My aunt died of pancreatic cancer in January of 2024 after about 18 months with it. I'm sad that another few years might have saved her, but I'm happy that this will happen to a lot fewer families in the future. This is what clinical trial abundance means - fewer deaths like hers.
Although I'll say that to truly cure it and not merely extend survival, we need to really address resistance mutations and tailor treatments to a patient's specific resistance mutations. This is only feasible if we radically change our regulatory structure and the way we carry out trials.
I am delighted to hear this. My fit 62 year old wife was diagnosed out of the blue with advanced pancreatic cancer in 2009 and died 8 months later, just after our 40th anniversary and the birth of our first grandchild.
Between this and Derek Thompson's post, daxonraxib is clearly having a Substack moment. But what's not mentioned so much is that it's quite toxic - 96% of patients have adverse reactions, 30% grade 3 or higher (of 5, 5 being death). You gain 8 months of life in exchange. I can't tell anyone facing this choice how to think about it. But I think we can all agree that we're still offering patients a pretty awful deal. Why?
A bit of background for the lay person: Cancer often has mutations in proliferative signaling pathways. These are networks of molecular switches that together tell a cell to divide, among other things. In many cancers, mutations jam these switches on, and so researchers have focused heavily on drugging those mutated switches to shut them off. Because cancers are uniquely reliant on the jammed switches, silencing them with drugs can do more than stop them from growing: it can kill cancer cells, without the terrible toxicity of traditional chemotherapy.
Unfortunately, the response is always temporary. The lesson we've learned is that the cancer can route around the drug, not just with binding pocket mutations or amplifications, as Ruxandro mentions, but by just reactivating the pathway in different ways, or entering new states altogether. Oncology has responded by combining suppression of more and more targets in the same pathway at once, whether or not they are specifically essential to the cancer: going upstream to receptors on the cell surface, downstream to the cyclins in the nucleus, everything in between. We are headed toward a world of carpet-bombing the whole RAS-MAPK signaling pathway; inevitably, we hit a lot of normal tissues as well, tissues that you need to live. The consequence is longer progression-free survival, in exchange for increased toxicity. Increasingly these regimens are resembling traditional chemotherapy in their tradeoffs.
I see daxonrasib as another step in the escalation of this strategy. Ruxandro mentioned combinations, but it is basically a combination in a molecule, right? A pan-RAS inhibitor that hits 3 targets at once, which is why it works longer than the KRAS G12C/D inhibitors, and also why it's more toxic. What I find really hopeful about daxonrasib is that the biochemical innovations behind it may be applied to other, better protein targets in the future.
I work as a medical writer in oncology, mostly in CME, and as much as I appreciate the innovation, the toxicity and ultimately the lack of strong effects many treatments have on overall survival , combined with complex toxicity, is undeniable. Personally, if I was at a point of being eligible for an advanced immunotherapy agent I'd likely move straight to palliative care.
Thank you so much for this post! Any progress in treating pancreatic cancer has been so frustratingly slow. My father was diagnosed at stage 3b in October of 2005 and died in August 2006; 11 months. My family has been part of fundraising efforts by the only two research foundations exclusively dedicated to pancreatic cancer: the Lustgarten Foundation and the Pancreatic Cancer Action Network. We've watched the 5-Year Survival Rate rise from 4% to 13%, which is heartening, but so small an improvement compared to many other cancers. This seems like a significant step forward!!
That figure's a little off, it's showing Y64 forming a covalent bond with the drug, which it does not. There's some other questionable details in the structure also. This looks like it was generated by AI? Not sure I'm a fan of having AI revise scientific figures -it does look pretty, but the original figure is fine IMO.
Well written! I worked on a few as boards on this drug for Rev Med as a medical writer a few years back. The innovation is very impressive. It will be interesting to see how it competes with adagrasib and sotorasib, especially given the issues with bias in the sotorasib phase 3 trial.
Nice perspective. Echoing Sydney Brenner, we need to start thinking of diseases in general and cancers in particular as algorithmic perturbations, in order to accurately effectively address them therapeutically.
Seems like taking this treatment in parallel with an implantable iontophoretic system (like what is being developed by Continuity Biosciences) could be a longer term solution
My aunt died of pancreatic cancer in January of 2024 after about 18 months with it. I'm sad that another few years might have saved her, but I'm happy that this will happen to a lot fewer families in the future. This is what clinical trial abundance means - fewer deaths like hers.
