Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Updated safety and efficacy of a phase 1b/2 study (RAMP 205).

e16403 Background: Activating KRAS mutations in pancreatic ductal carcinomas (PDAC) occur in > 90% of patients (pts). Avutometinib (A) is a RAF/MEK clamp that potently inhibits MEK kinase while blocking compensatory reactivation of MEK. Defactinib (D) is a selective inhibitor of FAK, a target shown to mediate resistance. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing A/D + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Preliminary data suggest synergistic activity with this combination. Updated data on additional dosing cohorts are presented here. Methods: Eligible pts had histologically confirmed newly diagnosed metastatic PDAC and measurable disease, ECOG PS ≤1, adequate organ function, and no prior treatment for metastatic disease. Pts were treated in 3+3 cohorts with escalating oral doses of A and D in combination with IV doses of GnP on a 4-week schedule (Table). Results: At data cutoff (03Jan2025), 54 pts were enrolled and included in the safety analysis: 46% men, median age 59 years (range, 36-79), and 42.5% (23/54) ECOG PS of 1. Pts were enrolled in the following dose levels: DL1 (n = 12), DL0 (n = 6), DL-1 (n = 12), DL1a (n = 12), and DL2a (n = 12). The MTD has not been reached. There was one DLT: grade 3 febrile neutropenia in DL1, that resolved within 3 days. The most common treatment-related adverse events (all grades, all dose groups) were fatigue (63%), nausea (46%), neutropenia (46%), alopecia (41%), diarrhea (39%), anemia (30%), maculo-papular rash (30%), peripheral edema (28%), hyperbilirubinemia (24%), vomiting (24%), dermatitis acneiform (22%), thrombocytopenia (22%), and blurred vision (22%). The most common grade ≥3 treatment-related adverse events were neutropenia (39%), anemia (20%), fatigue (7%), and increased ALT (7%). Thirty-nine efficacy evaluable pts were enrolled at least 6 months prior to data cutoff. Objective Response Rate (ORR) and Disease Control Rate (DCR) for ≥4 cycles are listed in the Table. Conclusions: A/D + GnP have been combined in 5 dose cohorts. The MTD has not been reached. Enrollment and evaluation of mature data are ongoing to identify the recommended phase 2 dose. Clinical trial information: NCT05669482 . RAMP 205 dose levels and efficacy for patients enrolled ≥6 months prior to data cutoff. Dose Level A(mg) BIW* D(mg) BID* Gemcitabine (mg/m 2 ) Nab-Paclitaxel (mg/m 2 ) Days Chemo Dosing ORR% (n/N) DCR≥4 cycles% (n/N) 1 2.4 200 800 125 1,8,15 83% (5/6) 83% (5/6) 0 3.2 200 800 100 1,8,15 100% (1/1) 100% (1/1) -1 ^ 2.4 200 800 100 1,8,15 27% (3/11) † 82% (9/11) 1a # 3.2 200 800 125 1,15 33% (3/9) ◊ 56% (5/9) 2a 3.2 200 1000 125 1,15 25% (3/12) 58% (7/12) *Dosing 3 / 4 weeks. ^ 1 pt excluded from efficacy analysis due to no post baseline scan. # 3 pts excluded from efficacy analysis: 1 due to no post baseline scan and 2 due to incorrect histology per eligibility criteria. † Includes 2 unconfirmed responses. ◊Includes 1 unconfirmed response.