The First Phase 3 Checkpoint Immunotherapy Trial for MSS Colorectal Cancer

I usually only do this kind of “real-time trial news” post on my Facebook or Twitter accounts but this is such BIG news, I wanted to publish here as well to spread the word to the colorectal cancer (CRC) patient & caregiver portion of my Blog readership.

A PHASE 3 Immunotherapy Clinical Trial was registered today – including for MSS-CRC, the major type of CRC (95% of Stage IV) and the type I have! This is the first time ever that a checkpoint immunotherapy Phase 3 clinical trial has been announced for MSS-CRC!

This is the same immunotherapy combination (MEK inhibitor + PDL1 inhibitor) that I blogged about last week in my post: ASCO 2016 PREVIEW: CHECKPOINT IMMUNOTHERAPY ACTIVITY IN MSS COLORECTAL CANCER

Full data from the Phase 1 trial will be presented on Sunday June 5 at the ASCO annual meeting and I will update my blog once that data is released!  There are a number of things suggesting that the data will be very good though: The developing company is skipping over a Phase 2 trial and going directly to a randomized Phase 3 trial shooting for the fastest potential path for FDA approval (if Phase 3 data supports this!).

Today’s announcement was a surprise – at least to me – it is abnormal and bold… As I wrote in last week’s blog post; “This was not a low risk study to run – it was bold.  But as I have said before, big problems like MSS-CRC immunotherapy need bold solutions!”

I am waiting with baited breath for the full data on Sunday.  Like AACR-2016 (which I also could not go to), I know a lot of people going to ASCO who will be relaying data back to me ASAP!

Regardless of the data specifics, what is even more clear now with today’s Phase 3 trial announcement than when I wrote last week’s post – a major step scientific step forward has indeed occurred in the immunotherapy treatment of MSS-CRC, otherwise the Phase 2 trial would not be skipped………  Data specifics aside, this is something to scientifically cheer for!

People Partying

Of particular note:  They designed the Phase 3 trial enrollment to mimic the natural Stage IV CRC Patient Population (50% KRAS-wildtype, rest KRAS-mutant; 5% MSI-high, rest MSS) – which implies that they are attempting to get a very general FDA approval for “Stage IV CRC”. This is very interesting since MEK inhibitors have traditionally been used to target KRAS-mutant cancers – but the preclinical paper linked below established the possibility of an immune cell targeted effect which could be independent of tumor genetics.  I will be especially listening for KRAS-wildtype data in Sunday’s presentation since it was not included in the written abstract.


Here is the nuts & bolts summary for the trial (edited form of my Facebook post) – mostly of interest to fellow patients and their caregivers:


A VERY IMPORTANT new Phase 3 immunotherapy trial has been registered to start soon for CRC – details below.

Consider printing out the links to have an informed discussion with your MD(s) to determine with him/her/them if this trial would be an appropriate part of your treatment plan.

Full data is being released in an oral presentation at ASCO on Sunday (will be added to this blog then), hopefully a publication will arrive soon thereafter. Of note: I am hoping they will release data on KRAS-wildtype patients on Sunday since this was missing from the abstract.

Trial = NCT02788279:

It is based upon the Cobimetinib (MEK inhibitor) + Atezolizumab (PDL1 inhibitor immunotherapy) Phase 1 trial whose full results are coming out at ASCO on Sunday

Preclinical rationale for this combination:

Presumably based upon their belief in the strength of the Phase 1 data – the developing company is SKIPPING PHASE 2 and going directly into a randomized PHASE 3 trial set up for the possibility of accelerated FDA approval  (IF PHASE 3 DATA SUPPORTS!)

Phase 3 Trial Details:

360 patients across 42 locations

3-arm randomized study (1/3 chance of getting each arm by luck of draw). Arm 1: Patients will get Atezolizumab (PDL1 inhibitor alone). Arm 2: Patients will get the Cobimetinib (MEK inhibitor)+ Atezolizumab (PDL1 inhibitor) combination Arm 3: Patients will get the current standard of care drug Regorafenib as comparator

ENROLLMENT MIMICKING NATURAL STAGE IV CRC PATIENT POPULATION (50% KRAS-wildtype, rest KRAS-mutant; 5% MSI-high, rest MSS) – implies that they are attempting to get a very general FDA approval/labeling for “Stage IV CRC”.

– Relatively lenient in terms of past chemotherapy. Need to have either failed or been “intolerant to” two lines of chemo prior to trial

Can NOT have taken previously any of these: 1.) ANY immunotherapy 2.) Any MEK inhibitor 3.) Regorafenib

– Can not have had a second cancer within 3 years

– Can not have a history of autoimmune disease

– Additional exclusions apply (listed in the NCT link above)

Of note: Some patients mistakenly equate immunotherapy drugs as having no toxicity or side effects.  This is not the case – these are powerful drugs interacting with the immune system and in some patients, significant side effects can occur.  Until a larger number of patients are tested, this experimental combo’s full safety & toxicity profile will not be known.

Overall – there are some aspects which are not ideal for a current patients (e.g. some of the exclusion criteria, randomization) – but this is an ideal trial set up for a potential fast FDA approval to bring an immunotherapy to the MSS-CRC masses ASAP (IF PHASE 3 DATA SUPPORTS!)

I’ve been pounding my fist for a long time that I strongly believed checkpoint inhibitor combination therapy tricks would work soon in MSS-CRC. This is the next BIG SCIENTIFIC STEP FORWARD to hopefully prove that belief clinically!

