2021 EBMT | Rucotinib GVHD treatment journey, REACH3 research update

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only cure for many blood system diseases.

In recent years, the efficacy of allo-HSCT has continued to improve, coupled with the success of haplo-HSCT in my country, which has led to a rapid increase in the number of cases of hematopoietic stem cell transplantation in China.
However, graft-versus-host disease (GVHD) is still One of the main causes of death after transplantation.

Therefore, the prevention and treatment of GVHD is extremely important to ensure the success of transplantation and long-term survival after transplantation.

Whether it is acute GVHD (aGVHD) or chronic GVHD (cGVHD), glucocorticoids are the standard first-line treatment, but about 50% of patients can develop glucocorticoid resistance (SR) or glucocorticoid dependence (SD) (both Collectively referred to as glucocorticoid treatment failure).

At present, there is no standard second-line treatment plan after the failure of glucocorticoid therapy.

Rucotinib is an oral selective JAK1/JAK2 inhibitor that inhibits the proliferation and differentiation of inflammatory cells by inhibiting the JAK-STAT pathway.
It is currently one of the most effective drugs for the treatment of SR-GVHD.

Rucotinib is better than BAT in the treatment of SR-aGVHD.
In May 2019, the U.
S.
Food and Drug Administration (FDA) approved Rucotinib for SR-aGVHD patients over 12 years old [1], providing a new treatment for patients with aGVHD select.

The results of a multicenter randomized controlled phase III REACH2 study showed that in patients with grade II-IV SR-aGvHD ≥12 years old, the efficacy of rucotinib is better than the best available treatment (BAT), which can significantly improve the overall remission of patients Rate (ORR, ORR on day 28 was 62.
3% vs 39.
4%, P<0.
001) [2]. The updated REACH2 results at the 47th Annual Meeting of the European Society for Blood and Bone Marrow Transplantation (2021 EBMT), which opened today, showed that rucotinib has a long-lasting effect and the median duration of response (DOR) is longer than that of the BAT group (163 days vs 101 days) , The median failure-free survival (FFS; 4.
86 months vs 1.
02 months, P<0.
0001) and the median event-free survival (EFS; 8.
18 months vs 4.
17 months) were also longer than those in the BAT group.

Moreover, the rate of hormone discontinuation in the rucotinib group was higher on day 56 (22.
1% vs 14.
8%); the average European five-dimensional health scale (EQ-5D-5L) reported by patients in the rucotinib group at 24 weeks The health level is also higher (76.
4 vs 63.
1).

In addition, patients who crossed over from the BAT group to the rucotinib group had an ORR of 67.
3% on the 28th day after the crossover, confirming that rucotinib still showed its effectiveness after other treatments failed [3].

(Data may be updated at the meeting) There is no doubt that rucotinib is better than BAT rucotinib in the treatment of SR-cGVHD in aGVHD.
So in cGVHD, what is the effect of rucotinib in cGVHD? The REACH3 study gave us the answer.

Figure 1 REACH3 study design REACH3 is a multi-center randomized controlled phase III study that compared the efficacy of rucotinib and BAT in patients ≥12 years of age with moderate to severe SR/SD-cGvHD (Figure 1).

The main research results announced at the 2020 ASH Conference showed that the 24-week ORR of the Rucotinib group was significantly higher than that of the BAT group (49.
7% vs 25.
6%; P<0.
0001), and the median FFS was significantly longer than that of the BAT group (not reaching vs 5.
7 Month; P<0.
0001), and the improved Lee symptom score (mLSS) remission rate of the rucotinib group was significantly higher than that of the BAT group (24.
2% vs 11.
0%; P=0.
0011) [4].

Rucotinib has achieved good results in the treatment of SR/SD-cGvHD, but it is also of important clinical significance to determine which patients can better benefit from rucotinib treatment.
At today's EBMT annual meeting, REACH3 research Also updated its subgroup analysis results [5]. A total of 329 patients in the REACH3 study were randomly assigned to the Rucotinib group (n=165) or the BAT group (n=164).

The baseline characteristics between the two groups are balanced.

The median age is 49 (range 12-76) years.

As of the data cut-off date (May 8, 2020), 204 patients (62.
0%) had discontinued the drug, mainly due to lack of efficacy (rucotinib, 14.
5%; BAT, 42.
7%).

The patients were divided into groups based on demographic characteristics, cGVHD history, and transplant-related history, and then subgroup analysis was performed to analyze odds ratios (OR; rucotinib vs.
BAT) of ORR.

OR>1 and the confidence interval falling on the right side proved that the ORR of rucotinib was significantly better than that of the BAT group in this subgroup of patients.

Patients were grouped according to different baseline characteristics.
In most subgroups, the 24-week ORR of the Rucotinib group was significantly higher than that of the BAT group (Figure 2); however, some subgroups had too few patients Draw a clear conclusion.

Patients with moderate cGVHD (59.
5% vs 32.
5%; OR, 3.
05 [95% CI, 1.
59-5.
84]) and patients with severe cGVHD (40.
7% vs 19.
0%; OR, 2.
92 [95% CI, 1.
46-5.
84]) Zhonglu The ORR of the cotinib group was significantly higher than that of the BAT group.

It can be seen that regardless of the severity of cGVHD, the efficacy of rucotinib is better than the best available treatment.

Among the subgroups of patients who failed glucocorticoid therapy defined by different standards, Rucotinib was also more effective than BAT (Figure 2).

Regardless of the history of transplantation (including pretreatment plan, T cell exhaustion, source of stem cells, donor relevance, donor HLA matching status, donor type/HLA matching status, and donor/recipient gender matching), Luke The ORR of the tinib group was higher than that of the BAT group (Figure 2).

Regardless of whether the patient has a previous history of aGVHD, the efficacy of rucotinib is better than that of BAT (Figure 2).

In addition, a subgroup analysis based on the affected organs is underway.

(Data may be updated at the meeting) Figure 2 The results of the subgroup analysis of the REACH3 study.
In summary, rucotinib has shown clinically significant benefits in different subgroups of SR/SD-cGVHD patients.
The results of the subgroup analysis are similar to The results published on ASH are consistent.

In most patient subgroups, the 24-week ORR of the rucotinib group was significantly higher than that of the BAT group.

Explore how to use rocotinib in children with GVHD less than 12 years old? Children ≥12 years old and adults with SR-GVHD, whether it is acute or chronic, the data of REACH2-3 have proved the effectiveness of rocotinib, so how should children with GVHD who are younger than 12 years old take the medicine? REACH4 and REACH5 are prospective, multi-center, single-cohort phase I/II clinical studies designed for children with aGVHD and cGVHD in children less than 12 years old respectively, aiming to evaluate the efficacy, dose selection and dose selection of rucotinib in pediatric patients.
Security issues.

Both studies set different dosage groups according to age groups, and the dosage of drugs is more conservative and more cautious.

At present, both REACH4 and REACH5 are in the enrollment stage, and we look forward to the early announcement of the research results, and hope that the research results can support Rucotinib as a new treatment option for patients with GVHD less than 12 years old.

References: [1] https:// N Engl J Med 2020 ; 382:1800-1810.
DOI: 10.
1056/NEJMoa1917635.
[3] 2021 EBMT Annual Meeting, Abstract #OS8-4.
[4] 2020 ASH Annual Meeting, Abstract Oral#77.
[5] 2021 EBMT Annual Meeting, Abstract # OS9-2.
MCC number JAK21031696 is valid for 2022-03-13, and the information is expired and deemed invalid.

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