An Expert Report on BAY-3498264: A Novel SOS1 Inhibitor for KRAS-Mutated Cancers

Executive Summary

This report provides an exhaustive analysis of BAY-3498264, an investigational, oral, small-molecule inhibitor of Son of Sevenless Homologue 1 (SOS1) developed by Bayer for the treatment of advanced KRAS-mutated solid tumors. The therapeutic rationale for this agent is predicated on a significant unmet need in oncology: the limited durability of first-generation direct KRAS G12C inhibitors, which is largely driven by feedback reactivation of the MAPK signaling pathway. By selectively inhibiting the RAS-SOS1 interaction, BAY-3498264 is designed to block this adaptive resistance mechanism, thereby enhancing the depth and duration of response when used in combination with KRAS-targeting agents.

Preclinical data, notably from the American Association for Cancer Research (AACR) 2025 Annual Meeting, provide a robust validation of this hypothesis. Studies in relevant cell lines and patient-derived xenograft models demonstrate that BAY-3498264 prevents the rebound of phospho-ERK signaling induced by the KRAS G12C inhibitor sotorasib and exhibits marked synergistic anti-tumor activity when used in combination. These findings strongly support the advancement of BAY-3498264 into clinical development.

Bayer initiated a first-in-human Phase I clinical trial (NCT06659341) in November 2024. This open-label, dose-escalation study is evaluating BAY-3498264 in combination with sotorasib in patients with advanced solid tumors harboring the KRAS G12C mutation. The primary objectives are to establish the safety, tolerability, and recommended Phase II dose of the combination. The trial's design, which includes patients who have previously progressed on a G12C inhibitor, is strategically positioned to provide early and compelling evidence of the drug's ability to overcome acquired resistance.

BAY-3498264 enters a competitive landscape focused on next-generation strategies to target KRAS-driven cancers. Key competitors include other SOS1 inhibitors and SHP2 inhibitors, which target a different node in the same feedback loop. Bayer's strategic decision to develop this asset in-house, as part of a broader precision oncology pipeline, reflects a high degree of confidence in its internal discovery capabilities and the potential for a favorable tolerability profile compared to alternative approaches.

In conclusion, BAY-3498264 is a scientifically well-founded asset targeting a validated and commercially significant mechanism of resistance in oncology. Its future success will be contingent upon the clinical data from NCT06659341, which will be critical in validating its safety profile, on-target pharmacodynamic effects, and preliminary efficacy. Positive outcomes from this trial would represent a major de-risking event and position BAY-3498264 as a potentially pivotal component in the future treatment paradigm for KRAS-mutated cancers.

Section 1: The KRAS Conundrum: A Persistent Challenge in Oncology

1.1 The KRAS/MAPK Pathway as a Central Oncogenic Driver

The Kirsten rat sarcoma (KRAS) viral oncogene homolog is a member of the RAS superfamily of small GTPases and stands as one of the most frequently mutated oncogenes in human cancer.[1] KRAS mutations are particularly prevalent in some of the most difficult-to-treat malignancies, including non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer.[1] Under normal physiological conditions, RAS proteins function as molecular switches, cycling between an inactive GDP-bound state and an active GTP-bound state. Upon activation by upstream signals, they trigger a cascade of downstream signaling, most notably the mitogen-activated protein kinase (MAPK) pathway, which is essential for regulating fundamental cellular processes such as proliferation, differentiation, and survival.[2]

Oncogenic mutations, such as the common G12C substitution, lock the KRAS protein in a constitutively active, GTP-bound "on-state." This leads to persistent, unregulated activation of the MAPK pathway, promoting uncontrolled tumor growth and survival, making KRAS a key therapeutic target.[1] For decades, however, the biophysical properties of the KRAS protein, particularly its smooth surface and high affinity for GTP, rendered it "undruggable" by conventional small-molecule inhibitors.

