizer. With an antibody–drug conjugate, the native antibody works not only through its regular mechanisms but also through the antibody–antigen complex, in this case T-DM1 with HER2, that is internalized by the cell and then metabolized intracellularly. Once metabolized, the complex releases the DM1 chemotherapy intracellularly, which causes cytotoxicity and cell death. This has the dual advantage of delivering the cytotoxic drug exactly where you want it while reducing the systemic effects because the chemotherapeutic agent is not circulating freely in the bloodstream.

The international, randomized, open-label phase III KATHERINE study compared T-DM1 with trastuzumab as adjuvant therapy for patients with HER2+ EBC who had residual disease after neoadjuvant therapy.^22,23 Of importance, this study was designed to enroll patients (N = 1486) who did not achieve a pCR and had residual invasive disease in breast or axillary LNs after standard neoadjuvant chemotherapy with HER2-targeted therapy. Patients who were eligible for this trial had T1-4 and N0-3 stage breast cancer without metastatic disease. The primary endpoint was IDFS, and the secondary endpoints were distant recurrence-free survival, OS, and safety.

Patients in the KATHERINE study were stratified based on clinical stage at presentation, hormone receptor status, type of preoperative HER2-targeted therapy, and nodal status after preoperative therapy. After preoperative therapy, approximately one half (46.6%) of the patients had node-positive disease. The patients who were eligible and enrolled on KATHERINE were high risk. One fourth of them had locally advanced disease with T4 lesions or N2-N3 disease. Approximately 72% of patients were hormone receptor positive in the T-DM1 and the trastuzumab arms of the study.

Of importance, 18% of patients in both arms received pertuzumab and trastuzumab in the neoadjuvant setting. Therefore, the KATHERINE study does not completely reflect the standard of care today, where pertuzumab is typically added to anti-HER2 therapy with trastuzumab and chemotherapy in the neoadjuvant setting to improve the probability of achieving pCR, and would typically be continued as adjuvant therapy in the absence of a pCR. So, keep that in mind when comparing the KATHERINE study to our current status of treatment and our current standard of care.

At 3 years, there was an 11% improvement in the rate of IDFS with T-DM1 compared with trastuzumab (88.3% vs 77.0%, respectively; HR: 0.50, 95% CI: 0.39-0.64; P <.001).²² The rate of distant recurrence was reduced substantially (10.5% for T-DM1 vs 15.9% for trastuzumab) as was locoregional recurrence (1.1% for T-DM1 vs 4.6% for trastuzumab). The rate of death without a previous event was nearly identical (0.3% vs 0.4%) and the rate of contralateral breast cancer events was similar for T-DM1 and trastuzumab (0.4% vs 1.3%).

All prespecified subgroups benefited similarly with T-DM1 compared with trastuzumab regardless of hormone receptor status, preoperative HER2-directed agent, or nodal status after preoperative therapy. The HRs for these subgroups ranged from 0.44-0.54.

Secondary endpoints in KATHERINE included the rate of distant recurrence and OS. The rate of distant recurrence was lower with T-DM1, with 89.7% free from distant recurrence at 3 years compared with 83.0% with trastuzumab alone (HR: 0.60, 95% CI: 0.45-0.79). At 3 years of follow-up in this patient population, there is a trend toward improvement in OS with T-DM1 treatment (HR: 0.70; 95% CI: 0.47-1.05), but longer follow-up is needed to get a full understanding of any OS improvement.

There was more toxicity associated with T-DM1 compared to trastuzumab, as expected but treatment in both arms was generally well tolerated and most AEs were grade 1/2.^22,23 The most common AE was fatigue, which was reported in one half of the patients treated with T-DM1 compared with approximately one third of those treated with trastuzumab alone. There was a substantial difference between the treatment arms with nausea (42% for T-DM1 vs 13% for trastuzumab), but almost all AEs were grade 1/2 with T-DM1. A substantial increase in decreased platelet count (29% vs 2%) was seen with T-DM1 treatment, with most events being grade 1/2 and some grade 3 events, but this was not necessarily of much clinical consequence. There was also some increase in liver function tests, including aspartate aminotransferase and alanine aminotransferase, which were more common with T-DM1 (28% and 23%, respectively). Only 6% of patients receiving trastuzumab alone experienced increased aspartate aminotransferase and alanine aminotransferase. There was also an increase in sensory neuropathy with T-DM1 (19% vs 7%), including a small amount of grade 3.

The KAITLIN trial was an international, randomized, open-label phase III trial.^24,25 Patients enrolled on this study (N = 1846) were high risk with HER2+ EBC and if they were node negative, they had to be hormone receptor negative with a tumor >2 cm in diameter. The KAITLIN study looked at the use of T-DM1 plus pertuzumab in an adjuvant setting vs the standard therapy of a taxane plus trastuzumab/pertuzumab after anthracycline-based therapy. The design of this study better matches what we would expect from our standard control arms today. The coprimary endpoints were IDFS in both the node-positive and the ITT populations, and secondary endpoints included OS, secondary malignancies, and disease-free survival. 

At 3 years, the use of trastuzumab/pertuzumab plus taxane led to a 3-year IDFS rate of 94% in those with node-positive disease.²⁴ The use of T-DM1 plus pertuzumab was not better than taxane plus trastuzumab/pertuzumab in the node-positive population with a similar 3-year IDFS rate of 93%. A similar trend was also seen in the ITT population, where again the results were very similar between arms (93%vs 94%). The KAITLIN trial failed to meet its coprimary endpoints, and therefore, T-DM1 plus pertuzumab after anthracycline-based therapy has not been recommended as a treatment option in place of standard taxane plus trastuzumab and pertuzumab in the adjuvant setting.