Genmab Drops Two Antibody Assets, Including Another ProfoundBio ADC

Genmab Discontinues Two Antibody Programs, Including ProfoundBio ADC

Genmab has discontinued two clinical programs: GEN1286, an antibody-drug conjugate (ADC) from its 2024 ProfoundBio acquisition, due to an unfavorable benefit-risk profile in a Phase 1/2 trial for advanced solid tumors, and GEN1057, a bispecific antibody from its DuoBody platform, due to marginal anti-tumor activity in a Phase 1 trial for malignant solid tumors. These follow previous discontinuations of GEN1160 and GEN1107, leaving rinatabart sesutecan (Rina-S) as the sole remaining asset from the $1.8 billion ProfoundBio acquisition. The company emphasizes its rigorous internal evaluation framework for advancing assets.

• Genmab terminated the GEN1286 program, an antibody-drug conjugate acquired through the $1.8 billion ProfoundBio deal, due to an unfavorable benefit-risk profile. This Phase 1/2 trial, which launched post-acquisition, enrolled only 23 out of an anticipated 260 patients with advanced solid tumors before its discontinuation in March, as reported on ClinicalTrials.gov.
• Separately, Genmab also scuttled GEN1057, an investigational bispecific antibody developed using its proprietary DuoBody technology, which originated from a 2012 collaboration with Johnson & Johnson’s Janssen unit. The Phase 1 trial for malignant solid tumors was halted due to marginal anti-tumor activity observed in patients whose disease had progressed on standard of care therapy, according to ClinicalTrials.gov.
• With the discontinuation of GEN1286, rinatabart sesutecan (Rina-S) remains the last clinical candidate from Genmab’s $1.8 billion ProfoundBio acquisition. Rina-S, an ADC targeting folate receptor alpha (FRα), is currently being studied in Phase 3 trials for endometrial and ovarian cancer, as well as a mid-stage study for non-small cell lung cancer, positioning it as a potentially best-in-class asset.
• These program cuts align with Genmab’s rigorous internal evaluation framework and high threshold for advancing assets, as confirmed by a company spokesperson. Despite the discontinuations, Genmab reported a 25% revenue growth in the most recent quarter compared to 2025, indicating continued disciplined investment in its late-stage portfolio, which includes Epkinly and Rina-S.

Navigating the Evolving Landscape for Advanced Solid Tumors

The treatment landscape for advanced solid tumors has undergone substantial transformation over the past five years, with several breakthrough therapeutic approaches reshaping clinical practice. Most notably, ultra-low-dose nivolumab emerged as a significant advancement in 2026, with the DELII phase III trial demonstrating superior overall survival compared to chemotherapy (5.88 vs 4.70 months, HR 0.80, P=0.022) while maintaining a more favorable safety profile with fewer grade ≥3 treatment-related adverse events (42.5% vs 60.8%). Concurrently, the identification of PD1 mRNA expression as a pan-cancer biomarker through the SOLTI-1904 ACROPOLI trial revealed promising efficacy across 19 histologies, achieving objective response rates of 17.9% in PD1-high tumors and extending responses to traditionally immunotherapy-resistant cancers including pancreatic and microsatellite-stable colorectal cancers.

Precision medicine approaches have evolved significantly through enhanced molecular profiling capabilities and novel therapeutic modalities. Antibody-drug conjugates have emerged as particularly effective agents, demonstrating the highest objective response rates (31.9%) and disease control rates (68.1%) in late-line settings, with superior median progression-free survival compared to genomically-matched therapies (4.0 vs 1.9 months). Tumor mutational burden validation studies confirmed TMB-high cancers (≥10 mutations/Mb) as predictive of improved outcomes with immune checkpoint inhibitors, showing significantly longer overall survival (HR 0.72, P=0.01) and progression-free survival (HR 0.62, P=0.003) across multiple cancer types. Additionally, comprehensive circulating tumor DNA profiling using FoundationOne Liquid CDx identified actionable targets in 64% of 1,772 patients with metastatic solid tumors, facilitating matched therapy recommendations for 56% of cases.

The safety and tolerability profile of immunotherapies has been refined through comparative analyses demonstrating that PD-L1 inhibitors confer superior tolerability compared to PD-1 inhibitors, with significantly reduced treatment discontinuation due to immune-related adverse events (OR 0.38, 95% CI 0.16-0.88). Novel combination strategies have expanded therapeutic options, including bispecific antibodies like FS118 targeting LAG-3 and PD-L1, achieving disease control rates of 54.8% in patients with acquired PD-(L)1 resistance. Meanwhile, innovative approaches such as mRNA vaccines have shown modest but meaningful clinical activity with pooled objective response rates of 10.0% and favorable safety profiles, while the integration of palliative radiotherapy with systemic treatments demonstrated substantial overall survival improvements in metastatic colorectal cancer patients (50.8 vs 32.2 months).

