New Era for Targeting HER2 Beckons in Breast Cancer and Beyond | OncLive

New Era for Targeting HER2 Beckons in Breast Cancer and Beyond

September 3, 2020

Precision medicine advancements are opening a new chapter in the development of anticancer therapies that target the HER2 pathway, resulting in 3 approvals for breast cancer in less than a year and raising hopes for attacking other cancer types.

Precision medicine advancements are opening a new chapter in the development of anticancer therapies that target the HER2 pathway, resulting in 3 approvals for breast cancer in less than a year and raising hopes for attacking other cancer types.

In the breast cancer arena, the FDA approved 2 new drugs, fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa), and an expanded indication for neratinib (Nerlynx).1-3 Margetuximab, a novel monoclonal antibody (mAb), is hot on their heels, with developer MacroGenics seeking approval following promising phase 3 outcomes.4-6

Efforts to expand HER2-targeted therapy into other HER2-positive cancer types have met with less success over the years. Except for trastuzumab (Herceptin) in gastric cancer,7 there are no approvals outside of breast cancer, and multiple clinical trial failures have underscored that all HER2positive cancers are not created equal.8

Now, however, ongoing clinical trials of novel HER2-targeted therapies in gastric, colorectal (CRC), and non–small cell lung cancers (NSCLCs) are showing promise.9-12

Meanwhile, investigators are exploring the role of HER3, which preferentially partners with HER2 to drive oncogenic signaling in propelling resistance to HER2-targeted therapy.13-15 To date, HER3-targeted mAbs have demonstrated limited clinical efficacy, but the development of a HER2-HER3 bispecific antibody is generating early enthusiasm.16,17

Overall, a variety of approved and novel therapies are in the pipeline for targeting HER2 in a range of tumor types (Table).

Table. Select HER2–Targeted Agents in Clinical Development

An Early Coup for Personalized Medicine

HER2 belongs to a family of tyrosine kinase receptors that includes 3 other members— HER1 (better known as EGFR), HER3, and HER4. (HER1-4 are also called ERBB1-4). All share a common structure: an extracellular portion containing the ligand-binding and dimerization domains, a transmembrane portion, and an intracellular portion possessing tyrosine kinase activity.8,13-15,18

The receptors are present as monomers in the membrane in a “closed” state, until binding of their respective ligands triggers a conformational change to an “open” state, exposing the dimerization domain. Receptors pair up via homo- or heterodimerization and phosphorylate one another at key tyrosine residues, which serve as binding platforms for adaptor proteins that facilitate the activation of downstream signaling cascades, including the PI3K/AKT, MAPK, and JAK/ STAT pathways. Ultimately, the signals converge in the nucleus to regulate the expression of genes that control key cellular processes (Figure).8,13-15,18

HER2 is unique in that it has no known activating ligands and is always in an open state, ready to pair up with another receptor. HER3, meanwhile, possesses little or no tyrosine kinase activity and is dependent on heterodimerization for its activation following binding of the HER3 ligand, heregulin. Yet, HER3 is the family member with the most phosphorylation sites, many of which are able to directly recruit PI3K; thus, it is thought to act as a signal amplifier, potently activating downstream signaling through heterodimerization with other members of the HER family— preferentially, HER2.8,13-15,18

More than 3 decades ago, HER2 was identified as an oncogene and found to be frequently overexpressed in human breast cancer.19,20 Although gene amplification is the most common type of HER2 alteration in breast cancer, protein overexpression—which is strongly linked to HER2 gene amplification—and HER2 gene mutations also occur, and HER2 signaling is aberrantly activated in around 20% of breast cancers.8

HER2-targeted drugs for the treatment of HER2-positive breast cancer are a prime example of the power of precision medicine in oncology. The mAb trastuzumab has become standard of care for both metastatic and early-stage HER2-positive breast cancer and has changed the general course of this disease.8,21,22

Over the years, trastuzumab was joined by another HER2-targeted mAb, pertuzumab (Perjeta). With its distinct HER2 binding site, pertuzumab is approved as part of a dual HER2-targeted regimen with trastuzumab and chemotherapy in the metastatic, neoadju-vant, and adjuvant settings.23

Lapatinib (Tykerb), an orally bioavailable small molecule tyrosine kinase inhibitor (TKI) that blocks intracellular HER2 kinase activity, and an antibody-drug conjugate (ADC), ado-trastuzumab emtansine (T-DM1; Kadcyla), composed of trastuzumab linked to an antimitotic drug, are also approved in the metastatic setting.8 In May 2019, T-DM1 gained an indication for the adjuvant treat-ment of patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant taxane and trastuzumab- based therapy.24

