First Steps Down the HER3 Pathway in NSCLC Signal Early Success

Disease progression and acquired resistance to approved EGFR tyrosine kinase inhibitors have resulted in a treatment void in the third- and later-line settings for patients with non–small cell lung cancer.

Disease progression and acquired resistance to approved EGFR tyrosine kinase inhibitors (TKIs) have resulted in a treatment void in the third- and later-line settings for patients with non–small cell lung cancer. Targeted approaches in these settings rely on the identification of overexpression of resistance mechanisms such as MET amplification. Otherwise, options for patients without actionable genomic alterations rely on treatment with chemotherapy, which has limited efficacy.1

The identification of an overexpressed, targetable mutation would present a pathway forward for investigators. One such target under exploration is HER3.

Intracellular tyrosine kinase activity is limited in HER3, making this member of the EGFR family a prime target for investigators hoping to overcome resistance in non–small cell lung cancer (NSCLC).2,3 Findings from studies conducted over the past 15 years have identified that PI3K/AKT signaling and the upregulation of HER3 play key roles in the resistance to EGFR-targeted therapies.4

In an analysis of tissue samples from patients with NSCLC, HER3 expression was identified in 82.7% of the primary tumors, 86.6% of lymph nodes, and 91.2% of brain metastases.5 Other studies have noted that overexpression of HER3 (immunohistochemistry [IHC] staining 2+ or 3+) was identified in 42.2% NSCLC tissue samples with 70.7% of samples demonstrating expression at any level (IHC 1+ to 3+).6

Although HER3 expression has been identified as a favorable target, which resulted in several investigational studies, no agents have been approved by the FDA. However, in December 2021 the FDA granted a breakthrough therapy designation to novel antibody-drug conjugate (ADC) patritumab deruxtecan.7

Overcoming Resistance Hurdles

Designed with a cell membrane–permeable payload, the development of the first-in-class ADC overcomes the limitations experiences with monoclonal antibodies alone.1,8 Patritumab deruxtecan leverages a similar linker-payload design used with fam-trastuzumab deruxtecan-nxki (Enhertu)—specifically, patritumab covalently linked to a topoisomerase I inhibitor payload using a tetrapeptide-based cleavable linker.8

The first avenue of exploration to harnessing the utility of HER3 expression in NSCLC is in the post EGFR-TKI setting. Investigators have previously noted that tissue samples from patients who developed EGFR-TKI resistance had greater expression of HER3 than prior to treatment.8

Building on the foundational data from preclinical models, a phase 1/2 study (NCT03260491) of patritumab deruxtecan was initiated for patients with metastatic or unresectable NSCLC harboring an EGFR mutation who experienced disease progression after systemic treatment (FIGURE1). The recommended dose was determined to be 5.6 mg/kg via intravenous infusion once every 3 weeks. Efficacy analysis was conducted among patients who received the dose in the dose escalation phase and those enrolled to the dose-expansion cohort (n = 57).1

The confirmed overall response rate (ORR) via independent central review was 39% (95% CI, 26.0-52.4%) with 1 complete response and 21 partial responses reported. Further, 19 patients had stable disease as the best reported response for a disease control rate of 72% (95% CI, 58.5%-83.0%). At a median follow-up of 10.2 months, 32% of patients remained on treatment. The median duration of response was 6.9 months (95% CI, 3.1-not estimable [NE]).

Responses were similar among patients who had received prior osimertinib (Tagrisso) and a platinum-containing chemotherapy regimen (n = 44) with a confirmed ORR of 39% (95% CI, 24.4%-54.5%). One patient had a complete response, 36 had partial responses, and 30 had stable disease for a disease control rate of 68% (95% CI, 52.4%-81.4%).

Survival data for both groups were also similar. Specifically, the median progression-free survival (PFS) among all patients was 8.2 months (95% CI, 4.4-8.3) and the median overall survival (OS) was NE (95% CI, 9.4-NE). In the subgroup of patients who received prior chemotherapy and osimertinib, the median PFS was 8.2 months (95% CI, 4.0-NE) and the median OS was NE (95% CI, 8.2-NE).1

Of note in terms of safety was the incidence of interstitial lung disease (ILD), a known treatment-related adverse effect (TRAE) associated with trastuzumab deruxtecan. The safety analysis was conducted in the subgroup of 57 patients who received the recommended dose and across all dosing cohorts (n = 81). Treatment-related ILD was reported in 4 patients, all of whom were in the 5.6mg/kg cohort and investigators noted that all cases were resolved with drug discontinuation. Two patients had grade 1 ILD, 1 patient had grade 2 ILD, and 1 patient had grade 3 ILD.

