FDA Approves Pemigatinib for Myeloid/Lymphoid Neoplasms With FGFR1 Rearrangement

Srdan Verstovsek, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, discusses the study that led to the recent FDA approval of pemigatinib for patients with relapsed or refractory myeloid/lymphoid neoplasms and an FGFR1 rearrangement.

Transcript:

Srdan Verstovsek: Hello, I'm Srdan Verstovsek, a professor of medicine in the leukemia department at MD Anderson Cancer Center in Houston, Texas.

Oncology Learning Network: What is pemigatinib?

Pemigatinib is a new medication for some of our patients with myeloproliferative neoplasms, or MPNs. It's an inhibitor of fibroblast growth factor receptor, in short FGFR, which is important. It’s a specific targeted inhibitor of this particular protein, which is highly expressed in some patients with myeloproliferative neoplasms—chronic conditions of the bone marrow that leads to uncontrolled growth of the blood cells and, unfortunately, untimely death. It's a huge new development for us to have this new drug, pemigatinib, at our disposal for everyday management of some patients with MPNs.

OLN: What data led to this approval?

Patients with myeloproliferative neoplasms, or MPNS, have specific abnormalities in chromosomes. Chromosomes carry genes. When you do the bone marrow biopsy, which is the standard practice of tests for patients that have a blood and bone marrow condition, you also send a sample to a special lab to look at whether there are chromosomes that are broken. And sometimes, that's the case. And I'm saying that because a chromosome abnormality that involves chromosome 8 at a specific site—we call this 8p11—abnormalities that involve 8p11 activate the gene called FGFR. Fibroblast growth factor receptor 1. And that drives the disease process.

Now you have a connection here with pemigatinib. FGFR active gene makes a protein that drives the disease process, makes cells grow without control, and unfortunately leads to untimely death—historically within a year, s year and a half, people would be dying unless they do a bone marrow transplant.

We now have a true development in the phase 2 open-level clinical study that was globally led by myself and other colleagues in the field. We have a transformative medication that has a potential to eliminate disease in the great majority of the patients, because basically it inhibits the driver of the disease process. So within a few months, more than 80% of the patients would eliminate the disease, would normalize the blood cell count. We would not be able to find any evidence of abnormalities in that chromosome from 8p11 anymore.

It's day and night. It's just a new development which is a transformative, a wonderful development for these patients with myeloproliferative neoplasms with the chromosome abnormality 8p11. Something that has never been seen in the field of myeloproliferative neoplasms that I care about 100% in my time.

OLN: What is the current treatment landscape for these patients?

In fact the full name of this disease is myeloid and lymphoid neoplasms with eosinophilia driven by FGFR. This entity was identified as the full-fledged disease only about 10 years ago. It was in the past all combined in one broad spectrum titled myeloproliferative neoplasms. But since about 2016, it was identified on its own because of the specific driver of FGFR protein drives the disease process. In the past there was nothing to do about it other than give patients chemotherapy, either oral chemotherapy or investigational agents or some standard intensive chemotherapy, making people stay in a hospital for a month or 2 to try to eliminate disease. And after that, if we were lucky, that's the truth, do a bone marrow transplant to try to save the patient's life.

Unfortunately, this disease was most of the time a refractory to intensive chemotherapy. Many tried some investigational therapies, off-level use of medications for some other disease to control this condition. And even if you would get the patients through the transplant, the transplant most of the time would not provide long-term control. That's why we say that the average survival in the past, regardless what you did, was about a year or a year and a half. And only some patients are going through a transplant would be lucky enough to be alive for a long period of time. Now we have this medication that really limited disease and we have patients on the clinical study that are taking pill a day without any evidence of disease for 5 years. So, imagine what a revolution we have provided to these patients.

What is the safety profile of pemigatinib?

While we have extraordinary benefits: taking a pill a day, you eliminate a disease, your blood count normalizes, you may have a big spleen, big liver, big lymph nodes—all of this goes away, you feel better, the symptoms normalize, weight goes up and you continue enjoy life fully. But you may have some side effects. The side effects are related to inhibition of the growth of the hair, body hair, and the nails, as well as abnormality in phosphate levels in the body of the patient. Occasionally there might be some influence on the eyes, so we need to look at the eyes, and those side effects that are related growth of the cells that are not malignant, like nails or the hair, can be dealt with by dose adjustments.

