World Lung 2025 – backing for Bristol’s pivotal HER3 conjugate moves

In an intensely contested lung cancer space, Bristol Myers Squibb appears poised to add another competitor, following data presented at the World Conference on Lung Cancer. Its SystImmune-originated bispecific ADC izalontamab brengitecan looks to be succeeding where others, such as Merck & Co’s HER3 ADC patritumab deruxtecan, have failed. 

World Lung featured two SystImmune-sponsored phase 1/2 studies as late-breakers. One tested iza-bren in first-line EGFR-mutant NSCLC, where the project was combined with AstraZeneca’s third-generation EGFR inhibitor Tagrisso, while the other concerned a late-line setting, where it was given as monotherapy.

The front-line results look particularly impressive. However, it's worth noting that across all the datasets presented SystImmune zeroed in on just one iza-bren dose, 2.5mg/kg, which appeared to perform best despite being at the lower end of the doses tested.

Cross-trial comparisons

In first-line EGFR-mutated NSCLC Tagrisso monotherapy has been available in the US since 2018, while its combination with chemo was approved in February 2024. Meanwhile J&J’s Rybrevant plus Lacluze received approval in August 2024 and delivered overall survival data this year from the Mariposa trial, showing this doublet outperformed Tagrisso monotherapy. The final overall survival analysis from the Flaura2 trial of the Tagrisso/chemo combo will be presented at World Lung on Sunday.

During Saturday's late-breaking presentation, data from the BL-B01D1-203 study revealed that 2.5mg/kg iza-bren plus Tagrisso yielded a confirmed overall response rate of 95% in 40 first-line EGFR-mutated patients, at a median follow-up of 12.8 months. All responses observed were partial. 

On a cross-trial basis the data look impressive against results produced by Tagrisso and Rybrevant, although it’s worth bearing in mind that this is a small, early study that was carried out in China. And, considering all iza-bren doses up to 4.5mg/kg, confirmed ORR came in at 81%, which is in line with Tagrisso.

Cross-trial comparison in first-line EGFRm NSCLC

Note: *2.5mg/kg dose only. Source: OncologyPipeline.

Still, the ADC’s safety profile when combined with Tagrisso seemed impressive. Only two cases of ILD were reported (one grade 2 and one grade 3), representing a marked improvement versus other ADCs, and particularly compared with Merck Co’s anti-HER3 ADC patritumab deruxtecan, which faced significant safety problems. 

The remainder of the adverse events were largely similar to Tagrisso’s known safety profile, with a discontinuation rate of 12%. 

While these are early findings SystImmune started a phase 3 trial in this indication earlier this year, testing a Tagrisso combo versus Tagrisso alone, and this should give a better idea of how the agents stack up. However, this is only being conducted in China. 

Third-line EGFR

In addition to first-line data, results were also presented at World Lung from a subgroup of post-TKI, chemo-naive patients enrolled into the BL-B01D1-203 and BL-B01D1-101 studies. 

These phase 1/2 trials comprised 171 patients across doses up to 6mg/kg, and including first-line subjects and those who had received multiple lines of chemo. SystImmune zeroed in on 50 post-TKI, chemo-naives given 2.5mg/kg, where with a median follow up of 15.4 months the overall response rate was 56%. 

The safety profile across all 171 patients appeared favourable, with only one grade 1 ILD reported and a treatment discontinuation rate of 1.2%. 

Looking ahead, Bristol plans to initiate the Izabright-Lung01 phase 2/3 trial in October. This global study will focus on patients with EGFR-mutated NSCLC who have experienced disease progression on EGFR tyrosine kinase inhibitors.