MSI High Rectal Cancer

[madchemist89]

Has anyone seen the latest NCCN rectal guidelines showing neoadjuvant/definitive immunotherapy for MSI high patients as category 2B recommendation. Does anyone know what data this recommendation is based on? I'm hoping it's not that 12 person study.

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[medgator]

It might be with that cat rec

 

[Fpg1245]

Has anyone seen the latest NCCN rectal guidelines showing neoadjuvant/definitive immunotherapy for MSI high patients as category 2B recommendation. Does anyone know what data this recommendation is based on? I'm hoping it's not that 12 person study.

Why wouldn’t it be? not Aware of any larger study that has resulted for this yet.

 

[Ray D. Ayshun]

I think there's good data in metastatic setting as well, from which it is reasonable to extrapolate.

 

[Palex80]

It is the 12 person study!

But let's be fair... it's the first time the med. oncs managed to cure a sold tumor without surgery, after testicular cancer.

 

[madchemist89]

It's concerning that it was even added if that was the level of evidence. There are med oncs who are going to try treating rectal cancer with immuno.

 

[medgator]

It's concerning that it was even added if that was the level of evidence. There are med oncs who are going to try treating rectal cancer with immuno.

Not if they have some vault ownership

 

[Fpg1245]

It's concerning that it was even added if that was the level of evidence. There are med oncs who are going to try treating rectal cancer with immuno.

This is the type of power med onc/pharma complex has.

Meanwhile you want another fx of RT…be prepared to run the gauntlet of ROs atbthe ready to kill you if you don’t have at least 10 studies behind it. NOM?? I hope you don’t actually need your job or like referrals.

Rad onc needs to get over itself and to attach yourself to something powerful like Med Onc to survive. This type of **** is just gonna keep happening.

 

[Gfunk6]

I was in a conference last weekend and one of my peer Rad Oncs mentioned that all MSI rectal cancers in his region were not receiving any radiation. I haven't seen it yet in my neck the woods but figure it will come eventually.

 

[Fpg1245]

I was in a conference last weekend and one of my peer Rad Oncs mentioned that all MSI rectal cancers in his region were not receiving any radiation. I haven't seen it yet in my neck the woods but figure it will come eventually.

The thing idk is are they actually cured. If it recurs then what? Rechallenge? Do SOC?

It’s a 2B Rec but I’m sure MO can convince patients to give it a try.

 

[deleted1111261]

As a patient, I would try that first.

 

[CaesarRO]

I was in a conference last weekend and one of my peer Rad Oncs mentioned that all MSI rectal cancers in his region were not receiving any radiation. I haven't seen it yet in my neck the woods but figure it will come eventually.

In your region are there a lot of those?

I can't recall the exact prevalence off the top of my head but it was something like 20% of rectal cancers are MSI High.

As Simul said, I'd rather get that first as a patient.

We'll probably have a role to play for the failures, if any.

 

[FindMeOnTheLinks]

In your region are there a lot of those?

I can't recall the exact prevalence off the top of my head but it was something like 20% of rectal cancers are MSI High.

As Simul said, I'd rather get that first as a patient.

We'll probably have a role to play for the failures, if any.

I thought it was more like <10%

The most insane thing about this whole to me is, not only is it based on only 16 patients, but in the published manuscript only 12 of them had follow up longer than 6 months (with a median fu of 12 months in that group). They even admit in the paper that they could not report the primary endpoint - sustained complete response at least 12 months - because the results are not mature. And yet somehow this makes it into nccn. Will probably work out in the end but it’s pretty insane to me how this could find its way into guidelines with data this immature. Guess med oncs were going to do it either way….

 

[beamteam7]

I thought it was more like
The most insane thing about this whole to me is, not only is it based on only 16 patients, but in the published manuscript only 12 of them had follow up longer than 6 months (with a median fu of 12 months in that group). They even admit in the paper that they could not report the primary endpoint - sustained complete response at least 12 months - because the results are not mature. And yet somehow this makes it into nccn. Will probably work out in the end but it’s pretty insane to me how this could find its way into guidelines with data this immature. Guess med oncs were going to do it either way….

