A Comprehensive Report on Acasunlimab (GEN1046/BNT311): A Novel Bispecific Antibody for CPI-Refractory Malignancies

Executive Summary

Acasunlimab, also identified by the development codes GEN1046 and BNT311, is an investigational, first-in-class bispecific antibody at the forefront of next-generation immuno-oncology therapeutics.[1] Engineered using Genmab's proprietary DuoBody® technology platform, this molecule is designed as an Fc-inert bispecific antibody that concurrently targets two critical immune regulatory pathways: Programmed Death-Ligand 1 (PD-L1) and 4-1BB (CD137).[2] Its innovative mechanism of action is twofold, combining the established principle of immune checkpoint inhibition with a novel, safety-engineered approach to T-cell co-stimulation. Acasunlimab simultaneously blocks the inhibitory PD-1/PD-L1 axis while delivering a conditional, PD-L1-dependent agonistic signal to the 4-1BB receptor on T cells and Natural Killer (NK) cells, a design intended to localize potent immune activation within the tumor microenvironment and mitigate systemic toxicities.[5]

The clinical development program has primarily focused on addressing the significant unmet medical need in patients with malignancies that have progressed on or after standard-of-care checkpoint inhibitor (CPI) therapy. The most compelling clinical data to date emerge from the randomized, Phase 2 trial (NCT05117242) in patients with previously treated, PD-L1-positive metastatic non-small cell lung cancer (mNSCLC). In this challenging patient population, the combination of acasunlimab with the anti-PD-1 antibody pembrolizumab, administered on a once-every-six-weeks (Q6W) schedule, demonstrated a remarkable median Overall Survival (mOS) of 17.5 months and a 12-month OS rate of 69%.[8] These results stand in stark contrast to the historically poor outcomes with standard chemotherapy in this setting.

The safety profile of acasunlimab, particularly in combination with pembrolizumab, is considered manageable, with the majority of treatment-related adverse events (TRAEs) being Grade 1 or 2.[3] However, hepatotoxicity has been identified as a notable adverse event of special interest, requiring diligent monitoring. The Q6W dosing schedule was associated with a more favorable safety profile, including a lower incidence of severe liver-related events and treatment discontinuations compared to a more frequent Q3W schedule.[3]

Strategically, the acasunlimab program underwent a significant pivot in August 2024, when Genmab assumed sole responsibility for its continued development and potential commercialization after its partner, BioNTech, opted out for portfolio-related reasons.[4] Genmab is now advancing acasunlimab into a pivotal, international Phase 3 trial (NCT06635824), which will compare the acasunlimab-pembrolizumab combination against docetaxel in CPI-refractory mNSCLC.[17] Acasunlimab remains an investigational agent with no marketing approvals from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[19]

In conclusion, acasunlimab represents a highly promising therapeutic candidate with the potential to establish a new standard of care for patients with CPI-refractory mNSCLC. Its impressive survival benefit in Phase 2 trials positions it as a potential breakthrough, though this promise must be weighed against a safety profile that necessitates careful clinical management. The successful execution of the ongoing Phase 3 trial will be the ultimate determinant of its future role in the oncology armamentarium.

Pharmacology and Mechanism of Action: A Dual-Targeting Immunomodulatory Strategy

The therapeutic concept underpinning acasunlimab is rooted in the sophisticated understanding of T-cell regulation and the mechanisms by which tumors evade immune surveillance. By simultaneously modulating both an inhibitory and a co-stimulatory pathway, acasunlimab is designed to overcome the limitations of existing immunotherapies and reinvigorate a potent, targeted anti-tumor immune response.

The Scientific Rationale for Bispecific Targeting of PD-L1 and 4-1BB

The advent of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has revolutionized the treatment of numerous malignancies, including NSCLC.[21] These agents function by blocking the interaction between the PD-1 receptor on activated T cells and its ligand, PD-L1, which is often overexpressed by tumor cells. This interaction serves as an "off switch" or brake on the immune system, leading to T-cell exhaustion and immune tolerance of the tumor. By inhibiting this checkpoint, therapies like pembrolizumab effectively release the brakes on the immune system, restoring the ability of T cells to recognize and eliminate cancer cells.[6]

Despite this paradigm shift, a substantial proportion of patients, estimated at 70–85%, either do not respond to initial PD-1/PD-L1 blockade (primary resistance) or develop resistance after a period of clinical benefit (acquired resistance).[21] This clinical reality underscores the need for therapeutic strategies that go beyond simply removing inhibitory signals. One of the key mechanisms of resistance is the persistence of a dysfunctional or "exhausted" state in tumor-infiltrating lymphocytes (TILs), which may require an active, positive signal to restore their full effector function.

This is the scientific foundation for targeting 4-1BB (also known as CD137 or TNFRSF9), a co-stimulatory receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily.[6] Unlike PD-1, which is an inhibitory receptor, 4-1BB is an inducible co-stimulatory molecule expressed on activated T cells and NK cells. Engagement of 4-1BB provides a potent "go" signal that promotes T-cell proliferation, survival, cytokine production, and cytolytic activity.[6] Preclinical studies have consistently demonstrated that combining PD-(L)1 blockade with a 4-1BB agonist can act synergistically to reinvigorate exhausted CD8+ TILs and produce durable anti-tumor responses, a more potent effect than either agent alone.[1] Acasunlimab was engineered to deliver both of these complementary actions—releasing the PD-L1 brake and stepping on the 4-1BB accelerator—within a single molecule.

Molecular Engineering: The DuoBody® Platform and the Significance of an Fc-Inert Backbone

Acasunlimab is a recombinant, humanized immunoglobulin G1 (IgG1​) bispecific antibody developed using Genmab's proprietary DuoBody® technology.[3] This platform enables the efficient generation of stable, full-length bispecific antibodies by facilitating a controlled exchange of antibody half-molecules (one heavy and one light chain) from two different parent antibodies, resulting in a heterodimeric molecule with two distinct antigen-binding arms.[22]

A critical and deliberate feature of acasunlimab's design is its "Fc-inert" or "Fc-silenced" backbone.[2] The fragment crystallizable (Fc) region of a standard antibody interacts with Fc receptors (

FcγR) on various immune cells, such as macrophages and NK cells, triggering effector functions like antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).[23] While beneficial for some therapeutic antibodies, this activity proved to be a major liability for early-generation 4-1BB agonistic antibodies. Systemic engagement of 4-1BB, amplified by non-specific cross-linking via Fc receptors, led to widespread, off-target immune activation and severe, dose-limiting toxicities, most notably hepatotoxicity.[23]

By introducing specific mutations into the Fc region, acasunlimab's ability to bind to Fc receptors is abrogated. This engineering choice is not merely a safety enhancement but is fundamental to the drug's core mechanism. By eliminating Fc-mediated effects, the design ensures that any immune activation is driven solely by the intended, antigen-specific interactions of its binding arms. This allows the innovative conditional agonist activity to function as designed, without the confounding and toxic effects of non-specific systemic activation.

