National Center for Health Research: February 26, 2020
National Center for Health Research’s Public Comments on Cyramza for Metastatic Lung Cancer at FDA Oncologic Drugs Advisory Committee Meeting
Thank you for the opportunity to share our views today. The National Center for Health Research understands the need for effective new treatments for metastatic lung cancer. However, the data provided by the sponsor does not provide evidence that Cyramza improves survival, and it may worsen quality of life.
Although there are not yet enough long-term data to determine how Cyramza affects patients’ survival, the data that are available are not promising. Survival rates are almost identical with the drug or placebo (HR 0.92). It is important to note that the survival rates were never significantly different, but the difference was smaller as longer-term data were analyzed. We agree with the FDA that based on the confidence intervals, the drug could potentially worsen survival by about 30% — or could possibly improve survival by 30%. That risk of shortening overall survival is especially important because of the other risks of the treatment.
Let’s look at the number of deaths that occurred within 30 days of treatment in the RELAY trial. Of the 221 patients taking Cyramza, 6 died from adverse events, compared to none in the placebo arm. FDA specified that one of these was caused by drug treatment, while a second may have been caused by the drug. Although the FDA agrees with Lilly’s assessment that the other deaths are not caused by the drug or drug combination, those data aren’t made available so we can’t draw conclusions. But even if it is only 2 deaths, that’s almost 1% of the patients – not an irrelevant number! Since this shows that Cyramza can be fatal for these patients, and there is no currently no evidence that it significantly increases overall survival on average for lung cancer patients, the FDA expressed a great deal of concern about this indication. If Cyramza benefits any specific types of patients in terms of overall survival, there is no evidence of who those patients are likely to be.
Patients treated with Cyramza had a 7 month improvement in progression-free survival. This may be meaningful to patients if it is also associated with an improvement in quality of life. However, the data from the RELAY trial do not support this. The sponsor spins these results to conclude that the quality of life of life is not worse in patients taking Cyramza, but in fact, patients in the placebo group had fewer symptoms, such as shortness of breath, pain, and daily activity level, as measured by the Lung Cancer Symptom Scale. Our Center has worked with many seriously ill patients over the years, and we’ve found that patients care about two outcomes: 1) will they live longer and 2) what will their quality of life be in the days, weeks, months, or years they have left. The only patients that care about progression free survival are the ones that don’t understand what it means. When patients are told a drug is promising based on progression free survival, it is confusing and frankly misleading to most patients. They think it means they will live longer.
The results of the research are also worrisome regarding the FDA’s measures of specific adverse events. 72% of patients treated with Cyramza experienced a grade 3 or higher adverse events compared to only 54% of patients treated with placebo.
- 29% of patients treated with Cyramza experienced a serious adverse event compared to
21% of placebo-treated patients.
- Bleeding and hemorrhage occurred twice as often in patients treated with Cyramza,
compared with placebo.
- Grade 3 hypertension was roughly 5x more common among those treated with Cyramza
compared with placebo. Overall hypertension was roughly 4x as prevalent among the
Cyramza group. I disagree with the sponsor’s assertion that hypertension is no big
deal. In fact, heart disease is the #1 killer of men and women in the U.S. and
hypertension is called “the silent killer.” Yes, there are medications for it, but they also
have side effects that can be debilitating.
Overall, the study’s results suggest that when Cyramza is combined with erlotinib and compared with placebo plus erlotinib, the potential benefits of Cyramza do not outweigh the known risks. Given the data provided, there is no justification for rushing to approve this particular treatment.
We respectfully request that you advise FDA to not approve this indication for Cyramza without evidence that it improves overall survival enough to outweigh the risk for adverse events and reduced quality of life.
After FDA’s Cancer Director Dr. Richard Pazdur instructed the Advisory Committee at length that progression free survival was acceptable evidence for approval even if there was no evidence of overall survival, and even if more effective treatments were already available, the Advisory Committee voted 6 in favor of approval and 5 opposed.
The National Center for Health Research can be reached at email@example.com or at (202) 223-4000.