I don’t think it would be ethical to do a RCT where some patients get placebo immunotherapy. Agree will be nice to have longer term outcomes, which we will get. I think question here is does adding RT and immunotherapy together provide better durable long term control compared to immunotherapy alone? How should we sequence it?

 

[sirspamalot]

2B or not 2B... linac is the question

 

[beamteam7]

I don’t think it would be ethical to do a RCT where some patients get placebo immunotherapy. Agree will be nice to have longer term outcomes, which we will get. I think question here is does adding RT and immunotherapy together provide better durable long term control compared to immunotherapy alone? How should we sequence it?

The limb sparing sarcoma NCI trial only had 43 patients.

 

[seper]

I’m starting to see these patients getting immunotherapy alone in NY-NJ major centers.
If there is a problem, we will find out soon

 

[fiji128]

I’m starting to see these patients getting immunotherapy alone in NY-NJ major centers.
If there is a problem, we will find out soon

Radiation, the treatment of last resort! So excited for the future!

 

[TheWallnerus]

It's concerning that it was even added if that was the level of evidence. There are med oncs who are going to try treating rectal cancer with immuno.

Level of evidence is not necessarily related to the size of the sample. If I made a new coin with heads on one side and tails on the other and reported flipping it twelve times and got heads 12/12 times, I have highly likely made a significantly different coin versus other pre-existing coins (one must accept I am not a liar, falsifier, hustler, etc).

 

[evilbooyaa]

The 12 patient series were mismatch repair deficient.

https://www.nejm.org/doi/full/10.1056/NEJMoa2201445

Is that the same as microsatellite instability-high?

These are separate papers. The dostarlimab is in MMR-deficient. Which yes, MMR-deficient does have MSI component, but not all MSI are MMR-deficient? I'm not really

Neoadj/"Definitive" Immunotherapy is now preferred and is a Cat 2A rec.

Seems very early. Discussion seems to be getting updated.

Probably the first thing to try, TBH. Maybe it's like Nigro but for rectal cancers.

 

[stanley getz]

As a patient, I would try that first.

Strongly disagree, pembro colitis and pneumonitis are far worse than anything rectal RT can contribute.

 

[diogenese]

There is a European MSI neo-adjuvant study also showing excellent responses -- can get synopsis here https://dailynews.ascopubs.org/do/podcast-advances-neoadjuvant-io-msi-h-dmmr-colorectal-cancer

Obviously need longer follow up --- but to me, this seems very very very likely to work.

 

[communitydoc13]

very very likely to work.

I find it hard to believe that most of us would want to radiate Lynch syndrome/MSI high patients up front at this point. I would not subject myself to XRT in this setting even with the prelim data we have. I certainly would not submit to total neoadjuvant with chemorads if I had this molecular profile. That multiple groups have demonstrated remarkable response outcomes is reassuring. (The biggest risks in this type of setting (remarkable signal) are that a single research group misrepresented findings, had some absurd patient selection or did something unscrupulous.)

I have no problem with the 2B rec.

I don’t think it would be ethical to do a RCT where some patients get placebo immunotherapy

Yep. When signal is this good, you don't placebo.

 

[TheWallnerus]

Is the phrase “placebo immunotherapy” an oxymoron. Discuss.

 

[communitydoc13]

Is the phrase “placebo immunotherapy” an oxymoron. Discuss.

Well in MSI high rectal cancer (where path response rates seem to be 100% and pCR is very high) it is at this point.

For most solid tumors, IO offers nothing like this. It is also not free at all (cost or toxicity wise).

 

[Palex80]

Recently saw a patient progressing locally while on dostarlimab. It doesn't always work.

 

[RickyScott]

Level of evidence is not necessarily related to the size of the sample. If I made a new coin with heads on one side and tails on the other and reported flipping it twelve times and got heads 12/12 times, I have highly likely made a significantly different coin versus other pre-existing coins (one must accept I am not a liar, falsifier, hustler, etc).View attachment 369713

same was true with the first pts treated with penicillin. Dont always need stats when faced with something obvious.

 

[goodkerma]

I have zero arguments about IO alone (no chemo surgery or RT) for those patients. They do very well- hard to justify anything else- haven’t seen a local failure yet though a few metastatic patients have undergone “immune escape” and progress after a certain time, some remain cured.