Figure. Key Elements of the HER2 Signaling Pathway

Emerging Options for HER2-Positive MBC

The treatment paradigm for HER2-positive metastatic breast cancer (MBC) involves trastuzumab plus pertuzumab and chemotherapy as the preferred frontline treatment option and T-DM1 as standard second-line therapy. Beyond this, treatment options include combinations of chemotherapy and trastuzumab and/or lapatinib, and efficacy is limited.18 Three promising strategies have been added to second- and third-line options since December 2019: neratinib, tucatinib, and trastuzumab deruxtecan.24

Neratinib

Neratinib, a pan-HER TKI that blocks the activity of HER1, HER2, and HER4,25 was initially approved by the FDA in 2017 for extended adjuvant treatment of early-stage HER2-positive breast cancer.3

On the basis of the phase 3 NALA trial (NCT01808573), neratinib is now approved in combination with capecitabine for the treatment of HER2-positive MBC previously treated with 2 or more anti-HER2–based regimens.3 Overall, 621 patients were randomized to receive neratinib 240 mg once daily and capecitabine 750 mg/m2 twice daily or a combination of lapatinib and capecitabine.26

The neratinib combination reduced the risk of disease progression or death by 24% compared with the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .006), according to results presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. Treatment-emergent adverse events (TEAEs) were similar in the 2 arms, except for a higher rate of grade 3 diarrhea in the neratinib arm.26

Tucatinib

The HER2-selective TKI tucatinib27 was approved in April 2020 in combination with trastuzumab and capecitabine for the treatment of HER2-positive MBC previously treated with 1 or more HER2targeted therapies.2 In the HER2CLIMB study (NCT02614794), 612 patients received tucatinib at 300 mg twice daily or placebo in combination with trastuzumab and capecitabine.27

The primary end point was progression- free survival (PFS) in the first 480 patients randomized (320 to the tucatinib arm, 160 to placebo). Median PFS was 7.8 months (95% CI, 7.5-9.6) vs 5.6 months (95% CI, 4.2-7.1), demonstrating a 46% reduction in the risk of disease progression or death in the tucatinib arm (HR, 0.54; 95% CI, 0.42-0.71; P < .001). Median overall survival (OS) was 21.9 months (95% CI, 18.3-31.0) vs 17.4 (95% CI, 13.6-19.9) months, corresponding to a 34% reduction in the risk of death in the tucatinib combination arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005).27

Among the 291 patients with brain metastases at baseline, median PFS was 7.6 (95% CI, 6.2-9.5) vs 5.4 months (95% CI, 4.1-5.7), translating into a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.340.69; P < .001). Median OS for this cohort was 18.1 (95% CI, 15.5-not reached) vs 12.0 months (95% CI, 11.2-15.2), for a 42% reduction in the risk of death (HR, 0.58; 95% CI, 0.40-0.85; P = .005).27,28

The most common AE in both arms was diarrhea, mostly grade 1 or 2, with higher frequencies of all grades in patients treated with tucatinib. The most common grade 3 or higher AEs in the tucatinib arm were palmar-plantar erythrodysesthesia syndrome, diarrhea, elevated aspartate and alanine aminotransferases, and fatigue.27

Trastuzumab Deruxtecan

Trastuzumab deruxtecan is an ADC composed of a HER2-targeted mAb linked to a topoisomerase I inhibitor payload via a cleavable linker. The agent is approved for the treatment of patients with HER2positive MBC who have received 2 or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast01 trial (NCT03248492).1

Among the 184 patients treated at the recommended phase 2 dose (5.4 mg/kg), the objective response rate (ORR) was 60.9%, with most responders (54.9%) experiencing a partial response (PR), and the median duration of response was 14.8 months (range, 13.8-16.9). The most common AEs included nausea, fatigue, hair loss, vomiting, and constipation. Notably, interstitial lung disease (ILD) occurred in 13.6% (n = 25) of patients overall, with 4 experiencing grade 5.29 The prescribing information contains a boxed warning advising health care providers and patients about this risk.30

Margetuximab

Although trastuzumab is a well-established component of breast cancer therapy, there is some debate among investigators about how well it inhibits HER2 expression or signaling and the role that its Fc domain plays in promoting antitumor activity.31,32 The Fc domain of trastuzumab can engage Fc gamma receptors (FcγRs) on the surface of immune cells to direct their effector functions.32 However, the majority of individuals, including patients with breast cancer, have an FcγR polymorphism that reduces the receptor’s binding affinity to trastuzumab, and there is some evidence that these patients do not respond as well to this agent.

