Abstract CT036: Bioavailability of MK-3475A (pembrolizumab with berahyaluronidase alfa; “subcutaneous pembrolizumab”) in participants with advanced or metastatic solid tumors

Abstract Background: Pembrolizumab is approved for treatment of multiple cancers as an intravenous (IV) infusion. Subcutaneous (SC) administration offers more convenience and flexibility in the clinic. We report results of the phase 1, open-label, 3475A-C18 study (NCT05017012) of MK-3475A (pembrolizumab with berahyaluronidase alfa [MK-5180], a variant of human hyaluronidase developed and manufactured by Alteogen Inc., for SC administration; “pembro SC”). Methods: Participants (pts) with unresectable advanced melanoma, metastatic non-small cell lung cancer (NSCLC), or advanced or metastatic renal cell carcinoma (RCC) were sequentially allocated to arms 1 (pembro SC 650 mg at 165 mg/mL) and 2 (pembro SC 650 mg at 130 mg/mL). In both arms, treatment cycles alternated between pembro SC Q6W and pembro 400 mg IV Q6W for 4 cycles, followed by ≤14 cycles of pembro IV Q6W; as appropriate, pts received platinum-doublet chemo (NSCLC) or axitinib (RCC). Blood samples for pharmacokinetic (PK) analyses were collected pre (cycles 1-4) and post (cycles 1-3) dose. Primary objectives: characterize the PK profile of pembro SC and estimate its bioavailability. Secondary objectives: evaluate anti-drug antibodies (ADA) against pembro SC; assess safety and tolerability of pembro SC. Tertiary objectives: evaluate systemic concentrations of and ADA against MK-5180. Results: 90 pts received pembro SC: 46 in arm 1, 44 in arm 2. 36% of pts had melanoma, 34% RCC, and 30% NSCLC. Median (range) PK results for pembro SC in cycle 1 were similar in arms 1 & 2: Cmax: 44.5 µg/mL (19.4-79.6) & 51.2 µg/mL (23.5-112); Ctrough: 15.1 µg/mL (3.76-36.1) & 16.0 µg/mL (0.595-44.4); AUC0-6wk: 1280 µg·day/mL (562-2382) & 1287 µg·day/mL (529-2648); Tmax: 6 days (3-10) & 5 days (2-10). Bioavailability and absorption rate were not meaningfully different between the two arms; mean estimated bioavailability of pembro SC was 61% (95% CI 58%-64%, CV 22%) and absorption rate was 0.301/day (95% CI 0.278-0.324, CV 43.7%). Pembro SC absorption phase was similar regardless of tumor type, injection site, or body weight. ADAs against pembro were detected in 2/83 (2%) evaluable pts. No pts had measurable MK-5180 concentrations after pembro SC dosing in the absence of positive predose samples. ADAs against MK-5180 were detected in 3/83 (4%) evaluable pts. On physical exam, 4 (9%) pts in arm 1 and 4 (9%) in arm 2 had injection site AEs in cycle 1; all events were nonserious and most were mild (grade 1). Conclusions: Pembro SC had an estimated bioavailability of 61%. Both formulation strengths (130 mg/mL and 165 mg/mL) had similar absorption PK and safety profiles. Systemic absorption of MK-5180 was negligible. Given the totality of data, pembro SC 790 mg Q6W at 165 mg/mL was selected for further clinical development, as it is expected to achieve exposures consistent with pembro IV 400 mg Q6W and allows for a smaller injection volume. Citation Format: Oscar Reig Torras, Graham Cohen, Byoung Chul Cho, Carlos Rojas, Cathryn Walton, Laura Medina, Richard Khanyile, Zsuzsanna Papai, Mallika Lala, Gina Song, Omobolaji Akala, Corlia Coetzee. Bioavailability of MK-3475A (pembrolizumab with berahyaluronidase alfa; “subcutaneous pembrolizumab”) in participants with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT036.