 

[Fpg1245]

I have zero arguments about IO alone (no chemo surgery or RT) for those patients. They do very well- hard to justify anything else- haven’t seen a local failure yet though a few metastatic patients have undergone “immune escape” and progress after a certain time, some remain cured.

What percentage are MSI high anyway?
Also any new info on the MSKCC patients?

 

[pikachu]

What percentage are MSI high anyway?
Also any new info on the MSKCC patients?

Data bad but i think somewhere between 5-10%. On mobile atm but i’ll try to find an actual source and come back.

 

[Fpg1245]

Data bad but i think somewhere between 5-10%. On mobile atm but i’ll try to find an actual source and come back.

That seems awfully high. Maybe because only certain pops are being screened more than others. Or those patients end up at big centers like MSK.

I just haven’t seen one and we test…like a lot

 

[pikachu]

That seems awfully high. Maybe because only certain pops are being screened more than others. Or those patients end up at big centers like MSK.

I just haven’t seen one and we test…like a lot

Both these fairly large series quote MSI high rates around 6%.

https://onlinelibrary.wiley.com/doi/full/10.1111/his.14710

Association of mismatch repair status with survival and response to neoadjuvant chemo(radio)therapy in rectal cancer - npj Precision Oncology

Prior reports have indicated that defective mismatch repair (MMR) has a favorable impact on outcome in colorectal cancer patients treated with surgery, immunotherapy, or adjuvant chemotherapy. However, the impact of MMR status on response to neoadjuvant radiotherapy in rectal cancer is not well...

www.nature.com

 

[NotMattSpraker]

I have zero arguments about IO alone (no chemo surgery or RT) for those patients. They do very well- hard to justify anything else- haven’t seen a local failure yet though a few metastatic patients have undergone “immune escape” and progress after a certain time, some remain cured.

Very interested to see long term follow up of the trial cohort.

I agree this is a very exciting development for these patients. It will really awesome if some get long term control/cure.

 

[medgator]

Just saw my first pt. I think nccn still endorsees standard therapy if localized from what I'm reading. IO alone ok in metastatic msi high pts

 

[Palex80]

Just saw my first pt. I think nccn still endorsees standard therapy if localized from what I'm reading. IO alone ok in metastatic msi high pts

IO is now the preferred option for MSI-high tumors.

The patient I saw had an MSI-high tumor very close to the sphincter and is elderly.
IO was chosen to preserve the rectum, he is certainly not fit enough for TNT. He responded initially well to the dostarlimab, but later progressed locally while still on it. He will now be getting neoadjuvant CRT (long course), followed (likely) by an APR, capecitabine will likely not work in MSI-high, so the bar is low to drop it during neoadjuvant CRT if he experiences toxicity.

 

[medgator]

IO is now the preferred option for MSI-high tumors.
View attachment 376236


The patient I saw had an MSI-high tumor very close to the sphincter and is elderly.
IO was chosen to preserve the rectum, he is certainly not fit enough for TNT. He responded initially well to the dostarlimab, but later progressed locally while still on it. He will now be getting neoadjuvant CRT (long course), followed (likely) by an APR, capecitabine will likely not work in MSI-high, so the bar is low to drop it during neoadjuvant CRT if he experiences toxicity.

Must have been looking at a different part of the guideline. Thanks

 

[deleted1111261]

To base a change to preferred on a non randomized, dozen patient trial is absurd.

 

[Fpg1245]

To base a change to preferred on a non randomized, dozen patient trial is absurd.

Lots of unfounded exuberance surrounding these drugs.

 

[A_DeMichele]

I'm sure Dr. Nigro heard that his protocol was absurd!

 

[deleted1111261]

I'm sure Dr. Nigro heard that his protocol was absurd!

The guy I replaced was a resident at Harper Hospital at that time! He said it was really cool to be a part of that whole thing. Like many things in #radonc, the Nigro Protocol was invented by a surgeon - a proctologist!

 

[evilbooyaa]

To base a change to preferred on a non randomized, dozen patient trial is absurd.

