CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: November 06, 2023
Expiration: November 05, 2024
The Role of HER3 in Cancer
HER3 is a tyrosine kinase receptor belonging to the ERBB family, along with ERBB1 (EGFR), ERBB2 (HER2), and ERBB4 (HER4).1,2 HER3 has little intracellular tyrosine kinase activity by itself but is able to form heterodimers, particularly with EGFR and HER2, enhancing transphosphorylation and activation of downstream pathways.1,2 HER3 also can dimerize with non-HER partners including MET, PI3K, FGFR2, and others, forming heterodimers and activating pathways via these interactions. HER3 overexpression is found across numerous tumor types. In general, HER3 overexpression has been associated with worse overall survival (OS).
Investigational Agents Targeting HER3
Although no HER3-targeted agents are currently approved by the FDA, multiple therapeutic strategies targeting HER3 are in active investigation. These include monoclonal antibodies directed against HER3, bispecific antibodies that target both HER3 and a dimerization partner, as well as antibody–drug conjugates (ADCs) that allow HER3-directed delivery of highly cytotoxic payloads.2
Mechanisms of Resistance to Osimertinib in EGFR-Mutated NSCLC
In EGFR-mutated lung cancer, resistance to current EGFR tyrosine kinase inhibitors (TKIs) remains a major unmet need. Multiple mechanisms have been shown to contribute to the development of resistance to third-generation TKIs such as osimertinib. These include on-target mutations within EGFR, activation of alternative pathways, and transformation to other histologic types.3 However, each of these types of resistance accounts for only a small proportion of the total resistance mechanisms, and in many cases, the alterations associated with EGFR TKI resistance are unknown. EGFR-mutated NSCLC is associated with higher HER3 expression than EGFR–wild-type NSCLC, and HER3 expression levels are higher in the setting of EGFR TKI resistance.1,4 The overexpression of HER3 in these tumors suggests HER3 as a potential therapeutic target in EGFR-mutated NSCLC.5
Patritumab Deruxtecan: Novel HER3-Targeted Antibody–Drug Conjugate
HER3-DXd is a novel HER3-targeted ADC consisting of HER3 IgG1 linked via a cleavable tetrapeptide-based linker to the topoisomerase I inhibitor payload DXd, an exatecan derivative.6 Patritumab-DXd has a drug-to-antibody ratio of approximately 8, and the payload is highly potent with a short systemic half-life.7
Patritumab Deruxtecan in EGFR-Mutated NSCLC (Phase I): Efficacy With Diverse EGFR TKI Resistance
Initially, a multicohort phase I dose escalation and expansion study was undertaken to evaluate patritumab-DXd in NSCLC. The dose escalation phase enrolled patients with EGFR-mutated lung cancer with progression on an EGFR TKI.8 The dose expansion phase included 4 cohorts with varying treatment histories. Among 102 patients with EGFR-mutated NSCLC who received patritumab-DXd at 5.6 mg/kg, the objective response rate (ORR) was reported as 40.2% in an updated analysis presented at the 2023 Annual Meeting of the Japanese Society of Medical Oncology.8 Responses were observed across a range of EGFR TKI resistance mechanisms and HER3 expression levels.
HERTHENA-Lung01: Phase II Study of Patritumab Deruxtecan in EGFR-Mutated NSCLC
Subsequently, patritumab-DXd was evaluated in the multicenter, randomized, open-label phase II HERTHENA-Lung01 trial, which enrolled patients with advanced EGFR-mutated NSCLC progressing on their most recent systemic therapy. Prior treatment with an EGFR TKI was required. The protocol was amended to require prior osimertinib. Prior platinum-based chemotherapy also was required. Patients with inactive or previously treated asymptomatic brain metastases were allowed. Pretreatment biopsy was required, but there was no selection by HER3 expression. The primary endpoint was confirmed ORR by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR) by BICR, progression-free survival (PFS), and OS.
Results from a cohort of 226 patients who received patritumab-DXd at a fixed dose of 5.6 mg/kg intravenously every 3 weeks were presented by Yu and colleagues at the 2023 World Conference on Lung Cancer and published in the Journal of Clinical Oncology.6,9 The efficacy analysis was conducted after a median follow-up of 18.9 months, and the median treatment duration was 5.5 months.
