ASCO 2016 Preview: Checkpoint Immunotherapy Activity in MSS Colorectal Cancer
As I promised in my last post “Czech Please!” it is now ASCO season, so be prepared for a science post… This one is a little hardcore – but bear with me, I tried to keep unessential scientific details to a minimum and as the title indicates (major spoiler alert!), I think it has a very important message! One, with my eyes misting up a bit, I have been yearning to write for a long time…
The American Society of Clinical Oncology (ASCO) annual meeting always gets a lot of attention. From oncologists, from scientists, from advocacy organizations and importantly from Stage IV patients. Why? Because it is one of the preeminent meetings that occur each year where the latest in clinical trial results are released. For Stage IV cancer patients, these results – although the data released is often only preliminary from small trials – help set the stage, following appropriate medical discussions with their MD(s), for potential new therapeutic strategies via clinical trial participation.
Although the data released is often only preliminary and in need of confirmation (and in fact it is important to note that data does not always confirm in subsequent larger trials!), in the “currently incurable” Stage IV world where I and thousands of my fellow cancer survivors live… this preliminary data takes on many forms of importance: physical, mental and emotional. In conjunction with medical discussions with an appropriately experienced medical team, this preliminary data gives strategic guidance… it gives tactical guidance… it gives HOPE. Yes, it is only preliminary data – but to be frank, often the available lifespans of Stage IV patients do not allow the luxury of waiting for full confirmation before taking preliminary trial data into consideration as we make medical decisions.
All of this added together gives a weight to the preliminary data released at conferences such as ASCO – a level of gravity that few outside of the Stage IV patient population truly appreciate. In conjunction with this weight, is a feeling of HOPE when signs of any potential steps forward are seen!
Last week, the written abstracts were released for ASCO-2016, which is taking place in Chicago on June 3-7. I helped write a summary of some of the potentially most interesting CRC experimental therapeutics poster/talks for Fight Colorectal Cancer. Instead of repeating that information on this blog, I invite you to read that list of abstracts HERE.
Instead, I wanted to focus this column on what I think will be the big experimental therapeutics clinical trial news story coming out of ASCO-2016 for the CRC world: what appears to be the first signs of significant checkpoint immunotherapy activity in non-MSI-high (MSS) colorectal cancer, the major form of the CRC!
As I have written about extensively in the past, for various reasons MSS-CRC (which are about 95% of Stage IV cases including my own) has proven much more resistant to immunotherapy treatments than the comparatively rare MSI-high form of CRC. The high response rate of the PD-1 inhibitor pembrolizumab in MSI-high CRC patients was the big CRC story coming out of ASCO-2015 last year!
Over the past year, the CRC patient population has been electrified as we witness more and more of our MSI-high brothers and sisters responding very favorably to PD-(L)1 inhibitor treatments. Anecdotally, the response rate appears to be quite high, appearing to confirm the small preliminary trial published in the New England Journal of Medicine. Although this observation is only anecdotal, it has been a true medical miracle to witness our friends tell stories of PD-(L)1 inhibitor activity with often low side effects over and over and over…
This has caused an interesting dichotomy in the CRC patient population. We in the MSS-CRC community are overjoyed to see many of our close friends who happen to be MSI-high see their lives turn around. At the same time however, it is hard not to witness feelings of unease within the same CRC patient groups as MSS-CRC patients were not seeing signs of immunotherapy clinical progress being published on our front of the war. We were thrilled to be witnessing very joyful parties for our close friends but we were doing this somewhat as outsiders looking in…
Until potentially now.
When the ASCO abstracts were released at 5:00 PM EDT on May 18, word quickly started to spread through the MSS-CRC patient community. Was it true? Was there really a sign of significant checkpoint immunotherapy progress against non-MSI-high (MSS) colorectal cancer??
The purpose of this column is not to answer that question conclusively – since I am writing it prior to the June 5 data presentation. The only information released so far is the written abstract – but the data released certainly appears to be promising, at the very least at the scientific and abstract level!
Which abstract was everyone talking about?
Abstract 3502 “Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC)”
Remember back to ASCO-2015 – the results of a clinical trial were released looking at PD-1 inhibitor immunotherapy in CRC where the two major types of CRC were separately analyzed for response. PD-(L)1 inhibitors are the famous immunotherapies that have been generating continuous news headlines across many cancer types over the past few years. The comparatively rare MSI-high form of CRC showed a high response rate to PD-1 inhibitor monotherapy whereas patients with the much more common non-MSI-high (MSS) form of CRC showed a dismal response rate – only 10% with a maximum efficacy of only stable disease (SD) – with no tumor shrinkage seen. The study, both released at ASCO-2015 as well as published simultaneously in the New England Journal of Medicine made huge news and waves around the scientific & medical world. For the first time, there was a genetic “biomarker” to determine if a patient was likely to respond to PD-1-based checkpoint immunotherapy.
It left MSS-CRC patients knowing that they needed something more than PD-1 inhibitor monotherapy to hope for a significant response from immunotherapies. But what?? A small number of combination trials have been set up to enroll MSS-CRC but unfortunately they are not large in number… MSS-CRC appears to have enough immunogenic mutations to be amendable to immunotherapies but its tumor microenvironment is very immunosuppressive – from an immunological point of view it is termed a “cold tumor”.
On top of that, there is a very reasonable worry that various tested strategies meant to address the immunosuppression of MSS-CRC tumors may appear to fail in clinical trials unless patients are carefully chosen to match the co-therapy’s mechanism of action, due to the wide number of ways that a MSS-CRC tumor could be mechanistically immunosuppressed. That was a major point made by the Fight Colorectal Cancer/Cancer Research Institute joint CRC Immunotherapy Expert Roundtable that I have been involved with over the past few months and its recent presentation at AACR-2016: a single co-therapy strategy may not have a significant response rate without e.g. proper binning of patients using a diagnostic technique such as immunoscore or other biomarkers.
