Watching the Calendar

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.

Lorie and Michael Becker enjoying ice cream in Bethesda, MD

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).

Roller Coaster

It’s been a couple of weeks since my last clinical post, so I wanted to provide an update following this week’s NIH appointments.

Michael Becker pleural effusion

Xray images of Michael Becker’s chest showing pleural effusion both before and after drainage

First, surgical insertion of my Aspira® drainage system has dramatically improved the pleural effusion in my left lung. It’s essentially a chest tube/catheter that allows me to drain the fluid buildup on an as-needed basis into drainage bags at home. The image to the right shows before and after chest x-ray images that demonstrate just how blocked my left lung was before being drained (nearly 2/3 blocked). It also shows how my left lung is now “close” to normal following drainage.

Second, I’ve been on prednisone (steroid) to help “sculpt” the inflammatory response, which is also helping keep the fluid from building up so quickly in my left lung. Whereas I was emptying 100 mL or more on a daily basis previously, I am now only draining 15-20 mL every other day or so.

Now that the pleural effusion can be managed, attention returned to whether or not to resume treatment with M7824, a completely novel, first-in-class, bispecific fusion protein (see prior posts for more details). My last infusion of M7824 was several weeks ago.

Following another CT scan and constructive discussion with the NIH team, we came to the conclusion that there is essentially a tug-of-war occurring between the cancer in my lungs and my body’s immune system, the latter of which appears to be benefiting from M7824. The hope is that eventually M7824 will tip the scale in favor of my body’s immune system and control the cancer.

Michael D. Becker receiving IV infusion with M7824 – a novel, first-in-class, bispecific fusion protein on May 16, 2017

Accordingly, the decision was made to keep moving forward with M7824 and I received an infusion on Tuesday, May 16, 2017. As with past administrations, there were no issues and I returned home to Pennsylvania with Lorie later that evening.

The pleural effusion will be monitored closely and managed via the catheter and steroids. As long as there are no major issues in terms of fluid in my lung, I will continue to receive an infusion of M7824 every other week. A repeat CT scan will be done in a month or so to reassess the situation.

Honestly, Not Such a Good Friday

This past Wednesday, I had a thoracentesis procedure in which a needle was inserted into the pleural space between my lungs and chest wall. This procedure was done to remove excess fluid, known as a pleural effusion, from the pleural space to help me breathe easier.

Michael Becker blogging from his laptop at NIH on April 15, 2017

During the procedure, Dr. Elliot Levy, an interventional radiologists at NIH trained in radiology and minimally invasive procedures, drained 1.5 liters from the pleural space. Almost immediately, I felt better and even while I was being wheeled back to my recovery room, I asked my wife Lorie to grab me a turkey sandwich from the cafeteria as I was quite hungry. It’s possible the large amount of fluid on my left side was putting some pressure on my stomach, which could help explain why I haven’t had much of an appetite lately.

By Thursday, however, the fluid was returning, prompting yet another thoracentesis procedure on Friday to remove 1.5 liters of fluid. The rapid nature of the fluid buildup means that I will most likely have an Aspira® drainage system surgically installed to conveniently let me drain the fluid buildup at home via a small catheter and drainage bags. That procedure is planned for Monday, so I have been staying at NIH since Wednesday and will be here over the weekend.

More importantly, however, a CT scan was also done on Friday morning with disappointing results. The cancer nodules grew since the last CT scan on March 7, 2017. This reflects true disease progression as opposed to “pseudo-progression” as discussed in a prior post. I have been taken off the clinical study with M7824.

My individual results do not reflect poorly on the future of M7824, but rather underscore that we still have a lot to learn about immunotherapy and cancer. While I may not have benefited from the drug, the resulting knowledge and clinical data may help guide future development and I am proud to play a part in that process.

At this point, if I received no further treatment and went on hospice, my likely survival would be about two months – although every patient is different. I have scheduled an appointment with my oncologist at MSKCC to discuss the pros and cons of chemotherapy at this stage, but the balance between quality of life and quantity of life is not trivial and I haven’t made a firm decision to go in this direction. Chemotherapy may only add a month or two of survival with a negative impact on my quality of life.

While I have been very open about my disease since originally being diagnosed in December 2015 and enjoy blogging, I will now be focusing much more time with my wife and daughters and finishing up my memoir, which I hope to have published. This will unfortunately mean less time for updating this blog and responding to emails.

Thank you to everyone who has offered their best wishes, thoughts, and prayers during my cancer journey. Having such an amazing support network of family, friends, and social media contacts has been a great source of strength and inspiration. Special thanks to my wife, Lorie, who has been by my side the entire time.

