Final results and preliminary correlative analysis of a phase I study of anetumab ravtansine in combination with checkpoint inhibitors and gemcitabine in mesothelin-positive advanced pancreatic adenocarcinoma (NCI10208).

4205 Background: Anetumab-ravtansine (AR) is an ADC composed of IgG1 targeting the protein mesothelin (MSLN) linked to DM4, a tubulin inhibitor ( Spiliopoulou, ASCO 2022 ). Here, we present the final analysis of a phase I study evaluating AR in combination with nivolumab, ipilimumab, or gemcitabine in patients (pts) with metastatic pancreatic adenocarcinoma (PDAC). Methods: Eligible pts had histologically confirmed MSLN-positive PDAC (≥5% expression by IHC), ECOG 0–1, and progression after ≥1 prior line of systemic therapy. The dose-escalation phase included: AR + nivolumab (ARM1), AR + nivolumab + ipilimumab (ARM2), and AR + gemcitabine + nivolumab (ARM3). The latter was chosen for dose-expansion. Two dose levels of AR: DL1 5.5 mg/kg and DL2 6.5 mg/kg (RP2D) were evaluated. Blood and tissue-based correlative analysis included paired tumor biopsies on C1D7 and C2D7 for comparison of immune cell shifts by multiplex immunofluorescence. Results: As of the final data cutoff on 15/11/2023, 46 pts were treated: ARM1 (n = 11), ARM2 (n = 13), ARM3 (n = 10), and dose expansion (n = 12). Median age was 66 years (40–83), the majority were males (52.2%) and had received prior gemcitabine (63%). The median number of prior treatment lines was 2 (1–5). Among 44 evaluable pts, 95.7% experienced some treatment emergent adverse events, with G1/2 and G≥3 occurring each at 47.8%. Dose limiting toxicities occurred in 6 pts (13%): 2 in ARM2DL2 (upper gastrointestinal hemorrhage and G3 thrombocytopenia), 2 in ARM3DL2 (G3 AST and G3 ALT elevation), and 1 in each of the dose expansion DL2 (G3 AST and G3 ALT elevation). Blurred vision occurred in 13%, peripheral neuropathy in 6.5%, pneumonitis in 4.3%, and keratitis in 2.2%, most of them being G1/2. No treatment-related deaths occurred. Among 41 evaluable pts, 1 (2.2%; ARM3DL2) had a complete response, 20 (43.5%) had stable, and 20 (43.5%) had disease progression. The median duration of treatment was 7.9 (1.9-32.9) weeks which was statistically longer in pts with stable disease than those with progressive disease as best response (16.4 vs 6.3 weeks, respectively; p < 0.05). Twenty-seven pts were included in the multiplex immunofluorescence, and no statistically immune-cell shifts were detected between C1D7 and C2D7. Conclusions: AR had an acceptable safety profile in PDAC and the 6.5 mg/kg was identified as the R2PD. Evidence of clinical benefit was observed with some pts with prolonged disease stabilization and one complete response in a setting of limited therapeutical options. Correlative analysis to identify predictive biomarkers for treatment benefit is ongoing. Clinical trial information: NCT03816358 .