Mets Day 1034: I'm joining the nivolumab trial

For the past two weeks I have been doing a lot of follow-up research on the best clinical trial for me. On Friday, January 30, I met with Dr. Alex Spira at Inova Fairfax. I had previously spoken with his clinical trial nurse, which evolved into several email exchanges. Eventually she realized that the technical and detailed nature of my questions put me outside the realm of most patients, and she forwarded my emails to Dr. Spira for direct response. He told me that the MPDL-3280a trial he was running was closed to patients like me who had previous platinum-based chemotherapy. He nonetheless offered to meet with me and evaluate other clinical trial options. When we met, he reviewed my clinical trial options, and recommended that I pursue the nivolumab trial at Hopkins. He said that a PD-1 or PD-L1 drug was probably the most promising option at this point. He also offered to keep following me and be available if I had further questions, which I appreciated.

On Monday, February 2, I came across a recent article in Lancet Oncology said that MPDL3280a worked best in patients with PD-L1-positive tumor-infiltrating immune cells. I also did some research on Foundation Medicine, and their cancer genome testing program. I sent emails to Drs. Apolo and Aragon-Ching, asking whether my tumor tested had been tested for that characteristic, and if so, whether it should influence the trial I should join. Dr. Apolo responded that, when NIH did the sequencing of my cancer, they did not test whether my immune cells were PD-L1-positive. In a later conversation, she explained that there was a lot of debate in the cancer research community over how to measure for PD-L1-positive characteristics: was it 1% of all cells, or 5% of all cells, or more? In addition, she said that researchers were learning that PD-L1 expression was not an immutable static trait, but could vary over time, and was not fully understood. She urged me to go ahead with a PD-1 or PD-L1 trial regardless of whether my tumor had been tested for that characteristic, because it was one of the trials that showed great promise.

(What is the difference between PD-1 and PD-L1?  "PD" stands for Programmed Death. As I understand it, PD-1 is an inhibitory T-cell co-receptor - a type of protein - that negatively regulates T cell responses. PD-L1 is a ligand of the PD-1 protein that is expressed on the tumor. The theory is that interactions between PD-1 and the PD-L1 ligand can lead to antitumor immune suppression. The PD immunotherapy drugs in development are designed to engage PD-1 on effector T cells, allowing T cells to fight cancer. Scientists are still trying to figure out which type of tumors respond best to PD drugs, as well as figuring out the proper dosages without causing unacceptable side effects on the patient. That's what these trials are for.)

PD-1, an inhibitory T-cell co-receptor, or PD-L1, a ligand expressed on the tumor. It is thought that interactions between PD-1 and the ligands PD-L1 or PD-L2 can lead to antitumor immune suppression; the compounds in development are designed to interrupt those interactions, allowing T cells to fight cancer. - See more at: http://www.onclive.com/conference-coverage/nyl-2013/PD-1-and-PD-L1-Inhibitors-Expected-to-Change-the-Landscape-of-Lung-Cancer-Treatment#sthash.nfZRBoJ5.dpuf

PD-1, an inhibitory T-cell co-receptor, or PD-L1, a ligand expressed on the tumor. It is thought that interactions between PD-1 and the ligands PD-L1 or PD-L2 can lead to antitumor immune suppression; the compounds in development are designed to interrupt those interactions, allowing T cells to fight cancer. - See more at: http://www.onclive.com/conference-coverage/nyl-2013/PD-1-and-PD-L1-Inhibitors-Expected-to-Change-the-Landscape-of-Lung-Cancer-Treatment#sthash.nfZRBoJ5.dpu

PD-1, an inhibitory T-cell co-receptor, or PD-L1, a ligand expressed on the tumor. It is thought that interactions between PD-1 and the ligands PD-L1 or PD-L2 can lead to antitumor immune suppression; the compounds in development are designed to interrupt those interactions, allowing T cells to fight cancer. - See more at: http://www.onclive.com/conference-coverage/nyl-2013/PD-1-and-PD-L1-Inhibitors-Expected-to-Change-the-Landscape-of-Lung-Cancer-Treatment#sthash.nfZRBoJ5.dpuf

PD-1, an inhibitory T-cell co-receptor, or PD-L1, a ligand expressed on the tumor. It is thought that interactions between PD-1 and the ligands PD-L1 or PD-L2 can lead to antitumor immune suppression; the compounds in development are designed to interrupt those interactions, allowing T cells to fight cancer. - See more at: http://www.onclive.com/conference-coverage/nyl-2013/PD-1-and-PD-L1-Inhibitors-Expected-to-Change-the-Landscape-of-Lung-Cancer-Treatment#sthash.nfZRBoJ5.dpuf

Anyway, Dr. Aragon-Ching responded to my email of last week saying that Dr. Spira had told her that he was going to request that my tumor samples be sent to Foundation Medicine for testing, and that I should check with him. I didn't recall discussing that with him on Friday, so I emailed him to find out. He responded in minutes, saying that even before we met, he had requested that my tissue on file at NIH be sent to Foundation Medicine. He said it would take several weeks to get results. I thanked him for his proactivity.

