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An antibody-drug conjugate (ADC) targeting the HER3 growth factor receptor had significant clinical activity in EGFR inhibitor-resistant non-small cell lung cancer (NSCLC), a preliminary clinical trial showed.

Patritumab deruxtecan (HER3-DXd) led to objective responses in 22 of 57 patients and stable disease in 19 others. Results were almost identical in a subgroup of patients previously treated with osimertinib (Tagrisso) and platinum-based chemotherapy. A third of patients with brain metastases responded to the drug.

Responses occurred across a diverse range of resistance mechanisms, reported Pasi Jänne, MD, PhD, of Dana Farber Cancer Institute in Boston, at the American Society of Clinical Oncology (ASCO) virtual meeting.

"HER3-DXd led to clinically meaningful and durable efficacy across a range of EGFR TKI [tyrosine kinase inhibitor] mechanisms in this population of patients that is often difficult to treat and with diverse resistance mechanisms or where you don't have a resistance mechanism," said Jänne. "Antitumor activity was observed across a wide range of baseline HER3 expression."

"HER3-DXd had a tolerable and manageable safety profile. There was a low rate of discontinuation due to adverse events," he noted.

Development of resistance remains a major limitation of treatment for advanced EGFR-mutant NSCLC, said ASCO invited discussant Nicolas Girard, MD, of Institut Curie in Paris. Combining an anti-HER3 and a topoisomerase inhibitor, HER3-DXd represents one of multiple emerging strategies to overcome resistance, which include antibodies paired with targeted agents and development of fourth-generation EGFR TKIs.

"The efficacy of HER3-DXd was high in the setting of heavily pretreated patients," said Girard. "Remaining questions include the impact of previous treatment sequences on efficacy and the clinical activity in patients with intracranial metastases."

"The striking finding of this study is reported activity of patritumab deruxtecan across all reported resistance mechanisms, including EGFR-related and non-EGFR/MET related," he added. "The search for a biomarker continues, as HER3 expression did not correlate with activity."

Platinum-based chemotherapy following EGFR TKI failure in NSCLC has limited efficacy, Jänne noted. To date salvage therapies after EGFR TKIs and platinum-based chemotherapy have demonstrated even less clinical activity. About 85% of NSCLC expresses HER3, and HER3 alterations are not known to be a resistance mechanism in anti-EGFR therapies for EGFR-mutated NSCLC.

Jänne reported findings from a phase I dose escalation/expansion trial in patients with locally advanced/metastatic EGFR-mutated NSCLC and disease progression on prior EGFR TKI treatment. The efficacy analysis included 57 patients treated with the phase II dose of HER3-DXd during dose-escalation or expansion. The safety analysis included 81 patients treated with all doses evaluated in the study.

Baseline characteristics were similar between the overall study population and the subgroup treated with the phase II dose. They had received a median of four prior therapies. All of the patients had received one or more prior EGFR TKI, and all but a few had received osimertinib and platinum-based chemotherapy. More than a third had prior exposure to immunotherapy.

Treatment with HER3-DXd resulted in an overall response rate of 39% in the 57-patient subgroup and in 44 patients who had prior exposure to both osimertinib and platinum-based chemotherapy. The disease control rate (DCR, response plus stable disease) was 72%. The median time to response was 2.6 months and median duration of response was 6.9 months. Median progression-free survival (PFS) was 8.2 months in the 57-patient subgroup and in the 44 patients with prior osimertinib and chemotherapy exposure.

An analysis of antitumor activity by brain metastasis status showed an objective response in eight of 25 patients with brain metastases and stable disease in 12 others, resulting in a DCR of 80%. Median PFS was 8.2 months. In 27 patients without a history of brain metastases, the response rate was 41%, DCR 67%, and median PFS 8.2 months.

"Durable responses were observed regardless of prior treatments or history of brain metastases," said Jänne.

HER3 expression in 43 evaluable tumors showed no association with clinical activity or with time since last EGFR TKI dose. Early clearance of EGFR exon 19 deletion or L858R mutations in circulating tumor DNA was associated with best overall response and PFS, he added.

HER3-DXd had a manageable safety profile, Jänne continued. Six of the 57 patients discontinued because of treatment-emergent adverse events (TEAEs). Grade ≥3 TEAEs occurred in 42 (74%) patients and grade ≥3 treatment-related AEs in 31 (54%).

Four patients developed interstitial lung disease (ILD) during treatment with HER3-DXd, reaching grade 3 severity in one patient. Jänne said investigators did not identify any clinical or laboratory factors associated with ILD.

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