Collecting More Information

Following Tuesday’s news that several of the tumors in my lungs actually increased in size and a new spot appeared on my spleen, Lorie and I headed back to the NIH on Thursday for more tests to help better guide subsequent treatment decisions.

The first test was a CT image of my brain taken Thursday mid-afternoon, which would be used to rule out the spread of cancer to that particular organ. Patients with brain metastases are often excluded from clinical trials due to historically dismal survival and concerns about blood brain barrier drug penetration. Fortunately, we learned the next morning that this test came back negative for cancer progression to the brain.

The second test on Friday was an image-guided biopsy of a single lung nodule to help guide between cancer progression and inflammation as the reason for the increase in size seen on the recent CT scan on the lungs. In my case, a core needle biopsy was performed, which is less invasive than surgical biopsy and doesn’t require general anesthesia.

Early Friday morning, Dr. Elliot Levy, an interventional radiologists at NIH trained in radiology and minimally invasive procedures, met with us first to discuss the procedure. He pulled up a cross sectional image of my lungs, which showed several of the suspicious nodules.

CT scan of my lungs, showing target nodule for biopsy with two lines representing potential needle angles for biopsy. Other nodules within the lungs circled in red, which could be more dangerous to biopsy.

One in particular was located in the pleural cavity – normally a thin membrane that lines the surface of the lungs and the inside of the chest wall outside the lungs. In the bottom of my left lung, however, fluid built up in the pleural cavity where one of the nodules was located. Dr. Levy explained to us how this nodule could be biopsied without puncturing the lung lobe, which can result in a longer hospital stay.

Sometimes, a collapsed lung (pneumothorax) occurs after a lung biopsy.  As a precaution, a chest x-ray is taken after the procedure to check for this before sending the patient home.

After meeting with Dr. Levy, I was escorted back to the biopsy procedure room and placed on my right side on a table. I was consciously sedated, produced by the administration of two medications: a single dose of fentanyl given intravenously that can produce good analgesia for 20-45 minutes, and midazolam, which has a fast-acting, short-lived sedative effect when given intravenously, achieving sedation within one to five minutes and peaking within 30 minutes. The combination produces an altered level of consciousness that still allows a patient to respond to physical stimulation and verbal commands, and to maintain an unassisted airway. Midazolam is a primary choice for conscious sedation because it causes patients to have no recollection of the medical procedure.

Dr. Levy worked out of sight behind me to perform the biopsy, as he went through my back side. I was fairly nervous going into the procedure, but everything went extremely well with absolutely no pain or unexpected events due to the sedation.

After recovery, a subsequent chest x-ray confirmed that the lungs were indeed fine after the biopsy and we left NIH shortly thereafter to head back home to Pennsylvania.

Thumbs up; recovering after biopsy procedure at NIH

The preliminary results from the biopsy should be available early this week. If the biopsy shows ample evidence of immune stimulation, an argument could be made to stay on the current drug and that the “pseudoprogression,” or the initial radiologic appearance of an increase in tumor burden, might actually be inflammation and followed by tumor regression. A remote possibility in my type of cancer, but worth confirming.

Should the biopsy results instead demonstrate increased tumor burden, then we could consider switching to another investigational agent or even chemotherapy to shrink the tumors before proceeding again with one of the immunotherapy clinical trials.

Lorie and Michael Becker in front of cherry blossoms

Determined to stay positive, Lorie and I took advantage of the warm spring day on Thursday to stop outside NIH and snap a picture in front of some cherry blossoms. Unfortunately, snow and cold returned on Friday for the commute home.

We’ll know more this week, so stay tuned…

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.

Positive Mental Attitude (PMA)

Monday evening, my wife Lorie and I traveled to Bethesda, MD in advance of my third infusion with M7824, a completely novel, first-in-class, bispecific fusion protein (see prior posts for more details). However, this was my first time being infused as an outpatient in the day hospital, as prior infusions required a short stay in the hospital for blood work, observation, etc. As with the first two infusions, everything went smoothly yesterday, with no adverse reactions during or following treatment. We caught a 9pm train home and were in bed by 12:30am ET.

image

Caught sleeping on the Amtrak train ride home by Lorie on February 21, 2017. Long day!

As I posted on social media throughout the day while at the NIH, I was truly humbled by the outpour of support – especially hearing from people I haven’t seen in years or decades. Amid the sea of political rants and opinions via these channels, it was nice to be reminded that social media can be a positive experience. Throughout the emails, Tweets, and posts, a lot of people remarked that I sound and appear “surprisingly positive” and “happy.” And truth be told – they’re RIGHT.

Sure, I have advanced cancer – and I’m not Pollyanna about what the future may have in store for me as a result. But, I was very fortunate to participate in a clinical study with a quite promising, investigational immunotherapy that has, so far, had no negative impact on my day-to-day quality of life. That is a very stark contrast from what I experienced after going through chemoradiation. While the outcome is far from certain, participating in this clinical study has given me every reason to “hope” that the therapy will work. And it is that hope that gets me up in the morning…smiling…ready to face the new day.

