Asco 2022 – looking beyond Enhertu in Her2-low cancer

Enhertu continues to show that it can hit Her2-expressing cancer cells that other drugs cannot reach, priming the Daiichi Sankyo and Astrazeneca asset for dominance across the Her2 space. That means serious competition for players in what now must be called Her2 high. Roche has the most to lose here, although newer products will also suffer – the launch of Seagen’s Her2 kinase inhibitor Tukysa has already been stopped in its tracks after a mere two years by Enhertu’s arrival. In the newly defined Her2-low space there will also be repercussions. The impressive Destiny-Breast04 data likely consign Gilead’s Trodelvy to a last-resort option, given this ADC’s weaker showing in Tropics-02. What of others eyeing this niche? Not many active trials can be found on of agents specifically going after Her2 low. Most are ADCs – step forward again Seagen, which paid $200m up front for ex-Asia rights to Remegen’s Her2-targeted ADC, disitamab vedotin. Meanwhile, a trispecific from Sanofi and a radiotherapeutic from Bayer provide different mechanistic approaches to watch. Safety is Enhertu’s weak spot so there is room for improvement here; on efficacy, though, a high bar has been set.

Aiming low: selected active trials seeking Her2-low patients
Project  Mechanism  Company  Details 
Disitamab vedotin (RC48) Anti-Her2 ADC Seagen/Remegen Remegen has a ph3 breast cancer trial ongoing in China recruiting Her2 low only; Seagen has said it plans to start a ph3 in Her2 low
Zanidatamab + evorpacept Anti-Her2 MAb Zymeworks + ALX Oncology Ph1/2 trial has Her2-low cohort
MRG002 Anti-Her2 ADC Shanghai Miracogen Ph2 breast cancer trial ongoing in China recruiting Her2 low only
Cinrebafusp alfa (PRS-343) Anti-Her2 x 4-1BB bispecific Pieris A ph2 gastric or GEJ adenocarcinoma trial has a Her2-low cohort (Tukysa combo)
Trastuzumab duocarmazine (SYD985)  Anti-Her2 ADC Byondis/Medac Ph1 trial has a Her2-low cohort 
SAR443216 Anti-CD3xCD28xHER2 trispecific  Sanofi  Ph1b trial has Her2-low cohorts
BAY2701439 Thorium-227-Her2 MAb conjugate  Bayer Ph1 trial has a Her2-low cohort 
IBI315 Her2xPD-1 bispecific  Innovent  Ph1 trial possibly has Her-low cohort, company has said it intends to move into Her2 low
Runimotamab (RG6194) Her2xCD3 bispecific  Roche  Potential for low Her2 cohort in large phase 1 trial (Her2 criteria undefined)
ARX788 Anti-Her2 ADC Ambrx  Ph1b has a Her2-low cohort 
A166 Anti-Her2 ADC Sichuan Kelun/Sorrento Ph1/2 trial allows low Her2 expression 
Source:, company communications, Evaluate Pharma & Journal of Clinical Oncology.

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