The Phase 3 HERTHENA-Lung02 trial has demonstrated that patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), significantly improved progression-free survival (PFS) compared to platinum-based chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who had previously been treated with EGFR tyrosine kinase inhibitors (TKIs). This outcome highlights the potential of patritumab deruxtecan as a valuable treatment option for this patient population with limited second-line therapies.
The global, multicenter, open-label trial compared patritumab deruxtecan (5.6 mg/kg every three weeks) to four cycles of pemetrexed and platinum chemotherapy in 586 patients across Asia, Europe, North America, and Oceania. Patients had EGFR-activating mutations (exon 19 deletion or L858R) and had experienced failure on third-generation EGFR TKI therapy such as osimertinib, lazertinib, aumolertinib or alflutinib. The primary endpoint was PFS assessed by blinded independent central review (BICR), with secondary endpoints including overall survival (OS), objective response rate, duration of response, and safety.
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, stated, "These results from HERTHENA-Lung02 demonstrate the potential of patritumab deruxtecan to become an important treatment option for certain patients with EGFR-mutated non-small cell lung cancer with prior tyrosine kinase inhibitor treatment." Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck, added, "We are encouraged by these results demonstrating a statistically significant progression-free survival improvement compared to platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who received prior tyrosine kinase inhibitor treatment."
NSCLC and EGFR Mutations
Lung cancer is the leading cause of cancer-related deaths worldwide, with nearly 2.5 million new cases diagnosed globally in 2022. NSCLC accounts for approximately 85% of all lung cancers, and EGFR-activating mutations are present in 14% to 38% of NSCLC tumors. Up to 70% of NSCLC cases are diagnosed at an advanced stage, leading to poor prognosis and worsening outcomes after each line of therapy. After initial treatment with EGFR TKIs, many patients experience disease progression, underscoring the need for new therapeutic approaches.
HER3 as a Target
HER3, a member of the HER family of receptor tyrosine kinases, is expressed in approximately 83% of primary NSCLC tumors and 90% of advanced EGFR-mutated tumors after EGFR TKI treatment. Its expression is associated with poorer treatment outcomes, including shorter relapse-free survival and reduced overall survival. Currently, there are no approved HER3-directed therapies for any cancer.
Patritumab Deruxtecan: A Novel ADC
Patritumab deruxtecan (HER3-DXd) is an investigational HER3-directed ADC utilizing Daiichi Sankyo’s proprietary DXd ADC Technology. It comprises a fully human anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The drug is being evaluated as monotherapy and in combination with other therapies across multiple clinical trials.
The safety profile observed in HERTHENA-Lung02 was consistent with previous patritumab deruxtecan trials, with most interstitial lung disease (ILD) events being low grade (grade 1 and 2). However, two grade 5 ILD events were reported.
Daiichi Sankyo and Merck plan to present the full HERTHENA-Lung02 data at an upcoming medical meeting and share the results with global regulatory authorities to discuss potential next steps for approval.
