Executives from BridgeBio Oncology Therapeutics NASDAQ: BBOT outlined the company’s strategy to build what they call the “Best in RAS” pipeline during an Oppenheimer-hosted discussion, emphasizing internally discovered programs aimed at improving target coverage across RAS-driven cancers and enabling combination regimens with better tolerability.
Focus on RAS-driven tumors and “optimal target coverage”
Company representatives said their overarching thesis is that treating “the most frequent and deadliest oncogene,” RAS, requires designing inhibitors and targets that improve the depth and breadth of target coverage for patients. The team described two main approaches:
- Direct RAS inhibition through inhibitors designed to bind both the active (“on”) and inactive (“off”) states.
- Selective pathway disruption via a “RAS PI3Kα breaker” that blocks RAS-driven activation of PI3Kα while avoiding broader PI3Kα kinase inhibition that has historically been associated with hyperglycemia.
BBO-8520: KRAS G12C “on/off” inhibitor and pembrolizumab combination
The company’s lead program, BBO-8520, was described as a direct KRAS G12C inhibitor designed to inhibit both the on and off state. Management argued that inhibiting the on state matters because it is the signaling-competent form, while the off state was characterized as biologically inactive.
Discussing clinical data previously shared by the company, management cited a 65% response rate and said 83% of patients eligible for a six-month follow-up passed the six-month landmark. Across dose levels, they cited 68% six-month progression-free survival (PFS).
On safety, the team emphasized “very little” liver toxicity as monotherapy and said liver toxicity remained low when 8520 was combined with pembrolizumab. They attributed the tolerability to the on-state covalent mechanism, which they said can achieve efficacy at lower free-drug levels, potentially improving therapeutic index.
In combination data, management said all three first-line patients responded in the pembrolizumab combination, including patients with “very low TPS score.” They also cited approximately a 40% response rate in “heavily pretreated” lung cancer patients who had received both a checkpoint inhibitor and a G12C therapy, in combination with pembrolizumab. Looking ahead, they said the company is moving forward with a pembrolizumab expansion at 500 mg and stated they did not need to de-escalate dosing due to liver toxicity, which they contrasted with what they described as dose reductions and higher rates of grade 3 toxicities seen with other “off” inhibitors in PD-1 combinations.
Management said a key determinant of “best-in-class” positioning for 8520 will be whether durability continues to hold as the dataset matures, particularly in frontline combination settings at active dosing with minimized liver toxicity.
BBO-818: pan-KRAS program positioned for broader alleles and combinations
The company also highlighted BBO-818, described as a pan-KRAS inhibitor that incorporates learnings from BBO-8520. Management said 818 is able to bind KRAS directly and inhibit both on and off states, with potent inhibition of KRAS G12D and G12V as well as other alleles.
On differentiation, management pointed to an early clinical safety signal, stating they have not observed rash, stomatitis, or mucositis to date, while cautioning that more data will be needed to confirm the profile. They framed the program around a pan-KRAS (rather than pan-RAS) strategy, referencing mouse work they said showed knocking out all RAS is lethal, while knocking out KRAS alone can be efficacious in cancer models and tolerable in adult mice due to compensation by other RAS family members in normal tissues.
In terms of next steps, management highlighted interest in colorectal cancer combinations, referencing prior validation in the KRAS G12C space using EGFR antibodies. They said that if 818’s profile continues to progress as seen so far, the company believes it may have an opportunity to combine with EGFR inhibitors such as cetuximab in colorectal cancer.
BBO-10203: “RAS PI3Kα breaker” aims to avoid hyperglycemia and enable MAPK/PI3Kα depth
The third program, BBO-10203, was presented as an orthogonal approach designed for combination use. Management described it as a first-in-class protein-protein interaction inhibitor that covalently binds the RAS-binding domain of PI3Kα and blocks RAS from activating PI3Kα, while not acting as a PI3K kinase inhibitor.
The company emphasized that selectivity is intended to come from biology: RAS-driven activation of PI3Kα was described as important in tumorigenic settings but less important in normal physiology and, notably, hyperglycemia. Management stated that to date they have observed zero hyperglycemia and zero glucose elevations, and said the study is enrolling patients without restrictions related to HbA1c or glucose levels—contrasting this with other inhibitors in the pathway that commonly have restrictions and still observe hyperglycemia.
The company said combination cohorts are open and enrolling with standard of care in three settings:
- HER2-amplified disease with trastuzumab
- Hormone receptor-positive disease with fulvestrant
- KRAS-mutant settings with chemotherapy
Management also discussed the long-standing challenge of achieving simultaneous deep inhibition of MAPK and PI3Kα due to toxicity with earlier approaches (such as MEK inhibitors combined with PI3Kα inhibitors). They argued the breaker mechanism may enable this by targeting PI3Kα activation specifically in RAS-driven contexts.
On expectations for 10203 alone, management said they did not expect strong monotherapy activity and characterized PI3K-pathway inhibitors as generally producing low monotherapy response rates, with combinations viewed as the key development path.
Upcoming data and financial position
Management said they expect “convergence” of readouts across all three programs in the second half of this year. They highlighted additional 8520 plus pembrolizumab data focused on durability, continued progress for 818 including a planned colorectal cancer combination with cetuximab, and results from 10203’s three open combination cohorts. They also said combinations of 10203 with 8520 and with 818 are planned to open internally later in the year.
On resources, management stated the company had a cash balance of $425 at year-end to support executing these combination studies.
About BridgeBio Oncology Therapeutics NASDAQ: BBOT
BridgeBio Oncology Therapeutics NASDAQ: BBOT is a publicly traded biotechnology company focused on discovering and developing therapies for cancer. The company concentrates on translating scientific insights into clinical-stage programs aimed at addressing oncology indications with unmet medical need.
BridgeBio Oncology’s activities center on research and development of investigational therapeutics, advancing drug candidates through preclinical studies and clinical trials. Its work typically involves in-house discovery efforts and collaborations with academic and industry partners to identify targets, optimize compounds, and generate the clinical data needed to support regulatory development.
Public information about BridgeBio Oncology Therapeutics’ specific programs, geographic operations and leadership is limited in the sources available here.
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