A phase 1b / 2 study of JK06, a 5T4-targeted antibody drug conjugate, in patients with unresectable locally advanced or metastatic cancer

5T4, a Type I transmembrane glycoprotein, has limited expression in normal adult tissues but is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 and WNT signaling pathways contributing to epithelial to mesenchymal transition and correlates with poorer clinical outcomes among a range of cancers, such as NSCLC, CRC and ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels and poor intrinsic internalization kinetics. Patients with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive intravenous JK06 monotherapy once every 3 weeks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two dose levels to identify RP2D in NSCLC and breast cancer. Fresh and archival tumor biopsies are collected for retrospective correlation of 5T4 expression to efficacy and safety. Responses are assessed every 9 weeks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. To date, sixty-nine (69) refractory metastatic solid tumor patients (n = 38 in dose escalation; n = 31 in cohort expansions) have been treated, median age of 61.5 years and > 74% of treated patients have had ≥ 3 prior lines of therapy. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (30%), alopecia (16%), decreased appetite (10%), dry eye (10%) and peripheral sensory neuropathy (PSN) (10%). At the target doses being considered for optimization, four patients (out of 62 treated patients) have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, keratitis and PSN, that resolved, with one able to continue treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Three patients underwent dose reductions, and three additional patients were discontinued due to TRAEs. One patient sustained Gr 5 treatment-related pneumonitis at a higher dose that is not being evaluated in cohort expansion. Among 13 response-evaluable NSCLC patients in dose escalation, a 38% ORR has been observed, with 1 confirmed complete response (cCR) and 4 confirmed partial responses (cPR) (one with CNS response), with the longest continuing therapy for 51 weeks. One of six evaluable breast cancer patients (17% ORR) achieved a cPR and remained on treatment for > 27 weeks. To date, JK06 demonstrates promising clinical activity among refractory NSCLC and breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated dose escalation data and initial expansion cohort data will be presented.