AstraZeneca's entry into the game has started to reverse the battle for Pan-KRAS inhibitors technology route.

In the past few years, the discussion surrounding the Pan-KRAS inhibitor technology route has almost exclusively focused on one question: is the Pan-RAS molecule binder represented by Revolution Medicines' RMC-6236 molecule better? Or is the Pan-KRAS small molecule inhibitor represented by Jacobio-B (01167)'s JAB-23E73 molecule better? RMC-6236 inhibits three types of RAS, including KRAS, HRAS, and NRAS, while JAB-23E73 only inhibits KRAS, and tumorigenesis is closely related to KRAS. The academic community has not reached a consensus on which one is better. This issue has become more than just a debate over technical routes since AstraZeneca entered the game. What truly determines the direction of the KRAS race is a more fundamental and brutal reality - when a target enters the platformization, combination, and globalization stage, competition no longer only occurs between molecules, but also between corporate systems. After AstraZeneca took over the global development of Gastroenteric Pan-KRAS inhibitors project for $2 billion, the nature of this competition changed. The game of KRAS inhibitors is no longer "Gastroenterics vs Revolution", but AstraZeneca vs Revolution. I. Why "competition between molecules" is not the fundamental competition in the pharmaceutical industry If we only look at the molecular level, the differences between RMC-6236 and Gastroenteric Pan-KRAS are not complex. RMC-6236 has shown clear clinical activity in pancreatic cancer and lung cancer, but at the same time, its toxicity burden is equally clear and heavy. Phase I data shows that the incidence of rash is close to ninety percent, with about eight percent having grade three or above skin toxicity. Looking at the data from the second-line PDAC, in the 300mg dose group (N=76), 34% of patients had grade three or higher TRAE, and 42% of patients needed dose adjustments. Such a molecule can be used as a monotherapy in the second line, but once used in combination with other drugs in the first line, the toxicity window becomes the biggest obstacle in clinical practice. In contrast, Gastroenteric Pan-KRAS is still in the early stages. According to the 2025 interim report data, JAB-23E73 has not observed dose-limiting toxicity, skin toxicity was only observed at grade one, no grade three or above skin toxicity was observed, and no grade three or above liver toxicity was observed, while multiple objective remission cases have been seen. At least in the current visible data window, its safety profile is significantly "cleaner". More importantly, for AstraZeneca, a molecule with better safety is more likely to have an advantage in the future landscape of KRAS inhibitor combination therapy. If this competition only took place in the laboratory or early clinical stages, Revolution would clearly be faster. But the problem is, KRAS is not a target that can be won just by having an "advantage". It is destined to enter the first line, to enter combination therapy, and to enter the long-term administration scene, and the stages that it tests have never been just about the molecule itself, but about how many resources a company has to complete clinical development. II. Searching for over a decade, AstraZeneca finally completes the KRAS gap One overlooked point is that AstraZeneca has been searching for the KRAS track for over a decade. As early as 2012, AstraZeneca introduced the KRAS inhibitor AZD4785 from Ionis, but it stopped at a phase I trial in 2019. Later, internal attempts were made with the KRAS G12C inhibitors AZD4625/AZD4747, but they also did not progress. In 2023, AstraZeneca acquired the KRAS G12D inhibitor UA022 from the Chinese company YuSenJianHeng for $25 million, stating their clear intention to continue to expand in the KRAS G12D track. According to clinicaltrials website data, this project had enrolled 17 patients since entering clinical trials in October 2024, with no further patients enrolled afterward, indicating it may have stopped. It wasn't until AstraZeneca acquired Gastroenteric's JAB-23E73 for $2 billion that the market understood that for AstraZeneca, a KRAS inhibitor was much needed in their oncology product line, and JAB-23E73 filled that gap. This was also the first multinational corporation involved in the global Pan-Kras and Pan-Ras inhibitor pipeline transaction. For AstraZeneca, the ultimate goal of Pan-KRAS is not just to demonstrate its effectiveness in a small population, but to become the foundation of the era of combination therapy. This requires the molecule to have a wide enough safety window to withstand the toxicity pressure from multiple mechanisms such as chemotherapy, immunotherapy, and ADC. This is where the advantage of Gastroenteric's Pan-KRAS inhibitor and AstraZeneca's capabilities complement each other. A smaller molecule with a more controllable safety profile and no observed dose ceiling is more suitable for being added to AstraZeneca's expertise in "multi-combinations, multi-line" clinical systems. In other words, Gastroenteric is providing the type of molecule that AstraZeneca is most willing to invest in. What's more, AstraZeneca has a complete portfolio of combination therapy assets, with key drugs in their pipeline including PD-1 durvalumab, EGFR Tagrisso, Her2 ADC trastuzumab deruxtecan, and Trop 2 ADC Datopotamab deruxtecan. Most drugs entering the first line will require combination therapy, whether with PD-1, chemotherapy, or ADC. Currently, there is no clear combination plan for JAB-23E73, but AstraZeneca's pipeline provides a set of possibilities for JAB-23E73 to be directly integrated into their existing system. This internal synergistic advantage is something that any biotech company cannot replicate. III. The competition behind the "product" is actually a "resource" competition Revolution Medicines is a highly focused biotech on the RAS pathway, and there is little dispute about the depth of its pipeline layout. But it is ultimately a biotech company, and in terms of funding, global clinical operational experience, global registration system maturity, sales channels, KOL