1.2 The Breakthrough and Limitations of Direct KRAS G12C Inhibitors

The therapeutic landscape for KRAS-mutated cancers was transformed with the regulatory approval of the first direct KRAS G12C inhibitors, sotorasib and adagrasib.[3] These agents exploit a unique cysteine residue present in the G12C mutant protein, allowing for covalent and selective inhibition. Their approval represented a landmark achievement, offering the first targeted therapy for this specific patient population.[3]

However, the clinical performance of these first-generation inhibitors as monotherapy, while a significant advance over prior standards of care, has been characterized by notable limitations. Clinical trials have demonstrated modest objective response rates and, critically, a limited duration of response, with a median time to progression of less than one year for both approved agents.[3] This clinical reality underscores a persistent and significant unmet medical need for strategies that can deepen and prolong the response to KRAS inhibition. The rapid development of acquired resistance has become the central challenge to be overcome.

1.3 The Feedback Reactivation Loop: The Achilles' Heel of KRAS Inhibition

Intensive preclinical research has elucidated the primary mechanism underpinning the limited durability of KRAS G12C inhibitors: an adaptive feedback reactivation of the MAPK pathway.[3] When the pathway is suppressed by a direct KRAS inhibitor, the cell initiates a compensatory signaling response to restore homeostasis. A crucial node in this feedback loop is Son of Sevenless Homologue 1 (SOS1), a guanine nucleotide exchange factor (GEF).[2] SOS1 interacts with RAS proteins to facilitate the exchange of bound GDP for cytosolic GTP, a necessary step for RAS activation.[3]

In the context of KRAS G12C inhibition, this feedback mechanism leads to a "rebound" in MAPK signaling, as SOS1 promotes the reactivation of wild-type RAS isoforms or remaining uninhibited mutant KRAS, thereby circumventing the therapeutic blockade.[2] This on-treatment feedback reactivation is now understood to be a principal driver of acquired resistance and a key factor limiting the clinical efficacy of KRAS G12C inhibitor monotherapy.[3]

The discovery of this adaptive resistance mechanism has fundamentally reshaped the drug development paradigm. The initial focus on developing a single "magic bullet" against KRAS has evolved into a more sophisticated, data-driven strategy centered on rational combinations. The challenge is no longer simply to inhibit the mutant KRAS protein, but to simultaneously block the cell's predictable adaptive response. This has created a clear and valuable market opportunity for a new class of "enhancer" drugs designed specifically to be used in combination with direct KRAS inhibitors. The development of BAY-3498264 is a direct response to this opportunity. Furthermore, because the SOS1-mediated feedback loop is a general feature of the RAS/MAPK pathway and not specific to the G12C mutation, a successful SOS1 inhibitor could have far-reaching implications. While the initial development focuses on the validated G12C target, a positive proof-of-concept for SOS1 inhibition in this setting would validate the target for combination with future inhibitors of other KRAS mutations (e.g., G12D, G12V), potentially expanding the long-term therapeutic utility of the approach across the broader landscape of RAS-driven cancers.

Section 2: BAY-3498264: Pharmacological Profile and Mechanism of Action

2.1 Drug Candidate Profile

BAY-3498264 is an investigational small-molecule drug being developed by Bayer.[5] It is administered orally and is classified as a selective inhibitor of Son of Sevenless Homologue 1 (SOS1).[1] The compound was developed in-house within Bayer's research and development organization, positioning it as a core asset within the company's precision molecular oncology pipeline rather than an in-licensed or acquired product.[1] This internal discovery effort distinguishes it from other programs in Bayer's portfolio that have originated from external partnerships or acquisitions, such as those with Vividion Therapeutics or MOMA Therapeutics.[7]

2.2 A Deep Dive into SOS1 Inhibition

The mechanism of action of BAY-3498264 is centered on the disruption of a critical protein-protein interaction within the RAS/MAPK signaling cascade. SOS1 functions as a guanine nucleotide exchange factor (GEF) for RAS proteins. In this role, it binds to inactive, GDP-bound RAS and catalyzes the dissociation of GDP, allowing the more abundant cytosolic GTP to bind in its place. This nucleotide exchange switches RAS to its active, signal-transducing conformation.[3]

BAY-3498264 is designed to be a potent and selective inhibitor of the direct interaction between SOS1 and the RAS protein.[3] By occupying the RAS-binding pocket on SOS1, the drug prevents SOS1 from engaging with and activating KRAS. This blockade effectively neutralizes the adaptive feedback loop that is triggered by direct KRAS G12C inhibitors. Without the catalytic activity of SOS1, the cell's ability to reactivate the MAPK pathway via RAS is significantly impaired.[2]

