On January 14, 2021, the Food and Drug Administration (FDA) approved crizotinib for the treatment of pediatrics patients and young adults with relapsed or refractory ALK-positive systemic anaplastic large cell lymphoma (ALCL).
In an interview with Journal of Clinical Pathways, Yael Mossé, MD, Children’s Hospital of Philadelphia, PA, discusses the data that led to this approval, how this combination fits into the treatment paradigm for pediatric ALCL in the real-world setting, and the value of this drug in comparison to other treatment options for this disease.
What is crizotinib?
Dr Mossé: Crizotinib was first developed as a small molecule oral therapy to target a protein called MET. In 2006, when Pfizer took this drug into clinical trials, we thought that it was going to be a really important MET inhibitor in cancer.
Then it turned out that it also targets this gene called ALK. It's a really smart way to design a drug. Whereas chemotherapy targets all rapidly dividing cells in the body, these new targeted small molecules only bind to cells in the body where, for example with crizotinib, either MET or ALK are abnormally turned on.
It's a very specific therapy only for patients whose tumors had genetic alterations in these proteins.
What data led to this approval in pediatric ALK‑positive ALCL?
Dr Mossé: There's a pretty rich history there. In 2008, we first discovered that ALK is mutated in the germline of patients with neuroblastoma who have the inherited form of the disease, but when you go back to the history of what ALK is, ALK was actually cloned in 1994 by Steve Morris and Thomas Look.
Back then, it was cloned out of a cell line that was developed from a child who had anaplastic large cell lymphoma. We knew in 1994 that the majority of children with this rare form of lymphoma that we call ALCL, have ALK alterations that we call ALK fusions.
Back then, no pharmaceutical company was interested in developing a drug for a very orphan disease. In 2007, the Japanese discovered ALK translocations in about 5% of adults with non‑small cell lung cancer. That's when pharmaceutical companies began developing drugs to target ALK. A year later, we discovered a very different genetic way of turning on ALK in neuroblastoma.
I give you all that background because the rationale for opening the phase 1 clinical trial within the children's oncology group to look at the safety and the activity of crizotinib was really meant for neuroblastoma.
We knew that there were these rare patients with ALK‑positive ALCL that, for the most part, did well, but about 25% of these patients suffer a relapse and salvage therapies can be quite toxic, include bone marrow transplant. When we opened the clinical trial in 2009, we designed it in sich a way that there would always be a way to enroll patients who have ALK‑positive ALCL.
Many lymphoma experts told me that there wouldn’t be so few patients with relapsed ALK‑positive ALCL who would enroll because they're so rare and there are other therapies for them, chemotherapies. That's how it all started.
Fast‑forward from 2009 to about a decade later, we were able to enroll 26 pediatric patients with ALK‑positive ALCL who either relapsed on therapy or who relapsed shortly after the completion of therapy. The saying “when you build it, they shall come,” is exactly what happened.
We started, early on in the dose‑finding phase, to see these incredibly robust and sustained responses. It blew us away. We were truly humbled by what we were seeing, not just that the disease was going away so quickly but that it was staying away.
Ultimately, it's that package of data from these 26 patients that led to the FDA approval. What I will tell you is that when we wrote the trial in 2008, we never envisioned that we would use these data to go to the FDA. It was not an ideal data set. The FDA asked for a lot of the missing pieces that we didn't have.
At the end of the day, because the data was so compelling and the patients did so well and had such substantial benefit from an oral drug, that's why it got approved. There was no way anyone could not approve this.
What is the current treatment landscape for pediatric ALK‑positive ALCL?
Dr Mossé: The current treatment for pediatric ALK-positive ALCL is fairly intensive chemotherapy, mostly inpatient. It lasts anywhere from 6-9 months. It includes high doses of steroids, which have significant side effects, in addition to a broad range of different chemotherapeutic drugs that have, again, side effects on a lot of different organs.
Over the decades this therapy has proven to be effective for about 70% of patients, where they are cured. When we say cure in pediatric oncology, we do mean cure. We mean the disease does not come back ever.
There's a cost to that, meaning that there are late effects from the therapy. Then there's that group of patients who relapse either during therapy or shortly after the therapy ends. For those patients, as I mentioned earlier, there are options but all are involve more chemotherapy.
There had been for a long time the thought that this is such a chemotherapy‑responsive disease that these patients benefit even from stem cell transplantation, where they are given lethal doses of chemotherapy and then rescued using their own stem cells or stem cells that belong to someone else, matched to their tissue type.
That has been shown to be an effective therapy as well, but you can only imagine the significant risks of undergoing transplantation as well as the late side effects. It is a tough therapy for these patients, no doubt.