Conditional 4-1BB Agonism: A Strategy to Mitigate Systemic Toxicity

The central innovation of acasunlimab is its mechanism of conditional 4-1BB agonism. The 4-1BB-binding arm of the antibody is designed to act as a potent agonist, but only when it is cross-linked or clustered on the surface of a T cell. In the absence of such cross-linking, the antibody has minimal to no agonistic activity. Acasunlimab achieves this targeted cross-linking by leveraging its second arm, which binds to PD-L1.[3]

The activation sequence is as follows: acasunlimab first binds to PD-L1, which is expressed on tumor cells or other immune cells within the tumor microenvironment (TME). This binding effectively "tethers" the antibody to the tumor site. Once anchored, the antibody's free 4-1BB binding arm can then engage with 4-1BB receptors on nearby activated T cells or NK cells. This simultaneous binding to both PD-L1 on one cell and 4-1BB on another creates a cellular bridge, forcing the 4-1BB receptors on the T-cell surface to cluster together. This clustering mimics the natural physiological activation of the receptor and triggers the potent co-stimulatory signal.[4]

This elegant design ensures that the powerful 4-1BB agonism is spatially restricted to the sites of disease where PD-L1 is present, such as the TME and tumor-draining lymph nodes.[22] This localized activation is intended to maximize the anti-tumor effect while minimizing the risk of systemic, off-target immune-related adverse events, particularly the hepatotoxicity that plagued earlier, non-conditional 4-1BB agonists.

Preclinical Evidence Supporting the Therapeutic Hypothesis

An extensive body of preclinical research provides a robust foundation for the clinical development of acasunlimab. In vitro studies using primary mouse and human immune cells have consistently shown that acasunlimab enhances T-cell and NK-cell function through its conditional 4-1BB stimulation, while simultaneously blocking the PD-1/PD-L1 inhibitory axis.[7] These studies demonstrated that the molecule promotes dose-dependent T-cell proliferation, increases the secretion of key pro-inflammatory cytokines such as interleukin-2 (IL-2) and interferon-gamma (

IFN−γ), and potentiates antigen-specific T-cell-mediated cytotoxicity against tumor cells.[7]

The therapeutic hypothesis was further validated in multiple in vivo animal models. In syngeneic mouse tumor models (such as CT26 and MC38), a mouse-surrogate version of acasunlimab exhibited potent anti-tumor activity, leading to complete tumor rejection in a significant fraction of animals, including in models that were unresponsive to PD-L1 blockade alone.[7] The anti-tumor effect was even more pronounced when acasunlimab was combined with a separate anti-PD-1 antibody. In humanized mouse models expressing human PD-1, PD-L1, and 4-1BB, the combination of a chimeric acasunlimab and pembrolizumab strongly inhibited tumor growth, induced durable complete tumor regressions, and established long-lasting immunological memory, as evidenced by the fact that cured mice were protected from tumor re-challenge.[2]

Mechanistically, these preclinical studies offered critical insights that directly informed the clinical strategy. It was observed that the combination of acasunlimab with full PD-1 blockade amplified the depth and duration of the anti-tumor immune response by promoting an autocrine IL-2–CD25 signaling loop. This led to an increased proportion of highly potent, granzyme B-positive (GZMB+) stem-like CD8+ TILs, which are thought to possess superior effector function and self-renewal capacity.[22] Furthermore, pharmacokinetic and pharmacodynamic modeling revealed that the doses of acasunlimab required for optimal 4-1BB activation resulted in only partial blockade of the PD-1/PD-L1 axis.[22] This finding provides a compelling biological explanation for the observed synergy with a dedicated PD-1 inhibitor like pembrolizumab. The addition of pembrolizumab ensures complete blockade of the PD-1 receptor from both its ligands (PD-L1 and PD-L2), allowing acasunlimab to focus on delivering its maximal 4-1BB co-stimulatory signal, thereby achieving a more comprehensive and potent immune activation than either agent could achieve alone.

The Acasunlimab Clinical Development Program

The clinical development of acasunlimab has been pursued through a systematic and evidence-driven program, progressing from broad, early-phase safety and dose-finding studies to targeted, indication-specific trials designed for potential registration. The strategy has centered on heavily pretreated patient populations with a high unmet medical need, particularly those who have become refractory to standard-of-care checkpoint inhibitors.

Overview of Clinical Strategy

The clinical journey for acasunlimab began with a first-in-human (FIH), Phase 1/2a trial (NCT03917381) designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of the agent in patients with a wide range of advanced solid tumors.[19] This foundational study employed a dose-escalation design to identify the recommended Phase 2 dose (RP2D) and subsequently opened expansion cohorts to gather more data on specific tumor types and treatment combinations.[19] Based on encouraging early signals, particularly in non-small cell lung cancer, the program pivoted to more focused, later-stage trials. The primary strategic focus became the development of acasunlimab in combination with a PD-1 inhibitor for patients with metastatic NSCLC who had progressed on prior CPI-containing therapy.[2] The program has also expanded to investigate other CPI-refractory settings, such as advanced cutaneous melanoma, reflecting a broader strategy to target tumors where PD-L1 is expressed and where reinvigorating an exhausted T-cell response is a rational therapeutic goal.[24]

Key Clinical Trials

The acasunlimab clinical program is composed of several key studies, each designed to answer specific questions regarding the drug's safety, efficacy, and optimal use.