An important strategic consideration in Bayer's approach is the choice to target SOS1 rather than other nodes in the feedback pathway, such as the protein tyrosine phosphatase SHP2. Preclinical rationale suggests that inhibiting SOS1 could achieve a similar therapeutic effect to SHP2 inhibition but with a potentially more favorable tolerability profile.[3] This hypothesis is based on the distinct biological roles of the two proteins. A superior safety profile would be a significant clinical and commercial advantage, and validating this is a key objective of the ongoing first-in-human trial.

2.3 Rationale for Combination Therapy

The development of BAY-3498264 is exclusively focused on its use as a combination agent. The primary therapeutic hypothesis is that by co-administering a direct KRAS G12C inhibitor (e.g., sotorasib) with a SOS1 inhibitor like BAY-3498264, a more profound, comprehensive, and durable suppression of the MAPK pathway can be achieved.[2] The KRAS inhibitor provides the initial, direct blockade of the mutant oncogene, while the SOS1 inhibitor acts as a "firewall," preventing the cell from escaping this blockade via the feedback reactivation mechanism.

Preclinical studies have provided direct evidence for this two-pronged mechanism. Specifically, the data show that while sotorasib alone causes an initial drop in the phosphorylation of ERK (a key downstream marker of MAPK pathway activity), this is followed by a "rebound" of phospho-ERK as the feedback loop engages. The addition of BAY-3498264 was shown to inhibit this rebound, resulting in a more sustained suppression of the pathway.[3] This combination is therefore expected to translate into deeper and/or longer-lasting tumor responses in patients compared to what can be achieved with KRAS inhibitor monotherapy.[3]

The development of BAY-3498264 as an oral agent is a critical strategic decision.[1] This allows for a convenient, all-oral combination regimen with existing oral KRAS inhibitors. Such a regimen is preferable for both patients and healthcare systems compared to combinations involving intravenous agents, which require clinic visits for administration. This logistical simplicity could significantly enhance market adoption and patient adherence, providing a competitive advantage if the combination proves to be safe and effective.

Section 3: Preclinical Evidence Package

3.1 In Vitro and In Vivo Characterization

The preclinical data supporting the clinical development of BAY-3498264 are robust and were highlighted at the American Association for Cancer Research (AACR) 2025 Annual Meeting in a poster presentation titled "Discovery and characterization of BAY 3498264: a small molecule inhibitor targeting the RAS-SOS1 interaction" (Abstract #4373).[3] This presentation detailed the compound's characterization as a potent, selective, and orally bioavailable inhibitor of the SOS1-RAS interaction.[3]

The core therapeutic hypothesis was validated through a series of rigorous experiments:

• Mechanism of Action Confirmation: In in vitro studies using KRAS G12C mutant cell lines, BAY-3498264 effectively inhibited the rebound of phosphorylated ERK (p-ERK) that is induced by treatment with the KRAS G12C inhibitor sotorasib. The combination of BAY-3498264 and sotorasib resulted in a more prolonged inhibition of ERK phosphorylation than was seen with sotorasib alone, providing direct preclinical evidence that the drug blocks the intended feedback reactivation pathway.[3]
• Synergistic Anti-proliferative Activity: In a panel of in vitro proliferation assays, the combination of BAY-3498264 with various MAPK pathway inhibitors demonstrated a marked synergistic effect in inhibiting cancer cell growth, significantly outperforming single-agent activity.[3]
• In Vivo Efficacy and Tolerability: The combination of BAY-3498264 with sotorasib was tested in in vivo cancer models, including cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring the KRAS G12C mutation. The combination was reported to be well tolerated and exhibited a clear combination benefit, enhancing both the depth and duration of anti-tumor response compared to sotorasib monotherapy.[3]

Crucially, the preclinical investigation was not limited to combinations with KRAS G12C inhibitors. The data presented at AACR indicated that BAY-3498264 also demonstrated a combination effect with other MAPK pathway-directed therapies.[3] This finding is of high strategic importance, as it suggests that the utility of BAY-3498264 may not be restricted to the KRAS G12C patient population. It hints at a broader potential role for the asset as a "backbone" therapy to be combined with various inhibitors along the RAS/MAPK pathway (e.g., MEK inhibitors, other mutant-selective KRAS inhibitors) to treat a wider range of RAS-driven malignancies. This expands the drug's long-term strategic value beyond its initial development path.

