The Faces of Successful Colorectal Cancer Immunotherapies: Vol. 1
I wanted to expand the normal scope of my personal blog in today’s post. Not just for the sake of expansion but importantly because I believe strongly in today’s topic! After a bit of introductory science, I will be profiling two fellow CRC patients currently in immunotherapy clinical trials – to illustrate the preliminary signs of immunotherapy success of checkpoint PD-1 pathway inhibition in a significant percentage of patients with MSI-high CRC. These may be the first Stage IV cancer clinical trial participants you have ever met – in my current life I am surrounded by heroes like them every day. I think this post will have a positive impact both on readers who have been touched by CRC as well as on my fellow scientist readers. If you agree after reading it, I ask that you share it with every CRC patient you know.
My The Currently Incurable Scientist monthly column that published yesterday, “Releasing the PD-1 Brakes in MSI-high CRC Patients”, was all about explaining in a brief, easily understood way the importance of CRC patients knowing and getting tested for their “Microsatellite (MSI) status”. I want to explain here how incredibly important I believe knowing your MSI-status is for all CRC patients. The test for it can be ordered by a doctor using archived tissue samples. This personal blog post is a deeper dive into the topic, consider it the Director’s Cut…
The PD-1 pathway exists for good reason: to protect the body from autoimmune disease by “putting brakes on the immune system”. In cancer, tumors can sometimes hijack this system to escape immune attack. PD-(L)1 inhibitors therefore “release the immune system brakes” allowing the immune system to successfully attack tumors in some patients!
To briefly restate the key message: based upon preliminary clinical trial data, MSI-status appears likely to be a very good “biomarker” to predict which CRC patients will most likely respond to the current hottest immunotherapies (PD-(L)1 inhibitors), at least when these drugs are used alone as monotherapies.
The preliminary clinical trial data using the PD-1 inhibitor Keytruda (pembrolizumab) was presented at ASCO-2015 and published in the New England Journal of Medicine. In the small trial, 9 out of 10 evaluable “MSI-high” CRC patients showed disease control (4 with at least 30% tumor shrinkage & 5 with stable disease of at least 3 months). Although the data shown is in very small patient numbers, it is simply too striking to ignore unless proven otherwise with subsequent clinical data. This is especially true in the Stage IV world where lives are literally at stake and to be blunt, many patients’ “life timelines” do not have the luxury of waiting for full data confirmation before strategizing treatment and clinical trial choices with their MD. That is not a medical opinion (I’m not a MD!) but it is certainly my personal opinion as a Stage IV patient!
Dung Le et al. ASCO-2015. Used with permission for non-profit, non-promotional educational purposes.
Microsatellite Instable-high (MSI-high; “Mismatch-repair deficient”) CRC patients appear most likely to respond to monotherapy PD-1 pathway inhibition; Microsatellite Stable (MSS; “Mismatch-repair proficient”) CRC patients appear much less likely to respond. This is of course based upon data currently in hand from a very small trial.
Scientifically this clinical observation would make a lot of sense since MSI-high tumors both usually have much higher numbers of mutations which can catch the immune system’s attention as well as often large numbers of immune cells already present near the tumor. That situation is a match made in Heaven in the world of immuno-oncology!
Larger trials using PD-(L)1 inhibitors against MSI-high CRC are in progress and their results are eagerly being anticipated. If the results of the small preliminary trial are confirmed, this would be the biggest scientific leap in the treatment for MSI-high CRC patients in decades!
So if you are a CRC patient reading this, if your MSI-status is not already known, as a fellow patient I suggest you print out that New England Journal of Medicine paper and discuss MSI testing with your MD! You could also discuss with your MD that the American Gastroenterological Association now recommends that all CRC patients be screened for the possibility of Lynch Syndrome which is overlap testing for MSI-status. Inherited Lynch Syndrome + ~10-15% of “sporadic” CRC patients are MSI-high.
Multiple PD-(L)1 inhibitor trials are currently in progress and open to MSI-high CRC patients – both in the case of monotherapies as well as various experimental drug combination cocktails. If you have MSI-high CRC, the Cancer Research Institute’s Immunotherapy Trial Finder is a great information resource to find these trials to discuss with you doctor.
