CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: December 17, 2024
Expiration: June 16, 2025
Investigational Agents Targeting HER3
Helena Yu, MD:
HER3 has been a target of interest in lung cancer as well as in solid tumors using mAbs for the past 2 decades. Initially, mAbs were assessed as monotherapy in different settings, including EGFR-mutated lung cancer.23
Preclinical data suggest that HER3 is relevant in EGFR-mutated lung cancer–acquired resistance as described above; thus, this patient population has been a focus when developing HER3-targeted therapies.23
Earlier attempts at targeting HER3 focused on HER3-directed mAbs, including patritumab and seribantumab. These agents were studied as monotherapy as well as in combination with EGFR inhibitors and standard cytotoxic chemotherapy.23
These agents were generally well tolerated, with manageable adverse event profiles. However, even in a select patient population with EGFR-mutated lung cancer, they showed no clear benefit. More recent HER3-targeted therapies include ADCs and bispecific antibodies.24,25
Past efforts with HER3-targeted therapies include patritumab plus erlotinib. A phase I study showed that this combination was well tolerated and compatible with a favorable pharmacokinetic profile in Japanese patients with advanced NSCLC.25 Another phase II study with the combination of seribantumab plus erlotinib did not show improved progression-free survival (PFS) in patients with EGFR wild-type NSCLC.25 Finally, a phase II study of seribantumab plus docetaxel showed that this combination failed to improve PFS in patients with previously treated advanced histidine-rich glycoprotein–positive NSCLC.24
ADCs: Key Principles
Helena Yu, MD:
ADCs recently emerged as a powerful tool that combines mAbs with cytotoxic chemotherapy. This slide shows the standard structure of an ADC, which includes a specific mAb as well as a cytotoxic chemotherapy payload. These 2 components are connected by a cleavable linker. Each of the components can be modified to maximize effectiveness and benefit certain populations.10
Key principles for ADC development include selection of the mAb, which needs to bind to target antigens on the tumor cell surface.10
The cytotoxic payload needs to be relevant and effective in the specific type of cancer that is being treated. Some frequently used payloads include microtubule inhibitors (eg, MMAE), as well as DNA-damaging agents, like topoisomerase 1 inhibitors. The linkers need to be stable initially and then selectively release the drug once the ADC has been endocytosed into the target cell. Unstable linkers can lead to a bystander effect, also killing nontarget cancer cells.10
ADCs: Mechanism of Action
Helena Yu, MD:
The mechanisms of actions follow several steps, as indicated in this slide. First, the antibody of the ADC selectively binds to an antigen expressed on the surface of the tumor cell, such as HER3. Then, after binding to the cell surface, the ADC is internalized or endocytosed within the cancer cell. The ADC is then processed within the endosome or lysosome, and the payload is subsequently cleaved from the antibody. This cleavage leads to cytotoxic cell death by various different mechanisms.26,27
Other ways that ADCs can be effective include the bystander killing effect, where a free payload that may be membrane permeable acts on adjacent cancer cells, or via antibody-dependent cytotoxicity, where ADCs engage with immune effector cells to elicit antitumor immunity.26,27
3 Drug-Related Components and Patient-Related Variables Relevant to ADCs
Helena Yu, MD:
Drug- and patient-related components also affect ADC efficacy. The term drug-to-antibody ratio is often used when discussing the drug payload; this refers to how many payload molecules are bound to a single antibody within an ADC. The higher the drug-to-antibody ratio, the more potent the ADC. The specific antibody used may also affect potency. Certain antibody epitopes may be more primed to initiate an immune response.26,28
Patient-related variables largely include antigen expression on a given tumor, which may vary from patient to patient or among tumor sites within a given patient. Prior therapies also influence ADC potency. A patient could develop resistance after having undergone treatment with a chemotherapeutic agent with a similar payload.26,28
HER3-DXd in EGFRm NSCLC (Phase I): Efficacy With Diverse EGFR TKI Resistance
Helena Yu, MD:
HER3-DXd is a novel HER3-directed ADC that has been assessed primarily in lung cancer with EGFR mutation, but is also being studied in breast and colon cancers. HER3-DXd is a human anti-HER3 IgG1 mAb conjugated to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker with a drug-to-antibody ratio of 7.6.29,30 The aim of the initial phase I dose-escalation study was to identify the appropriate dose of HER3-DXd for further studies. In this study, escalating doses of HER3-DXd were assessed in patients with EGFR-mutated lung cancer that had progressed on prior EGFR TKI therapy and platinum-based chemotherapy.31
The figure here shows that most patients experienced tumor shrinkage with HER3-DXd. Of importance, as shown in the rows below the figure, HER3-DXd appears to be effective against various EGFR driver mutations, including exon 19 deletion, L858R, and atypical EGFR-activating mutations.31