3.2 Strategic Context from Scientific Communications

Bayer has consistently positioned BAY-3498264 as a cornerstone of its precision molecular oncology strategy. Company communications emphasize the drug's innovative approach to targeting a key driver of tumor cell survival and growth.[1] The initiation of the Phase I trial was framed as a significant step in addressing the high unmet medical need for patients with KRAS-mutated cancers, particularly NSCLC, pancreatic cancer, and colorectal cancer, which are known to be driven by this oncogene.[1] The preclinical data package provides a direct and logical bridge to the clinical program, with the

in vivo demonstration of well-tolerated, synergistic activity with sotorasib offering a compelling, data-driven rationale for the specific combination being evaluated in the NCT06659341 trial. This strong preclinical foundation is a positive indicator for the development program.

Section 4: The Clinical Program: The NCT06659341 First-in-Human Trial

The transition of BAY-3498264 from preclinical research to clinical evaluation is marked by the initiation of a first-in-human study designed to rigorously assess its safety, pharmacokinetics, and preliminary activity in the intended patient population. This trial represents the critical first step in validating the therapeutic hypothesis in humans.

4.1 Study Design and Methodology

The ongoing clinical trial is a Phase I, open-label, multicenter, dose-escalation study identified by the clinicaltrials.gov identifier NCT06659341.[1] The study, sponsored by Bayer, is titled "A Phase I Study of BAY3498264 Given Together With Sotorasib in Participants Who Have Advanced Solid Cancers With Specific Genetic Changes Called KRASG12C Mutation".[1]

The trial initiated in November 2024 with an estimated enrollment of 104 participants and a projected primary completion date in early 2027.[6] The study employs a sophisticated design with three distinct parts: an initial dose-escalation phase, a backfill cohort, and a dose-expansion phase.[14] This structure allows for the initial determination of a safe dose range, followed by the enrollment of additional patients at selected dose levels to gather more robust safety and preliminary efficacy data.

A key feature of the study protocol is the dosing schedule. Participants first receive BAY-3498264 as a monotherapy for a seven-day run-in period. Following this, they begin combination therapy, receiving oral BAY-3498264 along with the standard approved dose of oral sotorasib. The combination treatment is administered in 21-day cycles and continues until disease progression or unacceptable toxicity.[14] This run-in period is a prudent and standard design element in first-in-human combination trials, as it allows for the characterization of the safety and pharmacokinetic profile of the investigational agent alone before assessing the potential for additive or synergistic toxicities.

4.2 Target Population and Endpoints

The trial is enrolling patients with histologically confirmed advanced or metastatic solid tumors that harbor a documented KRAS G12C mutation.[14] Eligible patients must have experienced disease progression after at least one prior line of standard-of-care systemic therapy and have no further standard treatment options available.[14] The protocol explicitly permits the enrollment of patients who have received prior treatment with a KRAS G12C inhibitor, a strategically critical inclusion criterion.[15]

The primary endpoints of the study are focused on safety, tolerability, and dose-finding. These include [14]:

• The incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs).
• The number of participants experiencing dose-limiting toxicities (DLTs) during the initial 28-day evaluation period.
• The determination of the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BAY-3498264 when given in combination with sotorasib.
• Establishment of the Recommended Phase II Dose (RP2D) for future studies.

The secondary and exploratory endpoints are designed to assess the drug's pharmacokinetic profile and preliminary anti-tumor activity. These include [14]:

• Pharmacokinetic parameters of BAY-3498264, including maximum plasma concentration (Cmax​) and area under the concentration-time curve (AUC), after both single and multiple doses.
• Objective Response Rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

4.3 Strategic Implications of the Trial Design

The design of NCT06659341 reflects a clear and aggressive clinical development strategy. By allowing the enrollment of patients who have already progressed on a KRAS G12C inhibitor, Bayer is directly testing the core value proposition of BAY-3498264—its ability to overcome acquired resistance. A positive efficacy signal in this heavily pre-treated, G12C inhibitor-refractory population would be a powerful de-risking event for the program. It would provide much stronger validation of the mechanism than demonstrating activity in treatment-naïve patients and could potentially support an accelerated development pathway.

