Earlier this week, Lorie and I made our biweekly visit to the National Institutes of Health (NIH) for my infusion of the experimental agent M7824. The two day trip was uneventful and included a variety of imaging and other diagnostic tests, including an ultrasound of my spleen and a chest x-ray to monitor the pleural effusion in my left lung.
Fortunately, all of the tests came back fine and I was cleared to receive my regular infusion of M7824. As with all the previous treatments, there were no adverse reactions and we returned home later that evening.
However, with the month of July rapidly approaching, I can’t help but start to feel quite anxious. This is due to the published results from Bristol-Myers Squibb’s “CheckMate 141” phase 3 trial with Opdivo® (nivolumab), an anti-programmed death 1 (PD-1) monoclonal antibody also known as a checkpoint inhibitor. In that study, 361 patients with recurrent squamous-cell carcinoma of the head and neck (SCCHN) whose disease had progressed within 6 months after platinum-based chemotherapy were assigned, in a 2:1 ratio, to receive Opdivo every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival.
Treatment with Opdivo resulted in longer overall survival than treatment with standard, single-agent therapy. The median overall survival was 7.5 months (95% confidence interval [CI], range 5.5 months to 9.1 months) in the Opdivo group versus 5.1 months (95% CI, 4.0 months to 6.0 months) in the group that received standard therapy.
Recall from prior posts that M7824 is a completely novel, first-in-class, bispecific fusion protein of an avelumab-like, anti-PD-L1 antibody linked to two molecules of TGF-beta trap. Therefore, I always viewed M7824 as a “potentially” superior alternative to Opdivo given its added mechanism of action, hence my strong interest in participating in the M7824 clinical trial.
Assuming for a moment that M7824’s treatment effect is at least comparable to Opdivo, and considering that my disease recurred around December 2016, an expected survival of 7.5 months would translate to the July/August 2017 timeframe.
To be fair, an apples-to-apples comparison of Opdivo and M7824 isn’t possible. However, the results of Bristol-Myers Squibb’s “CheckMate 141” trial serve as a contemporary data set for checkpoint inhibitors in the treatment of recurrent SCCHN and are definitely something that I keep my eye on.
Barring any surprises, I’ll continue biweekly treatment with M7824 and then repeat imaging in July to see whether or not my disease has progressed. In the meantime, I’ll continue to savor simple moments like enjoying ice cream on a warm summer evening with my wife (see photo).
First, my apologies for the length of time from my last clinical update. I’m not generally a superstitious person, but I wanted to wait for a few formalities to be addressed before posting.
Previously, I referenced that my next therapy would likely be at Memorial Sloan-Kettering Cancer Center (MSKCC) and include Opdivo® (nivolumab), a form of immunotherapy called a “checkpoint inhibitor.” What is that, you ask? Human cells carry certain proteins on their surface that enable them to escape attack from the body’s immune system. Some cancer cells wear one of those same proteins, called programmed death ligand 1 (PD-L1), which renders the cancer cells invisible to the body’s immune system. Blocking either PD-L1 or its receptor, programmed death 1 (PD-1), appear to be Achilles’ heels for multiple tumor types. Coincidentally, I covered the exciting early developments in the checkpoint inhibitor field in July 2013, which you can read by clicking here.
My concern is that across clinical studies in numerous cancer types, only about 20% of patients receiving checkpoint inhibitors have a durable response. For these patients, the benefits tend to last for years – perhaps even indefinitely. Exciting, yes. But for the other 80% of patients, the results are less dramatic. For example, in the recurrent head and neck cancer study for Opdivo, the median overall survival was 7.5 months for patients that received Opdivo versus 5.1 months for patients that received standard therapy options (cetuximab, methotrexate, or docetaxel). Clearly, Opdivo was superior to standard therapies and definitely worth considering. But the median overall survival is the time period lying at the midpoint of a frequency distribution of observed values, such that there is an equal probability of falling above or below it. The prospect of being in the 80% group with less than a year to live forced me to consider alternatives.
Fortunately, I became aware of a clinical trial for an investigational agent called M7824, a bifunctional fusion protein targeting PD-L1 and TGF-β, that was developed by EMD Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. M7824 is currently being studied in a Phase 1 trial for patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT02517398). The principal investigator for the study is James L. Gulley, M.D., Ph.D., F.A.C.P. of the National Institutes of Health, Center for Cancer Research. In addition to his role as Chief of the Genitourinary Malignancies Branch, Dr. Gulley is also Director of the Medical Oncology Service, Office of the Clinical Director. He is an internationally recognized expert in cancer immunotherapy and I’ve had the honor of knowing him professionally for more than a decade – starting back when I was at Cytogen Corp (just an amazing individual and I cannot say enough good things about him!). Other key members of my fabulous team so far include Dr. Julius Strauss, Lead Associate Investigator for the study and Fellow Physician in Oncology at the National Institutes of Health, Andrea D. Burmeister, Physician Assistant, and Elizabeth Lamping RN, BSN, Research Nurse Specialist.