• NCT03917381 (GCT1046-01): This Phase 1/2a study served as the entry point for acasunlimab into clinical testing. Initiated in May 2019, this open-label, multi-center trial enrolled patients with various malignant solid tumors who had exhausted standard treatment options.[19] The initial dose-escalation phase (Phase 1) was crucial for establishing the RP2D and characterizing dose-limiting toxicities. The subsequent expansion phase (Phase 2a) evaluated acasunlimab at the RP2D, both as a monotherapy and in combination with docetaxel, pembrolizumab, or pembrolizumab plus chemotherapy in specific tumor cohorts.[19] Early results from this trial demonstrated a manageable safety profile and provided the first signals of clinical activity and pharmacodynamic immune effects consistent with the drug's mechanism of action, paving the way for further development.[31]
• NCT05117242 (GCT1046-04): This randomized, open-label Phase 2 trial is the source of the most significant clinical data for acasunlimab to date. The study specifically enrolled patients with PD-L1-positive (Tumor Proportion Score ≥1%) metastatic NSCLC whose disease had progressed after treatment with a PD-(L)1 inhibitor and platinum-based chemotherapy.[12] The trial's three-arm design was instrumental in defining the optimal therapeutic strategy, comparing acasunlimab monotherapy against two different combination regimens with pembrolizumab (dosed every three weeks or every six weeks).[12] The primary efficacy endpoint was Overall Response Rate (ORR), with key secondary endpoints including Overall Survival (OS) and Progression-Free Survival (PFS).[3] The highly encouraging survival data from this trial directly informed the design of the subsequent pivotal study.[8]
• NCT06635824 (ABBIL1TY NSCLC-06): This ongoing, international, randomized Phase 3 trial is the pivotal study intended to support regulatory approval. Building directly on the findings from the Phase 2 trial, ABBIL1TY NSCLC-06 is designed to definitively evaluate the efficacy and safety of the optimal acasunlimab regimen (100 mg acasunlimab plus 400 mg pembrolizumab administered Q6W) against the established standard of care, docetaxel.[17] The trial is enrolling the same patient population of PD-L1-positive mNSCLC patients who have progressed after prior CPI and platinum chemotherapy.[17] The primary endpoint is OS, a gold-standard measure for demonstrating clinical benefit in oncology.[18] A positive outcome in this trial would be practice-changing for this patient population.
• NCT06984328 (ABBIL1TY MELANOMA-07): This Phase 2, randomized, open-label trial extends the investigation of acasunlimab to another key immuno-oncology indication: relapsed/refractory, unresectable locally advanced or metastatic cutaneous melanoma.[30] The study enrolls adult patients whose disease has progressed on or after prior CPI-containing therapy. It employs a 1:1 randomization to evaluate acasunlimab as a monotherapy versus acasunlimab in combination with pembrolizumab, both administered on a Q6W schedule.[30] The primary endpoint is ORR, with secondary endpoints including Duration of Response (DOR), PFS, and OS.[30]
• NCT04937153 (GCT1046-02): This Phase 1 dose-escalation trial was conducted specifically in Japanese patients with advanced solid malignancies.[37] Such regional studies are often required by regulatory authorities like Japan's Pharmaceuticals and Medical Devices Agency (PMDA) to assess the safety, tolerability, and pharmacokinetics of a new drug in the local population, ensuring there are no significant ethnic differences in drug metabolism or toxicity before proceeding to larger trials in the region. The study evaluated acasunlimab both as a monotherapy and in combination with pembrolizumab.[37]

The following table provides a consolidated overview of these key clinical trials.

ClinicalTrials.gov ID	Trial Identifier	Phase	Indication(s)	Patient Population	Status (as of late 2024/early 2025)	Primary Interventions
NCT03917381	GCT1046-01	I/II	Malignant Solid Tumors	Advanced/metastatic solid tumors, refractory to standard therapy	Active, not recruiting	Acasunlimab monotherapy; Acasunlimab + Pembrolizumab; Acasunlimab + Docetaxel
NCT05117242	GCT1046-04	II	Metastatic NSCLC	PD-L1+, previously treated with CPI and chemotherapy	Active, not recruiting	Acasunlimab monotherapy; Acasunlimab + Pembrolizumab (Q3W & Q6W)
NCT06635824	ABBIL1TY NSCLC-06	III	Metastatic NSCLC	PD-L1+, previously treated with CPI and chemotherapy	Recruiting	Acasunlimab + Pembrolizumab (Q6W) vs. Docetaxel
NCT06984328	ABBIL1TY MELANOMA-07	II	Cutaneous Melanoma	Relapsed/refractory, unresectable locally advanced or metastatic, post-CPI	Recruiting	Acasunlimab monotherapy vs. Acasunlimab + Pembrolizumab (Q6W)
NCT04937153	GCT1046-02	I	Advanced Solid Tumors	Japanese patients with advanced solid malignancies	Active, not recruiting	Acasunlimab monotherapy; Acasunlimab + Pembrolizumab

Clinical Efficacy in Metastatic Non-Small Cell Lung Cancer (mNSCLC)

The most mature and compelling clinical data for acasunlimab have been generated in the setting of metastatic non-small cell lung cancer, a disease area with a profound and growing unmet need for patients who have progressed on first-line immunotherapies.

The Unmet Need in CPI-Relapsed/Refractory mNSCLC

First-line treatment for patients with advanced or metastatic NSCLC without actionable oncogenic drivers is dominated by regimens containing an anti-PD-1 or anti-PD-L1 checkpoint inhibitor, either as monotherapy for tumors with high PD-L1 expression or, more commonly, in combination with platinum-based chemotherapy.[21] While these therapies have significantly improved long-term survival for a subset of patients, the majority—between 70% and 85%—will ultimately experience disease progression due to primary or acquired resistance.[21]

For this large and growing patient population, subsequent treatment options are starkly limited and offer marginal benefit. The established standard of care is single-agent chemotherapy, typically docetaxel, which is associated with low response rates in the range of 10–14% and significant toxicity.[14] Numerous clinical trials attempting to introduce novel combinations in this second-line, post-CPI setting have failed to demonstrate a survival advantage over docetaxel, leaving a critical therapeutic void.[14] It is against this backdrop of limited efficacy and high unmet need that the results for acasunlimab must be evaluated.