Margetuximab, another emerging treatment option, is an Fc-engineered mAb that has the same affinity for HER2 as trastuzumab but has greater binding to the low-affinity FcγR allele compared with trastuzumab.32,33

In the phase 3 SOPHIA trial (NCT02492711), margetuximab (15 mg/kg q3w) in combination with chemotherapy was compared with trastuzumab plus chemotherapy in 536 patients with HER2-positive MBC who progressed following 2 or more antiHER2 therapies including pertuzumab. In the intention-to-treat population, the median PFS for patients who received margetuximab (n = 266) was 5.8 (95% CI, 5.52-6.97) vs 4.9 months (95% CI, 4.17-5.59) for those in the trastuzumab arm (n = 270), which translated into a 24% reduction in the risk of disease progression (HR, 0.76; 95% CI, 0.59-0.98; P = .033). The therapy had a more pronounced effect in patients carrying the low-affinity FcγR allele.4

At the second interim analysis, there was a trend toward improved OS, but this did not reach statistical significance. The median OS was 21.6 months (95% CI, 18.86-24.05) with margetuximab vs 19.8 months (95% CI, 17.54-22.28) with the trastuzumab-based combination (HR, 0.89; 95% CI, 0.691.13; P = .326). In a prespecified exploratory analysis, OS was prolonged by 4.3 months with margetuximab compared with trastuzumab in patients carrying the low-affinity FcγR polymorphism (23.7 vs 19.4 months, respectively); this difference was also nonsignificant (HR, 0.79; 95% CI, 0.611.04; P = .087).5

The 2 arms had similar rates of grade 3 or higher AEs and serious AEs, with comparable overall safety profiles. The incidence of infusion-related reactions was higher in the margetuximab arm, but these were predominantly grade 1 or 2 and associated with the first dose.4,5

The FDA is scheduled to make a decision on a biologics license application for margetuximab by December 18, 2020.6

Beyond Breast Cancer

Aberrant HER2 signaling is seen in a variety of other cancer types besides breast cancer, including in NSCLC, CRC, and gastric cancer.8 The spectrum and frequency of HER2 alterations vary among cancer types, and unraveling the clinical implications beyond breast cancer has proved more challenging.

HER2 is overexpressed in approximately 20% of gastric cancers, but much more heterogeneously than in breast cancer.8 A similar proportion of patients with NSCLC display HER2 overexpression, although marked overexpression, defined as an immunohistochemistry (IHC) score of 3+, is less common.34 HER2 mutations also are reported across tumor types, with the highest frequencies in bladder cancer (13%), breast cancer (4%), CRC (3%), and NSCLC (3%).35

Although this knowledge presents the possibility of targeting these cancer types with HER2-directed therapy, success has been limited to date, with the exception of trastuzumab, which is approved for frontline treatment of HER2-positive metastatic gastric/gastroesophageal junction (GEJ) cancer.7

Trastuzumab Deruxtecan

Newer drugs are showing more promise. Trastuzumab deruxtecan is being evaluated in NSCLC, gastric cancer, and CRC. In the DESTINY-Gastric01 trial (NCT03329690), the agent was evaluated with physician’s choice of chemotherapy in patients with HER2-positive advanced gastric/GEJ cancer that had progressed on at least 2 prior therapies. Participants who received trastuzumab deruxtecan had a median OS of 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (95% CI, 6.9-10.7) for those treated with chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P = .01). The ORR also was higher for trastuzumab deruxtecan at 51% vs 14% for chemotherapy (P < .001). The most common grade 3 or higher AEs were decreased neutrophil and white cell counts, anemia, and reduced appetite, and 10% of patients in the trastuzumab deruxtecan group experienced drug-related ILD or pneumonitis; none were grade 5.9

At the 2020 ASCO Virtual Scientific Program (2020 ASCO), results from 42 patients with HER2-mutant NSCLC treated with trastuzumab deruxtecan in the ongoing DESTINY-Lung01 trial (NCT03505710) demonstrated a confirmed ORR of 61.9%. Grade 3 or higher TEAEs included decreased neutrophil count and anemia, and there were 5 cases of drug-related ILD; all were grade 2.10

Also presented at 2020 ASCO were data from the DESTINY-CRC01 trial (NCT03384940) from patients with HER2positive metastatic CRC who received at least 2 prior regimens. Patients were enrolled in 3 cohorts based on HER2 expression levels. Among patients with the highest HER2 expression (IHC3+ or IHC2+/in situ hybridization positive), the ORR was 45.3%.