Next update will be on Sunday.  Then it will be crossing fingers that the Phase 3 data turns out well…

16 Comments on “The First Phase 3 Checkpoint Immunotherapy Trial for MSS Colorectal Cancer

  1. This is so very exciting Tom! We need this boost as in our case, Jim is on his way to a new fork in the road – going to SCCA since our options have been exhausted at our local Oncology Center. I keep praying for something like this or a total miracle. Perhaps our prayers may be answered sooner than we had hoped. We’ll be anxiously waiting for your update. Thank you so much for posting these updates!


  2. As always when I read anything you write, I am in awe! This is me, too! I am so hoping that the data will be convincing. I needed this good news! Thank you! Mary


  3. Dear Tom,
    thank you very much for your detailed information. I have read all inclusion/exclusion criteria and I am afraid that one exclusion criteria can cause that a lot of patients could be excluded from this trial: ANY IMMUNOTHERAPY, which could mean that any treatment with cetuximab and/or bevacizumab is an exclusion criteria. Would it be possible to check what kind of immunotherapy means ANY? I am little worried about this exclusion criteria.


    • Hi Kopec – although there are some aspects of cetuximab and bevacizumab’s mechanism of activity which are related to the immune system, I believe they would NOT count as previous immunotherapies in the context of the exclusion criteria for this and most other immunotherapy trials. As one example, that exclusion criteria is referring to previous use of PD-(L)1 inhibitors plus other immunotherapies which are currently in clinical trials. I can’t give an exhaustive list of what would exclude people but prior use of the two drugs you mentioned should be fine for this & most immunotherapy trials unless they are specifically mentioned by name. Thanks for reading & your comment- Tom


  4. Obviously, this trial may or may not constitute good news for most cancer patients, I’m wondering why they’re excluding persons with “a history of autoimmune disease”?

    To a layman like myself, the answer is obvious that with an overactive immune system already, those suffering from autoimmune disorders like my SLE diagnosis might skew the data. However, I was wondering if there might be other issues of concern for people with autoimmune disorders and Stage IV CRC regarding immunotherapy for their CRC?

    Are there concerns immunotherapy might not work or that it might make the patient worse or if approved could these immunotherapies be used off-label in those with CRC and an autoimmune disorder? I’m asking because when I check with my oncologist about the MSI therapies (it turns out I’m MSS) he said my SLE would be a concern and might eliminate me as a candidate for immunotherapy. Is there just not enough data yet or is there data of adverse reactions in those with both CRC and autoimmune diseases like SLE?


    • Hi Rick, Thanks for your comment & questions. My belief is that they put these standard exclusion criteria into experimental therapeutic immunotherapy trials due to potential safety concerns – i.e. activating the immune system could make a pre-existing autoimmune disease worse, potentially to the point of danger. This worry may or may not have been proven clinically but conceptually I think it is a valid concern. That being said, in the melanoma patient population where multiple immunotherapies are FDA approved – in the clinic, oncologists see a lot of melanoma patients who have both melanoma and autoimmune diseases and I believe they are attempting to find ways to dose safely and are generating now starting to generate data how much of a safety concern there is.


  5. Pingback: ASCO 2016 Presentation: A Major Step Forward in the Immunotherapy of MSS Colorectal Cancer | AdventuresInLivingTerminallyOptimistic

  6. Pingback: První klinická studie fáze 3 s imunoterapií zaměřenou na kontrolní uzly imunitní reakce pro pacienty s MSS-kolorektálním karcinomem | Dobrodružství_terminálně_optimistického_života


  8. Pingback: Interview of a Colorectal Cancer Immunotherapy Breakthrough Principle Investigator | AdventuresInLivingTerminallyOptimistic

  9. Hi- I am in this trial- unfortunately was randomized to the immunology only arm- the problem/risk you take with a phase 3 trial. Side effects so far are fine- digestive issues, but I feel so much better being off chemo. Will keep you posted!


    • HI Anne – Thank you for the comment – best of luck on the trial, please do keep us posted! I’m glad you are tolerating it much better than chemo! -Tom


  10. Not sure where to pose this question, but here we go. My husband (Stage IV MSS- High) finished Medi4376 in May 2015. Followed by radiation in hopes of stirring up his immune system which it did and we got the congrats on his 47th birthday. Fast forward to November and the previously necrotic tumor is showing a thickening of the exterior wall. Back on Medi4376 we go in hopes it works again to control. My questions are 2..Have you heard of results regarding whether there has been a response to re-treatment of PD-1 and second are there any trials that allow a previous Immunotherapy recipient to participate in such as combination therapies? Most I have seen do not allow previous immuno trials.

    Cheers..Your blog gives me great hope. We live parallel lives.


    • Hi Sandra – in terms of your first question (retreatment) – that data may be out there but I don’t personally know it. In terms of your second question – it is becoming more and more common for trials to allow patients to have previously been treated by immunotherapies, as the use of immunotherapies becomes more wide-spread. If you look at my recently published MSS-CRC curated trial finder (, I think at least 1/3 of the immunotherapy trials allow previous exposure to a PD-1 inhibitor. There is a data field/column especially to note that possibility for each trial. This trial finder, is aimed at the MSS-CRC patient population (and your husband is in contrast MSI-high) – but a large majority of the trials should also allow MSI-high CRC patient participation. Best of luck to him and you! -Tom


    • Hi Dmitry – no, there have not been any results yet released. Perhaps they will release interim, preliminary results at ASCO-2017 in June. -Tom


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