There is a standard dosing of the pemigatinib that is applied at the beginning. We attempt to eliminate disease right away over a few months, and then based on the toxicity profile, if we have abnormalities that I described, then we dose-adjust and almost every time, we are able to, through those modifications, alleviate those problems and make people continue therapy forever basically. That's the goal—to control the disease. It’s hardly ever that the side effect profile leads to discontinuation therapy.

What advice do you have for practicing oncologists that are interested in using pemigatinib for their patients?

Myeloproliferative neoplasms are chronic conditions of the bone marrow that makes cell grow without control. People are aware usually of more common conditions like polycythemia where the red blood cells and whites and platelets grow, or essential thrombocythemia, with high platelets. This particular entity MPN with FGFR1 activation, myeloid/lymphoid neoplasms with eosinophilia given by FGFR1 is not very well recognized at all.

As I mentioned, the entity was only put on the map not even 10 years ago. But there is an easy way to recognize a patient who would be a potential candidate for pemigatinib therapy and that is the abnormalities in chromosomes. Chromosome 8p11 is involved, and that is included in the standard routine test that people do when they do the bone marrow biopsy. So, everybody should be aware of a new development of a specific FGFR inhibitor pemigatinib for patients with myeloproliferative neoplasms that have the 8p11 chromosome abnormality.

I should also say that many patients with 8p11 may have some other unusual features. While they have an uncontrolled growth of the bone marrow cells, they may also have enlarged lymph nodes or the spleen or the liver. They may have a lymphoma perhaps, or may have acute leukemia that is mixed into the clinical presentation as well. So one needs to be open-minded about the clinical presentations of these patients with myeloid/lymphoid neoplasms with FGFR activation. But always pay attention to the abnormalities in chromosomes, and if you see 8p11 abnormality, then that's the patient for pemigatinib.

What are the next steps for investigating pemigatinib in this or other populations?

Because of the diversity of patients’ clinical presentations, most of the time they are chronic myeloproliferative neoplasm patients with too many cells. And in that setting, when the disease is chronic, then the pill a day works very well 80 to 85% of the time. There is still room to improve to 100%. Adding another agent in this setting in chronic conditions, perhaps additional active agents that are generally known to suppress or eliminate malignant cells, nonspecific rather, makes sense. But I think the major development will be in those patients that present unusual clinical scenarios: patients with lymphoma, acute leukemias.

While the pill is active, and it can potentially eliminate disease, because of aggressiveness of these conditions like acute leukemia, you can imagine cells grow very fast, you can eliminate the disease with a pill a day. But I think in the future it makes sense to combine intensive chemotherapy with a pill a day, with pemigatinib, to derive the best outcome for that patient. So if the disease is more aggressive by type, then the more aggressive approach might be a combination of the chemotherapy with the pemigatinib together. I think that this is going be a next step to understand how to combine it. Do you give the pill alone first and follow by the intensive chemotherapy, for example, or the other way around, or two together? How to derive the best benefit for the most aggressive cases?

Is there anything else pertaining to this approval or the study findings that you would like to add?

Historically our goal was to try to eliminate disease and then get to bone marrow transplant. And even after bone marrow transplant, many patients would relapse, and unfortunately that was the reality. But now with pemigatinib, I expect higher rate of our elimination disease, complete cytogenetic response, no evidence of the 8p11 anymore. We can therefore see that minimal patients will be subject to the bone marrow transplant.

And one of the questions actually is whether there would be a need absolutely in every single case to aim for a bone marrow transplant anymore, because through the study we now know that people can stay disease-free for years to come, which has never been the case before. But even if the patients go through with the bone marrow transplant, then after the transplant, it’s very wise to continue to treat the patients with a very low dose of pemigatinib to prevent the relapse.

So even with that approach, a transplant after the success of just taking the pill, one would need to optimize the care by giving more of the pemigatinib at a lower dose as a maintenance after the transplant to prevent the undesirable relapse. We are learning as we go, but we are learning from other such successes in other conditions. It's a major transformative event, and we have a lot to learn, but we are extremely happy that these people now have a positive outlook.