MRG003 Plus HX008 as First-Line Treatment for EGFR-Positive Locally Advanced or Metastatic Penile Squamous Cell Carcinoma

Penile squamous cell carcinoma (PSCC) is a superficial tumor that could theoretically be detected early. However, due to social stigma and privacy concerns, patients often delay seeking medical attention until the disease reaches an advanced stage. For advanced PSCC, systemic therapy plays a crucial role in disease management. Currently, there is limited literature on palliative chemotherapy for advanced or recurrent cases, and prospective controlled studies are lacking.

Both the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) guidelines recommend chemotherapy as the first-line treatment. However, chemotherapeutic agents show limited efficacy in penile squamous cell carcinoma, with single-agent response rates (e.g., bleomycin, methotrexate, 5-FU, cisplatin) below 20%. Treatment options after chemotherapy failure are also scarce. Combination chemotherapy regimens, such as TIP (paclitaxel, ifosfamide, cisplatin) or PF (cisplatin + 5-FU), demonstrate higher response rates (30-50%).

Based on our preclinical research and clinical experience, the investigators believe that investigating the efficacy and safety of combining EGFR-targeted therapy, immunotherapy, and chemotherapy in PSCC is warranted. This study aims to explore a novel and effective treatment option for EGFR-positive locally advanced or metastatic PSCC patients by combining an EGFR-targeted antibody-drug conjugate (MRG003) with a PD-1 inhibitor (HX008).

MRG003 is an EGFR-targeted ADC composed of three key components: Anti-EGFR monoclonal antibody (JMT101), Potent cytotoxic payload (monomethyl auristatin E, MMAE), and Cleavable linker (valine-citruline, vc linker). MRG003 is synthesized by conjugating chemically synthesized vc-MMAE with CHO cell-expressed JMT101.

HX008 is a novel neutralizing and blocking monoclonal antibody targeting human programmed death-1 (PD-1) independently developed by Hanchong Biotechnology. As a human immunoglobulin G4/kappa (IgG4/κ) subtype antibody, it exhibits high binding affinity to PD-1 and selectively blocks the interaction between PD-1 and its ligands programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), thereby activating T lymphocytes, enhancing lymphocyte proliferation, and promoting cytokine secretion, particularly interferon-gamma (IFN-γ). The primary pharmacodynamic studies of HX008 included in vitro PD-1 binding affinity assessment, cross-species binding specificity analysis, blockade of PD-1/PD-L1 and PD-1/PD-L2 interactions, T cell activation evaluation, as well as in vivo antitumor activity testing in both HCC827 human non-small cell lung cancer (NSCLC) xenograft models and PD-1 humanized genetically engineered mouse (HuGEMM) MC38 syngeneic colon tumor models. HX008 received clinical trial approval (No. 2017L04642) from China's National Medical Products Administration (NMPA) on August 28, 2017, and has since been undergoing multiple clinical trials in China for the treatment of various malignant tumors.

Clinical studies have demonstrated that the combination therapy of Adcetris® (Brentuximab Vedotin) and Nivolumab in a phase I/II clinical trial for relapsed or refractory Hodgkin lymphoma showed superior efficacy. Among 62 patients who received four cycles of combination treatment, 61% achieved complete response (CR), significantly higher than the CR rates of 34% and 9% observed with Adcetris® and Nivolumab monotherapies, respectively, indicating enhanced therapeutic benefits from the combination. When administered at their respective recommended phase II doses (RP2D) (BV 1.8 mg/kg, Nivo 3 mg/kg, every 3 weeks), the combination was well-tolerated, with a safety profile consistent with those of the individual agents. Additionally, increased levels of pro-inflammatory cytokines and chemokines were observed during combination therapy, suggesting synergistic effects between ADC and immunotherapy.

Similarly, preliminary results from a phase I clinical trial (NCT03288545) evaluating Padcev® (Enfortumab Vedotin) plus Pembrolizumab as first-line treatment for locally advanced or metastatic urothelial carcinoma demonstrated a significantly higher objective response rate (ORR) with the combination (71%) compared to Padcev® (44%) or Pembrolizumab (21%) monotherapies. At their respective RP2D doses (EV 1.25 mg/kg, Pembro 200 mg, every 3 weeks), the combination exhibited favorable tolerability, with a safety profile similar to that of each drug alone. These preclinical and clinical findings strongly support the synergistic antitumor effects of combining immune checkpoint inhibitors with ADCs, providing robust evidence for the potential of PD-1/PD-L1 immunotherapies in combination with ADC-based treatments.

This trial will evaluate the efficacy and safety of MRG003 (recombinant humanized anti-EGFR mAb-MMAE conjugate) combined with HX008 (recombinant humanized anti-PD-1 mAb) as first-line therapy in EGFR-expressing locally advanced or metastatic PSCC patients. MRG003 (2.0 mg/kg, IV, Q3W) and HX008 (200 mg, IV, Q3W) will be administrated on enrolled patients. Treatment continues until disease progression, intolerable toxicity, withdrawal, death, or sponsor termination. After treatment completion, all patients will undergo survival follow-up every 3 months until death, loss to follow-up, consent withdrawal, or study termination by the sponsor.