HER3-DXd also appears to be effective when different mechanisms of resistance are identified within a given tumor. Specifically, efficacy is seen with on-target EGFR alterations, MET amplification, other bypass signaling alterations, and unknown mechanisms of resistance.31
Of importance, there have been efforts to identify a biomarker that might predict response. Expression of the antibody target (in this instance, HER3) is a natural possibility for use as a biomarker. However, in this phase I study, the degree of HER3 expression on the tumor cell surface did not seem to predict or be associated with the response to HER3-DXd.31
HERTHENA-Lung01: Phase II Study of HER3-DXd in EGFRm NSCLC
Helena Yu, MD:
Based on promising phase I data, the HERTHENA-Lung01 study, a multicenter, open-label, randomized, 2-arm phase II study of HER3-DXd in patients with EGFR-mutated lung cancer who had progressed on both EGFR TKIs and platinum-based chemotherapy, was initiated. Patients with asymptomatic brain metastases were allowed, and patients were not selected based on HER3 expression.32
In this study, 2 different dosing schedules of HER3-DXd were initially assessed: a fixed dose of 5.6 mg/kg given intravenously every 3 weeks, and an uptitration schedule where escalating doses of HER3-DXd were given. Based on emerging data from the phase I study, the uptitration cohort was closed after 51 patients were enrolled, and the study then focused on the HER3-DXd fixed dose of 5.6 mg/kg.32
In total, 226 patients were enrolled in the fixed-dose cohort, and the primary endpoint was confirmed objective response rate (ORR) by blinded independent central review (BICR).32
HERTHENA-Lung01: Responses in EGFRm NSCLC
Helena Yu, MD:
The confirmed ORR in all patients in HERTHENA-Lung01 was approximately 30%. The disease control rate (DCR) in patients treated with HER3-DXd was 73.8%. The median progression-free survival (mPFS) was 5.5 months, and the median overall survival was 11.9 months.32,33
Many patients with EGFR-mutated lung cancer will ultimately develop brain metastases. Thus, understanding the central nervous system (CNS) efficacy of novel agents is critical. Thirty patients in HERTHENA-Lung01 had measurable, untreated brain metastases. Among this subset of patients, the confirmed CNS ORR was 33.3%, demonstrating efficacy in the CNS similar to that systemically.32,33
Furthermore, the CNS DCR among patients treated with HER3-DXd was 76.7%, and the median duration of response (DoR) in the CNS was 8.4 months.32,33
HERTHENA-Lung01: Antitumor Activity Across EGFR TKI Resistance Mechanisms
Helena Yu, MD:
This figure shows the percent tumor shrinkage experienced by all patients enrolled in HERTHENA-Lung01. Most patients had some degree of tumor shrinkage. When patients were separated based on the type of EGFR TKI resistance, the response rate was similar among those with EGFR-dependent resistance, EGFR-independent resistance, and no identified resistance mechanism.32
HERTHENA-Lung01: Correlative Biomarker Analyses
Helena Yu, MD:
Archival or biopsy tissue was collected from all patients prior to enrollment to assess HER3 expression. HER3 expression was assessed by H-score among patients who had a complete or partial response, stable disease, or progressive disease. There was no separation in regard to HER3 expression via H-score among these 3 groups. Of consequence, it does not appear that HER3 expression is a viable biomarker that predicts patient response to HER3-DXd.33
HERTHENA-Lung01 CNS Analysis: Cumulative Incidence of CNS Progression, Non-CNS Progression, and Death
Helena Yu, MD:
When assessing the CNS efficacy of HER3-DXd within HERTHENA-Lung01, patients with a history of brain metastases were separated from patients without a history of CNS metastases. When focusing on the subgroup with a history of brain metastases, the rate of CNS progression was relatively low, and the majority of patients who did progress did so systemically. Similarly, in patients without a history of brain metastases, the rate of CNS progression was exceedingly low, with systemic progression dominating in cases of progressive disease.33
HERTHENA-Lung02: Ongoing Phase III Study of HER3-DXd in EGFRm NSCLC
Helena Yu, MD:
Based on promising data from HERTHENA-Lung01, HERTHENA-Lung02, a global, randomized, open-label, phase III study of HER3-DXd in lung cancer with EGFR mutation, was initiated.34
For this study, patients with metastatic EGFR-mutated lung cancer with common EGFR-activating mutations (ie, exon 19 deletion or L858R) were enrolled. Patients received prior EGFR TKI therapy, but no prior chemotherapy was allowed. Patients with stable brain metastases were also allowed, and tumor tissue was required for HER3 expression assessment.34
Patients were randomized 1:1 to receive HER3-DXd vs standard of care (platinum-based chemotherapy) after EGFR TKI. The primary endpoint was PFS by BICR, and key secondary endpoints included PFS as assessed by the investigator, ORR, DoR, and safety (NCT05338970).34
Izalontamab Brengitecan: EGFRxHER3 Bispecific ADC
Karen Reckamp, MD, MS:
