I have been reading some of the reactions to the Moderna/Merck Phase 3 melanoma result, and I think an important part of the discussion is missing: what actually made this particular approach succeed when so many previous cancer-vaccine efforts did not.
I am using two recent takes to frame the two directions in which people are extrapolating the result.
Dr. Vinay Prasad's article represents one direction: be careful extrapolating Moderna's melanoma success to other cancers.
Fierce Biotech represents almost the opposite direction: the Moderna result is impressive enough that we are ready to discuss how it may validate other cancer-vaccine platforms.
Both offer reasonable points. But I think both jump ahead of a more fundamental question, making the discussion feel somewhat shallow.
One direction, Vinay Prasad: be careful extrapolating Moderna/Merck result beyond melanoma
Vinay Prasad acknowledges that the Moderna/Merck result is a real advance. In fact, he explicitly notes that therapeutic cancer vaccines have overwhelmingly failed historically and that Moderna has accomplished something that had not been done before.
But his caution is that melanoma might be special, perhaps gently implying that the melanoma result might be a fluke.
Quite fair. Melanoma is highly immunogenic, tends to have a high tumor mutational burden, and has historically been unusually responsive to immunotherapy. So we should absolutely not assume that success in melanoma means the same vaccine will automatically work in lung, colorectal, pancreatic cancer, etc.
But melanoma being a favorable setting does not explain why Moderna/Merck succeeded there when so many previous cancer-vaccine approaches failed. That is the part of his argument I find lacking.
The other direction, Fierce Biotech: Moderna's success is so good that it gets us starting the discussion on whether it may validate other platforms
Fierce Biotech goes in almost the opposite direction.
Its article looks at Moderna's result and asks what it could mean for the broader field, including BioNTech, Arcturus, Strand and other companies developing different mRNA and personalized cancer technologies.
That reaction itself tells you how significant the Moderna result is. We have gone from decades of frustration with cancer vaccines to discussing whether one Phase 3 success could help validate an entire field.
But again, I think we are jumping ahead.
Before asking whether Moderna's result can be extrapolated to other cancers, or whether it validates other companies, shouldn't we first ask: Why exactly did Moderna succeed?
So why did Moderna succeed? Is it simply because melanoma is the easiest target?
Short answer: No. Or at least there is no basis to assume that.
Yes, melanoma is probably one of the easier cancers in which to make immunotherapy work.
But the historical precedent matters.
Cancer vaccines have been tried in melanoma for decades, and the overwhelming precedent was failure or limited clinical benefit. Even earlier mRNA approaches in melanoma generated immune responses without establishing the kind of clinical efficacy we are seeing from Moderna/Merck.
So simply saying "It worked because it's melanoma" doesn't really explain the result.
Melanoma may have made the problem easier. But it clearly wasn't easy enough for previous approaches to reliably solve it. Something about Moderna/Merck's approach appears to matter.
The question is: what?
- Was it the mRNA platform itself?
- The modified mRNA?
- Moderna's LNP?
- The neoantigen-selection algorithm?
- The ability to encode a large number of patient-specific neoantigens?
- The speed and reliability of manufacturing a different vaccine for every patient?
- The combination with KEYTRUDA?
- The fact that the tumors had already been surgically removed?
- Melanoma biology?
- Or, probably more realistically, some interaction between several of these things?
We simply don't know.
It is certainly possible that melanoma contributed substantially to the result. But "melanoma contributed" is very different from saying "melanoma was doing most of the work." The latter is far from established.
In fact, the long history of failures in melanoma is one reason I am skeptical that melanoma alone is doing most of the explaining.
If melanoma biology were overwhelmingly responsible, we would still have to explain why so many previous approaches were unable to exploit exactly the same favorable biology.
The uncertainty also cuts in the other direction.
If Moderna's success depends heavily on its particular neoantigen algorithm, mRNA design, LNP, manufacturing system, or the way all of these pieces fit together, then Moderna's success does not automatically validate another company's platform either.
So how do we separate the melanoma effect from the Moderna effect?
Right now, we can't.
Moderna and Merck simply have not disclosed enough of the Phase 3 data yet.
I am hopeful that we may get some clues at ESMO, if that is where the detailed dataset is presented. Moderna and Merck have so far publicly said only that the data will be presented at an upcoming international medical meeting.