Analysis of the Phase 2 Trial (NCT05117242)

The randomized, open-label Phase 2 trial (NCT05117242) was designed to assess the efficacy and safety of acasunlimab in this precise patient population. The study enrolled patients with confirmed PD-L1-positive (TPS ≥1%) mNSCLC who had documented disease progression on or after receiving at least one prior line of therapy containing an anti-PD-(L)1 agent for metastatic disease.[12]

The study randomized patients into three treatment arms to compare monotherapy against two combination schedules with pembrolizumab:

• Arm A: Acasunlimab monotherapy (100 mg intravenously [IV] every 3 weeks for two cycles, followed by 500 mg IV every 6 weeks).[12]
• Arm B: Acasunlimab (100 mg IV) in combination with pembrolizumab (200 mg IV) administered Q3W.[12]
• Arm C: Acasunlimab (100 mg IV) in combination with pembrolizumab (400 mg IV) administered Q6W.[12]

The patient population, as of the January 9, 2024 data cut-off presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, comprised 98 enrolled patients, of whom 63 had centrally confirmed PD-L1 positive status and were included in the primary efficacy analyses.[12] This was a heavily pretreated cohort, representative of the real-world challenge; 86% had received prior pembrolizumab, and 64% had been treated with a concurrent regimen of a CPI plus chemotherapy, indicating a high degree of resistance to standard immunotherapy.[12]

Efficacy Outcomes: A Detailed Comparison

The results from the NCT05117242 trial, particularly from the Q6W combination arm, have been described by clinical oncology analysts as among the most promising seen in the second-line, PD-1 progressed NSCLC setting.[13]

• Overall Survival (OS): The OS data revealed a dramatic and clinically meaningful difference between the treatment arms. The standout result was in Arm C (Combo Q6W), which demonstrated a median OS of 17.5 months and a landmark 12-month OS rate of 69%.[3] In stark contrast, Arm B (Combo Q3W) showed a median OS of 8.6 months, and Arm A (Monotherapy) had a median OS of just 5.5 months.[3] The profound survival benefit observed with the less frequent Q6W dosing schedule was a pivotal finding of the study.
• Response Rates (ORR) and Disease Control Rate (DCR): While the survival data were striking, the confirmed ORRs were more modest, a common feature of immunotherapies that may confer long-term stability rather than rapid tumor shrinkage. The confirmed ORR was 13% in Arm A, 21% in Arm B, and 22% in Arm C (some reports cite 17-18% for the combination arms, likely reflecting different data cut-offs or patient subsets).[9] More indicative of the treatment's biological effect was the Disease Control Rate (DCR), defined as the percentage of patients achieving a complete response, partial response, or stable disease. The DCR was highest in Arm C at 75%, compared to 65% in Arm B and 50% in Arm A, suggesting that the combination therapy, particularly the Q6W regimen, was effective at halting disease progression in the majority of patients.[3]
• Progression-Free Survival (PFS): The PFS data further supported the superiority of the combination regimens. The 6-month PFS rates were 0% for monotherapy (Arm A), 18% for the Q3W combination (Arm B), and nearly double that at 33% for the Q6W combination (Arm C).[12] This indicates that a third of patients on the Q6W schedule remained free of disease progression at the 6-month mark, a significant achievement in this refractory population.

The following table summarizes these key efficacy outcomes.

Efficacy Endpoint	Arm A (Monotherapy)	Arm B (Combo Q3W)	Arm C (Combo Q6W)
Median Overall Survival (mOS)	5.5 months	8.6 months	17.5 months
12-Month OS Rate	Not Reported	Not Reported	69%
Confirmed Overall Response Rate (ORR)	13%	21%	22%
Disease Control Rate (DCR)	50%	65%	75%
6-Month Progression-Free Survival (PFS) Rate	0%	18%	33%

The data clearly demonstrate a dissociation between the modest objective response rates and the exceptionally strong overall survival benefit in the Q6W combination arm. This suggests that the primary therapeutic value of the acasunlimab-pembrolizumab combination may lie in its ability to induce durable disease control and fundamentally alter the natural history of the disease for a significant portion of patients, rather than simply inducing rapid tumor regressions. Such a pattern is often observed with effective immunotherapies, where survival curves separate over time, reflecting a long-term benefit for patients who achieve stable disease or a response.

Furthermore, the marked superiority of the Q6W schedule over the Q3W schedule in both efficacy (a doubling of mOS) and safety (as detailed later) is a critical observation. This is not simply a matter of convenience but points to a fundamental biological principle. Pharmacodynamic analyses from the trial showed that the Q3W regimen led to sustained target engagement, whereas the Q6W regimen resulted in intermittent engagement.[27] The prevailing hypothesis is that this intermittent stimulation provides a necessary "resting period" for T cells, preventing the chronic activation that can lead to T-cell exhaustion and functional impairment. This allows for a more robust and sustained anti-tumor immune response over the long term, providing a compelling biological rationale for the superior clinical outcomes observed with less frequent dosing.[27] This insight was instrumental in selecting the Q6W regimen for the pivotal Phase 3 trial.

Emerging Clinical Data in Other Malignancies

While mNSCLC has been the primary focus of late-stage development, the clinical program for acasunlimab includes investigations into other solid tumors, particularly those where resistance to standard checkpoint inhibition represents a major clinical challenge.

Cutaneous Melanoma (NCT06984328)

The rationale for investigating acasunlimab in advanced melanoma is strong. Similar to NSCLC, immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are the standard of care for metastatic melanoma and have led to durable, long-term remissions for many patients.[41] However, a substantial number of patients, up to 40–50%, either do not respond to initial therapy or develop acquired resistance over time, creating another population with high unmet medical need.[41]

To address this, the Phase 2 ABBIL1TY MELANOMA-07 trial (NCT06984328) was initiated.[30] This randomized, open-label study is enrolling adult patients with unresectable locally advanced or metastatic cutaneous melanoma whose disease has progressed on or after prior CPI therapy. The trial's design mirrors the successful structure of the NSCLC Phase 2 study, randomizing patients 1:1 to receive either acasunlimab monotherapy or acasunlimab in combination with pembrolizumab, with both arms utilizing the Q6W dosing schedule that proved superior in NSCLC.[30] The study aims to evaluate the efficacy and safety of these regimens, with the primary endpoint being ORR. This trial will be critical in determining if the promising activity seen in lung cancer can be translated to another major immuno-oncology indication.