Aside from reiterating my strong personal beliefs on the importance of knowing your MSI-status, I wanted to use today’s post for something very special. I wanted to profile two MSI-high patients who are currently in PD-(L)1 inhibitor immunotherapy clinical trials to show you the faces & stories of the people behind these groundbreaking studies. I hope hearing their stories is inspirational to my fellow cancer patients. I also hope hearing and seeing them is inspirational to my fellow scientists who are currently working on next generation cancer immunotherapies. As a person with “a foot in both camps” it has always been a goal of this blog to bring these two components of the cancer world together to inspire each other!
A Very Important Disclaimer
Before I dive into the profiles, I have to mention that PD-1 pathway inhibition does NOT have a 100% response rate even for MSI-high CRC and significant toxicity is possible. Thus, although Leta and Stephen are doing great so far on the therapies in terms of both efficacy and safety – there is no guarantee that their experience will be similarly experienced by another patient. That is simply the nature of medicine (especially experimental medicines!) – all patients are different in terms of efficacy & side effect/toxicity response. Keeping that in mind, here are their inspirational personal stories…
Leta Withers – CRC Immunotherapy Pioneer
Leta was a happy wife & mother of 3 boys, aged 9, 13 & 16 when she first experienced the symptoms of colon cancer at only 46 years old. As is often the case for patients under 50, her symptoms were mistakenly attributed to other causes until she insisted on a colonoscopy. She had been warned that due to her age, insurance probably wouldn’t cover it – but Leta insisted since she had just had two friends under 45 diagnosed with CRC. Leta doesn’t back down easily when she sees an opportunity she knows she has to take.
They found an egg sized tumor in her right colon. 11 of 23 lymph nodes were positive for cancer so she was classified Stage 3C. After 4 months of the grueling cytotoxic XELOX/CAPOX chemotherapy cocktail, her scans were clean. Unfortunately only 3 months later, tumors were found in her lung, chest lymph node, ovary, and peritoneum. She was now declared inoperable Stage IV – or as I prefer to say, she was at that point declared currently incurable…
She was terrified in private. She knew what the prognosis for inoperable Stage IV CRC was. She flew to MD Anderson for a second opinion. It was there that she first heard about the “MSI-high” biomarker and the good responses they were seeing there in PD-(L)1 inhibitor trials. Leta is in the group of 10-15% of sporadic CRC patients who are MSI-high.
While researching an offered clinical trial combining two checkpoint immunotherapies: a PD-1 inhibitor Opdivo (nivolumab) + a CTLA-4 inhibitor Yervoy (ipilimumab) Leta started the standard second line cytotoxic chemo cocktail for CRC called FOLFIRI + Avastin (bevacizumab). Her tumors were responding to the treatment but she had a lot of “down days”. The treatment was rough on her.
Looking at her current quality of life and having performed a lot of self-education on checkpoint inhibitor immunotherapies & MSI-high CRC – Leta decided to do the clinical trial instead. Slots were very limited so she had to call many times over multiple months. She finally was offered a slot – but she needed to decide without delay whether to take the “Clinical Trial plunge” or continue standard chemo. She decided to go for the trial.
Leta signed the required paperwork and started the trial within days. In her own words: “It was nothing like the chemo I had endured. I left the chemo chair feeling terrific. No nausea, no pain, no fatigue! I was hungry and felt like myself! After the first treatment, I had wine and cheese and went shopping! Just a tad different than previous chemo.” The only side effect she has endured is elevated liver enzymes. She has had 3 scans so far – they have showed shrinkage or stability in all her lesions.
To close with her own words: “I credit this drug hugely with both my favorable scans and mostly the amazing quality of life it has given me back. I feel like my old self again. I don’t feel sick, and I have no down days anymore. I feel like I drew the lucky card to be MSI-high and have the chance to be on this trial!”
Pictured below are 1.) Leta looking over trial information papers and 2.) her feeling great while on trial. A video interview with her can be watched here.
Stephen Estrada – CRC Immunotherapy Pioneer
Stephen was diagnosed with Stage IV CRC at the very young age of 28. He was fresh out of school and excited to start his career. Life was fantastic until GI-symptoms became too great to ignore. Because of his young age, his symptoms were not taken seriously even during two trips to the ER. Thankfully his primary care physician took his concerns seriously and a tumor was found in his colon – but at the time of diagnosis it had already metastasized to his mesentery.
