Zongertinib Elicits Durable Responses in Pretreated Advanced HER2-Mutant NSCLC

Zongertinib (BI 1810631) continued to be efficacious and tolerable in patients with pretreated advanced non–small cell lung cancer (NSCLC) with HER2 mutations, according to updated findings from the phase 1 Beamion LUNG-1 study (NCT04886804) presented during the 2024 ESMO Asia Congress.1

At the time of the data cutoff date of August 29, 2024, zongertinib given at 120 mg (n = 75) elicited a confirmed objective response rate (ORR) of 71% (95% CI, 60%-80%; P < .0001). The disease control rate (DCR) was 93%. Notably, 55% of responders remained on treatment at the time of cutoff. The 6-month duration of response (DOR) rate was 73%, and the 6-month progression-free survival (PFS) rate was 69%.

“Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated advanced NSCLC harboring HER2 mutations,” Noboru Yamamoto, MD, PhD, of the Department of Experimental Therapeutics, National Cancer Center Hospital, in Tokyo, Japan, said in a presentation of the data. “[The agent] had a manageable safety profile, which was consistent with previous reports.”

About 2% to 4% of patients with NSCLC have tumors that harbor HER2 mutations and this is linked with a poor prognosis and higher likelihood of brain metastases. Yamamoto underscored the need for an effective and tolerable targeted option for these patients. Zongertinib is an irreversible TKI that was developed to selectively inhibit HER2 over EGFR which allows for the avoidance of unnecessary toxicity.

For the phase 1a portion of the study, patients with HER2-altered advanced solid tumors received zongertinib at escalating once or twice daily doses as part of 3-week cycles to identify the recommended dose for expansion in phase 1b. Two doses were taken to optimization: 120 mg once daily and 240 mg once daily. The maximum tolerated dose of the agent was not reached with either schedule.

Cohort 1 of the phase 1b portion of the research included patients with pretreated, advanced NSCLC harboring a HER2 TKD mutation. These patients were then randomized to receive a once daily dose of 120 mg or 240 mg. After an interim futility analysis, 120 mg once daily became the selected dose (n = 75). The primary end point of the study was confirmed ORR by central independent review and RECIST v1.1 criteria, and secondary end points included DCR, DOR, and PFS by central independent review and RECIST criteria.

Earlier data from cohort 1 of the phase 1b portion of the research were shared during the 2024 IASLC World Conference on Lung Cancer.2 When the agent was given at a dose of 120 mg (n = 75), the ORR was 66.7% (95% CI, 53.8%-77.5%; P < .0001) by blinded independent central review. The confirmed ORR per central review was 72.4% in the 120-mg group (n = 58) and 78.2% in the 240-mg group (n = 55). In the respective dosage groups, the DCRs were 94.8% and 100.0%. Intracranial responses occurred in 33% (95% CI, 19%-52%) and 40% (95% CI, 23%-59%) of patients in the respective groups.

The median age in those included in cohort 1 of phase 1b was 62 years (range, 30-80) and 68% were female. Moreover, 53% of patients were Asian, 32% were White, and 15% had missing information. Regarding prior lines of systemic therapy, 56% of patients received 1 prior line, 16% received 2 prior lines, and 28% received 3 or more prior lines. Most patients had an ECOG performance status of 1 (63%), a mutation type of A775_G776insYVMA (65%), and were never smokers (65%). Thirty-seven percent of patients had brain metastases.

Regarding safety, the majority of treatment-related adverse effects (TRAEs) were determined to be mild and manageable, according to Yamamoto, who added that no fatal TRAEs occurred. Moreover, no cases of interstitial lung disease were reported. AEs led to dose reduction for 5% of patients and treatment discontinuation of 3% of patients.

The most common TRAEs included diarrhea (all, 51%; grade ≥3, 1%), rash (27%; 0%), increased aspartate aminotransferase level (21%; 5%), increased alanine aminotransferase level (20%; 8%), nausea (15%; 0%), dry skin (12%; 0%), anemia (12%; 0%), pruritus (12%; 0%), and decreased neutrophil count (11%; 1%).

The randomized, phase 3 Beamion LUNG-2 study (NCT06151574) comparing the safety and efficacy of zongertinib with standard of care in the frontline treatment of patients with HER2-mutant advanced NSCLC is currently enrolling patients.

Disclosures: Dr Yamamoto reported honoraria receipt from Chugai Pharma, Daiichi Sankyo/UCB Japan, and Eisai. Research funding was received from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Carna Biosciences, Chiome Bioscience, Chuhai Pharma, CMIC, Daiichi Sankyo, Eisai, Eli Lilly, Genmab, GSK, InventisBio, Janssen, Kaken, Kyowa Kirin, Merck, MSD, Novartis, Ono, Otsuka, Pfizer, Ratuken Medical, Shionogi, Sumitomo Pharma, Taiho, Takeda, and Toray. He has participated as a speaker, consultant or advisor for Boehringer Ingelheim, Chugai Pharma, CMIC, Eisai, Healios, Merck, Mitsubishi Tanabe, Noile-Immune Biotech, Rakuten Medical, and Takeda.

References

1. Yamamoto N, Tu H-Y, Ahn M-J, et al. Zongertinib in patients with HER2-mutant NSCLC: updated analysis of Beamion LUNG-1. Ann Oncol. 2024;35(suppl 4):S1623-S1624. doi:10.1016/j.annonc.2024.10.642
2. Ruiter G, Tu H-Y, Ahn M-J, et al. Phase 1b analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2-mutant NSCLC. Presented at the 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL04.04.