Behind the FDA Approval: Pemigatinib for R/R Myeloid/Lymphoid Neoplasms

Srdan Verstovsek, MD, PhD

The phase 2 FIGHT-203 trial showed high rates of complete responses (CR) and complete cytogenetic responses in adult patients with relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement, leading to the FDA approval of pemigatinib (Pemazyre).

In the multicenter, open-label, single-arm FIGHT-203 trial (NCT03011372), 18 out of 28 patients with chronic phase disease in the bone marrow with or without extramedullary disease (EMD) who were treated with pemigatinib achieved CR of 78% (95% CI; 52-94%). The median time to CR was 104 days (range, 44-435), and the median duration of CR was not reached (range, 1+ to 988+ days).

Among the 4 patients with blast phase disease in the bone marrow with or without EMD, 2 achieved CR with pemigatinib treatment. The duration of response ranged from 1 to 94 days. Of the 3 patients with EMD only, 1 patient achieved CR with a duration of 64+ days.

For all 28 patients enrolled in the study, the cytogenetic CR rate was 79% (95% CI, 59%-92%).

Regarding safety, the most common toxicities were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%), and dizziness (21%). These adverse events occurred in more than 20% of the patients.

“For myeloid/lymphoid neoplasms with FGFR1 rearrangement, the lack of effective therapies, or long-lasting effective therapies meant that the average survival was 1 year to 1 year and a half. Now having pemigatinib as a therapy transforms the outcome of these patients. It is an incredible development for these patients,” Verstovsek said, in an interview with Targted Oncology^TM.

In the interview, Verstovsek discussed the FDA approval of pemigatinib, the FIGHT-203 trial, and possibilities for pemigatinib in the future.

TARGETED ONCOLOGY: Can you discuss myeloid/lymphoid neoplasms with FGFR1 rearrangement? What treatment options were available for these patients before pemigatinib?

Verstovsek: For myeloid/lymphoid neoplasms that are driven by an abnormality in a gene called FGFR1, the standard practice was to treat the patients with chemotherapy and see whether we could somehow get them to do the transplant. Otherwise, the chemotherapy, whether it was intensive chemotherapy in the hospital with intravenous medications, or oral chemotherapy- like hydroxyurea- was only used to control the disease. Even if we attempted to eliminate the disease with these interventions, the success rate was very low, and it only lasted for a few months at best.

For myeloid/lymphoid neoplasms with FGFR1 rearrangement, the lack of effective therapies, or long-lasting effective therapies meant that the average survival was 1 year to 1 year and a half. Now, having pemigatinib as a therapy transforms the outcome of the patients. It is an incredible development for these patients.

What background can you provide on the FIGHT-203 clinical trial?

A myeloid/lymphoid neoplasm with activation of gene FGFR1 is a rather rare condition. Testing for presence of active FGFR1 gene is not readily available. Individuals that have this disease, may present with myeloid disease like myeloproliferative neoplasm or acute myeloid leukemia or lymphoid disease like acute lymphoblastic leukemia or lymphoma. These are all possible presentations of this disease. These patients can be identified based on the analysis of chromosomes, however. When the bone marrow is obtained to diagnose any of these conditions, as a standard practice, we send a sample to a special lab to analyze whether there are any chromosomes that carry abnormalities. This is called karyotyping or cytogenetic testing. If the patients have abnormalities in chromosome 8p11, they are the ones that have activation of gene FGFR1. This is easy way to identify them, if you can just remember that 8p11 chromosomal abnormality activates the FGFR1.

It is not that common, but the marker that I described can help identify patients with FGFR1 activation in everyday practice. Because we detected chromosomal abnormality in one of my own patients few years ago, we included that patient with FGFR1 activation, in a clinical study and treated him with pemigatinib. That was a phase 1 study. He was one of many different types of patients with different diseases who responded to pemigatinib. He eliminated disease and that was unheard of. That led in part to the development of the phase 2 FIGHT-203 clinical study, which then led to approval of pemigatinib. Pemigatinib is now known to provide high level of clinical activity with about 80% of patients eliminating disease and that is testament to extraordinary transformational potential of the pemigatinib for these patients. Pemigatinib targets the FGFR1 protein that drives disease process.

This is how it started, with the identification of pemigatinib’s activity, realizing its potential, and with desire from an academic point of view and from the perspective of the company that produces pemigatinib, Incyte, to developed it. We all agreed that we cannot let this be forgotten. We engaged over several years to conduct FIGHT-203 study, to find those patients who had myeloid/lymphoid neoplasms with FGFR1 rearrangement around the globe. I am so happy to see that this medication is approved.Now we have to go out and teach colleagues to look for patients with unusual clinical presentations that may have 8p11 chromosomal abnormality. It should become standard practice to look for the 8p11 Chromosomal abnormality, since these are the patients that are suitable patients for pemigatinib.

What do you think is next for pemigatinib?

Of course, this is not the first indication for this medication. It is valuable in some solid tumors. From my perspective as a leukemia doctor, I would envision that from now on we're going to combine pemigatinib with chemotherapy in some cases, for example when the patient presents with acute leukemia. In these cases the chemotherapy may be effective, but because of the aggressiveness of that condition, a combination of pemigatinib with chemotherapy may be even more effective. I would therefore expect the next wave of exploration of the utility of pemigatinib in malignant hematology to be in combination with other agents in patients that have complicated clinical picture with more aggressive clinical entities.

How do think this FDA approval has impacted the landscape?

I am just extraordinarily happy that in myeloproliferative neoplasms with FGFR1 rearrangement, we have a new possibility for this small group of patients but with a very aggressive disease and be able to eliminate the disease in a high proportion of the patients. We can also potentially follow them longer and talk about the cure. This is not common at all in my field of myeloproliferative neoplasms.

REFERENCE:

1. Incyte announces FDA approval of Pemazyre® (pemigatinib) as the first and only targeted treatment for myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. News release. Incyte. August 26, 2022. Accessed August 30, 2022. https://bwnews.pr/3wzSxxH