Furthermore, while safety and efficacy are the headline endpoints, the pharmacokinetic and pharmacodynamic (PK/PD) data from this trial are of paramount importance. A key test for the program will be whether the preclinical mechanism translates to humans. Investigators and stakeholders will be closely monitoring for a clear correlation between the systemic exposure to BAY-3498264 (PK) and evidence of sustained on-target activity, such as the suppression of p-ERK in patient-derived samples (PD). Demonstrating this link is essential for validating the drug's mechanism of action in the clinical setting. A failure to show this on-target effect, even in the context of an acceptable safety profile, would raise significant questions about the program's long-term viability.

Table 1: Summary of NCT06659341 Clinical Trial Design
Trial Identifier	NCT06659341 1
Title	A Phase I Study of BAY3498264 Given Together With Sotorasib in Participants Who Have Advanced Solid Cancers With Specific Genetic Changes Called KRASG12C Mutation 1
Phase	Phase 1 1
Status	Recruiting 1
Sponsor	Bayer 1
Intervention	BAY-3498264 (oral SOS1 inhibitor) in combination with Sotorasib (oral KRAS G12C inhibitor) 14
Patient Population	Patients with advanced solid tumors harboring a KRAS G12C mutation who have progressed on prior therapy. Prior G12C inhibitor treatment is permitted. 14
Primary Endpoints	Safety, tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) of the combination. 14
Key Secondary Endpoints	Pharmacokinetics (Cmax, AUC) of BAY-3498264; Objective Response Rate (ORR) per RECIST v1.1. 14
Estimated Enrollment	104 participants 14
Start / Completion Dates	November 2024 – November 2027 14

Section 5: Competitive and Strategic Landscape

5.1 The Evolving KRAS-Targeted Therapy Market

The market for KRAS-targeted therapies has rapidly evolved from a state of therapeutic nihilism to one of intense innovation and competition. The initial wave, defined by the approval of direct KRAS G12C inhibitors, has now given way to a second wave focused on overcoming the limitations of these first-generation agents. The primary strategic objective for companies in this space is to develop rational combination therapies that can prevent or reverse acquired resistance, thereby improving patient outcomes. BAY-3498264 is positioned squarely within this second wave.

5.2 Direct Competitors: A Comparative Analysis

BAY-3498264 faces competition from other investigational agents designed to block the MAPK pathway feedback loop. These competitors can be broadly categorized into two main classes.

• Other SOS1 Inhibitors: Several companies are pursuing the same target as Bayer. Notably, Schrödinger has presented preclinical data for its selective SOS1 inhibitor, SGR-4174, which also demonstrated potent cell-killing activity across various KRAS-mutated cancer types and synergistic effects when combined with MEK or KRAS inhibitors.[18] The relative potency, selectivity, and tolerability profiles of these different SOS1 inhibitors will be a key point of differentiation as they advance through clinical development.
• SHP2 Inhibitors: The most clinically advanced alternative strategy for blocking the same feedback pathway involves the inhibition of SHP2 (Src homology region 2 domain-containing phosphatase-2). Multiple SHP2 inhibitors are in clinical development from companies such as Novartis and Revolution Medicines. As acknowledged in Bayer's own preclinical rationale, inhibiting SOS1 is hypothesized to achieve a similar therapeutic outcome as SHP2 inhibition, but with the potential for a better tolerability profile.[3] The comparative safety data that emerge from the respective Phase I trials of these two drug classes will be critical in determining which approach becomes the preferred combination partner for KRAS inhibitors.

