CR 444: Should I continue to ride this horse?

Over the past two weeks, the rash around my lower torso slowly dissipated. I’ve continued to have itching around my neck and upper back. The scars from the poison ivy on my legs are fading. It’s the least amount of itching I’ve had in months. The pharmacy actually had my drug ready ahead of schedule, and I was in and out of the Weinberg infusion center in near- record time.

Before today's infusion (number 39), I spoke with Dr. Hahn and the clinical trial nurse about whether I should continue participating in my clinical trial after the scheduled end of the two-year period. The nurse didn’t think that there would be any problem with that, and said that she would check to make sure that there would be no obstacles. Since the original two years run in February 2017, I have several months to obtain all of the necessary approvals.

Dr. Hahn and I had a long conversation about the pros and cons of continuing therapy. He confirmed my understanding that there is virtually no published data on whether continuing with immunotherapy for more than two years is worth it. Most importantly, there are no data to suggest that continuing with Opdivo will accomplish anything new. The science behind checkpoint immunotherapy is that the drug is supposed to teach my immune system to break through the cancer camouflage by ignoring the PD-L1 protein that the cancer cells were expressing to trick my immune system into not attacking the cancer. With that link broken, my immune system has attacked and destroyed all of my tumors. Dr. Hahn said that, if in fact the drug has worked as it was supposed to, then after it has done its work there is no reason to keep taking the drug. It’s no longer doing anything beneficial.

This view, however, is based upon the assumption that in fact I have no more cancer in my body. No one knows if that is the case. As I understand it, the traditional working assumption of oncologists is that metastatic urothelial cancer circulates systemically in the lymphatic system on a microscopic level, and from time to time may start growing tumors. CT scans are not precise enough to detect microscopic levels of cancer. My CT scans do not show any actively growing tumors, but they still detect a enlarged few lymph nodes where there used to be tumors. Dr. Hahn said that the presence of those slightly enlarged nodes is not clinically significant to him. The radiologists feel obligated to comment upon the slightly enlarged nodes since they were in the same location as the tumors. But he said that there is no evidence that they still have any actively growing cancer cells.

I asked about the fact that my cancer has multiple mutations, and that Nivolumab works on only one of those mutations. Dr. Hahn said that if any of those other mutations were going to going to start growing once the cancer cells that were expressing the PD-L1 protein had been destroyed, he would have expected to see that by now. He could not promise that those other mutations would never start growing, but the fact that they had not as of yet was indicative that they were not metabolically active.

We talked about teasing any information out of the published data, including the preliminary report on the trial I'm in (Checkpoint 032) that was made during the June 2016 ASCO meeting. That report regarding metastatic bladder cancer and nivolumab was limited to only about 80 patients, and showed a overall response of about 25%, and had little data regarding durability for those fortunate few who had complete responses. Another study was five-year review of the earliest patients who received Nivolumab (Opdivo) for metastatic melanoma. That April 2016 study found that 34% of patients were still alive after 5 years, and that there was a durability plateau after 48 months. Another study of the durability of Nivolumab on metastatic melanoma patients (Checkpoint 067) showed that nivolumab alone was almost as effective as nivolumab plus ipilumumab, and had far fewer side effects. Overall response rate was over 40%. Durability was still being measured. We also discussed studies on other checkpoint inhibitors, such as IMvigor 210, a phase II trial of Tecentriq (aka Atezolizumab, or MPDL3280A) on metastatic bladder cancer, which showed that 84% of those patients who responded to that checkpoint inhibitor had ongoing responses.

(84%) who responded to the anti­–­PD-L1 agent had ongoing responses - See more at: http://www.onclive.com/conference-coverage/gu-2016/update-affirms-atezolizumab-activity-in-bladder-cancer#sthash.NR5OeYf9.dpuf

(84%) who responded to the anti­–­PD-L1 agent had ongoing responses - See more at: http://www.onclive.com/conference-coverage/gu-2016/update-affirms-atezolizumab-activity-in-bladder-cancer#sthash.NR5OeYf9.dpuf

 

 

(84%) who responded to the anti­–­PD-L1 agent had ongoing responses - See more at: http://www.onclive.com/conference-coverage/gu-2016/update-affirms-atezolizumab-activity-in-bladder-cancer#sthash.NR5OeYf9.dpuf

I told Dr. Hahn that I had read those reports to suggest that there might be a slight benefit to continuing with immunotherapy. Dr. Hahn said that the studies didn’t support that inference. He said that there was insufficient information of how long the patients stayed on the drug, why they stopped taking the drug, and what type of cancers those who relapsed actually developed. Plus, the sample sizes were small, and the durability data was not specifically spelled out in most. The relevance is further strained by the fact only one of those studies were for bladder cancer. The bottom line is there simply is not any data available that answers my question of how long to continue my therapy. 

Dr. Hahn agreed that the risks to continuing primarily are limited to dermal toxicity, and whether the rashes that I’ve been having will get worse. I asked whether staying on Opdivo would increase the risk that my immune system might get so tired of immunotherapy that it turns on itself and I get an autoimmune disorder. Dr. Hahn said that there was no evidence that the risk of autoimmune disorder increased with time or dosage. If a patient’s immune system was going to overreact to immunotherapy, it likely would do it sooner rather than later. 

I asked whether there were any duration limits either recommended by the manufacturers, or imposed by FDA, on either Opdivo or Tecentriq. Dr. Hahn said there were none. Both had been approved for use on patients who had failed platinum-based chemotherapy, and were approved for therapy until disease progression. He said that, other than studying side effects or potential toxicities, there were no incentives by the manufacturers to limit the duration of use of their drugs. He suggested that eventually institutions and insurance companies would develop guidelines for how long they would administer and pay for these drugs, but those decisions had not yet been made.

Dr. Hahn said that patient peace of mind was the most powerful reason to continue with the therapy. Since the drug had worked and eradicated the metastatic cancer, why stop it? (That’s were I am.) But he said that he could not provide a strong rationale to continue taking Nivolumab once a patient had a durable complete response and had no evidence of disease for more than a year. He noted how the sponsor (Bristol-Myers Squibb) had amended the protocol to allow patients to suspend treatment and resume should the cancer return. He said how he sees many patients who travel great distances and considerable personal expense every couple of weeks to keep taking the drug. For those patients who have had a complete response, he would counsel them that the costs of continuing likely outweighed any benefit. This was especially true now that Tecentriq had been approved for use on metastatic bladder cancer (and Opdivo approval is likely forthcoming), so that if there was any recurrence, patients could resume therapy independent of a clinical trial.

The upshot of all of this is that Dr. Hahn is comfortable with my stopping receiving Opdivo, either in February 2017, or even earlier. If and when I do stop treatment (assuming it’s not because my cancer has come back), I’d still have regular CT scans to see whether I was still cancer-free. Those scans could be done anywhere and could be forwarded to him at Hopkins.

I’m going to mull this over for a while. In the past couple of weeks, Jennifer and I had talked about whether I should continue getting Nivolumab after next February. We’ve also talked about downsizing, and one of the things we discussed was whether it made sense to consider moving away from the DC area and my easy access to Hopkins. According to Dr. Hahn, I shouldn’t let that affect my decision. Jennifer and I had been leaning towards my continuing with the trial for as long as I could. After all, why stop with such a good thing? But if in fact the drug isn’t doing anything more, why stick with it? Maybe I’ve ridden this horse as far as it will go.