Axatilimab Leads to Strong Responses in Heavily Pretreated cGVHD

Catherine J. Lee, MD, MS

Associate Professor
Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, WA

Targeted Oncology: What led to the FDA approval of axatilimab as therapy for chronic graft-vs-host disease (cGVHD)?

Catherine J. Lee, MD, MS: The approval came from the phase 2 AGAVE-201 trial [NCT04710576]. AGAVE-201 was a phase 2, multinational, randomized trial of axatilimab at 3 different doses. The 3 doses here were 0.3 mg/kg every 2 weeks, 1.0 mg/kg every 2 weeks, and 3.0 mg/kg every 4 weeks. Patients who were eligible included [those who were] aged 2 years or older who had failed 2 or more prior lines. They had to have active GVHD. They could be on concomitant steroids, calcineurin inhibitors, or mTOR inhibitors, but they were not allowed to be on belumosudil [Rezurock], ruxolitinib [Jakafi], or ibrutinib [Imbruvica]. They had to come off those drugs before enrolling onto this study.

They randomly assigned the patients [to the 3 dose levels], and they followed the patients up into the first 6 cycles; that’s usually week 24 or 6 months. The common primary end point in these cGVHD trials was overall response rate [ORR] by the National Institutes of Health 2014 criteria, and the end point was considered met at the lower bound of the 95% confidence interval was greater than 30%. Secondary and exploratory end points included [clinically meaningful improvement in the modified] Lee symptom scale and organ-specific response rates, failure-free survival, overall survival, duration of response, and safety.

What were the efficacy outcomes of the AGAVE-201 trial?

In terms of response, it met its primary end point in all 3 doses.¹ The ORR was 50% or higher [in all 3 groups]. The dose of 0.3 mg/kg every 2 weeks was the FDA-approved dose based on the ORR of 74% and based on the best safety profile.

The organ-specific response rate was a secondary end point. There were responses in all organs involved, with complete responses [CRs] seen in 89% of patients with lower gastrointestinal [GI] involvement. Keep in mind there were only 9 patients with lower GI involvement. There were CRs [in 82%] of the upper GI and more partial responses [PRs] in the joints and fascia [56% PR and 20% CR], the lungs [31% PR and 16% CR], the liver [20% PR and 20% CR], the eyes [20% PR and 10% CR], and the skin [17% PR and 9% CR]. But this is still impressive, because most of these patients who [enrolled in] the trial had failed [to benefit from] belumosudil, ibrutinib, and ruxolitinib, and they're still getting a response with axatilimab.

[The investigators reported] organ-specific response rate based on duration of treatment [for] an aggregate of all the doses. Overall, more than 50% of patients responded by day 56 after treatment initiation, 78% of patients responded by day 84, and more than 97% of patients responded by day 168.

All responses in all these organs were observed by day 196, so that should give you an idea that by 6 months after initiating treatment in this trial, all responses were seen by 6 months. So, if you have a patient and you haven't seen anything by 6 months, then it's probably time to change drugs. In general, across ibrutinib, belumosudil, and axatilimab, the median time to first response is anywhere from 4 to 6 weeks. That’s a landmark time to keep in the back of your head. A fair [duration to try] any of these drugs is 3 to 4 months before deciding to add on another therapy or switching to another therapy.

What safety outcomes were reported for patients with cGHVD in the trial?

When you look at the safety data, the most common adverse events [AEs] were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Usually, we see elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, amylase, and lipase. AEs leading to discontinuation of axatilimab occurred in 6% of the patients in the FDA approved dose [vs 22% in the 1 mg/kg dose and 18% in the 3 mg/kg dose]. I still have to find out what those AEs were that led to discontinuation. For those who will be using axatilimab, know that hypersensitivity and infusion reaction can occur, which lead to changes in blood pressure or GI symptoms. You can temporarily hold the infusion or slow down the infusion, give some medications, and usually the remaining infusion goes well. In the clinical trial, periorbital edema was reported, usually starting around the third cycle or beyond, and then the periorbital edema would resolve, but it does take time to resolve. It was infrequent at the FDA approved dose of 0.3 mg/kg every 2 weeks.

_{DISCLOSURE: Lee previously reported advisory board participation for Sanofi, Kite, Kadmon, BMS, and Incyte; research funding from Incyte; steering board committee participation for Incyte; speakers panel participation for Kite; and consulting for Fresenius Kabi, Sanofi, and Mallinckrodt.}

_Reference:

_{1. Wolff D, Cutler C, Lee SJ, et al. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. 2024;391(11):1002-1014. doi:10.1056/NEJMoa2401537}