How does crizotinib fit into this treatment paradigm?
Dr Mossé: That is the million‑dollar question now that we know, in the relapse setting, that single‑agent crizotinib has shown anti‑tumor activity that is sustained for a long period of time.
So then how do we bring that forward and how do we integrate it into the upfront therapy? And how do we use this oral targeted therapy to start to peel off the chemotherapies we give upfront. That's what we need to figure out.
The ultimate goal, I think, would be not only just to add it on to our frontline therapy but then to reduce the toxicity of our therapy with the goal of curing the vast majority of these patients, and with less long-term toxicity. That's what we're working hard on, is how to do that.
What is the safety profile of crizotinib?
Dr Mossé: Crizotinib is an oral capsule that patients have to take twice a day, every day. That's tough. While it pales in comparison to the toxicity of chemotherapy, it's important to remind ourselves that a lot of these patients are adolescents, so we really have to stress the importance of compliance to these patients.
Secondly, it can cause upset stomach. This is something you can get past if you coat the stomach with an anti‑nausea medicine and take with food. It can also cause some diarrhea and mildly irritate the kidneys and the liver. All those things are reversible.
It can cause visual disturbances where, during the first couple of months, adults and adolescents say that they see spots occasionally in their peripheral vision. Those spots always go away and don’t cause any long‑term toxicity to vision. We don't fully understand why it happens, but the patients all adapt and the symptoms go away and do not interfere with quality of life.
Do you think that this approval will have an immediate impact in real‑world practice? What advice do you have for practicing oncologists that are interested in using this drug for their pediatric patients with ALCL?
Dr Mossé: Yes, I do think this will have an immediate impact. I get emails two, three times per week from physicians around the world, saying, "I have a patient with relapsed ALK‑positive ALCL. Should I give them chemotherapy? Should I take them to a transplant? What about crizotinib?"
In the real world now, these physicians, even in community practices, will be able to access and prescribe crizotinib, and allow their patients to have a normal quality of life with the ability to take an oral medication and have substantial benefit. I do think it will have immediate implications.
I'm working with Pfizer to develop a Peer Resource for physicians so that they have a reference guide because it's really important to understand how to give the drug successfully.
It can irritate the gut a little bit, so it's really important to take it on a full stomach. If you skip a meal and you take your crizotinib dose, then you don't feel good. It becomes a vicious cycle. I think that education is a really important part of how to make sure that our patients take the medicine without side effects.
I'm very excited about the immediate, real‑world delivery, to the community.
What are the costs associated with crizotinib? Are there any reimbursement hurdles from payers?
Dr Mossé: It's a tough thing for me to talk about more so from the academic perspective. What I can share is before the approval, we would prescribe crizotinib based on the experience that we had that led to the approval. We were often battling with insurance companies to get them to approve the cost of the drug.
If you don't have the coverage from the insurance, then my understanding is that this drug costs about $10,000-$12,000 per month. Now that if it's approved, it really should be covered by insurance and this should no longer be a worry for prescribing physicians as well as for families.
There were some patients who, even when the insurance would agree to approve it, before it was FDA‑approved, they had a copay that was fairly significant, a couple thousand dollars. That's a substantial burden for families who already have been paying so much for their child’s primary therapy. Now, my hope is that cost is no longer something that physicians and patients have to worry about.
What value does this drug offer in comparison to the other treatments for pediatric ALK-positive ALCL?
Dr Mossé: The value is really in quality of life and being able to get effective therapy as an outpatient. This allows patients to get their life back and be able to go to school and pursue the things they love. It's an oral medication and the visits can be just once a month after we know that patients are tolerating it. It really gives them back their life.
Is there anything else you would like to add?
Dr Mossé: This is really a story about persistence and taking something to the finish. There were many times along the way that both myself and my colleagues at Pfizer, who are so amazing, really felt like this just wasn't going to happen.
We never designed the original study in such a way to get the FDA the data they wanted, but when you see the benefit from the patient perspective, we persisted.
The approval is extremely gratifying. It's an enormous lesson for many of us. In academic medicine, we'll be designing trials very differently moving forward. They'll be done so that if there's a signal that is really positive, that the data will be there to be handed to the FDA to be reviewed for potential approval.
I think that Pfizer is really proud of this also, this accomplishment in pediatric oncology. It's an orphan disease. The market for non‑small cell lung cancer is much bigger, but they recognized the significant impact on this small population of patients. It's a great story and it’s been an mind-blowing privilege for me to be a part of it all.
Dr Mossé reports consultation payment from Pfizer.