Solid Tumors (NCT03917381)

The initial first-in-human trial, NCT03917381, included expansion cohorts that enrolled patients with a variety of advanced solid tumors beyond NSCLC, including endometrial cancer, cervical cancer, triple-negative breast cancer (TNBC), and squamous cell carcinoma of the head and neck (SCCHN).[1] While detailed efficacy results from these specific cohorts are not extensively reported in the available materials, the study provided crucial early validation of the drug's mechanism and therapeutic concept.

Notably, an expansion cohort specifically for patients with PD-(L)1-relapsed/refractory NSCLC within this FIH trial provided the first human evidence supporting the drug's potential in this setting.[32] Exploratory pharmacodynamic analyses from this cohort showed that treatment with acasunlimab elicited immune effects consistent with its proposed mechanism, including the induction of peripheral

IFN−γ and CXCL9/10, and the expansion of peripheral CD8+ effector memory T cells. Importantly, disease control rates were higher in patients whose tumors expressed PD-L1 and who had progressed more recently on prior anti-PD-1 therapy. These early findings provided the biological and clinical rationale to proceed with the larger, randomized Phase 2 trial in NSCLC.[32]

Safety and Tolerability Profile

A thorough evaluation of the safety and tolerability profile is paramount for any new oncology agent, particularly for an immunomodulatory drug with a potent mechanism of action. The clinical data for acasunlimab indicate a manageable safety profile, but also highlight specific adverse events that require careful clinical attention, with important differences observed between monotherapy, combination therapy, and dosing schedules.

Comprehensive Analysis of Treatment-Related Adverse Events (TRAEs)

Across the clinical program, the safety profile of acasunlimab has been characterized as manageable, with the majority of TRAEs reported as Grade 1 or 2 in severity.[3] The adverse event profile was generally consistent with what would be expected from the individual mechanisms of PD-L1 blockade and 4-1BB stimulation.

• Monotherapy (Arm A, NCT05117242): In patients receiving acasunlimab alone, the most frequently reported TRAEs (all grades) included constitutional and gastrointestinal symptoms. These were primarily asthenia (fatigue or weakness), reported in 17.4% to 22.7% of patients, diarrhea (17.4% to 18.2%), and nausea (17.4% to 18.2%). Anemia (13.6%) and liver-related events (13.0% to 13.6%) were also common.[3]
• Combination Therapy (Arms B & C, NCT05117242): When acasunlimab was combined with pembrolizumab, the spectrum of common TRAEs shifted, with immune-mediated events becoming more prominent. The most common TRAEs across the combination arms were liver-related events, fatigue, asthenia, and diarrhea.[3]

Adverse Event of Special Interest: Hepatotoxicity

Consistent with the known risks of both 4-1BB agonists and, to a lesser extent, checkpoint inhibitors, hepatotoxicity (liver-related adverse events, typically manifesting as elevated transaminase levels) emerged as the most significant adverse event of special interest.[12]

Liver-related events were the most common TRAE in the combination arms and the most frequent cause of Grade ≥3 adverse events.[12] A critical finding from the Phase 2 NSCLC trial was the difference in hepatotoxicity between the two combination dosing schedules. The incidence of all-grade liver-related AEs was substantially higher in the more frequent Q3W dosing arm (Arm B), reported at 28.6% to 29%, compared to 18.0% to 18.4% in the less frequent Q6W arm (Arm C).[3] This pattern also held for severe (Grade

≥3) liver events, which occurred in 13.3% of patients in the Q3W arm versus a lower rate in the Q6W arm.[12]

Importantly, the clinical characterization of these events suggests they are generally manageable. The transaminase elevations were reported to be largely asymptomatic and could be effectively managed with the administration of corticosteroids and/or temporary treatment delays or interruptions, according to standard clinical practice for immune-related adverse events. Notably, resolution of these events was reported to be more rapid in the Q6W arm, further supporting the superior safety profile of the less frequent dosing schedule.[3]

Discontinuation Rates and Comparative Safety

The overall safety advantage of the Q6W combination regimen was further evidenced by lower rates of severe TRAEs and treatment discontinuations. A lower incidence of Grade ≥3 TRAEs was observed in Arm C compared to Arm B.[3]

However, the rate of discontinuation due to adverse events was a notable concern across all arms, particularly the combination arms. In the Phase 2 NSCLC trial, AE-related discontinuation rates were reported as 18% for monotherapy (Arm A), a concerning 33% for the Q3W combination (Arm B), and a somewhat lower but still significant 25% for the Q6W combination (Arm C).[13] The fact that one-quarter to one-third of patients in the combination arms had to stop treatment due to toxicity is a critical finding. It suggests that while the therapy can provide profound and durable benefits for some, a substantial fraction of patients may not be able to tolerate it long enough to achieve that benefit. This underscores the clinical challenge of managing the toxicity profile and highlights the urgent need for biomarkers to better select patients who are most likely to benefit and least likely to experience severe toxicity.

The following table provides a comparative summary of the key safety findings from the Phase 2 trial.

Adverse Event	Arm A (Monotherapy)	Arm B (Combo Q3W)	Arm C (Combo Q6W)
Most Common TRAEs (all grades)	Asthenia, Diarrhea, Nausea, Anemia, Liver-related events	Liver-related events, Fatigue, Asthenia, Diarrhea	Liver-related events, Fatigue, Asthenia, Diarrhea
Liver-Related Events (all grades)	~13%	~29%	~18%
Grade ≥3 Liver-Related Events	8.7%	13.3%	Lower than Arm B
AE-Related Discontinuation	18%	33%	25%

Strategic Development and Regulatory Outlook

The development pathway for acasunlimab has been shaped by both promising clinical data and significant strategic decisions at the corporate level. Its progression towards potential market approval is now being solely championed by Genmab, with a clear regulatory strategy focused on the CPI-refractory mNSCLC indication.

