11/1/2024 Update on the clinical development of RAS inhibitors for pancreatic ductal adenocarcinoma
(see prior post from April 2024)
Progress since the last update has been amazing and I’m happy to share 4 key points today.
Updated Phase 1 interim results from RMC-6236
On October 25, 2024, Revolution Medicines presented updated interim results for pancreatic cancer patients in RMC-6236-001, a Phase 1 clinical trial of their pan-RAS inhibitor. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf
As a reminder, this is a single-arm trial of RMC-6236 in patients with RAS-mutant, recurrent metastatic cancer. Based on other clinical trials, the expected (benchmark) average survival for such patients is about 6 months. Among the patients in this study treated with higher dose levels, the overall survival had not yet been reached at 14.5 months and 89% percent of patients on the study were still alive after 6 months of treatment. About 90% of patients on the trial experienced “disease control” for some period of time (e.g. either tumor regressions or stable disease). The most common side effects were rash and GI symptoms, generally Grade I or II. Together these results are promising, though one must keep in mind that the trial is neither randomized, nor controlled.
New Phase 1 interim results for RMC-9805
RMC-9805 is a selective inhibitor of G12D-mutant RAS proteins, including KRASG12D, the specific mutation found in over one third of human PDAC cases. The first results from their Phase 1 trial of RMC-9805 (from RMC-9805-001) were released and included data from 71 PDAC patients who received different doses of the drug. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf
These results are very early and most patients are still on-treatment. So far, the Disease Control rate is 80% and the side effects seem to be less frequent and more mild than for RMC-6236 (which makes sense since this drug should not affect the normal RAS proteins in the rests of the body). It is too early to tell how durable the responses will be to this agent, but these results provide hope for a more tolerable treatment option for the large group of patients with this specific RAS mutation.
New Phase 2 clinical trial of RMC-6236 in first-line metastatic PDAC and colorectal cancer
RevMed has launched RMC-GI-102, a Phase 2 trial of RMC-6236 in combination with standard-of-care therapies for patients with first-line metastatic pancreatic cancer or colorectal cancer: https://clinicaltrials.gov/study/NCT06445062?intr=rmc-6236&rank=4#participation-criteria
This trial is for patients with:
This trial is already open at 17 locations around the United States.
New Phase 3 clinical trial of RMC-6236
Revolution Medicines has opened their Phase 3 registration trial of RMC-6236. https://clinicaltrials.gov/study/NCT06625320?intr=rmc-6236&rank=6
This trial is for patients with recurrent metastatic pancreatic cancer (2nd-line and beyond). So far it is only open at two locations, but many more will open soon! Of note, patients on this trial will be randomly assigned to receive either RMC-6236, or standard of care therapy (physician’s choice). That means that half of the subjects will not receive the RAS inhibitor. While this is obviously not what a patient wants to hear, it is a critical step for seeking FDA approval and the faster this drug as approved, the sooner it can be offered to all PDAC patients.
Questions:
Why would they randomize the Phase 3 trial? Why can’t they use historical data to compare to instead of randomizing? To get a drug approved by the FDA, you MUST have solid evidence that is effective and safe. Over the past half century, there have been many, many examples of drugs that performed very well in single-arm clinical trials for pancreatic cancer that subsequently were not successful in randomized trials, especially when measuring overall survival, which is the most important metric for patients. Assuming that RMC-6236 is actually effective for treating pancreatic cancer patients, the fastest way to get it to the most patients is through FDA approval. The fastest way to approval is to run a well-designed, randomized, controlled clinical Phase 3 trial. This is it.
It is worth noting that in the past, there have been a few examples of trials that were stopped early because the drugs worked so well that it would be unethical to continue treating patients with the control regimen. In the best case scenario, this would happen here and patients from the “standard of care” group could then receive RAS inhibitor. I have no idea if that is what will happen, but this would be a win for everyone involved!
Is it better to receive RAS inhibitor alone in the second-line, or combination RAS inhibitor with chemotherapy in the first-line? Truly, I don’t know. On the one hand, I could imagine the combination being really effective. On the other hand, I could also imagine it being really unpleasant in terms of side effects. Cytotoxic chemotherapy regimens such as FOLFIRINOX and gem/nab-paclitaxel are already difficult to tolerate for many patients. Time will tell if the combination is actually more effective than receiving the agents separately in different rounds.
I’ll update when more news is available. My best to all the patients, family members, and loved ones out there who have read this far. What I can tell you is that there are literally thousands of doctors, nurses, researchers, and workers, both at medical centers and in companies, who are working like maniacs to bring these drugs to patients as fast as humanly possible. You all are our motivation and our hope.
-KPO
(see prior post from April 2024)
Progress since the last update has been amazing and I’m happy to share 4 key points today.
