Although drugs that target HER2 have transformed the prognosis for many patients with breast cancer, the development of resistant disease remains a significant clinical challenge.
Although drugs that target HER2 have transformed the prognosis for many patients with breast cancer, the development of resistant disease remains a significant clinical challenge. Dual blockade strategies have become a new standard of care for HER2- expressing metastatic breast cancer and have also generated impressive results in earlystage disease.
Now a growing appreciation of the complexities of HER2-positive disease is helping to further carve out a niche for dual blockade in HER2-positive breast cancer, including the possibility of a chemotherapy-free treatment regimen for certain patients. Although increased toxicity is a concern, the looming question for most clinicians and patients is whether insurance providers will cover expensive new combinations. As a result, the most pressing need is to identify patients for whom the benefits justify the cost.
Meanwhile, researchers are also exploring dual HER2 blockade strategies in other malignancies, notably in metastatic colorectal cancer (mCRC), although clinical trial results thus far are limited.Therapies Multiply
HER2 is a member of a tyrosine kinase receptor family that plays a central role in cell growth, proliferation, survival, and differentiation via multiple signal transduction pathways (Figure). It is overexpressed in many cancers.
An estimated 18% to 20% of breast tumors overexpress the HER2 protein.1 Historically, HER2 overexpression has been associated with an aggressive and metastatic form of breast cancer that has a poor prognosis and a propensity for brain metastases.2,3 Amplification or overexpression of HER2 is also observed in 10% to 30% of gastric tumors. Additionally, HER2 overexpression is seen in other tumor types, such as ovarian, bladder, lung, and colorectal cancers.4
Initial FDA approval for trastuzumab (Herceptin) nearly 2 decades ago marked the beginning of a fruitful foray into targeted therapies for patients with breast cancer. Five drugs employing this approach have now been approved. In addition to trastuzumab, a monoclonal antibody (mAb), the FDA has approved pertuzumab (Perjeta), also a mAb; lapatinib (Tykerb), a small-molecule tyrosine kinase inhibitor (TKI); ado-trastuzumab emtansine (T-DM1; Kadcyla), an antibody—drug conjugate; and neratinib (Nerlynx), a kinase inhibitor.
Thus far, the strategy has had limited success in other tumor types.4 Trastuzumab is also indicated for HER2-positive metastatic gastric and gastroesophageal junction cancer, while afatinib (Gilotrif), an EGFR inhibitor that also targets HER2, is approved for non—small cell lung cancer.
Theories on Resistance Mechanisms
The success of the first-generation drugs in breast cancer has been tempered by the development of resistance in a significant proportion of patients, which limits long-term efficacy. Among possible mechanisms of resistance is the incomplete inhibition of the HER2 pathway, allowing for low levels of signaling to persist. To overcome this type of resistance, numerous studies are now exploring the combination of 2 HER2-targeting drugs with distinct mechanisms of action.
Most ongoing studies of dual HER2 blockade combinations are being conducted in breast cancer settings (Table). Novel combinations include the pairing of T-DM1 with neratinib, the latter of which the FDA approved in July as a single agent for extended adjuvant breast cancer treatment. Additionally, tucatinib, an investigational HER2 inhibitor that may be effective against brain metastases, is being evaluated in combination with T-DM1.
Several novel regimens also are under study in CRC, in which HER2 overexpression is typically observed in 3% to 5% of patients. The HERACLES trial combines trastuzumab and lapatinib in patients with heavily pretreated HER2-positive mCRC (NCT03225937). Results presented at the 2017 American Association of Cancer Research Annual Meeting this year showed the combination was well tolerated, with durable responses even among those with as many as 5 previous lines of therapy. The overall response rate was 30% and the clinical benefit rate was 70%.5Among HER2-targeting drugs, pertuzumab has set the pace for dual HER2 blockade strategies. It is approved in combination with trastuzumab and docetaxel for the first-line treatment of patients with HER2-positive metastatic breast cancer and as neoadjuvant therapy for patients with locally advanced or early-stage breast cancer.
Although they are both mAbs, trastuzumab and pertuzumab bind to different parts of the HER2 protein and have distinct effects on HER2 signaling. The portion of the HER2 receptor that protrudes from the cell is made up of 4 subdomains. Pertuzumab binds to domain II, a region that is involved in the dimerization process, and prevents HER2 from being activated by other HER receptors.
Trastuzumab, meanwhile, binds to domain IV, the exact function of which is unknown but which is not involved in receptor dimerization. Trastuzumab has been shown to block ligandindependent HER2 signaling and prevent HER2 cleavage. Both antibodies also induce antibody-dependent cellular cytotoxicity.