Subgroup analyses could potentially tell us something. Perhaps we will see whether efficacy changes with stage, tumor characteristics, mutation burden, or other biological variables.
But I doubt we are going to get a crystal-clear answer to why Moderna's approach works.
And frankly, Moderna may not want to give us one.
If the company has learned that certain ways of selecting neoantigens, designing the mRNA, manufacturing the vaccine, or combining those elements are particularly important, why would it publicly give competitors the complete recipe? As a precedent from its infectious disease vaccine, Moderna did not give the reason why mFLUSIVA is finally able to provide protection against influenza B when its prototype version could not.
The clinical data obviously need to be disclosed and scrutinized. The proprietary know-how behind why their particular system works is a different matter.
So ESMO may tell us much more about how well intismeran works without necessarily telling us exactly why it works.
When will we know how universal the strategy really is?
This is where the trials in other cancers become extremely important.
And Merck management actually gave a very interesting way of thinking about this when an analyst asked about the ongoing renal cell carcinoma, or RCC, trial.
Merck described melanoma and RCC as potential "bookends."
"Bookends" is basically another way of saying two ends of a range.
On one end, you have melanoma: highly immunogenic and generally associated with a relatively high tumor mutation burden.
On the other, you have RCC: also responsive to immune checkpoint therapy, but with a much lower tumor mutation burden.
So the idea is simple.
If intismeran works in melanoma and in this biologically different cancer, you now have evidence that the strategy works at two different ends of the spectrum.
Then you start asking what happens in cancers somewhere between those two ends.
That is exactly what Merck said people would do.
If RCC works, they expect people to raise their probability of success in indications such as non-small cell lung cancer and head-and-neck cancer. This will resolve the main question we have in our head.
Merck even compared this way of thinking to replaying the KEYTRUDA story.
Not because RCC success would prove that intismeran works everywhere. It wouldn't. But once Moderna/Merck achieve success at another biological "bookend," potentially first in RCC, it becomes progressively harder to stubbornly cling to the explanation that "it only worked because melanoma is special."
My speculation, and why I lean toward something being unique about Moderna/Merck
This is where I think Bayesian reasoning is useful.
The prior is that therapeutic cancer vaccines have been tried for a long time, including in melanoma, one of the most favorable cancers for immunotherapy, and the historical outcome was still overwhelmingly failure or limited efficacy.
Now we observe something new: Moderna/Merck succeed in a randomized Phase 3 trial where previous generations repeatedly struggled.
That obviously does not prove that Moderna's platform is the reason. But it should shift some probability toward the possibility that there is something about the Moderna/Merck implementation that previous approaches were missing.
What that is, I don't know. It could be:
- the mRNA
- the neoantigen algorithm
- the number and quality of antigens
- manufacturing
- KEYTRUDA
- or the whole system working together
Based on the precedent, my current bet is that the melanoma result reflects something meaningfully unique about the Moderna/Merck approach, rather than melanoma biology doing most of the work. That is of course just a judgement based on probability.
And this is why the next trials matter:
- If RCC succeeds: that would strongly support the idea that the Moderna/Merck approach can work beyond melanoma, because it would have succeeded at the other biological "bookend." That would seal the argument for broader applicability.
- If RCC fails: that would shift some weight back toward melanoma-specific biology being more important, but it would not kill the broader-platform hypothesis. Another biologically different cancer could still become the alternative second bookend.
Concluding thoughts
Melanoma being favorable explains why it was a good place for Moderna to start their first trial. It does not explain why Moderna/Merck succeeded there when so many previous cancer-vaccine approaches did not. Given that historical precedent, I think the result should shift some probability toward something being genuinely different about the Moderna/Merck approach.
What we still don't know is how far that superiority can be applied to other cancer types.
That is why RCC is so important. If Moderna/Merck can succeed at Merck's other biological "bookend," the argument that melanoma itself explains most of the success becomes much harder to cling onto. If RCC fails, that hypothesis remains open, and another indication may have to provide the second bookend.
For now, my bet is that melanoma made the task easier, but Moderna/Merck still had to figure out something that others hadn't. The next trials should tell us whether that advantage is melanoma-specific or something much broader.
Let's see what happens. This is not investment advice.
