A Phase 1b/2 Study of JK06, a 5T4-Targeted Antibody-Drug Conjugate (ADC), in Patients with Unresectable Locally Advanced or Metastatic Cancer.

3038 Background: 5T4, a Type I transmembrane glycoprotein, is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 & WNT signaling pathways contributing to epithelial to mesenchymal transition contributing to metastatic progression & correlates with poor clinical outcomes among a range of cancers, such as NSCLC, CRC & ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels & poor intrinsic internalization kinetics. Methods: Pts with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive IV JK06 monotherapy once every 3 wks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two doses of JK06 to identify an RP2D in NSCLC & breast cancer. Fresh & archival tumor biopsies are being collected for retrospective correlation of 5T4 expression to efficacy & safety. Responses are assessed every 9 wks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. Results: To date, 80 refractory metastatic solid tumor pts (n = 39 in dose esc; n = 41 in cohort expansions) have been treated, median age of 60 yrs, >70% treated with ≥ 3 prior lines of therapy, including >75% of treated pts with prior taxane exposure. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (35%), alopecia (18%), decreased appetite (18%), dry eye (10%) & peripheral sensory neuropathy (PSN) (9%). Among 70 pts have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, gait disturbance, keratitis, vomiting, corneal ulcer, & PSN, that resolved, with two continuing treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Four pts underwent dose reductions, and five additional pts were discontinued due to TRAEs. Among 19 response-evaluable NSCLC pts to date, a 32% ORR has been observed, with 1 confirmed complete response (cCR), 4 confirmed partial responses (cPR) (one with CNS response) & 1 with unconfirmed partial responses (uPR), with the longest continuing therapy for 51 wks. Responses have been observed in adenomatous, squamous & EGFR mutant NSCLC pts. One of seven evaluable breast cancer pts (14% ORR) achieved a cPR and remained on treatment for >27 wks. Conclusions: To date, JK06 demonstrates promising emerging clinical activity in refractory NSCLC & breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated safety & clinical activity data from both dose escalation & expansion cohorts, including the initial assessment of dose randomization, will be presented. Clinical trial information: NCT06667960 .