Antibody–drug conjugates targeting HER2-mutant or HER2-(non) amplified solid tumors: is HER2 an agnostic target?

KEYWORDS:

• Agnosticisms
• HER2
• HER2-amplified solid tumors
• HER2-mutant solid tumors

1. Introduction

Over the last few decades, the advent of new molecular technologies has led to the discovery of a many new potential pharmacological targets in solid tumors. In-depth and broadly available gene sequencing solutions shaped the paradigm shift from a histology-based to a genomics-driven approach for treatment decisions in oncology, up to the first histology-agnostic Food and Drug Administration (FDA) drug approval of pembrolizumab, for ‘any’ high-microsatellite instable or mismatch repair-deficient tumor, in 2017 [1]. This agnostic paradigm is based on the knowledge of a molecular feature that can present virtually in any cancer, conferring a universal sensitivity to agents targeting that feature. Additional other six histology-agnostic drugs reached the FDA approval [2,3]. According to these achievements, innovative biomarker-driven ‘pan-tumors’ clinical trials based on an agnostic intention have been designed; however, conflicting results have been obtained in clinical trials.

2. Human epidermal growth factor receptor 2 (HER2)

Historically, the identification of the HER2 has been viewed as milestone of precision oncology; yet, its role as a potential agnostic target has to be defined. HER2 is a transmembrane growth factor receptor, which gene (ERBB2) amplification leads to HER2 overexpression and subsequent tumor growth in many cancer types [4]. Apart from some different criteria depending on the primary tumor type, HER2 expression status is currently defined by IHC as ‘3+,’ in case of overexpression; ‘2+’ in case of equivocal overexpression; ‘1+,’ in case of low expression; ‘0,’ in case of absence of HER2 expression. For equivocal cases, reflex ISH test is performed.

HER2-directed monoclonal antibodies revolutionized the treatment of several HER2 overexpressing tumors, while in the setting of lower HER2 expression, clinical success took a longer time to come. The development of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs) has contributed to broaden the availability of effective HER2-directed agents, demonstrating remarkable efficacy in the post-trastuzumab-setting and also in HER2-mutated cancers [5].

To date, although HER2 has a key role in several solid tumors, the pattern and significance of the HER2-mediated oncogenesis and the predictive role of HER2 alterations are not necessarily overlapping across the several tumor types; as such, the use of HER2-targeting agents may result in a different magnitude of benefit, that is a function of the cancer type, and the overall disease contexture (Figure 1).

Figure 1. The spectrum of activity of HER2-targeting agents across solid tumors, according to HER2 status. Created with Biorender.com.

ADC, antibody–drug conjugate; CRC, colorectal cancer; HER2, Human Epidermal Growth Factor Receptor 2; ISH, in situ hybridization; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.

3. HER2-overexpression and amplification

In breast cancer (BC), HER2 overexpression defines an aggressive subtype, yet highly sensitive to anti-HER2 agents. Anti-HER2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy have contributed to remarkable improvements of survival outcomes in both early and metastatic setting [6,7]. Despite this success, HER2 overexpressing metastatic tumors will inevitably develop resistance, leading to disease progression. However, in the trastuzumab-resistant scenario, advances in anti-HER2 therapies development have provided new effective options as ‘sequence’ of anti-HER2 agents – that is the quintessence of HER2 targetability: the same target, different agents, clinical success. In some instances, novel agents like the brain-penetrant TKI Tucatinib, have ‘resolved’ historical challenges, for example through its activity in brain-progressing, pre-treated BC, as shown in the pivotal phase II HER2CLIMB study [8]. Yet, brain-active agnosticism has not been reported.

ADCs have expanded the scope even further by achieving significant results in the setting of resistance to trastuzumab. These drugs combine the role of antibodies as molecular ‘light switch’ with the cancer-directed delivery of cytotoxins. T-DM1 was the first FDA-approved anti-HER2 ADC, developed to overcome trastuzumab resistance in BC [9]. Then, trastuzumab deruxtecan (T-DXd) showed to be highly active in very pretreated BCs, receiving accelerated approval by FDA based on the findings of the early-phase DESTINY-breast01 trial, then confirmed in the phase 3 DESTINY-breast03 and -02 studies [10–12].

HER-2 actionability is a paradigm used in cancer treatment also in gastric cancer (GC), presenting HER2 amplification in 20%. Combination of trastuzumab with chemotherapy has showed to positively impact on patient prognosis. Despite initial success, the targetability paradigm of HER2 in GC has not been as successful as in BC, since T-DM1 and TKIs failed to improve outcomes in the post-trastuzumab setting [13,14]. As a result, in GC there is no standard ‘sequence’ of anti-HER2 agents for patient’s treatment. Even, the use of the double blockade frontline was not more effective than trastuzumab alone in this setting, confuting the paradigm that two antibodies are better, as consolidated in BC [15]. These discrepancies may be explained by many factors including GC’s HER2 heterogeneity, which represents a possible resistance mechanism to anti-HER2 drugs and cannot be embraced ‘just’ blocking the HER2 pathway [16]. The bystander effect seen with T-DXd deemed valuable in overcoming resistances; in fact, it was the first anti-HER2 agent to show survival benefit in HER2-positive advanced GC in the post-trastuzumab setting, in DESTINY-Gastric01 trial (median overall survival [mOS]: 12.5 vs 8.4 months) [17].