Rina-S and the Future of FRα-Targeted Therapies

Recent research has identified several promising therapeutic targets for advanced solid tumors, spanning from novel kinase inhibitors to innovative immune-based approaches. Multiple receptor tyrosine kinases have emerged as significant targets, including NIMA-Related Kinase 2 (NEK2), a serine/threonine kinase pivotal for centrosome separation and mitotic fidelity that has been recognized as a driver of oncogenesis and contributor to therapeutic resistance. NEK2 dysregulation causes chromosomal instability, metastatic progression, and immune evasion by disrupting centrosome dynamics and rewiring oncogenic pathways such as PI3K-AKT and Wnt/β-catenin, with overexpression correlating with poor prognosis and chemoresistance. Additionally, C-X-C chemokine receptor 4 (CXCR4), a G protein-coupled receptor implicated in tumor progression and therapy resistance, has attracted considerable attention for its role in promoting malignant cell survival through microenvironmental retention and activation of pro-survival pathways.

The therapeutic landscape has been further enriched by advances in engineered cell therapies and novel targeting strategies. T-cell engager platforms have expanded to target tumor-associated antigens including STEAP1, MUC16, and PRAME, following the clinical validation of tebentafusp in metastatic uveal melanoma and tarlatamab in small-cell lung cancer. Engineered T-cell therapies targeting cancer-testis antigens have emerged as a standard-of-care option in synovial sarcoma and are being expanded to other histologies. The FDA authorized six novel kinase inhibitors in 2025—zongeritinib, sunvozertinib, vimseltinib, mirdametinib, avutometinib, and defactinib—demonstrating particular clinical success in hematologic cancers and specific solid tumors such as non-small cell lung cancer.

Innovative combination approaches and metabolic targeting strategies represent another frontier in advanced solid tumor therapeutics. Proteasome inhibition with bortezomib has shown enhanced anti-PD-L1 therapy efficacy by stabilizing IFN-γ receptor α chain expression and enhancing IFN-γ-triggered DNA damage and STING activation. Metabolic targets focusing on glycolysis inhibition aim to overcome the immunosuppressive tumor microenvironment by targeting the Warburg effect, which shifts cancer cells toward glycolysis and produces immunosuppressive metabolites. CXCR4-targeted therapeutic strategies encompass peptide antagonists, radioligand therapies, small-molecule inhibitors, and monoclonal antibodies, while antibody-drug conjugates continue to be developed and optimized across multiple therapeutic targets for solid tumors.

ProfoundBio Acquisition: All Eyes on Rina-S After Pipeline Cuts

The recent announcement from Genmab regarding the discontinuation of two clinical programs, GEN1286 and GEN1057, sends a clear signal about the challenging realities of drug development, particularly in oncology. GEN1286, an antibody-drug conjugate (ADC) acquired through the $1.8 billion ProfoundBio deal, was halted due to an unfavorable benefit-risk profile in Phase 1/2 trials. This outcome is a stark reminder that even promising modalities like ADCs face significant hurdles in achieving the delicate balance between potent anti-tumor activity and acceptable tolerability. The failure of GEN1057, a bispecific antibody from Genmab's proprietary DuoBody platform, due to marginal anti-tumor activity in Phase 1, further underscores the complexities inherent in designing novel biologics that can effectively engage targets and elicit a therapeutic response.

These discontinuations, following earlier pipeline exits, have several critical implications for Genmab. Firstly, the strategic value of the ProfoundBio acquisition is now heavily concentrated on rinatabart sesutecan (Rina-S), the sole remaining clinical asset from that substantial investment. This places immense pressure on Rina-S's development trajectory, as its success is paramount to justifying the initial $1.8 billion outlay, increasing financial exposure.

Secondly, the repeated early-stage failures suggest a need for Genmab to rigorously re-evaluate its early-stage asset selection and development processes. While the company emphasizes its internal evaluation framework, the pattern of discontinuations could prompt a more conservative approach to pipeline advancement or deeper preclinical validation for future candidates, especially those integrated from acquisitions. This also carries a reputational risk, potentially influencing future M&A opportunities or collaborations.

Finally, these events highlight a broader industry trend: the high attrition rate in early-stage oncology development. For companies investing heavily in innovative platforms like ADCs and bispecifics, robust due diligence, diversified portfolios, and agile risk management strategies are not just beneficial, but essential. The path from promising preclinical data to a successful clinical product is fraught with challenges, and even well-resourced companies like Genmab are not immune to these realities. The focus now shifts to Rina-S and Genmab's ability to navigate its development successfully, transforming a high-stakes acquisition into a valuable asset.