5.3 Bayer's Strategic Position in Precision Oncology

The development of BAY-3498264 is a key component of Bayer's multifaceted and sophisticated strategy in precision oncology.[5] The company is pursuing multiple, distinct technological and biological approaches to cancer therapy, rather than relying on a single platform. This diversified portfolio includes:

• Targeted Therapies for Oncogenic Signaling: This pillar includes BAY-3498264 (SOS1 inhibitor) and sevabertinib (BAY 2927088), an oral inhibitor of mutant HER2 and EGFR.[9]
• Targeted Radionuclide Therapy: Bayer is building a portfolio of targeted alpha therapies, which use alpha-emitting isotopes like Actinium-225 linked to targeting moieties to deliver potent radiation directly to cancer cells.[7]
• Next-Generation Platforms via Subsidiaries and Partnerships: Bayer has made significant investments to access cutting-edge technologies, most notably through its acquisition of Vividion Therapeutics, a chemoproteomics company focused on drugging traditionally intractable targets.[7] Bayer also has strategic collaborations with companies like MOMA Therapeutics in the DNA Damage Response (DDR) space and Puhe BioPharma for a PRMT5 inhibitor.[11]

The development of BAY-3498264 in-house is a significant indicator of Bayer's confidence in its internal small-molecule discovery and development capabilities.[1] While the company has shown a willingness to acquire external innovation, the decision to advance an internally discovered asset against a high-value target like SOS1 suggests a belief that their compound is highly competitive. This strategic choice reflects a long-term commitment to the program, originating from their own laboratories.

This approach mirrors a broader trend in oncology, exemplified by the development of next-generation PARP1-selective inhibitors. First-generation PARP inhibitors target both PARP1 and PARP2, but their efficacy is largely driven by PARP1 inhibition, while their hematological toxicity is linked to PARP2 inhibition.[25] Consequently, companies like AstraZeneca (saruparib/AZD5305), Merck KGaA (M9466/HRS-1167), and Gilead (via the acquisition of XinThera) are developing PARP1-selective inhibitors to improve the therapeutic index.[27] The development of BAY-3498264 fits squarely into this industry narrative of creating more selective, next-generation inhibitors to overcome the limitations of first-in-class drugs.

Table 2: Competitive Landscape of KRAS Pathway Combination Agents
Compound Name	Developer	Target/Mechanism	Modality	Development Phase	Key Combination Partner(s)	Potential Differentiators
BAY-3498264	Bayer	SOS1 Inhibitor	Small Molecule	Phase 1	Sotorasib (KRAS G12C)	Potential for improved tolerability over SHP2 inhibitors; all-oral regimen. 1
SGR-4174	Schrödinger	SOS1 Inhibitor	Small Molecule	Preclinical	MEK / KRAS inhibitors	High selectivity for SOS1 over SOS2; broad activity across diverse KRAS mutations. 18
HBI-2376	-	SHP2 Inhibitor	Small Molecule	Phase 1	-	Targeting a more clinically advanced node in the feedback pathway. 44
TNO155	Novartis	SHP2 Inhibitor	Small Molecule	Clinical	Various	One of the leading SHP2 inhibitors in clinical development.
RMC-4630	Revolution Medicines	SHP2 Inhibitor	Small Molecule	Clinical	Sotorasib (KRAS G12C)	Advanced clinical program with demonstrated combination potential.

Section 6: Expert Analysis, Outlook, and Recommendations

6.1 Critical Assessment of BAY-3498264's Potential

BAY-3498264 represents a strategically sound and scientifically validated asset for Bayer. Its potential is rooted in its ability to address a clear, high-value unmet medical need: the limited durability of existing KRAS G12C inhibitors.

• Strengths: The drug is built on a strong scientific rationale that is directly supported by a robust preclinical data package. The mechanism of action—blocking the SOS1-mediated feedback loop—is a validated strategy for enhancing the efficacy of MAPK pathway inhibition. As an in-house asset from a major pharmaceutical company, it benefits from significant institutional expertise and resources.
• Weaknesses: The primary weakness is its early stage of development. As a Phase I asset, it still faces substantial clinical development risk. The ultimate safety and efficacy profile in humans remains unknown, and unforeseen toxicities could emerge.
• Opportunities: If successful, BAY-3498264 has the potential to become a best-in-class or first-in-class combination partner for KRAS inhibitors, capturing a significant share of a large and growing market. Positive data could lead to an accelerated development path, particularly if strong activity is observed in the G12C inhibitor-refractory population. Furthermore, the mechanism has the potential for expansion to other KRAS-mutant cancers as new direct inhibitors become available.
• Threats: The primary threat is competition. A number of companies are pursuing similar strategies with both SOS1 and SHP2 inhibitors. A competitor demonstrating a superior efficacy or safety profile, or simply advancing more rapidly through clinical development, could capture significant market share. There is also the risk that alternative resistance mechanisms emerge that are not addressed by SOS1 inhibition, or that the asset fails to demonstrate a clear clinical benefit in human trials.

