Informed Plea For Compassionate Use
First, as background context on myself: I have extensive clinical experience in oncology pharmacy, having interned for over four years at a major cancer center; my career is as an oncology writer focusing on pharma/biotech-sponsored projects in the area of adult oncology, being called upon to help researchers develop data presentations at congresses (example ASCO – American Society of Clinical Oncology) and peer-reviewed journal publications for pharma sponsored clinical trials. I have been writing extensively on cancer and cancer drugs for an oncologist audience for over 16 years beginning in 1998. I have witnessed the entire field evolve, for adults, from chemotherapy to these exciting new targeted therapies with the promise for better efficacy and better safety, too. You can ask anyone who knows me; they will say that I know a lot about cancer and cancer drugs. However, I am able to remain objective, despite the emotion. I don’t believe in giving patients treatments that will likely cause more harm than do good, just to do something.
I am strictly a volunteer in the childhood cancer community. This is my charitable “side project” and I have no personal connection to a child with cancer. As a general rule, I do not get involved in patient matters like this, but I am making one exception: for Nathalie Traller. And I’ll explain why:
Nathalie Traller is what I would call the “poster child patient” for whom compassionate use was actually intended for. The thing that everyone needs to remember is this: pediatric clinical trials of anti-PD1/PDL1 drugs are coming soon from Merck, BMS, and Genentech; the trials have been designed but the protocols have not been approved and are not yet recruiting (the timing is uncertain, delays happen for various reasons). Industry is to be commended for moving these agents into pediatric trials and recognizing their potential for childhood cancer however, things are not moving fast enough for Nathalie. She has a rare stage IV sarcoma for which no known effective options exist, and she simply cannot wait for these trials to start recruiting. Thus, she is such an excellent candidate for Compassionate Use, to serve as a bridge given her very unique situation; someone who would be a suitable participant in the forthcoming trials but who cannot wait because of her clinical situation, which can worsen at any given day. Waiting is not an option for stage IV cancer patients.
I have spent over 2 hours this weekend on the phone with Nathalie’s father Nathan who filled me in on Nathalie’s treatment history and clinical situation. When I learned about her via social media, I had questions in my own head and wanted to be sure that all other treatment options for her had been explored. So, I contacted Richard Plotkin for that particular reason. For example, has she been on the oral antiangiogenic agent Cediranib, which has shown promise specifically for ASPS and is in clinical trials? How about Sunitinib? The answers were yes and yes, and she progressed on both of them. I also wondered did they have her tumor tested for PD1 expression and a comprehensive panel of molecular biomarkers? The answers again were yes and yes.
The tumor testing is an important part of this story. Nathalie’s first systemic treatment was within an NCI Phase II clinical trial of Cediranib, which has shown promise for her particular cancer, ASPS. When she progressed on Cediranib, the NCI performed a surgery to resect an abdominal tumor. The family, being amazingly knowledgeable, requested further testing of her tumor samples. It turns out; her samples were VERY highly expressive of PD1, per the NCI’s assay. Some additional testing had been performed (including comprehensive tumor profiling through Foundation Medicine), but there was no clear identifiable target for treatment. When I learned all of this, I knew that they were 100% doing the right thing. This was no “grasping at straws” or making a “shot in the dark”.
The high PD1 expression of Nathalie’s tumor provides a very strong biologic rationale for serious consideration of anti-PD1/PDL1 therapy. This compassionate use request has its basis very much in science; that is largely why the medical community has been so supportive. Being PD1-positive is not a prerequisite for participating in most of the ongoing clinical trials of anti-PD1/PDL1, yet some trials are looking closer at this selected sub-group. Research is just beginning to shed light on the predictors of response (biomarkers) to anti-PD1/PDL1 therapy, but data derived from a BMS trial of Nivolumab (published in the New England Journal of Medicine) clearly show a higher propensity for response among patients with PD1-positive tumors. Basically, having a PD1-positive disease makes it more likely that the patient will respond to therapy, while some PD1-negative patients will respond too (yet the underlying basis is not yet clear). Thus, while no treatments are a slam dunk, the fact that Nathalie’s tumor is PD1-positive per the NCI testing, bodes well for Nathalie. PD1/PDL1 testing is not yet standardized or validated, and BMS, Merck, and Genentech each have their own assays however, the PD1 expression per the NCI tests is a major consideration in weighing the risks versus benefit of therapy, as it applies to Nathalie and only Nathalie.
Clinically, Nathalie has metastatic stage IV disease but good performance status (ambulatory, not bedridden) and no impairment of kidney, liver, or bone marrow function. This is important, as these factors play into a patient’s ability to even tolerate therapy. Most clinical trials require patients to be in “relatively good shape”, for someone with advanced cancer.
What Nathan Traller said in the CNBC piece is so very true: these newer treatments, including immunotherapy agents like PD1/PDL1, are not only exciting for their potential for improved antitumor activity, but also for their improved safety profiles. Yes, there are risks, but these immunotherapy agents have already been undergoing extensive clinical trial testing in adults, and we already know a lot about their toxicity profiles and appropriate measures for prevention or management. The concept of immunotherapy is not even new; different (and more toxic) immunotherapy options (like cytokines) have been used as anticancer agents for decades, it is just the PD1/PDL1 target that is new. Regardless, agents within the PD1/PDL1 class will be commercially available in the very near future, with regulatory submissions already underway i.e., these drugs did not just come out of test tubes or animal models. Safety data from the ongoing and completed clinical trials have been accumulating to allow the Traller family to make an informed decision about the use of these drugs for their daughter; they understand the concept of weighing risk-versus-benefit. Overall, unknowns about anti-PD1/PDL1 product safety should not be used as an argument as to why Nathalie should be denied access, in this particular case. The situation might be different for other patients, with earlier disease or with other treatment options worth pursuing.
Very importantly, please note that Merck already has an expanded access program underway for their anti-PD1 agent, MK-3475 (Pembrolizumab). This expanded access program is currently OPEN, and children as young as 12 (yes, twelve!) are eligible. The only problem is that it is restricted to metastatic melanoma, which is a rare cancer in children, but does occur. Nonetheless, this expanded access initiative serves to strengthen the argument as to why Nathalie should be granted Compassionate Use, considering that this program is currently providing anti-PD1 therapy to children, including those younger than Nathalie — it is just too restrictive from a tumor type standpoint.
If the patient in question were one of my daughters, with a rare stage IV PD1-positive tumor that has exhausted all other options (including antiangiogenic agents like Cediranib and Sunitinib), I would be doing precisely what the Traller family is doing: pursing anti-PD1/PDL1 therapy. Overall, I see Nathalie as the “poster child” for Compassionate Use, not just because of her age but because of the biology of her particular tumor coupled with a number of other clinical factors that would suggest the potential to do well on this treatment — which truly is her only viable option but a really good one considering her PD1-expressive tumor per NCI testing, with the potential to alter the course of her disease.
Nothing is a slam dunk, certainly not in cancer. But this treatment provides the opportunity to give Nathalie a real shot at life. Thus, I myself, made the exception to jump in and do what I can to speak up for her. But I have no magical powers for providing the drug, so we need to find others who will make an exception to allow her either (1) Compassionate Use or (2) participation in one of the ongoing “adult trials”, which she would be eligible for right now if it were not for being 15 instead of 18. I am optimistic that a lot of positive change is going to come from Nathalie’s ordeal – but we need to do everything we can to save her in the meantime, and making her wait for a pediatric trial with TBD timing (rather than providing her with the drug when she needs it, which is NOW) is not fair but so modifiable.
Laurie Orloski, PharmD
Publications Consultant / Childhood Cancer Advocate