I am sorry to hear that.
Although I'll say that to truly cure it and not merely extend survival, we need to really address resistance mutations and tailor treatments to a patient's specific resistance mutations. This is only feasible if we radically change our regulatory structure and the way we carry out trials.
I am delighted to hear this. My fit 62 year old wife was diagnosed out of the blue with advanced pancreatic cancer in 2009 and died 8 months later, just after our 40th anniversary and the birth of our first grandchild.
I'm sorry to hear this 😕
Between this and Derek Thompson's post, daxonraxib is clearly having a Substack moment. But what's not mentioned so much is that it's quite toxic - 96% of patients have adverse reactions, 30% grade 3 or higher (of 5, 5 being death). You gain 8 months of life in exchange. I can't tell anyone facing this choice how to think about it. But I think we can all agree that we're still offering patients a pretty awful deal. Why?
A bit of background for the lay person: Cancer often has mutations in proliferative signaling pathways. These are networks of molecular switches that together tell a cell to divide, among other things. In many cancers, mutations jam these switches on, and so researchers have focused heavily on drugging those mutated switches to shut them off. Because cancers are uniquely reliant on the jammed switches, silencing them with drugs can do more than stop them from growing: it can kill cancer cells, without the terrible toxicity of traditional chemotherapy.
Unfortunately, the response is always temporary. The lesson we've learned is that the cancer can route around the drug, not just with binding pocket mutations or amplifications, as Ruxandro mentions, but by just reactivating the pathway in different ways, or entering new states altogether. Oncology has responded by combining suppression of more and more targets in the same pathway at once, whether or not they are specifically essential to the cancer: going upstream to receptors on the cell surface, downstream to the cyclins in the nucleus, everything in between. We are headed toward a world of carpet-bombing the whole RAS-MAPK signaling pathway; inevitably, we hit a lot of normal tissues as well, tissues that you need to live. The consequence is longer progression-free survival, in exchange for increased toxicity. Increasingly these regimens are resembling traditional chemotherapy in their tradeoffs.
I see daxonrasib as another step in the escalation of this strategy. Ruxandro mentioned combinations, but it is basically a combination in a molecule, right? A pan-RAS inhibitor that hits 3 targets at once, which is why it works longer than the KRAS G12C/D inhibitors, and also why it's more toxic. What I find really hopeful about daxonrasib is that the biochemical innovations behind it may be applied to other, better protein targets in the future.
I work as a medical writer in oncology, mostly in CME, and as much as I appreciate the innovation, the toxicity and ultimately the lack of strong effects many treatments have on overall survival , combined with complex toxicity, is undeniable. Personally, if I was at a point of being eligible for an advanced immunotherapy agent I'd likely move straight to palliative care.
Thank you so much for this post! Any progress in treating pancreatic cancer has been so frustratingly slow. My father was diagnosed at stage 3b in October of 2005 and died in August 2006; 11 months. My family has been part of fundraising efforts by the only two research foundations exclusively dedicated to pancreatic cancer: the Lustgarten Foundation and the Pancreatic Cancer Action Network. We've watched the 5-Year Survival Rate rise from 4% to 13%, which is heartening, but so small an improvement compared to many other cancers. This seems like a significant step forward!!
That figure's a little off, it's showing Y64 forming a covalent bond with the drug, which it does not. There's some other questionable details in the structure also. This looks like it was generated by AI? Not sure I'm a fan of having AI revise scientific figures -it does look pretty, but the original figure is fine IMO.
Thanks for flagging. Yes, you're right.
Tbc, the intention was not to change it, but to have another background/font. Will update .
yeah I figured it was just for style
My mother died of pancreatic cancer in 1979. Diagnosis to death? Maybe 4 months.
I’m glad to hear there is good news.
Awesome piece, as always, Ruxandra! - Shahram
Thank you 🙏
Well written! I worked on a few as boards on this drug for Rev Med as a medical writer a few years back. The innovation is very impressive. It will be interesting to see how it competes with adagrasib and sotorasib, especially given the issues with bias in the sotorasib phase 3 trial.
Nice perspective. Echoing Sydney Brenner, we need to start thinking of diseases in general and cancers in particular as algorithmic perturbations, in order to accurately effectively address them therapeutically.
Maybe we need a Hong Kong for medical research?
Seems like taking this treatment in parallel with an implantable iontophoretic system (like what is being developed by Continuity Biosciences) could be a longer term solution