There were no responses in the other cohorts. Reported grade 3 or higher AEs were similar to rates in other studies of trastuzumab deruxtecan, and there were 5 drug-related cases of ILD, including 2 grade 5 events.11 Trastuzumab deruxtecan has been granted breakthrough therapy designations for NSCLC and gastric cancer indications based on data from the DESTINY-Lung01 and DESTINY-CRC01 trials, respectively.36

Margetuximab

Margetuximab is being studied in a phase 2/3 clinical trial in previously untreated HER2-positive gastric/GEJ cancer in combination with chemotherapy and/or a checkpoint inhibitor with anti–PD-1 mAb or dual PD-1/LAG3 inhibitor (MAHOGANY; NCT04082364). Results from a phase 1b/2 study of margetuximab plus pembrolizumab in previously treated HER2-positive gastric/GEJ cancer were recently published (NCT02689284).12

Among all 92 patients treated at the recommended phase 2 dose of 15 mg/kg margetuximab across dose escalation and expansion, the ORR was 18.48% and the disease control rate (DCR) was 53%. When patients were stratified by type of HER2 overexpression and PD-L1 status, the best responses were observed in PD-L1-positive subgroups with strong HER2 overexpression, such as the HER2 IHC3+ and PD-L1-positive subgroup (n = 25; ORR, 44%; DCR, 72%). There were no dose-limiting toxicities, and grade 3/4 treatment-related AEs included anemia and IRRs.12

Additional Novel Agents

Other novel drugs include Zymeworks’ bispecific antibody zanidatamab (ZW25), which has the combined HER2-binding profile of trastuzumab and pertuzumab.8,37 Zanidatamab has been awarded fast track designation for HER2-positive gastroesophageal adenocarcinoma.38 Results from an ongoing phase 1 trial (NCT02892123) in patients with a range of HER2-positive solid tumors demonstrated an ORR of 41%, all PRs.39 Phase 2 clinical trials in a number of other cancer types are ongoing, and Zymeworks is also developing ZW49, a bispecific ADC.37

Poziotinib and pyrotinib are 2 next-generation HER2-targeted TKIs. Pyrotinib is a pan-HER TKI, and poziotinib is designed to target exon 20 insertion mutations in both EGFR and HER2.40,41

Pyrotinib is conditionally approved in China to treat HER2-positive breast cancer.42 Results of a planned interim analysis of the phase 3 PHOEBE trial (NCT03080805) in patients with previously treated HER2positive MBC were presented at 2020 ASCO. Among 267 patients randomized to receive pyrotinib (400 mg) or lapatinib once daily in combination with capecitabine, median PFS was 12.5 vs 6.8 months (HR, 0.39; P < .0001). The most common grade 3 or higher AEs were diarrhea and hand-foot syndrome.43

Both drugs are being evaluated in phase 2 clinical trials in patients with previously treated NSCLC with HER2 exon 20 mutations, which confer resistance to currently available EGFR- and HER2-targeted TKIs.

Poziotinib (16 mg/day orally) produced an ORR of 42% in the first 12 evaluable patients in its trial (NCT03066206).44 For pyrotinib (400 mg daily), the ORR was 31.7% among 60 patients (NCT02834936). Both drugs had an acceptable safety profile.40

HER3: Another Piece of the Puzzle

Increased levels of HER3 expression have also been noted across numerous cancer types and are associated with tumor development and poor clinical prognosis. In addition, HER3 upregulation is implicated in resistance to other anticancer therapies, including HER2-targeted drugs, endocrine therapies, and EGFR inhibitors.13-15

Zenocutuzumab (MCLA-128) is a novel HER2-HER3 bispecific antibody described by developer Merus as having a unique “dock and block” mechanism: It binds to HER2 at a different epitope from that targeted by trastuzumab.17 This design allows zenocutuzumab to block both HER2-HER3 dimerization and HER3-heregulin binding.45

In a phase 2 study (NCT03321981), zenocutuzumab was combined with trastuzumab and vinorelbine in patients with HER2-positive MBC previously treated with up to 5 lines of HER2-targeted therapy. In results presented at 2020 ASCO, 37 patients were evaluable for response, and the clinical benefit rate at 24 weeks was 35.1%, with a confirmed ORR of 18.9%, including 1 complete response and 6 PRs. Grade 3/4 AEs included diarrhea, neutropenia, febrile neutropenia, and peripheral neuropathy.17

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