By Anna E. Mazzucco, Ph.D.
November 5, 2013
Thank you for the opportunity to speak today on behalf of the Cancer Prevention and Treatment Fund. My name is Dr. Anna Mazzucco, and after completing my Ph.D. in Cell and Developmental Biology from HarvardMedicalSchool I conducted research at the National Cancer Institute. I bring those perspectives today.
Our nonprofit organization conducts research, scrutinizes data in the research literature, and then explains the evidence of risks and benefits to patients and providers. Our president is on the Board of Directors of the Alliance for a Stronger FDA, which is a nonprofit dedicated to increasing the resources that the FDA needs to do its job. Our organization does not accept funding from pharmaceutical companies, and therefore I have no conflicts of interest.
Pediatric cancers represent a dire unmet medical need. Several pediatric cancers still cannot be cured, and patients relapse within a few years. Cancer immunotherapy is an area of great excitement and promise for addressing these issues, as we seek non-genotoxic strategies for pediatric patients who are uniquely vulnerable to the long-term effects of such treatments. Therapies of this class have shown the potential to synergize with existing standard of care, which is an essential aspect of the combination therapies ultimately required for curative care.
We support the FDA’s efforts to expedite medical advances for pediatric cancer patients, but this priority must not come at the cost of safety standards. Although distinct from the side effects resulting from traditional chemotherapy, nivolumab and MK-3475 have significant risks.
Three deaths occurred in the trials of nivolumab in advanced malignancy adult patients due to uncontrollable pneumonitis, out of 296 patients – 1%. Grade 3 and 4 adverse events occurred in 14% of these patients. The assertion that pediatric patients will tolerate nivolumab comparably to adults relies on a single ongoing study of a different drug, ipilimumab, in only 6 patients under the age of 12. While ipilimumab is also an immunomodulatory drug, it is a distinct agent with a different mechanism of action. Thus, critical safety data cannot be extrapolated from these studies. The Bristol-Myers Squibb studies do not include any preclinical data in non-adult primates. As the Bristol-Myers Squibb briefing document acknowledges, these drugs may have different and more pronounced effects in pediatric patients since their immune systems are still developing.
I have 4 recommendations that I respectfully suggest that you seriously consider:
#1. In the Merck preclinical studies, toxicity was evaluated in primates at an age roughly comparable to a “young toddler”, but the plan here calls for trials in infants as young as six months old. Before pediatric studies begin, longer-term preclinical studies of MK-3475 and nivolumab should be performed in primates at comparable stages of development so that human infants are not exposed to greater safety risks than those observed in adults. Until such studies are conducted, I hope you will urge the FDA to oppose the Bristol-Myers Squibb plan to initiate pediatric studies of nivolumab immediately at the adult dose of 3mg/kg, without any further preclinical studies. This could be fatal.
#2 The Bristol-Myers Squibb plan also includes pediatric trials using the combination of nivolumab with ipilimumab. This combination resulted in markedly increased toxicity in preclinical studies, which were conducted for only 4 weeks, and also in the study of human adults. In the melanoma study in adults, almost half of the patients (49%) experienced Grade 3 or 4 events. This percentage is higher than the 40% who showed a beneficial clinical response – in other words, the risks outweighed the benefits, with more patients experiencing serious adverse events than benefitting. Combination treatment was discontinued in 21% of patients in this trial due to these adverse events.
Other studies have indicated that these serious adverse events are not always reversible; for example 2% of patients taking ipilimumab in a Phase III trial had hypopituitarism, which can be permanent. This condition requires long-term hormone replacement therapy, but even that will not eliminate significant health risks. Tragically, those health risks would be exacerbated in young patients who are still developing. Longer preclinical studies are needed to evaluate safety before it would be ethical to begin combination trials with ipilimumab.
#3. The Bristol-Myers Squibb briefing document emphasizes the importance of early detection for management of adverse events. High doses of corticosteroids will undoubtedly be required to control drug-related adverse events. This could be dangerous for children. We agree with the FDA that the long-term effects of immune modulation should be carefully considered in the context of a pediatric population. The Pediatric Study Plan does not yet delineate specific steps for rapid clinical detection and management of these events, which will be more difficult in these patients. It is essential that those specific steps be delineated before research is conducted.
#4. Lastly, as the FDA has noted, the combination of these agents with others of non-overlapping mechanism of action should be a priority consideration in the ongoing studies in adults. We also agree with FDA that the threshold of PD-L1 expression used for patient selection should be modified for combination therapy where PD-L1 expression could be induced, therefore a lower initial threshold of expression may still identify a responsive patient population, and that the planned biomarker studies explicitly address this possibility. This will ensure that these agents are used to the greatest effect in all patients who need them.
In conclusion, the 4 steps I outlined above will help reduce the risks to children with pediatric cancer and also help assure that these therapies reach the patients most likely to benefit from them.