He underwent surgery followed by 6 months of the difficult FOLFOX cytotoxic chemotherapy cocktail. The chemo was very rough – his weight bottomed out at 110 lbs and he looked obviously very sick to everyone that saw him. A radiosurgery was attempted to remove a remaining tumor but it failed. Before his 30th birthday, Stephen was declared inoperable Stage IV. At that point, declared currently incurable.
He transferred his care to the University of Colorado Cancer Center. As is often the case in patients diagnosed that young, genetic testing revealed that Stephen has Lynch Syndrome – and he is also MSI-high. His new oncologist was familiar with good preliminary clinical trial results being seen with PD-1 pathway checkpoint inhibitors in MSI-high CRC patients. Based upon his new doctor’s advice, Stephen started a Phase 1 clinical trial of the PD-L1 inhibitor MPDL3280a (atezolizumab) + Avastin (bevacizumab).
In Stephen’s own words: “As I received my first infusion, I was overcome with severe back pain that lasted about two days…but after it left up, I realized that all my tumor induced pain seemed to have already faded away. The second infusion landed me in the hospital for 5 days when I started running a fever of 104. The strange thing is…I never felt very sick…just hot. A whole barrage of tests were ordered to see if there was an infection attacking me. Nothing ever came up and the fever was attributed to the MPDL3280a revving up my immune system and recognizing the cancer.”
Stephen has had 3 scans while on trial – after an initial shrinkage of his tumors, the 2 follow-up scans show stable disease. To close with his own words: “Besides my disease being held in check, the best thing is…I feel wonderful. I have gained about 40 lbs, I am able to be in the gym about 5 days a week, and I am currently in the process of returning back to work. Without this drug, I would be thin, ill, and potentially not alive.”
Pictured below are 1.) Stephen during chemo contrasted with him currently on PD-L1 immunotherapy and 2.) him exuberantly living life with a group of friends at a recent CRC patient advocacy event.
I have to thank both Leta and Stephen for allowing me to share their stories! I believe clinical trial participants are incredibly brave heroes. Incredibly brave because they are subjecting their bodies to medicines without fully known safety or efficacy. Heroes because the data generated using their bodies (whether positive or negative) is used to help guide the treatment of all other future & current CRC patients!
I think both Leta’s and Stephen’s stories illustrate both the hope and potential of the paradigm shift in cancer treatment towards immunotherapies currently sweeping through oncology. As a scientist – and as a Stage IV patient – it is truly amazing to see. Unfortunately there remains a lot of work left to do. Even in the cancer types with the highest response rates (e.g. melanoma) many patients do not respond. Even though some patients show very long term responses, most do not. There are also cancer types (e.g. MSS CRC – the kind of CRC I have) which are not responding well yet to immunotherapy drugs, based upon clinical data known as of today. For all these reasons – research is being done at a furious rate to “increase response rates” (i.e. increase the number of patients who respond) as well as to “increase duration of action” (i.e. increase the length of responses aiming for the ultimate goal = “forever” i.e. cures!).
Science is always full of surprises – both negative and positive – that is the nature of trying things for the first time. All I know for certain is that both response rates and duration of actions will increase – the only unknowns are the specific “whens” and “hows”.
I once again urge all CRC patients to discuss MSI testing with their MD. What we are seeing right now, illustrated by Leta and Stephen, is just the tip of the iceberg. I honestly believe the future of cancer immunotherapy will be breathtaking to behold. Fasten your seat belts…
July 2016 update:
Unfortunately Leta passed away in July of 2016 after describing her time on immunotherapies as the best time period of her Stage IV life. She was a fierce advocate for educating and empowering CRC patients for immunotherapy clinical trials – she reached tens of thousands of fellow patients worldwide through her advocacy and her legacy will live on! Her life & death illustrate both the preliminary promise in CRC immunotherapies as well as the need for additional clinical trial combination therapies even for the MSI-high CRC patient community.
Stephen continues to do amazingly well on his anti-PDL1 immunotherapy. He just passed the 2-year mark of his treatment with high efficacy, high durability and low side effects. He recently starred in an excellent short film for the Cancer Research Institute.