A drug-conjugated antibody (ADC) targeting the HER3 growth factor receptor has had significant clinical activity in EGFR Inhibitor-resistant non-small cell lung cancer (NSCLC) demonstrated a preliminary clinical study.
Patritumab deruxtecan (HER3-DXd) resulted in objective responses in 22 of 57 patients and stable disease in 19 others. The results were nearly identical in a subset of patients previously treated with osimertinib (Tagrisso) and platinum-based chemotherapy. One third of patients with brain metastases responded to the drug.
The responses occurred through a wide range of resistance mechanisms, Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute in Boston, told the American Society of Clinical Oncology (ASCO) virtual meeting.
“HER3-DXd has led to clinically meaningful and sustainable efficacy in a range of EGFR TKIs [tyrosine kinase inhibitor] mechanisms in this patient population which are often difficult to treat and with different resistance mechanisms or where resistance mechanisms are not available, “Jänne said.” Antitumor activity was observed over a wide range of expression of HER3 at baseline “.
“HER3-DXd had an acceptable and manageable safety profile. There was a low rate of discontinuation due to side effects, “he noted.
The development of resistance remains a major limitation of treatment for advanced patients EGFRmutant NSCLC, said ASCO has invited Nicolas Girard, MD, of the Institut Curie in Paris to discuss. HER3-DXd combines an anti-HER3 and a topoisomerase inhibitor and represents one of many emerging strategies to overcome resistance, including antibodies in combination with targeted agents and the development of fourth generation EGFR TKI.
“The efficacy of HER3-DXd was high in the setting of heavily pretreated patients,” Girard said. “Other questions include the impact of previous treatment sequences on clinical efficacy and activity in patients with intracranial metastases.”
The surprising finding of this study is the reported activity of patritumab deruxtecan in all reported resistance mechanisms, including: EGFR-related and unrelated-EGFR / MET related, “he added.” The search for a biomarker continues, such as: HER3 expression was not correlated with activity. ”
Platinum-based chemotherapy follows EGFR Failure of TKI in NSCLC has limited effectiveness, Jänne noted. To date, salvage therapies after EGFR TKI and platinum-based chemotherapy have shown even less clinical activity. Approximately 85% of NSCLC expresses HER3 e HER3 changes are not known as a resistance mechanism in anti-EGFR therapies for EGFR– Mutated NSCLC.
Jänne reported the results of a Phase I dose escalation / expansion study in patients with locally advanced / metastatic EGFR-Mutated NSCLC and disease progression with previous 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 phase II dose treated subgroup. They had received an average of four previous therapies. All patients had one or more precedents EGFR TKI, and all but a few had received osimertinib and platinum-based chemotherapy. More than a third had previously been exposed to immunotherapy.
Treatment with HER3-DXd resulted in an overall response rate of 39% in the subgroup of 57 patients and in 44 patients previously exposed to both osimertinib and platinum-based chemotherapy. The disease control rate (DCR, response plus stable disease) was 72%. The median response time was 2.6 months and the median response time was 6.9 months. Median progression-free survival (PFS) was 8.2 months in the subgroup of 57 patients and in 44 patients with prior exposure to osimertinib and chemotherapy.
An analysis of antitumor activity based on brain metastasis status showed an objective response in eight of 25 patients with brain metastases and stable disease in another 12, resulting in an 80% DCR. The median PFS was 8.2 months. In 27 patients with no history of brain metastases, the response rate was 41%, DCR 67%, and the median PFS was 8.2 months.
“Long-lasting responses were observed regardless of previous treatments or history of brain metastases,” Jänne said.
HER3 expression in 43 evaluable tumors showed no association with clinical activity or time since the last dose of EGFR-TKI. Early liquidation of EGFR exon 19 gold deletion L858R mutations in circulating tumor DNA were associated with improved overall response and PFS, he added.
HER3-DXd had a manageable safety profile, Jänne continued. Six of the 57 patients discontinued due to treatment-related adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 42 (74%) patients and Grade ≥ 3 treatment-related adverse events in 31 (54%).
Four patients developed interstitial lung disease (ILD) during treatment with HER3-DXd and achieved Grade 3 severity in one patient. Janne said the researchers did not identify any clinical or laboratory factors associated with ILD.
Last updated on 08 June 2021
The study was funded by Daiichi Sankyo.
Jänne revealed important relationships with Gatekeeper Pharmaceuticals, Loxo Oncology, Araxes Pharma, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eisai, Ignyta, Lilly, Merrimack, Mirati Therapeutics, Novartech, Roche, SFUTICAL Group, Pfizer, Silicon Therapeutics, Takeda, Voronoi, Astellas Pharma, Puma Biotechnology and Revolution Medicines, plus a patent / royalty / intellectual property interest.