HERTHENA-Lung01: Responses in EGFR-Mutated NSCLC
The confirmed ORR among 225 patients who received at least 1 dose of patritumab-DXd was 29.8%.9 Among the 209 patients who had previously received a third-generation EGFR TKI, the confirmed ORR was 29.2%. The disease control rate (DCR) was 73.8%, median DoR was 6.4 months, median PFS was 5.5 months, and median OS was 11.9 months. The intracranial response rate among 95 patients with brain metastases at baseline was 20.0% and among the 30 of those patients without prior radiotherapy was 33.3%.10
HERTHENA-Lung01: Antitumor Activity Across EGFR TKI Resistance Mechanisms
Similar to the experience in the phase I study, responses were observed across a range of resistance mechanisms. The confirmed ORR was 32.4% among patients with EGFR-dependent resistance mechanisms, 27.2% in patients with EGFR-independent resistance mechanisms, and 37.5% in patients with both types of resistance.9
HERTHENA-Lung01: Correlative Biomarker Analyses
Responses also were seen across a broad range of baseline HER3 levels with no clear correlation between HER3 overexpression and best overall response to patritumab-DXd.9 This was again similar to what was seen in the phase I experience.
HERTHENA-Lung01: Safety Summary
In terms of the AE profile in HERTHENA-Lung01, TEAEs were associated with treatment discontinuation in 7.1% of patients, dose reductions in 21.3%, and dose interruptions in 40.4%.9 In total, 95.6% of patients developed a TRAE; 15.1% of these were serious and 1.8% led to death from various causes. Grade ≥3 TRAEs developed in 45.3% of patients. The most common TEAEs of any grade were nausea (66%), thrombocytopenia (44%), decreased appetite (42%), and neutropenia (36%). The most common grade ≥3 TEAEs were thrombocytopenia (21%), neutropenia (19%), and anemia (14%).
ILD is a known risk of this class of drugs. ILD that was adjudicated as treatment related occurred in 5.3% of patients. These were primarily grade 1/2 (4%), with 2 grade 3 events (0.9%) and 1 grade 5 event (0.4%). The median time to onset of ILD was 53 days from the start of treatment.
Patients receiving patritumab-DXd should be aware of the toxicity profile. Gastrointestinal AEs such as nausea or appetite changes can typically be addressed with supportive measures. Cell counts should be monitored carefully given the risk of cytopenias. Given that ILD is a known AE of this drug and others in its class, patients should always be counseled to inform their care team if they notice a change in their breathing and should be assessed for signs of dyspnea at each clinic visit. However, grade 1 ILD is radiographically apparent but does not cause clinical signs. In accordance, scans should be examined carefully for any new ground-glass opacities or other changes suggestive of ILD.
HERTHENA-Lung02: Ongoing Phase III Study of Patritumab Deruxtecan in EGFR-Mutated NSCLC
Ongoing clinical trials are further evaluating the efficacy and safety of patritumab-DXd. HERTHENA-Lung 02 is a multicenter, randomized, open-label phase III study comparing patritumab-DXd administered at 5.6 mg/kg every 3 weeks against platinum-based chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC with EGFR activating mutations who have had 1-2 prior lines of EGFR TKI treatment, including progression after a third-generation EGFR TKI. Stable brain metastases are allowed. Tumor biopsy is required, but patients are not being selected based on HER3 expression.
The primary endpoint of the study is PFS by BICR. Secondary endpoints include PFS by investigator, ORR, DoR, DCR, time to response, and safety.
Ongoing Phase I Combination Study of Patritumab Deruxtecan With Osimertinib
An ongoing phase I study is evaluating the combination of patritumab-DXd and osimertinib in patients with locally advanced or metastatic NSCLC with EGFR activating mutations who have received prior osimertinib but no prior chemotherapy. Patients will receive osimertinib plus patritumab-DXd in a dose escalation. The primary endpoint of the dose escalation study is safety.
In the dose expansion phase, patients are randomly assigned to patritumab-DXd with osimertinib at the recommended combination dose or patritumab-DXd alone. The primary endpoint of the dose expansion phase is ORR by BICR. Secondary endpoints include ORR by investigator, DoR, DCR, time to response, PFS, OS, and safety.
