Jacobio Pharma and AstraZeneca have entered a global licensing agreement for Jacobio’s investigational pan‑KRAS inhibitor JAB‑23E73, in a deal worth up to $2 billion. AstraZeneca will pay $100 million upfront for exclusive rights to develop and commercialize JAB‑23E73 outside of China, while the companies will co-develop and co-commercialize the drug within China. The agreement provides Jacobio with potential milestone payments totaling $1.915 billion, plus tiered royalties on ex-China sales. This collaboration aims to accelerate the development of JAB‑23E73 internationally and leverage AstraZeneca’s oncology portfolio in combination strategies.
JAB‑23E73: A Pan‑KRAS Inhibitor Targeting Multiple Mutations
JAB‑23E73 is a small-molecule pan‑KRAS inhibitor designed to target multiple KRAS mutation subtypes. Unlike the first-generation KRAS G12C inhibitors that bind a specific mutant cysteine, JAB‑23E73 was developed using an induced allosteric platform to engage KRAS in both active (“ON”) and inactive (“OFF”) conformations. Notably, preclinical studies indicate JAB‑23E73 can inhibit a broad range of KRAS mutants (including G12C, G12D, and others) while sparing the related HRAS and NRAS isoforms.
In KRAS-driven tumor models, JAB‑23E73 induced significant tumor regressions without marked toxicity, suggesting a wide therapeutic window. These promising preclinical results led to ongoing Phase I trials in China and the United States to evaluate safety and preliminary efficacy in patients with advanced solid tumors harboring KRAS mutations. Early trial updates have hinted at anti-tumor activity in patients, although detailed efficacy data have not yet been published.
Mechanistically, JAB‑23E73’s ability to bind KRAS irrespective of its nucleotide state (GDP-bound or GTP-bound) could overcome a key limitation of KRAS G12C inhibitors, which require the mutant protein to cycle to the inactive GDP-bound form. By potentially targeting KRAS mutants in any state, a pan-KRAS inhibitor like JAB‑23E73 may inhibit signaling more comprehensively across diverse KRAS-driven cancers. This profile positions JAB‑23E73 as an innovative approach for difficult malignancies such as pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC), where KRAS mutations (especially non-G12C mutations) are common and historically intractable.
AstraZeneca’s KRAS Ambitions and Rationale
For AstraZeneca, this deal expands an oncology portfolio that has long sought to crack the KRAS paradigm. KRAS has been a focus for AstraZeneca since at least 2012, when it in-licensed an anti-KRAS antisense oligonucleotide (AZD4785) from Ionis – an approach that reached Phase I but was discontinued by 2019. AstraZeneca’s internal research yielded a covalent KRAS G12C inhibitor candidate (AZD4625), which was optimized to AZD4747, although these have not yet reached approval.
The company also moved to secure a KRAS G12D program in 2023 by licensing a preclinical inhibitor from Usynova. This breadth of efforts underscores the high therapeutic interest: KRAS is one of the most frequently mutated oncogenes in cancer, driving ~25% of all cancers (including ~90% of PDAC, ~40% of CRC, and ~30% of lung adenocarcinomas). Effective KRAS inhibitors thus represent a major unmet need across multiple tumor types.
By partnering on JAB‑23E73, AstraZeneca aims to capitalize on a broader KRAS-targeted strategy beyond KRAS G12C. “KRAS-mutated tumors drive profound unmet need for patients with pancreatic, colorectal and lung cancers,” noted AstraZeneca’s oncology R&D lead, adding that advancing KRAS inhibitors like JAB‑23E73 in combination with AstraZeneca’s diverse portfolio could “transform outcomes for patients”. The collaboration will integrate JAB‑23E73 into planned combination regimens – for example, pairing with other pathway inhibitors or immunotherapies – to potentially enhance efficacy and overcome resistance mechanisms. AstraZeneca’s experience in global clinical development and prior KRAS research efforts provide a strong foundation for advancing JAB‑23E73 through proof-of-concept trials and beyond.
Clinical Landscape of KRAS Inhibition in Lung Cancer
The first clinically successful KRAS inhibitors have focused on the KRASG12C mutation, which occurs in a subset of lung and colorectal cancers. Sotorasib (AMG 510) and adagrasib (MRTX849) are covalent KRAS G12C inhibitors that gained regulatory approvals for KRAS G12C-mutant NSCLC in 2021–2022. In the pivotal Phase II trial CodeBreaK 100, sotorasib achieved an objective response rate (ORR) of 37.1% and a disease control rate of 80.6% in previously treated KRAS G12C-positive NSCLC (Skoulidis et al. 2021).
Responses were durable (median response duration ~11 months) and translated to a median progression-free survival (PFS) of 6.8 months and a median overall survival (OS) of 12.5 months (Skoulidis et al., New England Journal of Medicine, 2021). These data, first reported by Skoulidis et al. (New England Journal of Medicine, 2021), led to accelerated FDA approval of sotorasib as the first KRAS-targeted therapy in lung cancer.