If you’ll indulge me, I would like to end this post with three requests:

  1. If you have a son or daughter, please talk to your doctor about the HPV vaccine, which protects against cancer of the cervix, vagina, and vulva in women; penis in men; and cancers of the anus and head/neck (including the base of the tongue and tonsils) in both men and women. HPV is a very common virus; nearly 80 million people are currently infected in the United States. About 14 million people, including teens, become infected with HPV each year, resulting in 30,700 cancers in men and women. HPV vaccination can prevent most of the cancers (about 28,000) from occurring.
  2. Help preserve federal funding levels by communicating with lawmakers about the critical importance of investing in medical research. There are far too many people suffering from cancer and this is not the time to cut the budget for the National Institutes of Health (NIH) by 18.3 percent, about $5.8 billion, as has been proposed. In an Op Ed by Harold Varmus appearing in the New York Times on March 22, 2017, he states that  only about 10 percent of the NIH’s budget supports the work of government scientists and that “over 80 percent of its resources are devoted to competitively reviewed biomedical research projects, training programs and science centers, affecting nearly every district in the country.” Harold Varmus, a professor at Weill Cornell Medicine and a co-recipient of the 1989 Nobel Prize in Physiology or Medicine, was the director of the National Institutes of Health from 1993 to 1999 and of the National Cancer Institute from 2010 to 2015.
  3. If you or someone you know is battling cancer or another disease, please talk to a physician about available clinical trial options. Clinical trials are a key research tool for advancing medical knowledge and patient care. Such trials are important to learn whether or not a new approach works well in people and is safe and which treatments or strategies work best for certain illnesses or groups of people.

Week Nine Just Fine

This is week #9 on clinical study, as I received my infusion of M7824 yesterday as planned. All of my pre-therapy vitals and bloodwork came back fine, which meant the treatment was a go. As with previous infusions, there were no issues during or after. Everything went just fine.

It was unfortunately a later night than expected, as Lorie and I just missed our 7:30pm train and had to catch one leaving the next hour. So, we ended up walking in the door at home around midnight. Could always be worse!

Following the discussion in my past few blog posts, I’ve been learning more about the concept of “pseudoprogression,” or the apparent growth of a tumor followed by sustained regression, which is common following treatment with checkpoint inhibitors. For example, I came across the video clip below by OncLiveTV that contains a discussion of “Pseudoprogression With Checkpoint Inhibitors in Non-Small Cell Lung Cancer,” where panelists explore the implications of this phenomenon for patients with NSCLC. While I do not have NSCLC, the overall concept of pseudoprogression with checkpoint inhibitors is relevant to my treatment and latest scan results – whereby the tumor growth exhibited could be from inflammation due to an ongoing positive immune response, or from an actual increase in the tumor that continues until the body’s immune system overpowers the cancer. It could also be a combination of the aforementioned. In any event, I think that pseudoprogression is an important concept for patients receiving some immunotherapies to better understand – especially when getting imaging results following treatment.

 

PS – anyone who knows me, knows that I’m a big Chicago Cubs baseball fan (having grown up in Chicago)…so I’d be remiss if I didn’t ask you to keep voting for retired catcher David Ross on this season’s ‘Dancing with the Stars’. In case you missed his debut performance, here’s a clip where he danced to Steve Goodman’s “Go Cubs Go” – while wearing Cubs gear.

Keeping the Faith with M7824

As evidenced by the extensive discussions following my biopsy from last Friday, a tumor is indeed a very complex structure. It comprises cancer cells and stromal cells, tumor infiltrating cells—both cells of the immune system and cells not by convention being of the immune system, as well as an extracellular matrix mainly of proteins and carbohydrates.

Following my recent CT scan, the hope from obtaining core biopsies from one of my lung nodules was to get a better sense of the cancer at a cellular level, which may help shed some light on whether or not treatment with M7824, a completely novel, first-in-class, bispecific fusion protein is working (see prior posts for more details).

In particular, the presence of immune system cells (T cells, or T lymphocytes) in tumor biopsies and their potential impact on prognosis have been studied for decades. T cells are a type of white blood cell that circulate around our bodies, scanning for cellular abnormalities and infections. Broadly speaking they can be divided into two different types, “killer” CD8-positive T-cells and “helper” CD4-positive T-cells. CD8-positive T cells are critical mediators of adaptive immunity. They include cytotoxic T cells, which are important for killing cancerous or virally infected cells, and CD8-positive suppressor T cells, which restrain certain types of immune response.