Grade 3 or higher TRAEs were reported among 54% of patients in the 5.6 mg/kg cohort and 47% among all treated patients. the highest incidence of grade 3 TRAEs were thrombocytopenia (30% and 26%, respectively), neutropenia (19% and 15%), and fatigue (14% and 10%).1

In a biomarker analysis, investigators used IHC to produce H-scores to quantify expression among 43 available tissue samples from the 5.6mg/kg cohort. Pretreatment, all samples had HER3 expression with a median H-score of 180 (range, 2-280). Investigators noted that confirmed responses were reported across H-scores, but that those with higher H-scores (≥ 150) were associated with complete response.1

Further, genomic analysis was conducted prior to treatment with patritumab deruxtecan and identified several EGFR-activating mutations, other EGFR-associated mutations, amplification, and non-EGFR mutations and fusions. Resistance mutations including the “gatekeeper” T790M mutation presented in 13 patients: 6 had a partial response, 4 had stable disease, 2 had disease progression, and 1 was not evaluable; the ORR was 46%. For those without T790M mutations, 23 patients were reported to have other known EGFR mutations that are associated with resistance. Among these patients the ORR was 35%, comprising 8 patients with partial responses, 7 with stable disease, 5 with progressive disease, and 3 who were not evaluable. Finally, among the 21 patients with other or unknown resistance mechanisms, the ORR was 38% with 8 patients with partial responses, 8 with stable disease, 2 with disease progression, and 3 who were not evaluable.1

Next Steps in Investigating HER3

Based on the promising early efficacy signals in the phase 1 study, investigators have initiated a phase 2 study, HERTHENA-Lung01 (NCT04619004), to evaluate the safety and efficacy of patritumab deruxtecan as a single agent for patients with EGFR-mutated NSCLC in the third-line setting following progression on at least 1 EGFR-TKI and 1 platinum-based chemotherapy regimen. All patients enrolled in the trial will receive patritumab deruxtecan and will be randomly assigned to the fixed dose of 5.6 mg/kg on day 1 of each 21-day cycle, or an up-titration regimen administered at 3.2 mg/kg in cycle 1, 4.8 mg/kg in cycle 2, and 6.4 mg/kg in cycle 3 forward. The primary outcome is ORR.

To enhance the applicability of patritumab deruxtecan, combination strategies with EGFR-TKIs may prove to be a synergistic treatment option as EGFR-TKIs have influence in the upregulation of HER3.8 Investigators of a multiarm, phase 1 study (NCT04676477) are evaluating patritumab deruxtecan in combination with osimertinib in both treatment-naïve and previously treated patients with EGFR-mutant NSCLC. Patients must have received prior osimertinib and experienced disease progression.

The study design of the dose-expansion cohort will include individuals who will receive the combination in the second-line setting and those who will receive the combination as a first-line treatment. Of note, the first-line expansion cohort will only be initiated if the recommended combination dose is efficacious with osimertinib is administered at 80 mg once daily.

Tissue analysis and observational end points of these studies may help to expand knowledge of the biology of HER3 and how it can be further leveraged as a marker for not only this population but in other tumor types where it is highly expressed.


  1. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor–resistant, EGFR-mutated non–small cell lung cancer. Cancer Discov. 2022;12(1):74-89. doi:10.1158/2159-8290.CD-21-0715
  2. Haikala HM, Jänne PA. Thirty years of HER3: from basic biology to therapeutic interventions. Clin Cancer Res. 2021;27(13):3528-3539. doi:10.1158/1078-0432.CCR-20-4465
  3. Lim SM, Kim CG, Lee JB, Cho BC. Patritumab deruxtecan: paving the way for EGFR-TKI-resistant NSCLC. Cancer Discov. 2022;12(1):16-19. doi:10.1158/2159-8290.CD-21-1429
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  5. Scharpenseel H, Hanssen A, Loges S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep. 2019;9(1):7406. doi:10.1038/s41598-019-43678-6
  6. Manickavasagar T, Yuan W, Carreira S, et al. HER3 expression and MEK activation in non-small-cell lung carcinoma. Lung Cancer Manag. 2021;10(2):LMT48. doi:10.2217/lmt-2020-0031
  7. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo. December 23, 2021. Accessed March 22, 2022.
  8. Yonesaka K. HER2-/HER3-targeting antibody-drug conjugates for treating lung and colorectal cancers resistant to EGFR inhibitors. Cancers (Basel). 2021;13(5):1047. doi:10.3390/cancers13051047

Funding from Daiichi Sanyko. Content Developed Independently by OncLive.