M7824 consists of a fully human monoclonal antibody against PD-L1 plus a transforming growth factor beta (TGF-β)-neutralizing trap component. This means that M7824 should confer all of the benefits of a checkpoint inhibitor against PD-L1, but with the added punch of neutralizing TGF-β. Dual targeting of the PD-L1 and TGF-β pathways makes sense because both are key immune evasion pathways with independent yet complementary functions.
The TGF-β signaling pathway is complex – resulting in either tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. In advanced disease, the tumor suppressor arm of TGF-β signaling is lost and, instead, tumor cells proliferate. Further, TGF-β overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior.
The more I researched TGF-β, the more encouraged I became about enrolling in the M7824 clinical trial – especially given the specific profile of my disease. Recall that I was diagnosed with human papillomavirus “HPV” positive, squamous cell carcinoma (SCC), which is cancer that begins from squamous cells, a type of skin cell. In addition to being one of the main types of skin cancer, cancers that involve the anus, cervix, head and neck, and vagina are also most often SCC.
Only a minority of people exposed to human papillomavirus develop HPV-related cancer, such as oropharyngeal cancer (lucky me!) or cervical cancer. In a paper published December 2014 in Cancer Research, Levovitz et al. demonstrated that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers, particularly those related to TGF-β signaling. In other words, it is possible that people carrying genotypes with such variants are more likely to have an HPV-positive tumor compared to patients with the wild-type genotype. The likely functional significance of altered TGF-β signaling in HPV-related cancers is further supported by the finding by Levovitz et al. that TGF-β receptor type 1 is significantly overexpressed in both oropharyngeal cancer and cervical cancer.
In a paper published in February 2015 in Cell, Oshimori et al. establish a surprising non-genetic paradigm for TGF-β signaling in fueling heterogeneity in squamous cell carcinoma (SCC) stem cells, tumor characteristics, and drug resistance. Armed with this insight as well as the relevance for HPV-positive cancers, I decided to enroll in the study and passed the screening process.
In December 2016, Dr. Gulley presented preliminary data from the ongoing Phase 1 study of M7824 at the 28th symposium on Molecular Targets and Cancer Therapeutics, also known as the ENA symposium. Early results were encouraging, with M7824 associated with complete (CR) and partial responses (PR) in patients with advanced refractory cancer.
Today is my first one-hour infusion of M7824 and I look forward to reporting on my experience with immunotherapy in subsequent posts. With just a few minutes remaining for the infusion – so far, so good!
During today’s appointment with my oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC), we received disappointing news that the biopsy of my chest lymph node contained the same cancer cells (squamous cell carcinoma) as the original tumor in my tonsil. This means that the cancer has spread to distant sites and, unfortunately, cure is now no longer an option.
I was already familiar with the synergy between radiation and other forms of therapy, especially immunotherapy. Coincidentally, we were exploring such synergies back at Cytogen Corp with the company’s skeletal targeted radiotherapy being combined with a poxvirus vaccine being developed by Dr. James Gulley at the NIH at the time. Small world.
As the trial is randomized, I may or may not be one of the patients to receive the added radiation therapy. However, both arms of the trial receive Opdivo – so I get an active drug in recurrent head and neck cancer in either case.
There has been a great deal of enthusiasm for checkpoint inhibitor products, such as Opdivo. However, in the recurrent head and neck cancer study by Bristol-Myers Squibb, the median overall survival was 7.5 months for patients that got Opdivo. The other patients that received standard therapy options (cetuximab, methotrexate, or docetaxel) had a median overall survival of 5.1 months. True, there were some ~20% patients that had durable responses with Opdivo, but the vast majority (80%) did not have a durable response.
The good news is that Opdivo is a form of immunotherapy and doesn’t have many of the severe side effects associated with both chemotherapy and radiation. Accordingly, it is expected that I will be able to continue working and not have any major issues throughout treatment, as they are rare. However, Opdivo can cause your immune system to attack normal organs and tissues in many areas of your body, and can affect the way these organs work.
I’ll be posting more updates in the coming week or so…
It’s that time of year again; where we get together with family and friends to celebrate the Thanksgiving holiday. It is also a time for reflection and appreciation, which has even greater meaning for me this year.