Michael D. Becker receiving IV infusion with M7824 - a novel, first-in-class, bispecific fusion protein

Michael D. Becker receiving his third IV infusion with M7824 – a novel, first-in-class, bispecific fusion protein on February 21, 2017

If anything has changed recently, it has been for the better. I’m now focusing my existing time and energy where I want, and it has been liberating. Death is always knocking on our doors, but it isn’t until the sound becomes louder later in life that you discover new priorities and sense of urgency. In this regard, I’ve started writing my memoir covering a +20-year biotechnology career and have been working with an amazing editor. I always enjoyed writing blogs and newsletters, but Lorie strongly encouraged me to finally write a book and it has been quite rewarding thus far. My goal is to get it done by late summer or so (30,000 words so far…), and I will definitely let everyone know more details via this blog as the project advances. I also recently started a coffee table book project to showcase my photography work over the past few years, with approximately 200 images selected and a draft layout complete. To fund the latter, I plan on launching a KickStarter campaign to finish the design and secure a larger order to reduce the per unit cost. And most importantly, through my disease openness and this patient blog, I’m exploring numerous opportunities to help raise awareness for currently available vaccines that can protect boys and girls against human papillomavirus (HPV) subtypes that most commonly cause anal, cervical, oropharyngeal, penile, vaginal, and vulvar cancers.

So, yes…I’m a cancer survivor and I’m positive because I have “hope” and will continue until life shows me otherwise. Inspired? Good…that’s my goal!

Finally, special thanks to everyone for the thoughts, gifts and support. Hearing from people I haven’t seen in years has also been amazing. A truly humbling experience and greatly appreciated.

Round Two

It’s been two weeks since my last blog update, so I thought it was about time for a status report.

Earlier today I had my periodic clinic evaluation at the NIH following last Wednesday’s second infusion of M7824. Recall M7824 is a completely novel, first-in-class, bispecific fusion protein of an avelumab-like antibody linked to two molecules of TGF-beta trap (see prior posts for more details). At 22 days into this Phase 1 study, I’m still feeling good and haven’t experienced any side effects. Blood work, vitals, etc. all okay.

Michael and Lorie Becker; Valentine's Day 2017

Michael and Lorie Becker; Valentine’s Day 2017

It was a quick roundtrip between home and the NIH today, which allows me to be back home to spend dinner with my Valentine, wife, best friend and birthday girl (ps – all the same person). Before I headed out for my appointment in the morning, we had a few minutes to exchange cards and snap a quick photo (see right).

I’m now done with the inpatient infusions for the study, so my next dose will be administered one week from today and I can go home afterwards. Here’s hoping for more, completely uneventful updates in the coming weeks!

 

Feelin’ Alright

Standing on the train platform this morning on my way to NYC, the late British rocker Joe Cocker’s version of Feelin’ Alright was playing over the sound system. Not only a good song to start the daily commute, it seemed an appropriate theme for this blog post.

It was exactly one week ago today that I received my first infusion of an experimental cancer immunotherapy agent, called M7824, as part of a Phase 1 clinical trial at the National Institutes of Health (NIH). Recall from my prior post that M7824 is a completely novel, first-in-class, bispecific fusion protein of an avelumab-like antibody linked to two molecules of TGF-beta trap. While very early in the process, I’m happy to report that so far I’m feelin’ alright.

As someone who has received three cycles of chemotherapy and a total radiation dose of 70 Gray over seven weeks, I can say with conviction that, so far, being treated with an immunotherapy agent has been a proverbial walk in the park. In fact, if it weren’t for the fact that this clinical study is not placebo controlled, I would seriously question whether or not I was in the active arm of the study.

For example, in contrast to chemotherapy and radiation, I haven’t experienced any of the hallmarks of traditional cancer therapy, such as nausea or fatigue, with the experimental immunotherapy agent. Important to note, however, every drug has side effects and checkpoint inhibitors like M7824 are associated with their own unique spectrum of immune-related adverse events. These include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. In some cases, these side effects can be managed with corticosteroids or diphenhydramine. Less frequently, clearly defined autoimmune systemic diseases, such as lupus, have been reported.

In fact, approximately 30-40% of patients treated with approved PD-1/PD-L1 checkpoint inhibitors (nivolumab/pembrolizumab) will have dermatologic complications. For most patients, dermatologic toxicity is the earliest immune-related adverse event experienced, with onset an average of 3.6 weeks after treatment initiation¹. Accordingly, it may be too early for me to be experiencing any such side effects.

Of course, having a “safe” drug is important – but for me, the real hope is that M7824 is effective in treating my recurrent disease. In this regard, in an interview with EP Vantage earlier this month, Luciano Rossetti, Merck KGaA’s head of R&D, told EP Vantage that M7824 is “the most exciting clinical asset in our pipeline right now” adding that it has yielded “spectacular” early data. You can read the full interview by clicking here.

I remain hopeful and strongly believe that my generation could be among the last to experience toxic upfront treatments like chemotherapy and radiation thanks to the many advances being made with immunotherapy.

References:

¹ Source: http://www.uptodate.com/contents/toxicities-associated-with-checkpoint-inhibitor-immunotherapy

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!

Cancer is Back

2017 isn’t off to a stellar start.

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 enrolled in a clinical trial with Bristol-Myers Squibb’s Opdivo© (nivolumab), a type of immunotherapy called a checkpoint inhibitor, and should start treatment next week assuming I meet the study criteria. While the drug was already approved by the FDA for recurrent head and neck cancer, the study will evaluate whether or not adding targeted radiation directed at one single lung node can improve outcomes.Opdivo

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…