The Genmab and BioNTech Partnership: A Strategic Pivot

Acasunlimab was initially developed under a collaborative agreement between Genmab, an international biotechnology company with deep expertise in antibody therapeutics, and BioNTech, a company renowned for its mRNA technology and expanding oncology pipeline.[3] The partnership leveraged Genmab's DuoBody® platform and BioNTech's immunomodulatory antibodies.[3]

However, in a significant strategic shift announced in August 2024, BioNTech opted not to participate in the further development of the acasunlimab program.[4] Despite publicly acknowledging the "encouraging" emerging clinical profile of the drug, BioNTech cited "reasons relating to its portfolio strategy" for the decision.[4] As a result, Genmab assumed sole responsibility for the continued development and potential future commercialization of acasunlimab.[4] Under the revised terms, Genmab will make certain milestone payments and pay a tiered single-digit royalty on net sales to BioNTech.[4]

This move firmly establishes acasunlimab as a cornerstone of Genmab's wholly-owned late-stage pipeline, placing both the full financial risk and the full potential commercial reward with the company.[4] While BioNTech's withdrawal from a promising asset could be interpreted in several ways—perhaps reflecting a different internal assessment of the benefit-risk profile, the high cost of Phase 3 development, or a strategic decision to focus more on its core mRNA platform—Genmab has expressed strong confidence in its ability to maximize the drug's potential and is moving forward aggressively with late-stage development.[16]

The Pivotal Phase 3 Trial (NCT06635824 / ABBIL1TY NSCLC-06)

The centerpiece of the current development strategy is the pivotal Phase 3 ABBIL1TY NSCLC-06 trial.[18] This multicenter, randomized, open-label, international study is designed to provide the definitive evidence required for regulatory submissions.

The trial's design is a direct reflection of the positive results from the Phase 2 study. It is comparing the efficacy and safety of the optimal regimen—100 mg of acasunlimab in combination with 400 mg of pembrolizumab, administered intravenously every six weeks—against the current standard of care, docetaxel (75 mg/m$^2$ IV every three weeks).[17] The study is enrolling patients with PD-L1-positive metastatic NSCLC whose disease has progressed during or after treatment with both a PD-(L)1 inhibitor and platinum-containing chemotherapy.[17]

The primary endpoint of the trial is Overall Survival, the most robust and clinically meaningful endpoint in oncology and the gold standard for regulatory approval in this setting.[18] Key secondary endpoints include Progression-Free Survival, Overall Response Rate, Duration of Response, and a comprehensive assessment of safety and patient-reported outcomes.[35] The trial, which began enrolling patients in late 2024, is expected to take several years to complete, with an estimated primary completion date in early 2027.[17] A positive result from this trial would be sufficient to form the basis of marketing applications worldwide.

Current Regulatory Status

As an investigational agent, acasunlimab has not yet been approved for marketing by any regulatory agency.

• FDA (U.S. Food and Drug Administration): Acasunlimab is currently in Phase 3 clinical development under FDA oversight.[34] It does not currently hold any special designations such as Breakthrough Therapy or Fast Track status, based on the available information. Its path to potential approval is contingent on the successful outcome of the ABBIL1TY NSCLC-06 trial.
• EMA (European Medicines Agency): Acasunlimab is not authorized for use in the European Union.[20] In a key procedural step, Genmab submitted an application for a Paediatric Investigation Plan (PIP) waiver to the EMA.[20] On July 24, 2024, the EMA's Paediatric Committee (PDCO) granted a product-specific waiver for acasunlimab for the treatment of lung cancer. The waiver was granted on the grounds that lung cancer is a disease that occurs only in adult populations, thus obviating the need for pediatric studies for this indication.[20] This decision is a standard part of the regulatory process and removes a potential hurdle for a future Marketing Authorization Application (MAA) for the adult population.

Expert Synthesis: Positioning Acasunlimab in the Future of Oncology

Acasunlimab stands at a critical juncture, with a profile characterized by potentially practice-changing efficacy in a population with high unmet need, counterbalanced by a notable but manageable safety profile. Its future trajectory will depend on the confirmation of its Phase 2 promise in the ongoing pivotal trial and its ability to carve out a unique position in an increasingly complex and competitive immuno-oncology landscape.

Critical Appraisal of the Benefit-Risk Profile

The core value proposition of acasunlimab lies in its potential to deliver a substantial overall survival benefit to patients with mNSCLC who have already progressed on standard-of-care immunotherapy. The median OS of 17.5 months observed with the Q6W combination regimen in the Phase 2 trial is unprecedented in this setting and represents a profound potential improvement over the outcomes expected with docetaxel chemotherapy.[8]

This remarkable efficacy must be carefully weighed against the associated toxicities. The safety profile is characterized by frequent, though mostly low-grade, adverse events. The primary concern is hepatotoxicity, which, while generally manageable with steroids and treatment modification, remains a significant clinical consideration.[13] The high rate of treatment discontinuation due to adverse events (25% in the Q6W combination arm) is a critical factor that will be scrutinized by regulators and clinicians. It suggests that while the therapy is highly effective for some, a significant minority of patients may not be able to tolerate it. The selection of the Q6W dosing schedule for the Phase 3 trial was a crucial decision, as this regimen demonstrated a clearly superior benefit-risk profile compared to the Q3W schedule, offering markedly better survival with a lower incidence of severe toxicity.[3] The ultimate regulatory and clinical success of acasunlimab will depend on whether the magnitude of its survival benefit is deemed to justify this toxicity burden in the context of the available alternatives.

Competitive Landscape and Market Positioning

Acasunlimab is a first-in-class agent and is currently the most clinically advanced PD-L1x4-1BB bispecific antibody in development in Western markets.[1] This leadership position provides a significant first-mover advantage. However, the field of bispecific antibodies and novel immunotherapies is dynamic and competitive. Other companies are exploring the same mechanistic space; for example, Elpiscience is developing ES101, another PD-L1x4-1BB bispecific antibody currently in Phase 1 trials, and Nanjing Leads Biolabs has a project advancing toward pivotal studies in China.[13] Furthermore, innovation is occurring across a range of dual-targeting strategies, with other bispecifics targeting combinations like PD-L1/CD27 or PD-1/ICOS also in development.[50] Acasunlimab's success will depend not only on its own data but also on how its profile compares to these emerging competitors over time.

Future Perspectives and Unanswered Questions

The path forward for acasunlimab, while promising, is accompanied by several key questions that will need to be addressed to fully realize its therapeutic potential.