It was the day before the Thanksgiving holiday in 2015 when I first discovered a suspicious lump protruding from the right side of my neck. The formal diagnosis of Stage IV oropharyngeal cancer would occur several weeks later, but I knew at the time that the palpable growth just below my jaw line was anything but benign.
As a senior executive working in the field of biotechnology, and in particular the area of oncology, being diagnosed with cancer was difficult – but hearing “Stage 4” was especially disheartening. While staging systems are specific for each type of cancer, in general the cancer stage refers to the size and extent of the disease and is assigned a number from 1 to 4. If my cancer was confined to the right tonsil (where it started…) and hadn’t spread elsewhere, I would have been diagnosed with Stage 1 disease. Localized spreading would have been Stage 2 and depending on the extent of involvement of nearby lymph nodes – progress to Stage 3. When cancer has metastasized, or spread to other organs or throughout the body, it can be classified as Stage 4 and may also be called advanced or metastatic cancer. Stage 4 usually carries a grim prognosis compared to earlier stages of the disease.
Accordingly, when one is diagnosed with Stage 4 cancer, the immediate concern is whether or not the individual will be able to survive the disease. For me, however, the bigger concern was surviving the treatments and their side effects. In particular, my experience licensing and launching a product to treat oral mucositis made me very familiar with this debilitating side effect from both radiation and chemotherapy.
When reviewing treatment options with Dr. David Pfister, my medical oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC), I was really hoping that I would be a candidate for recent advances, such as biologic agents and immunotherapies. This was due to my familiarity with their targeted and less toxic profiles, especially when compared with chemotherapy and radiation. In fact, back in early April 2010 I published a 150-page industry report titled “Cancer Vaccine Therapies: Failures and Future Opportunities” and later that year held the inaugural “Cancer Immunotherapy: A Long-Awaited Reality” conference that took place at the New York Academy of Medicine in New York. For more information and background on immunotherapy, read “Insight: Training immune system to fight cancer comes of age” by Bill Berkrot of Reuters.
Unfortunately, approved targeted agents like Erbitux® (cetuximab) still require combination with radiation therapy and its associated side effects. Immunotherapies, such as Opdivo® (nivolumab) and Keytruda® (pembrolizumab) were only recently approved by the FDA to treat head and neck cancer, but their initial indications are limited to patients with disease progression during or after chemotherapy. I remain hopeful that use of these and other new agents will expand to newly-diagnosed patients going forward and that ultimately we no longer rely upon chemotherapy or radiation to treat this disease.
Nonetheless, it is encouraging to see two new drugs approved to treat head and neck cancer this year and know that there are options for me in the unfortunate event that my disease returns. In this regard, I was glad to help ring the Nasdaq Stock Market Opening Bell last month to celebrate cancer immunotherapy advances and the one-year listing anniversary of the Loncar Cancer Immunotherapy ETF (Ticker: CNCR). I first met Brad Loncar (@bradloncar on Twitter), Chief Executive Officer of Loncar Investments, at my inaugural cancer immunotherapy conference and he was kind enough to extend me an invitation to the Nasdaq event.
Ultimately, I went through seven weeks of daily radiation and three cycles of chemotherapy at the start of this year, which as actor Michael Douglas was quoted “somehow seemed very accurately mapped to the seven circles of hell.” In 2010, Michael Douglas was also diagnosed with Stage 4 oropharyngeal cancer and went through the same treatment regimen at MSKCC in New York.
So, while this year started off rough (understatement), I am extremely lucky and thankful to have no evidence of cancer following treatment and to finally be free of “most” of the debilitating side effects from therapy. For example, in recent months I have noticed a dramatic improvement in both energy level and saliva output and have started to reverse a 40-pound decline in weight I experienced during and after treatment.
Aside from eternal gratitude for my wife and daughters’ love and support throughout the process, I would like to extend a special thanks to all of the healthcare providers at MSKCC for their superb care. From my “dream team” consisting of medical oncologist Dr. David Pfister, radiation oncologist Dr. Nancy Lee, and surgeon Dr. Benjamin Roman to amazing nurse practitioner Nicole Leonhart and all of the others who cared for me. I wouldn’t be here today without you!
For my family, friends, and colleagues – too numerous to name – thank you again to EVERYONE that helped in some way…the thoughts, emails, prayer chains, food deliveries, financial support, hospital visits, etc. were all greatly appreciated.
My next PET scan is scheduled for early February 2017 and I hope to report that all remains clear around that time.
PS – as a native of Chicago and loyal fan, I am also thankful to have witnessed the Cubs baseball team winning the World Series for the first time in 108 years in 2016! Go Cubs Go!