Dual targeting of HER2 with these antibodies was evaluated in the phase III CLEOPATRA trial in which 808 patients were randomized to receive trastuzumab and docetaxel with either pertuzumab or placebo. Initial results, which led to the FDA’s approval of pertuzumab in combination with trastuzumab, demonstrated a 6-month improvement in progression-free survival (PFS) in patients treated with dual HER2 blockade compared with the control group (18.5 months vs 12.4 months, respectively; HR, 0.62; P <.001), with a strong trend toward improved overall survival (OS).6
The benefit was confirmed in a final analysis of the trial, in which the level of OS attained was unprecedented in the first-line setting for metastatic breast cancer.7 CLEOPATRA heralded dual HER2 blockade as a new standard of care as firstline therapy for patients with metastatic disease who had not received chemotherapy or prior HER2 therapy in this setting.
Trastuzumab in combination with lapatinib has also been evaluated in phase III clinical trials. While mAbs target the extracellular domain of HER2, TKIs block the intracellular domain and prevent downstream signaling.
Final results of the EGF104900 trial, in which 291 heavily pretreated patients with HER2-positive metastatic breast cancer were randomized to receive lapatinib monotherapy or a combination of lapatinib and trastuzumab, demonstrated significant improvement with the combination in PFS (HR, 0.74; P = .011) and OS (HR, 0.74; P = .026).8 Not all patients benefited, however, including patients with hormone receptor (HR)—positive disease, those with an ECOG performance status of 0 or 1, or those with visceral or brain metastases. Additionally, efficacy came at a cost of greater toxicity, with particular concern over cardiac events.
When T-DM1 became available in 2013, expectations were high that it might replace trastuzumab as the standard of care in the frontline treatment of metastatic HER2-positive breast cancer and allow for a chemotherapy-free treatment regimen. Unfortunately, synergistic activity observed in the preclinical setting did not translate into clinical success. In the phase III MARIANNE trial, 1095 patients were randomized to receive T-DM1 alone, T-DM1 plus pertuzumab, or trastuzumab and a taxane. In both T-DM1 arms, PFS was noninferior, but not superior, to the control arm, although there were fewer discontinuations because of adverse events and health-related quality of life (HRQoL) was maintained for a longer period.9
The combination of neratinib with trastuzumab has been evaluated in the phase I FB-8 trial, a single-arm dose-escalation study, and resulted in significant clinical benefit in heavily pretreated patients.10 Similarly, phase Ib trial results for tucatinib in combination with trastuzumab and capecitabine demonstrated encouraging response rates among patients with metastatic breast cancer, including individuals with brain metastases.11 Those results prompted an increase in the projected enrollment in the HER2CLIMB trial testing the same triplet combination (NCT02614794).In patients with resectable, early-stage disease, the potential of dual blockade has been assessed as both neoadjuvant and adjuvant therapy. As in the metastatic setting, the double antibody combination has proved most effective to date.
The combination of pertuzumab, trastuzumab, and docetaxel was approved by the FDA as a neoadjuvant regimen in 2013 based on the phase II NeoSphere trial. The study enrolled 417 patients who were randomly assigned to 1 of 4 treatment regimens prior to surgery: trastuzumab plus docetaxel, pertuzumab plus trastuzumab with docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel.
In the NeoSphere trial, the combination of pertuzumab and trastuzumab with docetaxel was associated with a significant improvement in the pathologic complete response (pCR) rate compared with trastuzumab plus docetaxel, without substantially increased toxicity.12 These results were supported by another phase II trial, TRYPHAENA, which involved 225 patients.13
A recently published 5-year analysis of NeoSphere suggested that an improved pCR rate translated into improved PFS and disease-free survival (DFS). Five-year PFS rates were 86% for dual HER2 therapy and 81% for trastuzumab alone, while DFS rates were 84% and 81%, respectively.14
The combination of trastuzumab and lapatinib has also been shown to be effective in the neoadjuvant setting, based on the results of the NeoALTTO trial, in which 455 women with operable HER2-positive tumors were randomized to receive either lapatinib or trastuzumab monotherapy or a combination of the 2, followed by paclitaxel, prior to surgery. The pCR was significantly higher with the combination than with trastuzumab alone.15
A number of other phase II and phase III studies of this combination in the neoadjuvant setting have been performed. According to a meta-analysis of 767 patients enrolled in 4 neoadjuvant trials, pCR was 55.76% for the combination versus 38.36% for trastuzumab alone (odds ratio [OR]: 1.94; P <.0001).16 The likelihood of achieving pCR was higher in patients with HR-negative disease. As in the metastatic setting, there was also increased toxicity, including neutropenia and diarrhea.
Meanwhile, the combination of pertuzumab and T-DM1 again was disappointing. In the KRISTINE trial, it failed to improve pCR compared with the standard of care, pertuzumab plus trastuzumab with carboplatin and docetaxel. As in the MARIANNE trial, the T-DM1 regimen was associated with improved toxicity and longer maintenance of HRQoL.17
The I-SPY2 trial is using a novel adaptive design to evaluate numerous therapeutic strategies in the neoadjuvant setting in patients with stage II/III breast cancer at 16 sites across the United States and Canada. Two of the treatment arms involve dual HER2 blockade. Interestingly, this trial did demonstrate an improved pCR rate for pertuzumab in combination with T-DM1 of 55% compared with 22% for those who received paclitaxel plus trastuzumab. It should be noted, however, that the trastuzumab-alone arm underperformed and only 30 patients were enrolled in this arm.