• Biomarker Development: The significant rate of treatment discontinuations and the observed disconnect between a modest ORR and a strong OS benefit highlight a critical need for predictive biomarkers. Identifying which patients are most likely to derive long-term benefit and which are at the highest risk for dose-limiting toxicities will be essential for optimizing its clinical use. Early data suggest that tumoral PD-L1 expression and the spatial proximity of PD-L1+ cells to 4-1BB+ immune cells may be associated with response, but more robust and validated biomarkers are needed.[32]
• Expansion into Other Tumors: The compelling scientific rationale and the encouraging data in NSCLC provide a strong foundation for exploring acasunlimab in other tumor types. The ongoing Phase 2 trial in CPI-refractory melanoma is a logical next step. Success in these indications could broaden the potential impact of acasunlimab to a wide range of PD-L1-expressing solid tumors that are resistant to current immunotherapies.
• Long-Term Outlook: The ultimate determinant of acasunlimab's future will be the readout of the pivotal ABBIL1TY NSCLC-06 trial. If this study successfully confirms the magnitude of the survival benefit seen in Phase 2, acasunlimab, in combination with pembrolizumab, is poised to become a new global standard of care for second-line mNSCLC. Such an outcome would not only provide a desperately needed new option for patients but would also validate Genmab's strategic decision to take sole ownership of the program and solidify its position as a leader in the development of innovative, next-generation antibody therapeutics.