Izalontamab brengitecan is an EGFR-HER3 bispecific ADC that is currently being tested in a phase Ia/Ib dose-escalation/expansion study in patients with multiple tumor types including NSCLC. This ADC has a high affinity for human EGFR, a cathepsin B cleavable linker with a topoisomerase inhibitor payload, wild-type Fc IgG, and a low affinity for human HER3. The coprimary endpoints of this trial are dose-limiting toxicity, maximum tolerated dose, and recommended phase II dose. Key secondary endpoints include pharmacokinetics, antidrug antibody development, ORR, DCR, and DoR.35,36
Izalontamab Brengitecan: Response Rates in NSCLC
Karen Reckamp, MD, MS:
The data reported thus far were obtained from patients who received every-3-week dose regimens. Among all patients with NSCLC (n = 102), approximately 90% had received prior treatment with a median of 3 prior lines of therapy. Among these patients with advanced NSCLC, the ORR was 51%, the DCR was 87.3%, the median DoR was 8.5 months, and mPFS was 5.6 months.35,36
Among the patients with advanced NSCLC who had previously treated CNS metastases or no CNS metastases (n = 75), the ORR was 52%, and mPFS was 6.8 months. Among those with advanced NSCLC and untreated CNS metastases, (n = 27), the ORR was 48.1%, and mPFS was 4.1 months. Further, in patients with EGFR-mutated NSCLC (n = 40), the ORR was 67.5%, the DCR was 87.5%, the median DoR was 8.5 months, and mPFS was 5.6 months. Among those with EGFR wild-type NSCLC (n = 62), the ORR was 40.3%, the median DoR was not reached, and mPFS was 5.4 months.35,36
Izalontamab Brengitecan: Tumor Response in NSCLC
Karen Reckamp, MD, MS:
These figures show the best overall response with izalontamab brengitecan. The ORR was 51% in all patients with NSCLC (n = 102). Among those with EGFR-mutated NSCLC (n = 40), the ORR was 67.5%.35,36
Phase I Study of SHR-A2009, a HER3-Targeted ADC, in Advanced Solid Tumors
Karen Reckamp, MD, MS:
The HER3-targeted ADC SHR-A2009 is being evaluated in a phase I study of patients with multiple advanced solid tumors. SHR-A2009 comprises a fully human anti-HER3 IgG1 mAb with a cleavable peptide linker and a DNA topoisomerase 1 inhibitor payload. In this dose-escalation/expansion study, there are multiple cohorts that include patients who have NSCLC with EGFR mutations, NSCLC without EGFR mutations, and other solid tumors. The coprimary endpoints are safety, tolerability, and recommended phase II dose. Key secondary endpoints include preliminary efficacy, pharmacokinetics, and immunogenicity.37
SHR-A2009: Tumor Response in Advanced Solid Tumors
Karen Reckamp, MD, MS:
In all patients with solid tumors (n = 36), the ORR was 25%, the median DoR was 7 months, and 6-month PFS was 46.4%. Among patients with advanced NSCLC (n = 30), regardless of dose, the ORR was 30%, the median DoR was 7 months, and 6-month PFS was just less than 50%. These data were not subcategorized by the presence of an EGFR mutation. The waterfall plot on the right shows the best change in sum of diameters from baseline, expressed as a percentage, across all doses.37
SHR-A2009: HER3-Targeted ADC in NSCLC Cohort
Karen Reckamp, MD, MS:
In this phase I dose-escalation/expansion trial, there are 34 patients with EGFR-mutated NSCLC. All of them had received a prior EGFR TKI, and 29 had received a prior third-generation EGFR TKI. Across multiple cohorts subcategorized by dose, the ORR was 25%, the DCR was 72.2%, and the median DoR was 7 months. Even though these data are preliminary, early responses have been seen.37
Ongoing Phase I Combination Study of HER3-DXd With Osimertinib
Karen Reckamp, MD, MS:
We are also starting to see trials of combination therapies targeting HER3. For example, there is an ongoing international, open-label phase I trial of HER3-DXd with osimertinib in patients with an EGFR-activating mutation and no prior chemotherapy. This is a dose-escalation/expansion study in which patients will be randomized to HER3-DXd with osimertinib or HER3-DXd alone in the expansion phase. The primary endpoints are safety and ORR as assessed by BICR. Key secondary endpoints include safety, DoR, DCR, PFS, and overall survival (NCT04676477).
Role of Clinical Trial Referral in EGFRm NSCLC Management
Karen Reckamp, MD, MS:
Patients with advanced EGFR-mutated NSCLC have several treatment options for first- and second-line therapies. However, currently there are limited treatment options available for patients with advanced EGFR-mutated NSCLC and disease progression following standard first- and second-line therapies.38
Novel agents are in development that may offer benefits, such as HER3-targeted ADCs. An increasing understanding of the various mechanisms of resistance may help determine the right therapies for the right patients at the right time. This may also lead to the development of new therapies similar to how our understanding of the primary mechanism of resistance to first generation EGFR TKIs led to the development of osimertinib. Clinical trials have been the main source of major advances in treating EGFR-mutated NSCLC for the past 20 years, and they are always a good option for patients when other treatments are not available.38
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