HER3-DXd Significantly Improves PFS Vs Chemo in Advanced EGFR+ NSCLC

The safety profile of HER3-DXd in the HERTHENA-Lung02 trial was comparable with prior reports of the agent in this population, as investigators observed no new safety signals.

Treatment with patritumab deruxtecan (HER3-DXd) significantly prolonged progression-free survival (PFS) compared with platinum-containing chemotherapy among patients with previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR mutations, according to findings from the phase 3 HERTHENA-Lung02 trial (NCT05338970).¹

The statistically significant PFS improvement reported in the HER3-DXd arm compared with platinum plus induction chemotherapy with pemetrexed followed by maintenance pemetrexed reached the trial’s primary end point. Investigators will continue to assess overall survival (OS) outcomes, which were immature at the time of the analysis.

The safety profile of HER3-DXd in the HERTHENA-Lung02 trial was comparable with prior reports of the agent in this population, as investigators observed no new safety signals. Interstitial lung disease (ILD) events were typically grade 1/2, although two grade 5 events occurred.

Investigators will present further data from the HERTHENA-Lung02 trial at a future medical meeting and share their findings with regulatory health authorities across the world.

“These results from HERTHENA-Lung02 demonstrate the potential of patritumab deruxtecan to become an important treatment option for certain patients with EGFR-mutated [NSCLC] with prior tyrosine kinase inhibitor [TKI] treatment,” Ken Takeshita, MD, global head of Research & Development at Daiichi Sankyo, which codevelops HER3-DXd with Merck, stated in the press release.¹ “We plan to share these findings with regulatory authorities to discuss next steps.”

Developers designed HER3-DXd as an antibody-drug conjugate that targets HER3. The agent includes a fully human anti-HER3 IgG1 monoclonal antibody with various topoisomerase I inhibitor payloads delivered through tetrapeptide-based cleavable linkers.

In the international, open-label HERTHENA-Lung02 trial, patients who experienced disease progression following prior third-generation EGFR TKI therapies were assigned to receive HER3-DXd at 5.6 mg/kg every 3 weeks or 4 cycles of pemetrexed plus platinum-containing chemotherapy. Treatment in the comparator arm consisted of pemetrexed at 500 mg/m² intravenously plus cisplatin at 75 mg/m² or carboplatin at target area under the plasma concentration time curve of 5.² Those without progressive disease following 4 cycles of treatment in the comparator arm are eligible to continue therapy with maintenance pemetrexed.

The trial’s primary end point was PFS per blinded independent central review (BICR). Secondary end points included OS, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response, and safety. Investigators also conducted brain imaging to facilitate evaluation of other end points such as intracranial PFS based on BICR.

Patients 18 years and older with histologically or cytologically confirmed metastatic or locally advanced nonsquamous NSCLC not amenable to curative surgery or radiotherapy and documented EGFR-activating mutations detected via tumor tissue or blood sample were eligible for enrollment on the trial. Other requirements for study entry included having 1 or 2 prior lines of EGFR TKI therapy in the metastatic or advanced setting, documented radiographic disease progression after a third-generation EGFR TKI, willingness to provide a tumor biopsy, an ECOG performance status of 0 or 1, and adequate bone marrow reserve and organ function.

Those with any prior evidence of small cell or mixed disease histology in the archival tumor tissue, any prior history of ILD, clinically severe respiratory compromise, or prior or current leptomeningeal disease were unable to enroll on the trial.

“We are encouraged by these results demonstrating a statistically significant [PFS] improvement compared [with] platinum plus pemetrexed induction chemotherapy followed by pemetrexed maintenance chemotherapy in patients with locally advanced or metastatic EGFR-mutated [NSCLC] who received prior [TKI] treatment,” Marjorie Green, MD, senior vice president and head of oncology, Global Clinical Development at Merck, concluded.¹

References

1. Patritumab deruxtecan demonstrated statistically significant improvement in progression-free survival versus doublet chemotherapy in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer in HERTHENA-Lung02 phase 3 trial. News release. Merck. September 17, 2024. Accessed September 17, 2024. https://tinyurl.com/32t2pbjs
2. HERTHENA-Lung02: a study of patritumab deruxtecan versus platinum-based chemotherapy in metastatic or locally advanced EGFRm NSCLC after failure of EGFR TKI therapy. ClinicalTrials.gov. Updated August 28, 2024. Accessed September 17, 2024. https://tinyurl.com/v9e776pu