ALX Oncology (ALXO) Study Update summary

Study background and design

• Evaluated evorpacept, a CD47 blocker, in combination with zanidatamab, a bispecific HER2-targeted antibody, in metastatic breast cancer patients who were heavily pretreated, including prior T-DXd/Enhertu exposure.

• Phase 1b/2 trial included HER2-positive, HER2-low, and non-breast HER2-expressing tumor cohorts, focusing on unresectable, locally advanced, or metastatic cancers.

• Patients in the HER2-positive cohort had received a median of 6 prior therapies; all had at least three prior regimens, reflecting high unmet need.

• Central confirmation of HER2 status was required when feasible, highlighting tumor heterogeneity.

• The combination aims to provide a chemotherapy-free regimen for heavily pretreated patients, addressing limited post-Enhertu options.

Key efficacy and safety results

• In centrally confirmed HER2-positive breast cancer, ORR/CORR was 55–55.6%, disease control rate was 77.8–80%, and median PFS was 7.4 months.

• HER2-low cohort showed a 20% ORR/CORR and DCR of 40%, with PFS comparable to other post-T-DXd regimens.

• Responses were durable, with several patients on therapy for over 6 and 12 months; 71% of HER2-positive patients had target lesion reduction.

• Safety profile was favorable; most TRAEs were grade 1 or 2, with manageable infusion reactions, diarrhea, fatigue, and nausea; minimal cardiac toxicity and no grade 4/5 TRAEs or treatment-related deaths.

• No unexpected toxicities observed; regimen was chemotherapy-free and consistent with prior experience.

Clinical context and implications

• Current post-T-DXd/Enhertu options are limited, often involving chemotherapy with significant toxicity and modest response rates.

• The combination offers a non-chemotherapy alternative with promising efficacy and tolerability in a heavily pretreated population.

• Higher HER2 expression correlated with better responses, supporting the mechanism of enhanced antibody-dependent phagocytosis.

• Central HER2 confirmation is important due to tumor heterogeneity and evolving expression.

• The study supports further development of evorpacept combinations in the post-T-DXd/Enhertu setting and potentially other HER2-expressing cancers.