I don't know that we've seen as compelling single arm ph II data in my lifetime in oncology... Based on what we know right now it's what I'd want if I had that disease process.

 

[deleted1111261]

I don't know that we've seen as compelling single arm ph II data in my lifetime in oncology... Based on what we know right now it's what I'd want if I had that disease process.

That’s fair.

 

[NotMattSpraker]

I don't know that we've seen as compelling single arm ph II data in my lifetime in oncology... Based on what we know right now it's what I'd want if I had that disease process.

The phase II trial of protons over tace for HCC 😃

 

[TheWallnerus]

To base a change to preferred on a non randomized, dozen patient trial is absurd.

I don't know that we've seen as compelling single arm ph II data in my lifetime in oncology... Based on what we know right now it's what I'd want if I had that disease process.

Even if just a 1 in 4 chance (ridiculously optimistic) failure rate was estimated for all 12 people, the fact that all 12 would not have failure has a rough odds of (0.75)^12. And many would have guessed (0.25)^12 pre trial.

 

[Ray D. Ayshun]

Perhaps a 100% response rate is a surprise, but this wasn't just out of the blue. We have a mechanism that makes sense and plenty of good data in the metastatic setting. We shouldn't just stop investigating, but in context, its well supported and something that I too would want.

 

[evilbooyaa]

The phase II trial of protons over tace for HCC 😃

I won't argue against RT compared to TACE/TARE in localized HCC! That wasn't changing my preferences, ever since the Dan Wahl data about SBRT vs RFA for localized HCC....

Perhaps a 100% response rate is a surprise, but this wasn't just out of the blue. We have a mechanism that makes sense and plenty of good data in the metastatic setting. We shouldn't just stop investigating, but in context, its well supported and something that I too would want.

Agree that we should have long term f/u and maybe they'll all end up recurring. But, if they can get salvaged appropriately at that point, then is there patient harm? It'll take a LOT to really flip NCCN again IMO.

 

[NotMattSpraker]

I won't argue against RT compared to TACE/TARE in localized HCC! That wasn't changing my preferences, ever since the Dan Wahl data about SBRT vs RFA for localized HCC....



Agree that we should have long term f/u and maybe they'll all end up recurring. But, if they can get salvaged appropriately at that point, then is there patient harm? It'll take a LOT to really flip NCCN again IMO.

Haha just for the record, I was being facetious.

In my limited experience, the medical oncologists on NCCN are very biased in terms of level of evidence required to include it. I had one in the same meeting vote to approve a drug on a single arm ORR trial then question whether SBRT was "standard" enough for sarcoma to be included (there is like a big series published every 6 months). I see the same stuff all over Twitter.

I dont have a problem with the current guideline. As a prospective study, it should absolutely be included as an approved option. Whether it is preferred or not is a reasonable argument IMO (Im okay with it being preferred for now).

Remember NCCN levels of evidence have as much to do with panel consensus as the type of study.

 

[evilbooyaa]

Haha just for the record, I was being facetious.

In my limited experience, the medical oncologists on NCCN are very biased in terms of level of evidence required to include it. I had one in the same meeting vote to approve a drug on a single arm ORR trial then question whether SBRT was "standard" enough for sarcoma to be included (there is like a big series published every 6 months). I see the same stuff all over Twitter.

I dont have a problem with the current guideline. As a prospective study, it should absolutely be included as an approved option. Whether it is preferred or not is a reasonable argument IMO (Im okay with it being preferred for now).

Remember NCCN levels of evidence have as much to do with panel consensus as the type of study.

And as Jeff Ryckman has taught us, ROs are woefully underrepresented across pretty much all of NCCN. Discriminatory bastards.

 

[temujim]

Remember NCCN levels of evidence have as much to do with panel consensus as the type of study.

Key point. The NCCN guidelines are often about getting "permission" to do what a panelist wants to do/is doing at their institution as much as any evidence.

And not only are rad oncs underrepresented on NCCN boards, by and large they are milquetoasts.

 

[TheWallnerus]

And as Jeff Ryckman has taught us, ROs are woefully underrepresented across pretty much all of NCCN. Discriminatory bastards.

Wouldn’t mind this rad onc oversupply so much if NCCN could just be supplied