With only a few co-therapies in clinical testing meant to address its immunosuppression, MSS-CRC really needed a proof-of-principle of clinical progress/success to fully open up the clinical trial floodgates – something that had not happened — until perhaps now.
Ironically, I considered Abstract 3502 “Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC)” as a dark horse in the race. It was not high up on patients’ radar screens, for a number of reasons. First of all, the use of MEK inhibitors was believed to have more than one possible impact on the immune system based upon preclinical data, some of which may have actually hindered successful immunotherapy – not help it. The developing company believed otherwise and they published their preclinical rationale at approximately the same time the Phase 1 trial was already winding down. This was at a similar time point to rumors starting to swirl in the patient community of signs of success – but since it was a small trial – the rumors did not start up until basically the trial was ending. But the rumors were good.
The Abstract 3502 Clinical Trial (NCT01988896)
Abstract 3502 discloses for the first time the preliminary CRC data coming out of the exploratory Phase 1 clinical trial NCT01988896 entitled “Study of Atezolizumab in Combination With Cobimetinib in Participants With Locally Advanced or Metastatic Solid Tumors”. In brief summary, it is one of the oldest trials to examine MSS-CRC patients and it combined a PD-L1 inhibitor immunotherapy (atezolizumab) with a targeted agent MEK inhibitor (cobimetinib). Traditionally, MEK inhibitors were developed to have activity against “BRAF-mutant” and “KRAS-mutant” cancers but as recently disclosed, the company developing this combination therapy also intriguingly believes that a MEK inhibitor could have beneficial immunotherapy effects via interacting with the immune system itself. This lines up the possibility of this co-therapy being active in patients regardless of BRAF/KRAS-genetic status – but in the current abstract data release, they focus on patients who are both KRAS-mutant and MSS.
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!
Abstract 3502 – The Data Disclosed
As of last October, twenty-three CRC (22 KRAS-mutant, 1 KRAS-wildtype) patients were enrolled in the study. It was a small arm of the study. But the results, even for a small study, are very intriguing and they quickly caught the attention of both me as well as the MSS-CRC patient community. Out of those 23 patients: four patients had a “Partial Response (PR)” (tumor shrinkage of at least 30%) and five had “stable disease” (SD). At least three of the PR responders had MSS-CRC, the fourth had unknown status. Looking at the numbers, in this small trial – this shows an objective response rate of 4/23 (PR; 17%) and a clinical impact rate of 9/23 (PR+SD; 39%)! Compare that preliminary data to a ZERO objective response rate and a clinical impact rate (SD) of only 10% when a PD-1 inhibitor was dosed alone to MSS-CRC patients – if confirmed in a larger trial, this is a big step forward!
Mechanistically, according to the abstract, results from the serial biopsies showed enhanced PD-L1 upregulation, CD8 T-cell infiltration and MHC I expression on treatment. What does that scientific gobbly-gook mean? It means that the combination therapy appears to be positively impacting and activating the immune system as hoped…
Of course in addition to needing confirmation in larger trials (which are presumably starting soon!) at least one big question remains: how “durable” is the response? i.e. Once patients show a response, for how long does it last? This is a very pertinent question because in some tumor types, checkpoint inhibitor immunotherapies can be effective over a long term but in others… the impact can unfortunately be relatively short lived…
When the full data presentation occurs on June 5, the big pieces of data I will be looking especially out for are: 1.) Were there any signs of non-KRAS-mutant responses? and 2.) Updated information on the durability of response. Both pieces of information will go a long way to determine the magnitude that this study & experimental treatment strategy will have on the MSS-CRC field and patients as it enters into larger confirmatory trials. I will update this post after the full data presentation on June 5.
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.
Expanding the Immunotherapy Party Invite List
I think the impact of this study goes way beyond the data specifics however. Although I have been openly optimistic, many people have been nervous that MSS-CRC may be a tough nut to crack in terms of PD-1 co-therapies generating significant clinical responses. Even if the final statistics shift in confirmatory trials, this exploratory trial appears to refute that concern – and in that way I believe it is very powerful! In scientific circles, this is called a “proof-of-principle”. It now appears that MSS-CRC patients can obtain objective clinical responses via an appropriate PD-1 inhibitor co-therapy. This is what the scientific field was needing and looking for. Once a proof-of-principle is in hand and the strategy is “de-risked” – similar to what we saw with MSI-high CRC last year – the research flood gates will hopefully more fully open and many more MSS-CRC clinical trials initiated.
Although the abstract only discloses preliminary data from a very small trial (needing larger trial confirmation!) – with this study, the door to potential successful immunotherapy intervention in MSS-CRC has been further cracked open and is now being set up to hopefully be kicked open as hard and fast as science allows.
Data specifics aside… that is the HUGE impact of one little study like Abstract 3502 / NCT01988896. It gives scientific insight… it gives scientific guidance… it gives scientific Hope… to those that need it the most: us, in the Stage IV MSS-CRC patient population. Even with its small 23 patient size, that is a mighty powerful study indeed. I am now ever more terminally optimistic that additional immunotherapy co-therapy clinical trial steps forward will be identified for MSS-CRC, looking at the current clinical trial timelines – perhaps as soon as later this year. Speaking for myself and others, we MSS-CRC patients are more than ready to join the checkpoint immunotherapy party!
To science… to progress… to Life!