Despite contributions by other immune cell subsets, CD8-positive T cells have emerged as the predominant effector in most cancer immunotherapy settings¹. Accordingly, many immunotherapeutic strategies (including checkpoint inhibitors, such as anti-CTLA4, PD1, and PD-L1 antibodies) are dedicated to stimulating, enhancing and maintaining responses by tumor-reactive CD8-positive T-cells.

Favorable outcomes have been demonstrated in patients where high numbers of CD8-positive cells were found at the tumor site in patients with head and neck cancer, breast, colorectal cancer and also for others solid cancers. In one study, head and neck cancer patients whose tumors were densely infiltrated by CD3-positive and CD8-positive T cells had a significantly longer overall survival (OS) and progression-free survival (PFS) compared with patients whose tumors were poorly infiltrated².

While there seems to be a consensus that CD8 infiltration is a good prognostic marker in most malignancies analyzed, however, the impact of CD8-positive T cells on clinical outcome may differ and is difficult to quantify. Not only is the type of T cell important, but also its location, and moreover the specific phenotype and function of those cells in the particular environment.

Nonetheless, based on the preliminary results from my recent tumor biopsy and other factors, it appears that there is sufficient evidence of immune system activation in the vicinity of the tumor to indicate that the experimental agent M7824 may indeed be performing as we hoped. Accordingly, I am in 100% agreement with my doctor’s recommendation to continue on the therapy and will receive my next infusion this coming Tuesday at NIH. After a few more cycles of therapy, another CT scan will be taken in the future with the hope of demonstrating that the recent tumor growth was from treatment effect “pseudo-progression” rather than true disease progression, which has been previously described with immune checkpoint inhibitors like M7824.

References:

¹ Targeting CD8+ T-cell tolerance for cancer immunotherapy. Stephanie R Jackson, Jinyun Yuan, and Ryan M Teague. Immunotherapy. 2014 Jul; 6(7): 833–852.

² Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer. P Balermpas, Y Michel, J Wagenblast, O Seitz, C Weiss, F Rödel, C Rödel and E Fokas. British Journal of Cancer (2014) 110, 501–509. doi:10.1038/bjc.2013.640

 

 

 

Not as We Had Hoped

The results of today’s CT imaging procedure were not as we had hoped. Ideally, the dozen or so tumors in my lungs would have shown signs of shrinkage – indicating that the investigational drug was having a positive effect on the cancer. Instead, several of the tumors actually increased in size and a new spot even appeared in my spleen.

One of the hallmarks of immunotherapy, such as the checkpoint inhibitors, is the potential for a “delayed” response, which is not routinely seen with chemotherapy or other cytotoxic agents. Another biologic phenomenon unique to immunotherapy is “pseudoprogression,” or the initial radiologic appearance of an increase in tumor burden subsequently followed by tumor regression¹.

The CT imaging study cannot distinguish between cancer progression or inflammation as the reason for the increase in tumor size, so there is a chance that it’s due to inflammation and subsequent imaging tests in a month could demonstrate a reversal. However, it is also possible that the cancer isn’t responding to the investigational treatment.

To get more details, I’m undergoing a biopsy this Friday so that one of the lung tumors can be sampled. The preliminary information from that biopsy, which should be available next week, will help guide between cancer progression and inflammation. Decisions regarding how to proceed will depend on that outcome.

Needless to say, everyone’s hope was to have seen some sign of cancer regression on today’s CT scan and many teardrops were shed. The chances for a favorable outcome have diminished and must be acknowledged, but for now I’m persevering and will evaluate next steps following the biopsy results.

Sincere thanks to everyone who has offered their positive thoughts, prayers, and support. It is difficult to respond to each and every communication, but please know that I read “everything” and your time and effort is greatly appreciated. Special thanks to everyone at NIH for being so wonderful — even when faced with delivering bad news.

Now, more than ever, please keep all those positive vibes coming my way.

References:
¹ Amidst the excitement: A cautionary tale of immunotherapy, pseudoprogression and head and neck squamous cell carcinoma. Baxi SS, Dunn LA, Burtness BA.
Oral Oncol. 2016 Nov;62:147-148. doi: 10.1016/j.oraloncology.2016.10.007. Epub 2016 Oct 21.

Starting Treatment – Again

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.

Michael D. Becker being infused with M7824 for the first time

Michael D. Becker being infused with M7824 for the first time on 1/25/17 at NIH

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!