Works cited

1. Acasunlimab - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 15, 2025, https://synapse.patsnap.com/drug/4492c0932eaa446180af5394c7390841
2. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects - PMC, accessed September 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11987116/
3. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) | BioNTech, accessed September 15, 2025, https://investors.biontech.de/news-releases/news-release-details/investigational-acasunlimab-duobodyr-pd-l1x4-1bb-combination/
4. Genmab Takes Full Control of Acasunlimab Development Program, accessed September 15, 2025, https://ir.genmab.com/news-releases/news-release-details/genmab-takes-full-control-acasunlimab-development-program/
5. www.cancer.gov, accessed September 15, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/acasunlimab#:~:text=Through%204%2D1BB%20binding%2C%20acasunlimab,%3B%20programmed%20death%2D1)..&sa=D&source=editors&ust=1757922800251366&usg=AOvVaw27rFJnRByP6b_T8Zvo4uiH)
6. Definition of Acasunlimab - NCI Drug Dictionary, accessed September 15, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/acasunlimab
7. Acasunlimab (GEN1046) | Bispecific Antibody - MedchemExpress.com, accessed September 15, 2025, https://www.medchemexpress.com/acasunlimab.html
8. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity, accessed September 15, 2025, https://ml-eu.globenewswire.com/Resource/Download/2415ad8b-e418-4af8-b659-d059d53b5490
9. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) - GlobeNewswire, accessed September 15, 2025, https://www.globenewswire.com/news-release/2024/06/01/2891824/0/en/investigational-acasunlimab-duobody-pd-l1x4-1bb-in-combination-with-pembrolizumab-demonstrates-meaningful-clinical-activity-in-phase-2-trial-in-patients-with-previously-treated-met.html
10. Investigational Acasunlimab (DuoBody-PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) - FirstWord Pharma, accessed September 15, 2025, https://firstwordpharma.com/story/5862821
11. Phase 2 Trial: Acasunlimab and Pembrolizumab Show Activity in Treated Metastatic NSCLC, accessed September 15, 2025, https://synapse.patsnap.com/article/phase-2-trial-acasunlimab-and-pembrolizumab-show-activity-in-treated-metastatic-nsclc
12. Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated metastatic non-small cell lung cancer (mNSCLC): Initial results of a randomized, open-label, phase 2 trial. | Journal of Clinical Oncology - ASCO Publications, accessed September 15, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2533
13. ASCO 2024 – acasunlimab impresses on overall survival | ApexOnco - Oncology Pipeline, accessed September 15, 2025, https://www.oncologypipeline.com/apexonco/asco-2024-acasunlimab-impresses-overall-survival
14. Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated, accessed September 15, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.2533
15. Genmab Takes Full Control of Acasunlimab Development Program - BioSpace, accessed September 15, 2025, https://www.biospace.com/genmab-takes-full-control-of-acasunlimab-development-program
16. BioNTech halts development of Genmab-collaborated bispecific antibody acasunlimab, accessed September 15, 2025, https://synapse.patsnap.com/article/biontech-halts-development-of-genmab-collaborated-bispecific-antibody-acasunlimab
17. Study Details | NCT06635824 | Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) | ClinicalTrials.gov, accessed September 15, 2025, https://www.clinicaltrials.gov/study/NCT06635824
18. Genmab presses on with acasunlimab | ApexOnco - Oncology Pipeline, accessed September 15, 2025, https://www.oncologypipeline.com/apexonco/genmab-presses-acasunlimab
19. Study Details | NCT03917381 | GEN1046 Safety Trial in Patients With Malignant Solid Tumors | ClinicalTrials.gov, accessed September 15, 2025, https://clinicaltrials.gov/study/NCT03917381
20. European Medicines Agency decision P/00272/2024 of 24 July 2024 on the granting of a product specific waiver for acasunlimab (EM, accessed September 15, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-0272-2024-ema-decision-24-july-2024-granting-product-specific-waiver-acasunlimab-emea-003606-pip01-24_en.pdf
21. Primary and Acquired Resistance to Immunotherapy with Checkpoint Inhibitors in NSCLC: From Bedside to Bench and Back - PMC, accessed September 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11906525/
22. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects, accessed September 15, 2025, https://jitc.bmj.com/content/13/4/e011377
23. Acasunlimab, an Fc-inert PD-L1×4-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via comple - The Journal for ImmunoTherapy of Cancer, accessed September 15, 2025, https://jitc.bmj.com/content/jitc/13/4/e011377.full.pdf
24. Acasunlimab - BioNTech/Genmab - AdisInsight - Springer, accessed September 15, 2025, https://adisinsight.springer.com/drugs/800054549
25. Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation - Frontiers, accessed September 15, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1494206/full
26. 719 Acasunlimab combined with PD-1 blockade elicits complementary immune-modulatory effects and enhances anti-tumor activity in preclinical models | Journal for ImmunoTherapy of Cancer, accessed September 15, 2025, https://jitc.bmj.com/content/12/Suppl_2/A821
27. 655 Acasunlimab in combination with pembrolizumab reinvigorates ..., accessed September 15, 2025, https://jitc.bmj.com/content/12/Suppl_2/A752
28. Full article: An Fc-inert PD-L1×4-1BB bispecific antibody mediates potent anti-tumor immunity in mice by combining checkpoint inhibition and conditional 4-1BB co-stimulation, accessed September 15, 2025, https://www.tandfonline.com/doi/full/10.1080/2162402X.2022.2030135
29. Acasunlimab + PD-1 Blockade: Combining Forces to Boost Anti-Tumor Immunotherapy, accessed September 15, 2025, https://www.youtube.com/watch?v=qcUcA1epnWA
30. Study Details | NCT06984328 | Study of the Effectiveness and Safety ..., accessed September 15, 2025, https://clinicaltrials.gov/study/NCT06984328
31. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors - PMC - PubMed Central, accessed September 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9662884/
32. 516 Peripheral and tumoral immune activity in the expansion part of the first-in-human DuoBody®-PD-L1×4–1BB (GEN1046) trial - The Journal for ImmunoTherapy of Cancer, accessed September 15, 2025, https://jitc.bmj.com/content/9/Suppl_2/A546
33. Clinical trial details - OncoTrialsTrack - VHIO, accessed September 15, 2025, https://oncotrialstrack.vhio.net/clinical_trial/GCT1046-04
34. Investigational Acasunlimab (DuoBody® -PD-L1x4-1BB) in Combination with Pembrolizumab Demonstrates Meaningful Clinical Activity in Phase 2 Trial in Patients with Previously Treated Metastatic Non-small Cell Lung Cancer (mNSCLC) - BioSpace, accessed September 15, 2025, https://www.biospace.com/investigational-acasunlimab-duobody-pd-l1x4-1bb-in-combination-with-pembrolizumab-demonstrates-meaningful-clinical-activity-in-phase-2-trial-in-patients-with-previously-treated-metastatic-non-small-cell-lung-cancer-mnsclc
35. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06), accessed September 15, 2025, https://www.abbvieclinicaltrials.com/study/?id=GCT1046-06
36. Trial to Evaluate Acasunlimab and Pembrolizumab Combination Superiority Over Standard of Care Docetaxel in Non-Small Cell Lung Cancer (ABBIL1TY NSCLC-06) - Georgia CORE, accessed September 15, 2025, https://www.georgiacancerinfo.org/clinical-trials/detail/5748
37. Study Details | NCT04937153 | GEN1046 Safety and PK in Subjects With Advanced Solid Malignancies | ClinicalTrials.gov, accessed September 15, 2025, https://clinicaltrials.gov/study/NCT04937153
38. Treatment Options for Advanced Non-Small Cell Lung Cancer After Failure of Previous Immune Checkpoint Inhibitors and Chemotherapy: Meta-Analysis of Five Randomized Controlled Trials - MDPI, accessed September 15, 2025, https://www.mdpi.com/1718-7729/32/1/46
39. Outcomes in non-small cell lung cancer (NSCLC) patients treated with second-line therapy after progression or recurrence after initial first line immune checkpoint-based therapy. - ASCO, accessed September 15, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT381747
40. Acasunlimab (DuoBody-PD-L1x4-1BB) alone or in combination with pembrolizumab (pembro) in patients (pts) with previously treated metastatic non-small cell lung cancer (mNSCLC): Initial results of a randomized, open-label, phase 2 trial. - ResearchGate, accessed September 15, 2025, https://www.researchgate.net/publication/381411730_Acasunlimab_DuoBody-PD-L1x4-1BB_alone_or_in_combination_with_pembrolizumab_pembro_in_patients_pts_with_previously_treated_metastatic_non-small_cell_lung_cancer_mNSCLC_Initial_results_of_a_randomized_o
41. Medical Needs and Therapeutic Options for Melanoma Patients Resistant to Anti-PD-1-Directed Immune Checkpoint Inhibition - PMC - PubMed Central, accessed September 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10341224/
42. Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes? - MDPI, accessed September 15, 2025, https://www.mdpi.com/1422-0067/25/18/10120
43. Acasunlimab: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 15, 2025, https://go.drugbank.com/drugs/DB18932
44. BioNTech ends work on Genmab-partnered bispecific antibody acasunlimab, accessed September 15, 2025, https://www.fiercebiotech.com/biotech/biontech-ends-work-genmab-partnered-bispecific-antibody-acasunlimab
45. Genmab Takes Full Control of Acasunlimab Development Program - GlobeNewswire, accessed September 15, 2025, https://www.globenewswire.com/news-release/2024/08/05/2924128/0/en/Genmab-Takes-Full-Control-of-Acasunlimab-Development-Program.html
46. A Prospective, Open-Label, Randomized, Phase 3 Trial of Acasunlimab (GEN1046) in Combination With Pembrolizumab Versus Docetaxel in Subjects With PD-L1 Positive Metastatic Non-Small Cell Lung Cancer After Treatment With a PD-1/PD-L1 Inhibitor and Platinum-Containing Chemotherapy | UVA Health, accessed September 15, 2025, https://uvahealth.com/clinicaltrials/prospective-open-label-randomized-phase-3-trial-acasunlimab-gen1046-combination
47. Acasunlimab by BioNTech for Non-Small Cell Lung Cancer: Likelihood of Approval, accessed September 15, 2025, https://www.pharmaceutical-technology.com/data-insights/acasunlimab-biontech-non-small-cell-lung-cancer-likelihood-of-approval/
48. EMEA-003606-PIP01-24 - paediatric investigation plan - European Medicines Agency, accessed September 15, 2025, https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-003606-pip01-24
49. NCT04841538 | A Study of ES101 (PD-L1x4-1BB Bispecific Antibody) in Patients With Advanced Malignant Thoracic Tumors | ClinicalTrials.gov, accessed September 15, 2025, https://clinicaltrials.gov/study/NCT04841538
50. Bispecific Antibodies for Cancer Immunotherapy - Immuno-Oncology Summit 2019, accessed September 15, 2025, https://www.immuno-oncologysummit.com/19/Bispecific-Antibodies-Immunotherapy