Similarly, the Phase II KRYSTAL-1 trial established adagrasib in KRAS G12C-mutant NSCLC. Among 112 evaluable pretreated patients, adagrasib yielded a confirmed ORR of 42.9% (Jänne et al., New England Journal of Medicine, 2022). Median PFS was 6.5 months, and median OS reached 12.6 months (Jänne et al., New England Journal of Medicine, 2022). Notably, adagrasib showed activity against CNS metastases, with a 33% intracranial response rate in patients with brain lesions (reflecting its central nervous system penetration) (Jänne et al., New England Journal of Medicine, 2022).
However, adagrasib’s toxicity was somewhat higher: virtually all patients experienced TRAEs, with grade ≥3 events in 44.8% (including two grade 5 toxicities), and 6.9% discontinued due to adverse effects (Jänne et al., New England Journal of Medicine, 2022). Both sotorasib and adagrasib were approved for second-line treatment of KRAS G12C-mutant NSCLC, marking a historic breakthrough for a target once deemed “undruggable.”
Crucially, these approvals were based on single-arm trials in previously treated patients. To further quantify benefit, randomized trials were conducted. The Phase III CodeBreaK 200 trial compared sotorasib to docetaxel in KRAS G12C NSCLC, confirming a significant PFS improvement (median 5.6 vs 4.5 months, HR 0.66, p = 0.002). One-year PFS rates were 24.8% on sotorasib vs 10.1% on chemotherapy. Sotorasib also doubled the ORR relative to docetaxel (28.1% vs 13.2%) and achieved a higher disease control rate (82.5% vs 60.3%) (Johnson et al., ESMO Congress 2022).
Although no OS benefit was observed (crossover was allowed, and the study wasn’t powered for OS), the trial affirmed that an oral KRAS inhibitor can outperform standard chemotherapy in resistant lung cancer (Johnson et al., ESMO Congress 2022). These results cement the role of KRAS G12C inhibitors in lung cancer and underscore the need to extend such benefits to other KRAS variants.
Tackling KRAS in Colorectal and Pancreatic Cancers
Outside of lung cancer, KRAS mutations are prevalent but have proven more challenging to target effectively. In colorectal cancer, single-agent KRAS G12C inhibitors have yielded modest efficacy. Sotorasib monotherapy produced an ORR of ~10% in KRAS G12C-mutant CRC in early trials (with most patients achieving stable disease rather than tumor shrinkage). A major mechanism of resistance in CRC is feedback reactivation of upstream EGFR signaling when KRAS is inhibited. To address this, combinations of KRAS G12C inhibitors with EGFR antibodies have been explored.
Randomized Phase III trial (KRYSTAL-10) is ongoing to compare this combo against standard chemotherapy in second-line CRC. Similarly, sotorasib combined with panitumumab (an anti-EGFR) has shown improved response rates in KRAS G12C CRC, highlighting EGFR co-inhibition as a viable strategy to overcome adaptive resistance in colorectal tumors.
Pancreatic ductal adenocarcinoma (PDAC) presents another frontier. Over 90% of PDACs harbor KRAS mutations, predominantly KRASG12D (and to a lesser extent G12V and others), for which no targeted inhibitors were initially available. Neither sotorasib nor adagrasib (which target G12C, a less common variant in PDAC) have made a significant impact on PDAC outcomes. However, pan-RAS approaches that target multiple KRAS mutants are showing early promise. RMC-6236 (daraxonrasib) is a first-in-class RAS^ON inhibitor developed by Revolution Medicines, designed to bind the active GTP-bound form of RAS regardless of mutation subtype.
In an ongoing Phase I trial reported at ESMO 2023, RMC-6236 demonstrated notable efficacy in both pancreatic and lung cancers driven by various KRAS mutations (excluding G12C). Among 40 evaluable KRAS-mutant NSCLC patients (non-G12C), RMC-6236 achieved a confirmed ORR of 38%. In PDAC patients, RMC-6236 monotherapy led to an ORR of approximately 20%, with a disease control rate around 87% despite most patients being refractory to prior lines. Median PFS in second-line PDAC was reported at ~8.1 months in one cohort – an encouraging result in a setting where conventional chemotherapy often yields PFS of only ~3–4 months.
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Notably, responses were observed across tumors with diverse KRAS mutations (G12D, G12V, etc.), validating the drug’s broad mechanism (Arbour et al., Annals of Oncology 2023). The safety profile of RMC-6236 has been acceptable: in PDAC, ~96% of patients had TRAEs, but only ~22% experienced grade ≥3 events, and no treatment-related discontinuations were reported. The most common side effects have been manageable (rash, gastrointestinal symptoms, fatigue). These data have prompted a planned Phase III trial (RASolute-302) comparing RMC-6236 to standard chemotherapy in second-line KRAS-mutant PDAC. If successful, it could mark the first targeted therapy to improve outcomes in pancreatic cancer by directly countering mutant RAS signaling.