The combination of neratinib and trastuzumab is also being evaluated in the neoadjuvant setting. In the phase II FB-7 trial, it resulted in an improved pCR rate compared with the individual drugs.18In the adjuvant setting, enthusiasm for the role of dual blockade has been dampened by the results of the ALTTO trial. An analysis of findings for 8331 patients with operable HER2-positive breast cancer failed to demonstrate that the addition of lapatinib to trastuzumab improved pCR compared with trastuzumab alone. However, 10-year ALTTO follow-up results indicated a benefit of dual HER2 blockade among patients with HR-negative breast cancer.19
In the highly anticipated APHINITY trial, 4805 patients with operable, HER2-positive breast cancer were randomized to adjuvant trastuzumab and chemotherapy with either pertuzumab or placebo. In results presented at the 2017 American Society of Clinical Oncology Annual Meeting in June, the trial findings demonstrated a significant reduction in the risk of disease recurrence or death with the dual blockade arm, with no new safety signals. The absolute benefit for the overall study population, however, was relatively small, with an approximately 1% improvement in invasive DFS.20 Notably, the effect of dual blockade was most pronounced in patients with HR-negative disease, as in the ALTTO trial, and for participants with node-positive disease, prompting experts to suggest that the regimen be stratified for higher-risk subgroups.A number of outstanding questions and challenges have arisen as the feasibility of dual HER2 blockade has been explored. As our capacity to understand the genomic underpinnings of cancer has improved, HER2-positive disease has emerged as a heterogeneous group of tumors, with multiple subtypes, in which the efficacy of dual blockade varies.
There are 5 main molecular subtypes of breast cancer, based on the genes they express: luminal A, luminal B, HER2-enriched (HER2-E), triple-negative, and normal-like. About 10% to 15% of breast cancers fall into the HER2-E category and are characterized by high expression of the HER2 gene, as well as low expression of luminal genes, such as the HR genes ESR1 and PGR. However, the HER2-E subtype accounts for only about half of all HER2-positive cases. The other half display high expression of HR genes and are referred to as HER2-positive/HR-positive.
In addition, there is bidirectional cross-talk between the HER2 and estrogen receptor pathways, which can account for resistance to hormonal treatment or HER2-targeted therapies, regardless of the initial HER2 or HR status of the tumor. Thus, dual blockade could be effective in this patient population.
Several studies have demonstrated the benefit of adding HER2-targeted therapy to an aromatase inhibitor (AI) in this type of breast cancer. The phase II PERTAIN study showed that using dual HER2 blockade could improve outcomes even further. Among women with HER2-positive/HR-positive locally advanced or metastatic breast cancer treated with a combination of pertuzumab, trastuzumab, and an AI (anastrozole or letrozole), PFS was extended by more than 3 months compared with trastuzumab and an AI (median PFS, 18.9 months vs 15.8 months; HR, 0.65; P = .007). The combination was generally well tolerated, and although adverse events were more common in the triplet arm, the major concern about the potential for increased cardiac toxicity appeared unwarranted.21Historically, the trend in oncology therapeutics has been to add an increasing number of drugs to the standard of care in an attempt to improve efficacy; however, the disadvantages of this approach are skyrocketing costs and increasing toxicity. Several clinical trials of dual HER2 therapy have included arms in which the HER2-targeting drugs were used without chemotherapy; at least a subset of patients appear to benefit from this type of treatment de-escalation.
The greatest promise in this area to date has been in the neoadjuvant setting. In the NeoSphere trial, the pCR rate was 16.8% among patients who were treated with pertuzumab and trastuzumab without chemotherapy. A second trial examining this combination, WGS-ADAPT, included a chemotherapy-free arm and the pCR rate was 33.7%. Patients treated with pertuzumab plus T-DM1 in the KRISTINE trial, meanwhile, achieved a pCR rate of 44%.12,17,22
The TBCRC006 and TBCRC023 trials specifically examined the use of dual HER2 blockade without chemotherapy in the neoadjuvant setting in patients with HER2-positive breast cancer. The pCR rates in the trials were 27% and 24.2%, respectively.23,24
Although the pCR rate has been higher in the chemotherapy-containing arms in some trials, a deintensification strategy could still prove useful among patients who are not candidates for chemotherapy. The challenge now is to find ways to identify patients who would most benefit. The phase II PAMELA trial is a nonrandomized open-label study designed to evaluate the HER2-enriched subtype as a predictor of response to neoadjuvant dual HER2 blockade.
Patients enrolled in the trial were treated prior to surgery with lapatinib at 1000 mg/day and trastuzumab at 6 mg/kg every 3 weeks for 18 weeks; HR-positive patients also received endocrine therapy according to their menopausal status. The HER2-enriched subtype was a strong predictor of response to dual HER2 blockade without chemotherapy; pCR rates were 40.6% in patients with HER2-enriched tumors compared with just 10% in non—HER2-enriched tumors.25