HER2-overexpressing colorectal cancer (CRC) is a rare entity. Among several combination strategies, trastuzumab and tucatinib have recently achieved the FDA-approval for metastatic, RAS wild-type, HER2 overexpressing CRC [18]. Benefit of the double HER2-blockade was substantially more pronounced in HER2 3+ than HER2 2+/ISH=positive cancer (objective response rate [ORR]: 46.7% vs 20%) [19]. Furthermore, T-DXd demonstrated promising activity in both DESTINY-CRC01 and −02 trials in patients with HER2-overexpressing advanced CRC, in the post-trastuzumab setting, and notably in RAS-mutant CRC – that is a setting where anti-HER2 TKIs and trastuzumab had failed to show significant activity [20,21].

HER2-overexpression seems to represent an effective actionable biomarker across histologies by both anti-HER2 ‘naked’ antibodies and ADCs, particularly with T-DXd. As a matter of fact, DESTINY-PanTumor02 enrolling patients with HER2 3+ and 2+ cancers, regardless ERBB2 gene amplification, reported promising ad interim findings across malignancies with a total ORR of 37% and a median duration of response of 12 months [22]. In the setting of HER2-overexpression, agnostic activity of ADCs is likely to occur, yet not necessarily for all anti-HER2 drugs [22].

4. HER2-low expression

The advent of ADCs represented a demarcation line with the past: in particular, T-DXd was demonstrated to target cancer cells by using HER2 as a vulnerable back door, beyond their addiction to HER2 signaling. In DESTINY-breast04 trial, T-DXd demonstrated to be superior to standard chemotherapy in the setting of HER2-low BC, defined as HER2 1+ or 2+/ISH-negative (mOS 23.9 vs 17.5 months) [23*]. Cancers can be not addicted to HER2, but still benefit from HER2-directed agents, when HER2 is used as an ‘escamotage’ to tackle cancer.

Results obtained with ADCs in the setting of HER2-low non-BC cancers have been controversial. Preliminary results of T-DXd in HER2-low GC showed only a modest activity; in CRC, no responses were observed in DESTINY-CRC01 [20]. Furthermore, DESTINY-PANTumor02 included also patients with HER2 positive IHC 2+, possibly ‘HER2-low,’ reporting lower rates of confirmed ORR when compared to HER2 overexpression (61.3% in IHC 3+ vs 27.2% in IHC 2+), as per interim analysis [22,23].

In essence, HER2-low seems actionable with novel ADCs, but an agnostic paradigm seems far to be near the corner. The spectrum of actionability is largely variable, and the benefit retrieved in different tumor types ranging from substantial to insignificant activity with ADCs. Agnosticism cannot be indeed state in this setting.

5. HER2 activating mutations

Activating HER2 mutations as a potential actionable target among various cancer types showed heterogeneous findings. In the field of non-small-cell lung cancer, overexpression, amplification, and mutation of HER2 have been described. When compared to HER2 amplification or overexpression, HER2 mutations, particularly the exon20 alteration, have emerged as actionable mutations. In DESTINY-Lung01 study, T-DXd was tested in patients with HER2-mutant NSCLC, reporting a median progression-free survival (PFS) of 8.2 months [24]. In BC, neratinib has been the first FDA-approved drug to be tested in patients with HER2-mutation. In the SUMMIT trial, the triplet of neratinib, fulvestrant, and trastuzumab resulted in a PFS of 8.3 months in patients with HER2-mutated, hormone receptor-positive BC, that is deemed promising [25].

Overall, HER2 activating mutations may enhance sensitivity of cancers to HER2-directed agents, including TKI and novel ADCs. The agnostic paradigm for HER2 mutations is again very immature for the lack of data. Additionally, it is still unclear in what extent HER2 mutations intersect HER2 expression and oncogene addiction, and what is the major contributor of the sensitivity to targeted agents -a cogent clinically relevant question.

6. Expert opinion: is HER2 an agnostic target of ADCs?

In conclusion, anti-HER2 ADCs contributed to widen the treatment landscape of many tumor types. However, relevant differences in activity among histologies have been highlighted, and appear to be function of the agent considered, and the type of HER2 alteration. The biological role of HER2, the heterogeneity of its expression and specific molecular alterations, the response to different HER2-targeting agents differ across cancer types. Consequently, the link between HER2 expression and the specific histological contexture is inextricable and, should be considered in the evaluation of therapeutic approaches, beyond a ‘reductionistic temptation’ to ultimate agnosticism at any costs.

Within the HER2 landscape, further studies are needed to refine molecular-driven patient stratification on the road to a histology-agnostic drug development. In other words, if the biomarker comes before histology in the context of the agnosticism, the histology will become the most important biomarker to define treatment efficacy.

Declarations of interest

G Curigliano reports honoraria for speaker’s engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; honoraria for writing engagement: Novartis, BMS; honoraria for participation in Ellipsis Scientific Affairs Group; institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, and MedImmune. All the competing interests were outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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This paper was not funded.