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).

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

 

 

 

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…

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…

Biopsy Done

Very long day, so I’ll keep this post brief. Lorie and I stayed overnight in NY yesterday due to the early procedure scheduled this morning at MSKCC. My appointment was at 9:15am and I was scheduled for the operation to start around 10:40am. However, my slot got delayed and I didn’t head into surgery until around 2pm!

Michael D. Becker in the recovery room after a bronchoscopy

The good news, if there is any, is that thoracic surgeon Dr. Park was able to get sufficient tissue from the suspicious lymph node via the bronchoscopy approach and he didn’t need to do the surgical resection to go after the other nodules in my lungs.

The biopsy results will take a few days, but it is clear from the surgeon that the node they biopsied didn’t look “healthy.” Given that disease progression to the lungs is relatively common in advanced head and neck cancer, in my opinion the biopsy will most likely confirm spread of the original cancer to the lungs. Or, it could just be an unrelated new lung cancer just showing up now.

I hope to have more to report in the New Year but for now am relaxing in the passenger seat as Lorie drives us home. She’s such a trooper and I know my cancer returning isn’t easy for her.

Cancer: The Grinch that Stole Christmas

Of the +30 posts on this patient blog, this has been one of the hardest to write.

Lung metsIn the prior entry, I referenced that my next PET scan was scheduled for early February 2017. However, my radiation oncologist wanted to keep the PET scans consistent at six month intervals that resulted in moving the PET scan up to December 14 (last Wednesday). My prior PET scan was in June 2016.

Unfortunately, the latest PET scan did not contain good news. Multiple new spots consistent with malignancy showed up that were not visible six months ago. This includes activity in lung nodules, subcarinal/left hilar lymph nodes (near the trachea), and mild activity around the tonsils and in the region of the oral cavity. The results were confirmed by a subsequent CT scan this past Saturday.

In the world of medicine, however, cancer doesn’t exist until the abnormal cells are viewed under a microscope. Accordingly, I will soon need to have a biopsy taken from one or more of the suspicious areas highlighted on the PET scan. However, I don’t need to wait for that procedure and the subsequent results to know the outcome.

For head and neck squamous cell carcinoma (SCC), which was my initial diagnosis, pulmonary metastases are the most frequent and account for 66% of distant metastases¹. This information, combined with the imaging results, leaves very little chance that the biopsy results will be benign.

Michael D. Becker Awaiting PET Imaging

Michael D. Becker Awaiting PET Imaging on Dec 14 at MSKCC in NYC

The consultation for the biopsy procedure has been scheduled for late this week and the actual biopsy procedure still needs to be scheduled. If the biopsy confirms that cancer has indeed spread to my lungs, the next step will be a meeting with my oncologist to discuss treatment options, which will likely include recent advances, such as biologic agents and immunotherapies (e.g., checkpoint inhibitors).

¹ ORL J Otorhinolaryngol Relat Spec. 2001 Jul-Aug;63(4):202-7.
Incidence and sites of distant metastases from head and neck cancer.

² http://www.headandneckcancerguide.org/hnc-dev/adults/introduction-to-head-and-neck-cancer/distant-metastasis/

Pathology Results

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This afternoon, I received a call from my ENT confirming what I had already known or suspected – based on the biopsy results I had cancer.  In particular, squamous cell carcinoma.  Doctors describe cancer by its grade (G), which describes how much cancer cells look like healthy cells when viewed under a microscope. If the cancerous tissue looks very different from healthy tissue, it is called poorly differentiated or a high-grade tumor. The cancer’s grade can help the doctor predict how quickly the cancer will spread. In general, the lower the tumor’s grade (such as G1 or G2), the better the prognosis. In my case, unfortunately the cells were poorly differentiated (G3 or G4).

The cancer was in the enlarged lymph node, but that was only one of the locations where it had spread.  We needed to know where the cancer originated.  Based upon a review of the various markers evidenced in the pathology report, I grew increasingly concerned that the cancer started in my lungs.  The next step was to perform a PET/CT scan to reveal the primary source of the disease.