Xencor (XNCR) Study update summary

Study design and population

• Phase 1 XmAb819-01 evaluated IV XmAb819 in 119 patients with advanced ccRCC; 68 heavily pretreated patients were in expansion cohorts. All had prior ICI and VEGFR-TKI exposure.

• Expansion patients had a median of 3 prior regimens; 94% were IMDC intermediate- or poor-risk.

• XmAb819 is an ENPP3×CD3 bispecific T-cell engager in a 2+1 format, designed to preferentially bind and kill ENPP3-high tumor cells while sparing low-density normal tissue; ENPP3 was positive in 93.3% of evaluable tumor samples.

Efficacy findings

• Confirmed ORR at 100, 200 and 400 µg/kg was 30%, 44% and 45.5%, respectively; DCR was 86.7%, 64% and 81.8%.

• Confirmed ORR after prior HIF-2α inhibitor exposure was 34.8%, and was 45.2% after at least 2 VEGFR-TKIs; respective DCRs were 78.3% and 85.7%.

• At the Oct. 1 cutoff, the 400 µg/kg cohort (n=11) had 5 confirmed and 1 unconfirmed partial response; 6-month PFS was 82%, median PFS was not reached, and >70% remained on treatment.

• Among expansion-dose responders, 19 of 25 (76%) had ongoing responses; median time to response was 2.7 months. Median time on treatment was 7.0 months at the Sep. 1 cutoff and 7.9 months in the pooled 100–400 µg/kg population at the Oct. 1 cutoff.

• Responses continued to deepen, with some lasting nearly 2.5 years.

Safety and dose selection

• Adverse events were predominantly concentrated in priming; related TEAEs led to discontinuation in 5.9% of expansion-cohort patients, and no TEAE-related deaths were reported.

• Common Grade ≥3 related events included AST increase (35.3%), ALT increase (33.8%), rash (22.1%), hypotension (7.4%) and CRS (5.9%); cytokine-related events were described as manageable and transient.

• Rash was managed with antihistamines and steroids; transaminase elevations were self-limited, with median resolution in 7 days.

• The 400 µg/kg IV dose was selected as the proposed RP3D based on maturing efficacy and safety data; population PK modeling estimated an ~8-day terminal half-life, with predicted trough levels above the 80% cytotoxicity threshold at two-week dosing.