Background: Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell-directing activity. Ami monotherapy has demonstrated meaningful clinical activity in MET-driven advanced NSCLC, including in patients (pts) harboring MET exon 14 skipping mutations (METex14) (1) and MET amplification (amp) (2) Capmatinib (cap) is an intracellular-targeting MET TKI approved for METex14-mutated advanced NSCLC (3). Simultaneously targeting MET’s extracellular and intracellular regions could achieve more potent inhibition than either agent alone. Here, we report preliminary results and the identification of the recommended phase 2 combination dose (RP2CD). Methods: The open-label METalmark study (NCT05488314) includes a combination dose selection phase in pts with advanced NSCLC, followed by an expansion phase in pts with treatment-naïve METex14, refractory METex14, or MET amp (3 cohorts), lacking EGFR or ALK mutations. For phase 1 dose-selection, pts must have had disease progression on or intolerance to prior therapy. Dose levels assessed were DL0 at 700 mg (1050 mg if ≥80 kg) ami IV + 400 mg oral cap twice daily (BID) and DL+1 at 1050 mg (1400 mg if ≥80 kg) ami IV + 400 mg cap oral BID. Primary endpoints were dose-limiting toxicity (DLT) during Cycle 1, Days 1-28 and safety. Results: As of 8 Nov 2023, 18 pts were dosed, with a median follow-up of 3.3 months. There were 10 pts at DL0 (9 DLT evaluable) and 8 pts at DL+1 (all DLT evaluable). In the first DL0 cohort, 1 pt (of 4 DLT evaluable) reported a DLT, grade 3 nausea, prior to the adoption of nausea/vomiting recommendations. Among the remaining 5 DLT-evaluable pts at DL0, there were no DLTs, meeting prespecified criteria for escalation to DL+1. No DLTs were observed among the 8 pts at DL+1. Among all pts, the median number of prior lines was 3 (range, 1–5) and the following driver mutations were detected: EGFR Ex19del (6 pts) and L858R (6 pts), METex14 (4 pts), MET amp (2 pts), EGFR Exon 20 insertion (1 pt), and KRAS G12V (1 pt). There was 1 partial response (PR; MET amp+Ex19del), 2 unconfirmed PRs (1 METex14, 1 L858R; both ongoing), and 8 stable diseases observed as a best overall response. Preliminary PK data suggest similar exposure for the combination vs individual agents. Among the 8 treatment discontinuations, 6 were due to progressive disease, 1 withdrew consent, and 1 due to respiratory failure (unrelated to study treatments). Most common AEs were primarily EGFR- and MET-related. Rate of peripheral edema was 28% (5/18), none grade ≥3. Updated results will be reported at the meeting. Conclusions: RP2CD for ami+cap was identified as a combination of each approved dose. Initial safety profile of ami+cap does not appear to have additive MET-related toxicities. 1. Leighl JTO 2023;18(11):S93-94, OA21.04. 2. Haura JCO 2019;37:15_suppl, 9009. 3, Wolf NEJM 2020;383(10):944-957. Clinical trial information: NCT05488314.