On Tuesday, February 3, the clinical trial nurse from Johns Hopkins called me to set up an appointment with her and the doctors participating in the trial. She invited me to meet with her on Thursday to review the trial forms and answer my questions. We spent more than an hour talking about the trial. She confirmed that I met the clinical trial eligibility guidelines. She also said that the Phase I nivolumab-only cohort was closed, but that the Phase II trial was open. There are two cohorts in the Phase II trial; the first cohort gets 3 mg nivolumab and 1 mg ipilimumab every 3 weeks for 4 rounds, then 3 mg nivolumab only every other week thereafter. The second cohort gets 1 mg nivolumab and 3 mg ipilimumab every 3 weeks for 4 rounds, then 3 mg nivolumab only every other week thereafter. In either cohort, I'd get the nivolumab drug. Patients are randomized into each cohort, and they know which cohort they are in. She thought that I might want to wait for the Foundation Medicine DNA test results before making the final decision to enter her trial (or any other trial, for that matter). She is tentatively holding a place for me. I have a meeting scheduled with Dr. Noah Hahn next Tuesday. Should I enroll the nivolumab trial, he would coordinate my care with Dr. Dung Le, the principal investigator.

I sent Drs. Apolo and Aragon-Ching summaries of this news, and asked whether the different dosages of ipilimumab might put me at greater risk of side effects, given that I had two prior rounds of cheno. They both responded that the risks should be manageable, especially in light of my overall absence of co-morbidities and low tumor burden. Both endorsed the idea that I participate in that trial.

Last Friday, Memorial Sloan Kettering called to schedule an appointment for their nivolumab trial. I told the scheduler that I was already deep into discussions with Hopkins about the same trial. Keep us in mind in the future, they said. 

Last weekend, I did more research on nivolumab. According to the NCI drug dictionary, nivolumab is

A fully human monoclonal antibody directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation.

I learned that, in December 2104, the FDA gave approval to Bristol-Myers Squibb (BMS) for nivolumab for treatment of unresectable or metastatic melanoma. BMS's brand name for nivolumab is Opdivo. The FDA press release stated that

Opdivo works by inhibiting the PD-1 protein on cells, which blocks the body’s immune system from attacking melanoma tumors. Opdivo is intended for patients who have been previously treated with ipilimumab and, for melanoma patients whose tumors express a gene mutation called BRAF V600, for use after treatment with ipilimumab and a BRAF inhibitor.

BMS's January 27, 2015 release of its fourth quarter and full year 2014 results trumpeted its successes with Opdivo. BMS apparently is spending more than $100 million in different Opdivo clinical trials. Some biotech stock analysts think that Opdivo is going to be a blockbuster drug for BMS, with 2020 sales projected to be more than $7 billion. Big pharma indeed.

Today I went back up to Hopkins and met with Dr. Noah Hahn, head of Hopkins' urologic oncology group. He joined JHU last April from Indiana University, and looks to be another great advisor. Assuming I enroll into the trial, he would be personally following my case.  He seemed excited to work with a younger patient with few co-morbidities and low tumor burden -- he said that most of his patients were in their mid-70s or older and that many were battling other complications in addition to cancer. I had the required screening CT scan, EKG, and blood work. I also met again with the clinical trial nurse, who told me that she would submit my application to join the trial. She said that she expected me to be accepted by BMS with no problems. She would then be advised by BMS into which cohort I had been randomized. She said that she could work with me on scheduling my visits, as I am supposed to be in Utah early next month for a granddaughter visit, then in late March to Florida to visit my folks.

I feel good about this trial. As a result of my research, I have 4 well-respected oncologists endorsing my decision. I realize that the odds are low that I will have a complete response (e.g., all tumors shrinking to below pathological level). The odds are somewhat greater that I will have a partial response (e.g., more than 20% tumor shrinkage, but not a complete response), or stable disease (e.g., less than 20% shrinkage or growth). But there is also a 50% or more chance that my tumors will not respond, and keep growing. There is not enough data about nivolumab to show long-term results, and no one is expecting it to be a "cure" (e.g., complete response and no subsequent tumor development for 5 years). But this trial seems to be the right therapy at the right time.