Overview of Patritumab Deruxtecan Studies in NSCLC
To summarize the patritumab-DXd studies, we have seen data presented thus far for the phase I experience as well as the phase II HERTHENA-Lung01 study in patients previously treated with osimertinib and chemotherapy. Ongoing studies are in progress, including the randomized phase III HERTHENA-Lung02 study comparing patritumab-DXd and chemotherapy after osimertinib and a phase I study combining patritumab-DXd with osimertinib after prior osimertinib.
BL-B01D1: EGFRxHER3 Bispecific ADC
BL-B01D1 is a novel bispecific ADC directed against EGFR and HER3. At the 2023 European Society for Clinical Oncology (ESMO) Annual Meeting, Zhang and colleagues presented data from a first-in-human phase I study in patients with locally advanced or metastatic solid tumors.11 Patients were required to have an Eastern Cooperative Oncology Group performance status of 0/1, measurable disease, and failure of standard therapy or a lack of feasible treatment options.
BL-B01D1: Response Rates in NSCLC
In the NSCLC cohort (N = 102), BL-B01D1 was associated with a confirmed ORR of 39.2%.11 Ninety-two percent of these patients had received prior treatment with either an immune checkpoint inhibitor or TKI, and 89% had received prior platinum-based chemotherapy. The confirmed ORR was notably higher in the 40 patients with EGFR mutations compared with 62 patients with EGFR wildtype (52.5% vs 30.6%, respectively). Confirmed responses were seen in patients with treated or no brain metastases (41.3%; n = 75) and those with untreated brain metastases (33.3%; n = 27).
BL-B01D1: Tumor Response in NSCLC
The waterfall plots show best overall tumor responses for individual patients in the entire NSCLC cohort (N = 102) and the EGFR-mutated NSCLC subset (n = 40).11 Not shown on this slide, data previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting showed that responses in the EGFR-mutated cohort were observed in the setting of various EGFR mutations and other aberrations.12
BL-B01D1: Safety in All Tumor Types
Safety data include patients with all tumor types who received BL-B01D1 in an every-3-week dosing regimen (N = 369), which could have been 2.5 mg/kg on Days 1 and 8 or 4.5 mg/kg on Day 1 only.11 After a median follow-up of 3.9 months, 95% of patients had developed a TRAE; 20% of these were serious and 2% led to death from various causes. Grade ≥3 TRAEs developed in 61% and grade ≥4 in 31% of patients. The most common TRAEs were cytopenias, including leukopenia (65%; 32% grade ≥3), anemia (64%; 24% grade ≥3), neutropenia (59%; 36% grade ≥3), and thrombocytopenia (55%; 28% grade ≥3). Gastrointestinal AEs including nausea, decreased appetite, vomiting, and diarrhea also were notable. AE rates were slightly higher in patients receiving 1 4.5 mg/kg dose every 3 weeks compared with those receiving two 2-5 mg/kg doses. One instance of grade 2 ILD was observed.
SI-B001 (Izalontamab): EGFRxHER3 Bispecific Antibody
SI-B001 (izalontamab) is another bispecific antibody targeting EGFR and HER3. At ASCO 2023, Zhao and colleagues presented results of a multicenter, open-label phase II study evaluating the efficacy and safety of SI-B001 in combination with chemotherapy in patients with locally advanced or metastatic EGFR/ALK wild-type NSCLC with failure of prior first-line anti-PD-1/L1 therapy with or without platinum-based chemotherapy.13 Patients were required to have a good performance status (Eastern Cooperative Oncology Group performance status of 0/1), at least 1 measurable lesion, no autoimmune or inflammatory illnesses, and no or stable brain metastases.
The study included 3 cohorts. Cohort A evaluated SI-B001 plus platinum-based chemotherapy in the second-line setting after first-line anti–PD-1/PD-L1 monotherapy. Cohort B evaluated SI-B001 plus docetaxel in the second-line setting after first-line anti–PD-1/PD-L1 therapy and platinum-based chemotherapy. Cohort C evaluated SI-B001 plus docetaxel in the third line or later, after first-line anti–PD-1/PD-L1 and platinum-based chemotherapy. The primary endpoints were ORR and determination of the optimal dose for the combination. Secondary endpoints included PFS, DCR, DoR, and safety.