The pan-KRAS agent JAB‑23E73 will enter this landscape, aiming to provide a similar multi-mutational approach. While RMC-6236 targets all RAS isoforms (KRAS, NRAS, HRAS) in the “ON” state via a tri-complex mechanism with cyclophilin A, JAB‑23E73 appears to be KRAS-selective, potentially avoiding toxicity from NRAS/HRAS inhibition. This selectivity could be advantageous if it reduces off-target effects, though it means JAB‑23E73 must effectively cover the major oncogenic KRAS alterations (G12D/V/R, G13, Q61, etc.) to have broad utility.
JAB‑23E73’s ongoing trials will clarify which KRAS mutant tumors respond and how its efficacy compares to agents like RMC-6236. Notably, Jacobio has also indicated interest in combining KRAS inhibitors with other modalities – for example, using KRAS inhibitors as payloads in tumor-targeted ADCs, or pairing with immunotherapy and STING agonists – to further expand the impact on difficult tumors.
Future Directions and Combination Strategies
As multiple KRAS inhibitors advance, a key question is how to maximize their benefit and overcome resistance. Acquired resistance to KRAS G12C inhibitors can arise through various mechanisms: additional RAS mutations (including second-site mutations or activation of other RAS isoforms), upregulation of parallel pathways (EGFR, MET, PI3K), and cell lineage changes. Combination therapies are actively being pursued to address these challenges. In CRC, as discussed, vertical inhibition of the EGFR–RAS–MAPK pathway (combining EGFR blockade with KRAS inhibition) has proven fruitful.
In lung cancer, trials are examining combinations of KRAS G12C inhibitors with SH2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors, which may prevent the adaptive reactivation of RAS signaling. Early-phase studies of sotorasib or adagrasib with SHP2 inhibitors (like RMC-4630 or TNO155) have reported tolerable safety and some evidence of prolonged disease control, though mature results are pending. Another strategy is combining KRAS inhibitors with immune checkpoint inhibitors; while KRAS mutations can induce an immunosuppressive tumor microenvironment, there is interest in whether targeted inhibition might synergize with immunotherapy by promoting tumor antigen presentation or altering immune cell infiltration.
Beyond KRAS G12C, allele-specific inhibitors are emerging for other variants: for instance, Mirati’s MRTX1133 is a selective KRAS^G12D inhibitor that has shown potent tumor regressions in preclinical PDAC models (Hallin et al., Cancer Discovery, 2020) and recently entered early clinical trials. The development of KRAS^G12D inhibitors is crucial given the high prevalence of G12D in PDAC and CRC. If JAB‑23E73 successfully hits KRAS^G12D along with other alleles, it could offer a functional equivalent of combining a “basket” of allele-specific drugs in one. Still, resistance will likely require combination approaches; even a pan-KRAS inhibitor might be complemented by downstream MAPK pathway inhibitors (MEK or ERK inhibitors) or upstream blockers to prevent pathway escape.
Preclinical data for JAB‑23E73 showed that it produces dose-dependent suppression of phospho-ERK (a MAPK pathway readout) in tumors, supporting the rationale that it engages the intended pathway. Ongoing trials will inform whether JAB‑23E73 is best used as monotherapy or in rational combinations.
Trial design considerations are also evolving. Given the successes in lung cancer, new trials like KRYSTAL-12 (adagrasib vs chemo in second-line NSCLC) and CodeBreaK 300 (combining sotorasib with immunotherapy in first-line) are underway to potentially move KRAS inhibitors into earlier lines of therapy or new settings. In PDAC, the planned RMC-6236 Phase III will be one of the first randomized trials of a RAS-targeted drug in this disease, using PFS and OS as endpoints. For JAB‑23E73, future trials may involve biomarker-enriched cohorts (e.g. specific KRAS mutations or co-mutations like STK11 that might modulate response).
AstraZeneca’s involvement suggests that combination trials (such as JAB‑23E73 plus an EGFR inhibitor in CRC, or plus a PD-1/L1 inhibitor in lung, etc.) could be part of the development plan, especially since AstraZeneca can contribute agents like anti-EGFR antibodies, MEK inhibitors, or checkpoint inhibitors from its pipeline.
In summary, the Jacobio–AstraZeneca partnership around JAB‑23E73 reflects the maturation of the KRAS inhibitor field from single-mutation drugs toward pan-KRAS solutions. The deal injects significant resources and global expertise into developing this Phase I agent. Scientifically, JAB‑23E73 will be watched closely to see if its broad target profile can translate into clinical benefit for cancers like PDAC and KRAS-mutant CRC, where current targeted options are limited. It enters a competitive landscape alongside other next-generation RAS inhibitors such as RMC-6236 (pan-RAS) and allele-specific inhibitors for KRAS G12D and beyond.
By maintaining an evidence-based, combination-oriented strategy, the collaboration aims to ensure that JAB‑23E73’s development is grounded in rigorous clinical data and translational science rather than hype. If successful, pan-KRAS inhibition could become a cornerstone for treating the many patients whose tumors are driven by this notorious oncogene, fulfilling a long-sought goal in precision oncology.