ASCO 2016 Presentation: A Major Step Forward in the Immunotherapy of MSS Colorectal Cancer
To complete the trilogy of posts on the major new preliminary MSS Colorectal Cancer (CRC) immunotherapy results released today on the combination therapy of the MEK inhibitor cobimetinib + the PDL1 inhibitor atezolizumab, I’m excited to share the data released at ASCO-2016 this morning! Both drugs are already FDA approved for other types of cancer – this was the first examination of their combined use against MSS-CRC.
When dosed alone, neither MEK inhibitors nor PD(L)1 inhibitors have shown significant published clinical activity against MSS-CRC.
As the first story of the trilogy (and I recommend you read this backdrop to today’s MAJOR “step forward” news story) – I previously wrote first about the abstract & science background as well as the patient impact of this study in my post ASCO 2016 PREVIEW: CHECKPOINT IMMUNOTHERAPY ACTIVITY IN MSS COLORECTAL CANCER. I then wrote about the surprise development decision to skip the Phase 2 trial and go directly into a pivotal Phase 3 registration trial in the post THE FIRST PHASE 3 CHECKPOINT IMMUNOTHERAPY TRIAL FOR MSS COLORECTAL CANCER. That post also contains many Phase 3 trial recruitment details important to patients and caregivers who are interested in the trial.
After seeing the data released this morning at ASCO-2016, the developing company’s decision to move directly to a Phase 3 trial, although bold, is no longer surprising!
Due to potential copyright issues, I will not be including the actual slides in this post. But they are floating all over Twitter – look at my Twitter feed (@CurrentIncurSci) and you will see the ones publicly floating around from multiple sources. They show a very compelling scientific and preliminary medical story!
Of note this is still just preliminary data in a small trial (23 patients). But its signals are far enough away from known historical data that I think excitement of the therapy’s potential is very much warranted. Obviously the developing company agrees – that is why they are skipping the Phase 2 trial to attempt to speed up potential FDA approval to the fastest timelines possible.
Data Summary from today’s Abstract 3502 oral presentation: “Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC)”:
- Historical monotherapy data: Neither cobimetinib nor pembrolizumab (a related PD-1 inhibitor) have previously shown significant response rates in MSS-CRC when dosed alone.
- Combination Response Rate: 17% of patients had at least a 30% reduction in tumor size but including stable disease: ~40% of patients appeared to achieve clinical benefit. As long as it is durable, stable disease can sometimes be a very significant clinical benefit from immunotherapies not captured by traditional “response rate statistics” originally developed for chemotherapy drugs.
- Durability: This was a key question going into the presentation this morning since it was not addressed by the written abstract released a few weeks ago. A number of patients responded for >1 year, including some that are still responding as of today’s talk’s data cutoff. The response is durable in some patients. Because of the long term responders, a “median” (similar to an “average”) duration of overall survival response can not yet be calculated. 72% of patients were still alive at the 6-month mark. Keep in mind that these Phase 1 trials are usually tested in very late stage patients who have already exhausted many or all lines of approved therapies.
- Individual patient responses i.e. the “spider plots”: Spider plots are line graphs that track individual patient responses to a drug over time. They are especially important in looking at immunotherapy responses because the “median is not the message” – there can be some very long term responders to some immunotherapies regardless of what the “average of patient responses” is. Although the data is still being collected, the spider plot of MSS-CRC patients receiving this combination therapy visually looks similar to the spider plot of MSI-high CRC patients receiving a PD1-inhibitor monotherapy. A scientific question to be answered: Does MEK inhibition with cobimetinib convert some MSS tumors into a “MSI-high-like” status?
- KRAS-status: The trial was almost entirely KRAS-mutant patients, so it can not be said yet how the therapy behaves in KRAS-wildtype patients. This will be tested clinically in the randomized Phase 3 trial NCT02788279 which will include 50% KRAS-wildtype patients.
- Preliminary comparison to current standard of care regorafenib: 6 month survival of this new immunotherapy combination was 72% with as I said a median still not calculable since it includes some patients who were still responding >1 year into the therapy. The median survival for patients who take regorafenib (current standard of care) is 6.4 months, so there appears to be potentially a positive step forward in this initial preliminary data.
- Safety: Safety appeared to match know side effects of the drugs when they are used as single agents.
- PDL1 Biomarker Expression: So far, there is no clear correlation between PDL1 expression and response to the therapy.
- Getting even further into the scientific weeds: Cobimetinib alone increased CD8+ immune cell infiltration into the tumor as well as MCH I expression. This effect was enhanced using the combination therapy. What this means: Cobimetinib both alone & in combination with atezolizumab appears to activate the immune system to recognize and infiltrate tumors in multiple MSS-CRC patients
Update added June 9, 2016: Here is the official ASCO post-meeting write up of the study presentation
In a Nutshell
I have to stress again that these results are preliminary from a small 23-patient study. Sometimes small studies do not confirm in subsequent larger randomized studies. Also: unique combination therapy toxicities may emerge as additional patients are dosed.
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.
That being said… at the very least this study was a major scientific leap forward for the immunotherapy treatment potential of MSS CRC. The clinical benefit response rate (including stable disease) was quite high for a “first step forward” (40%) and it appears to compare favorably with historical data of standard of care. The pending randomized Phase 3 clinical trial will prove or disprove its preliminary signs of clinical activity as well as any potential superiority to current standard of care.
Repeating what I emphasized in the pre-ASCO post last week – the HUGE scientific impact of this preliminary clinical study is that IT SHOWS THAT YOU CAN SUCCESSFULLY TREAT AT LEAST SOME PATIENTS WITH MSS-CRC WITH IMMUNOTHERAPIES.
This is something I have openly strongly believed in and now there is clinical proof.
No matter how the final data shakes out in the randomized Phase 3 trial (response rates, durability etc) – that scientific statement is now both a fact and also incredibly important. It is the “proof-of-principle” people have been searching for to open up more fully the immunotherapy research floodgates for MSS-CRC!
I am not a MD, so I can not give medical advice. As a scientist & fellow patient, I do suggest that based upon today’s ASCO presentation, Stage IV MSS-CRC patients may want to consider printing out the ASCO abstract and discussing it with their MD(s) for medical advice in regards to the pending 42-site Phase 3 clinical trial.
Although the details of the preliminary clinical profile presented today need confirmation in the pending randomized Phase 3 clinical trial, this small preliminary study’s scientific impacts will be felt for years to come… So today is a day to CELEBRATE A SCIENTIFIC ADVANCE – a day of a significant scientific step forward, bringing us “one step closer” to the big eventual goal – a hoped for cure for “currently incurable” MSS-CRC.
PS: There was more promising info for both MSS and MSI-high CRC patients at ASCO this year – that will wait for a subsequent post…