- Updated results from the Phase 1 trial of the pan-RAS inhibitor RMC-6236
- First interim results from the Phase 1 trail of RMC-9805, a RASG12D-selective inhibitor
- New Phase 2 clinical trial of RMC-6236
- The launch of the Phase 3 registration trial of RMC-6236
Updated Phase 1 interim results from RMC-6236
On October 25, 2024, Revolution Medicines presented updated interim results for pancreatic cancer patients in RMC-6236-001, a Phase 1 clinical trial of their pan-RAS inhibitor. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf
As a reminder, this is a single-arm trial of RMC-6236 in patients with RAS-mutant, recurrent metastatic cancer. Based on other clinical trials, the expected (benchmark) average survival for such patients is about 6 months. Among the patients in this study treated with higher dose levels, the overall survival had not yet been reached at 14.5 months and 89% percent of patients on the study were still alive after 6 months of treatment. About 90% of patients on the trial experienced “disease control” for some period of time (e.g. either tumor regressions or stable disease). The most common side effects were rash and GI symptoms, generally Grade I or II. Together these results are promising, though one must keep in mind that the trial is neither randomized, nor controlled.
New Phase 1 interim results for RMC-9805
RMC-9805 is a selective inhibitor of G12D-mutant RAS proteins, including KRASG12D, the specific mutation found in over one third of human PDAC cases. The first results from their Phase 1 trial of RMC-9805 (from RMC-9805-001) were released and included data from 71 PDAC patients who received different doses of the drug. https://ir.revmed.com/static-files/87b6dcb4-94c9-4e79-9d8c-d21f2bb7aaaf
These results are very early and most patients are still on-treatment. So far, the Disease Control rate is 80% and the side effects seem to be less frequent and more mild than for RMC-6236 (which makes sense since this drug should not affect the normal RAS proteins in the rests of the body). It is too early to tell how durable the responses will be to this agent, but these results provide hope for a more tolerable treatment option for the large group of patients with this specific RAS mutation.
New Phase 2 clinical trial of RMC-6236 in first-line metastatic PDAC and colorectal cancer
RevMed has launched RMC-GI-102, a Phase 2 trial of RMC-6236 in combination with standard-of-care therapies for patients with first-line metastatic pancreatic cancer or colorectal cancer: https://clinicaltrials.gov/study/NCT06445062?intr=rmc-6236&rank=4#participation-criteria
This trial is for patients with:
- Metastatic pancreatic carcinoma or poorly differentiated pancreatic carcinoma, or
- RAS-mutated metastatic (or unresectable) colorectal adenocarcinoma
- RMC-6236 + 5FU-based cytotoxic chemotherapy (such as FOLFIRINOX)
- RMC-6236 + cetuximab, +/- mFOLFOX
- RMC-6236 + gemcitabine/nab-paclitaxel
This trial is already open at 17 locations around the United States.
New Phase 3 clinical trial of RMC-6236
Revolution Medicines has opened their Phase 3 registration trial of RMC-6236. https://clinicaltrials.gov/study/NCT06625320?intr=rmc-6236&rank=6
This trial is for patients with recurrent metastatic pancreatic cancer (2nd-line and beyond). So far it is only open at two locations, but many more will open soon! Of note, patients on this trial will be randomly assigned to receive either RMC-6236, or standard of care therapy (physician’s choice). That means that half of the subjects will not receive the RAS inhibitor. While this is obviously not what a patient wants to hear, it is a critical step for seeking FDA approval and the faster this drug as approved, the sooner it can be offered to all PDAC patients.
Questions:
Why would they randomize the Phase 3 trial? Why can’t they use historical data to compare to instead of randomizing? To get a drug approved by the FDA, you MUST have solid evidence that is effective and safe. Over the past half century, there have been many, many examples of drugs that performed very well in single-arm clinical trials for pancreatic cancer that subsequently were not successful in randomized trials, especially when measuring overall survival, which is the most important metric for patients. Assuming that RMC-6236 is actually effective for treating pancreatic cancer patients, the fastest way to get it to the most patients is through FDA approval. The fastest way to approval is to run a well-designed, randomized, controlled clinical Phase 3 trial. This is it.
It is worth noting that in the past, there have been a few examples of trials that were stopped early because the drugs worked so well that it would be unethical to continue treating patients with the control regimen. In the best case scenario, this would happen here and patients from the “standard of care” group could then receive RAS inhibitor. I have no idea if that is what will happen, but this would be a win for everyone involved!
Is it better to receive RAS inhibitor alone in the second-line, or combination RAS inhibitor with chemotherapy in the first-line? Truly, I don’t know. On the one hand, I could imagine the combination being really effective. On the other hand, I could also imagine it being really unpleasant in terms of side effects. Cytotoxic chemotherapy regimens such as FOLFIRINOX and gem/nab-paclitaxel are already difficult to tolerate for many patients. Time will tell if the combination is actually more effective than receiving the agents separately in different rounds.
I’ll update when more news is available. My best to all the patients, family members, and loved ones out there who have read this far. What I can tell you is that there are literally thousands of doctors, nurses, researchers, and workers, both at medical centers and in companies, who are working like maniacs to bring these drugs to patients as fast as humanly possible. You all are our motivation and our hope.
-KPO