resources, medical insurance pricing, and commercial negotiation capabilities, it is not at the level of an MNC. AstraZeneca has an annual revenue exceeding $50 billion, with oncology drug sales growing by over 24%, making it one of the top earners in the oncology drug market. The gap between Revolution and AstraZeneca is not in whether they understand KRAS, but in whether they can turn a molecule into a treatment paradigm. AstraZeneca maintains a vast clinical network globally, able to simultaneously advance multiple Phase III registration trials and conduct complex combination studies in multiple tumor types. The company's R&D strategy clearly states: to create "curative solutions based on combination therapies," rather than just optimizing a single drug. For a Pan-KRAS inhibitor that needs to be repeatedly validated in multiple indications such as pancreatic cancer, lung cancer, and colorectal cancer and move from one line to another, this execution is a decisive advantage in itself. The ability to conduct how many Phase III registration clinical trials is not only determined by clinical data and scientific basis but more crucially by how much money a company can invest. AstraZeneca has openly stated its goal to reach $80 billion in revenue by 2030, and in the second quarter of 2025, oncology sales had already exceeded $6.3 billion, making oncology an absolute growth engine. This means that if AstraZeneca believes that Pan-KRAS is the backbone of cancer treatment for the next ten years, then they have enough capital to lay out multiple Phase III trials, multiple indications, and combination therapy strategies globally, rather than choosing a conservative clinical trial design for a few indications to get approval first and then expand to other indications. Looking at the sales side of the competition, AstraZeneca already has a mature global sales team and market penetration pathways, while Revolution's RMC-6236 will be the company's first commercialized drug, and Revolution's cash reserves are less than $2 billion, facing the costs of Phase III trials and early commercialization, Revolution does not have abundant funds. It is difficult for a biotech with a single product and a top-tier global oncology drug sales company to compete in the commercialization capabilities, with the former's chances of winning the arm wrestling match being slim. IV. The underestimated key difference: manufacturing costs and scalability In recent industry discussions, one variable that has been rarely fully digested by the capital markets is coming to the surface - the differences in drug development pathways. RMC-6236 belongs to the molecular glue-related mechanism, with a complex and expensive synthesis pathway, high unit costs, high requirements for process stability, and scalability in production. Such molecules can be established in the development phase, but when they enter the commercialization stage of large-scale and long-term medication, they will directly pricing pressures, supply chain risks, and structural disadvantages in medical insurance negotiations. In contrast, Gastroenteric's Pan-KRAS inhibitor adopts a more traditional, mature small molecule pathway. This means lower unit costs, more predictable scaling capabilities, and the possibility of rapid replication production on a global scale. V. The misalignment of the capital markets: $7 billion Hong Kong dollars vs $15 billion U.S. dollars As of now, Revolution Medicines has a market value of approximately $15 billion U.S. dollars, while Gastroenteric's market value is only approximately $7 billion Hong Kong dollars. This means that in the eyes of the capital markets, there is a valuation gap of tens of times between the two companies. However, if we shift our perspective from "single molecule" to "system competition", this gap seems contradictory. Revolution needs to strive alone, while Gastroenteric's Pan-KRAS project is already embedded in AstraZeneca's global oncology empire. Clearly, the capital markets are still pricing based on old notions - considering Gastroenteric as a Chinese biotech and Revolution as an American star company. But the industry's reality has changed: the value of JAB-23E73 has transitioned from "Gastroenteric's molecule" to "the next backbone in the AstraZeneca system". Conclusion: The victory of KRAS is never determined by molecules alone The development history of many drugs tells us that the true value of a target does not belong to the first to prove it "works," but to those who ultimately turn it into a treatment standard. Revolution is one of the purest explorers in the RAS molecular glue field, but at this moment, it faces a global pharmaceutical giant AstraZeneca, which can turn molecules into systems and systems into standards. Gastroenteric is a pioneer in Pan-KRAS small molecule inhibitors, and for Gastroenteric, it is no longer a biotech competing with resources independently, but standing in a cancer empire driven by abundant resources for combination therapy. If JAB-23E73 can replicate the early data in subsequent trials, raising the safety ceiling, then the trend of the next decade's KRAS competition will largely depend on how fast the AstraZeneca machine runs. For the entire industry, Pan-KRAS is not just a popular molecule, it is being strategically positioned by giants as the core puzzle piece for the "next-generation cancer combination therapy platform". In Gastroenteric's pipeline, it is even more heartening to see the layout of tADCs loaded with KRAS inhibitors, as a second-generation product of KRAS inhibitors. KRAS is associated with 23%-25% of human tumors, and it is believed that in the next 20 years, there will be continuous iterative products. In a sense, being able to cure nearly a quarter of human tumors has already surpassed commercial value itself. In the long history of human victory over cancer, this is undoubtedly a milestone. It not only illuminates a beacon of hope for countless patients in desperate situations but also proves to the world that the relentless pace of human conquering cancer has never stopped, laying an indelible cornerstone for the research and breakthroughs in future cancer treatments.