SI-B001 (Izalontamab): Outcomes in EGFR/ALK Wild-type NSCLC
The greatest enrollment was in Cohort B, in which SI-B001 plus docetaxel was evaluated as second-line therapy after first-line anti–PD-1/PD-L1 therapy plus platinum-based chemotherapy in 42 patients. In this cohort, the combination was associated with an ORR of 31.0%, a DCR of 71.4%, and a median DoR of 4.2 months.13 Overall, in 52 evaluable patients, SI-B001 plus chemotherapy was associated with an ORR of 28.9% and a DCR of 75.0%. The most frequent grade ≥3 TRAEs were neutropenia (15%), myelosuppression (13%), and leukopenia (9%).
Ongoing Study of SI-B001 (Izalontamab) With Osimertinib for Recurrent Metastatic NSCLC
A multicenter, open-label phase II/III study is evaluating the combination of SI-B001 plus osimertinib in patients with locally advanced or metastatic NSCLC with an EGFR mutation status that varies by cohort. Cohort A is enrolling patients with progression on a third-generation EGFR TKI. Cohort B is enrolling patients with tumors that are negative for EGFR T790M with progression on any EGFR TKI. Cohort C is enrolling patients with EGFR exon 20 insertions. The primary endpoints are ORR and the optimal combination dose. Key secondary endpoints include PFS, DCR, DoR, and safety.
Zenocutuzumab: HER2xHER3 Bispecific Antibody
Zenocutuzumab is a HER2 x HER3 bispecific antibody that has been studied specifically in the setting of NRG1 fusion–positive tumors. NGR1 fusions are rare but actionable oncogenic drivers observed in some solid tumors, including lung cancers.14
Zenocutuzumab binds to both HER2 and HER3, blocking interactions between the NRG1 fusion protein and HER3 and preventing HER2/HER3 dimerization. In preclinical studies, zenocutuzumab has been shown to inhibit the growth of NRG1 fusion–positive tumor cells. Zenocutuzumab has been shown to induce clinical and radiographic responses in pilot studies in patients with NRG1 fusion–positive solid tumors.15
eNRGy: Phase I/II Study of Zenocutuzumab in NRG+ Solid Tumors
The phase I/II eNRGy II study and an Early Access Program were undertaken to evaluate single-agent zenocutuzumab in patients with locally advanced or metastatic solid tumors with NRG1 fusions previously treated or ineligible for standard of care. The primary endpoint for the combined evaluation was ORR by investigator. Results were presented at ESMO 2023 by Dr Alison Schram.16
Zenocutuzumab: Tumor Response in NRG1+ NSCLC
Among 105 patients with NRG1+ NSCLC, of whom 78 were evaluable for tumor response, the ORR was 37.2% and clinical benefit rate was 61.5%.16 Median DoR was 14.9 months (range: 7.4-20.4 months), with 81% still responding at 6 months and 57% at 1 year.
Zenocutuzumab: Safety in All Tumor Types
Safety data were reported for patients with all tumor types who received the recommended phase II dose of 750 mg every 3 weeks (N = 189).16 The most common TRAEs observed with zenocutuzumab were diarrhea (17%), infusion-related reaction (12%), fatigue (10%), and nausea (8%), with no TRAEs leading to discontinuation. Grade 3/4 infusion-related TRAEs were reported in 2% of patients. No grade 5 TRAEs were reported.
SHR-A2009: HER3-Targeted ADC
Another HER3-targeted ADC, SHR-A2009, recently had first-in-human trial results presented at ESMO.17 No dose-limiting toxicities have been observed thus far in 42 patients across solid tumor types, so the dose escalation phase is still ongoing. Grade ≥3 AEs have been primarily hematotoxicities, with 7.1% of patients discontinuing treatment because of a TRAE. There have been 2 cases of ILD in this study. In the cohort of patients with NSCLC, who largely have EGFR-mutated disease and are resistant to third-generation EGFR TKI, a 30% response rate has been seen across all dose levels.
Key Takeaways
In summary, HER3 is an active area of investigation as a therapeutic target in several cancer types. The ability of HER3 to heterodimerize with multiple partners could allow it to contribute to acquired resistance against numerous targeted therapies, including EGFR TKIs. This characteristic could make HER3-targeted therapy a valuable tool in NSCLC, as there is currently an unmet need for effective therapies for patients after EGFR TKI treatment failure. Multiple HER3-targeted therapies are in clinical development, including ADCs and bispecific antibodies.
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