6.2 Anticipated Clinical Trajectory and Future Development Pathways

Assuming the successful completion of the ongoing Phase I trial (NCT06659341) and the establishment of a safe and active recommended Phase II dose, the clinical trajectory for BAY-3498264 will likely accelerate. The most logical next step would be the initiation of a pivotal Phase II or Phase III registration-directed trial. This study would likely focus on a specific, well-defined patient population, such as second-line treatment for patients with KRAS G12C-mutated NSCLC who have progressed on or after first-line therapy.

Given the preclinical data showing synergy with multiple MAPK pathway inhibitors, Bayer may also explore the drug's potential in basket trials across various KRAS-mutated tumor types (e.g., colorectal, pancreatic). These studies could also evaluate combinations with agents other than sotorasib, such as MEK inhibitors or next-generation KRAS inhibitors targeting different mutations, thereby broadening the asset's long-term applicability.

6.3 Key Catalysts and Risk Factors

The development program for BAY-3498264 faces several key inflection points and potential risks that will be closely monitored by stakeholders.

• Key Catalysts:
• Initial Phase I Data: The first public disclosure of safety, tolerability, pharmacokinetic, and preliminary efficacy data from NCT06659341 will be the most significant near-term catalyst. A presentation at a major medical conference such as the American Society of Clinical Oncology (ASCO) or the European Society for Medical Oncology (ESMO) would be a major event.
• RP2D Selection: The successful identification of a well-tolerated and biologically active recommended Phase II dose will be a critical milestone that enables the start of pivotal studies.
• Initiation of a Pivotal Trial: The announcement and initiation of a Phase II/III trial would signal Bayer's commitment to advancing the asset toward registration and would be a major value-creating event.
• Key Risk Factors:
• Clinical Safety: The emergence of unexpected or severe toxicities in the combination setting could limit the therapeutic window and potentially halt development.
• Lack of Efficacy: The drug may fail to demonstrate a meaningful clinical benefit, particularly in the crucial population of patients with acquired resistance to KRAS inhibitors.
• Competitive Pressure: A competitor's program may advance more quickly or demonstrate a superior clinical profile, diminishing the market potential for BAY-3498264.
• Strategic Reprioritization: As with any large pharmaceutical pipeline, there is always a risk that internal strategic shifts could lead to the de-prioritization or termination of the program, irrespective of its scientific merit.

6.4 Concluding Remarks and Strategic Recommendations

BAY-3498264 is a high-potential asset that exemplifies the current paradigm of precision oncology: developing rational combination therapies to overcome adaptive resistance to targeted agents. Bayer is pursuing a scientifically sound strategy by targeting the SOS1-mediated feedback loop, and the preclinical evidence provides a strong foundation for clinical success.

For stakeholders, the key metrics to monitor from the initial clinical data will be threefold:

1. Safety and Tolerability: Does the combination with sotorasib have a manageable safety profile that is competitive with or superior to alternative approaches like SHP2 inhibition?
2. Pharmacodynamics: Is there clear evidence of on-target activity in humans, specifically a sustained suppression of p-ERK signaling at clinically achievable doses?
3. Preliminary Efficacy: Are there objective responses, particularly among patients who have previously progressed on a KRAS G12C inhibitor?

Positive signals across these three domains would substantially de-risk the program and position BAY-3498264 as a highly valuable asset in Bayer's oncology pipeline. Conversely, a failure in any one of these areas would represent a significant setback. Overall, BAY-3498264 is a program of high strategic importance, and the initial data from its first-in-human trial are eagerly awaited by the oncology community.

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