EHA 2020 | Phase III GRAVITAS-301 trial results on itacitinib plus corticosteroids for aGvHD

During the 25th Annual Congress of the European Hematology Association (EHA), the results from the phase III GRAVITAS-301 trial were presented by Robert Zeiser. This study investigated the efficacy of the Janus kinase 1 (JAK1) inhibitor, itacitinib, in combination with corticosteroids for the treatment of acute graft-versus-host disease (aGvHD). Allogeneic stem cell transplantation (allo-SCT) is a curative treatment option for many malignancies. Unfortunately, approximately 30–60% of patients receiving allo-SCT will develop Grade ≥ 2 aGvHD, which deteriorates patient outcomes and manifests as an important cause of mortality¹. So far, corticosteroids are the standard of care for the first-line treatment of aGvHD but approximately 60% of patients become corticosteroid-refractory following therapy.¹

To explore new therapeutic regimens for the corticosteroid-refractory population and for the treatment of aGvHD altogether, GRAVITAS-301 (NCT03139604) was undertaken. In January 2020, a press release announced that GRAVITAS-301 did not meet its primary endpoint of improving the overall response rate (ORR) at Day 28. Nevertheless, a summary of the full data with some new and interesting post-hoc analyses are presented below. For more information on the press release, please read here.

Study design

• Randomized, placebo-controlled, phase III trial
• Eligible patients were ≥ 18 years old, had received allo-SCT and developed Grade II–IV aGvHD according to the Mount Sinai aGvHD International Consortium (MAGIC) criteria
• Patients were excluded if they had evidence of an active infection, malignancy relapse or GvHD overlap syndrome, or if they had received:
  • ≥ 1 SCT
  • Corticosteroids for aGvHD for ≥ 2 days
  • Previous JAK inhibitor therapy
• N = 439 patients were randomized 1:1 to receive corticosteroids with either placebo (n = 220) or 200 mg itacitinib once daily (n = 219)
  • Corticosteroids in both arms consisted of 2 mg/kg methylprednisone daily or a prednisone equivalent or an appropriate dose per local guidelines
• Primary endpoint was ORR at Day 28. The initial statistical assumption of the study was a minimum 16% absolute improvement in ORR with itacitinib
• Secondary endpoints include 6-month non-relapse mortality (NRM) rate, duration of response, overall survival (OS), chronic GvHD incidence, failure-free survival, and safety
• Patient baseline characteristics were well-balanced between the groups and the main ones are shown in Table 1

Table 1. Key patient baseline characteristics in GRAVITAS-301¹

Baseline characteristic	Placebo arm (n = 220)	Itacitinib arm (n = 219)
GvHD, graft-versus-host disease; MAGIC, Mount Sinai Acute GvHD International Consortium
Median (range) age, years ≥ 65 years old, %	58.0 (19–77) 77.3	58.0 (18–78) 75.8
Male patients, %	58.6	62.6
MAGIC Grade, % 0 1 2 3 4 Missing	0.5 2.3 67.7 23.2 4.5 1.8	0.9 0.9 70.3 23.3 2.3 2.3
GvHD risk, % Standard High	74.5 25.5	76.7 23.3
Race, % White Black/African American Asian Other	88.2 2.3 1.8 5.9	89.5 3.7 1.8 4.6

Results

• The trial failed to meet its primary endpoint of ORR improvement at Day 28 mediated by itacitinib when compared with placebo. The response outcomes are shown below in Table 2
• Further subgroup analyses after patient stratification according to aGvHD risk did not reveal any statistically significant differences in terms of ORR. However, post-hoc patient stratification analysis revealed a significantly higher complete response rate in patients receiving itacitinib belonging to either risk groups (Table 3)

Table 2. Response rates in GRAVITAS-301 at Day 28 of treatment¹

Response rates	Placebo arm (n = 220)	Itacitinib arm (n = 219)	OR (95% CI); p value
CR, complete response; CI, confidence interval; OR, odds ratio; ORR, overall response rate; PR, partial response; VGPR, very good partial response
ORR, % (95% CI)	66.4 (59.7–72.6)	74.0 (67.6–79.7)	1.45 (0.959–2.204); p = 0.0782
CR, %	40.5	53.0	—
VGPR, %	15.0	12.3	—
PR, %	10.9	8.7	—

Table 3. Response outcomes at Day 28 of treatment from GRAVITAS-301 following post-hoc patient stratification by aGvHD risk¹

Outcome	Standard risk patients			High risk patients
CR, complete response; CI, confidence interval; OR, odds ratio; ORR, overall response rate Statistical significance is indicated by bold font
Placebo arm (n = 163)	Itacitinib arm (n = 162)	OR (95% CI); p value	Placebo arm (n = 57)	Itacitinib arm (n = 57)	OR (95% CI); p value
ORR	69.9%	78.4%	1.56 (0.96–2.58); p = 0.082	56.1%	61.4%	1.24 (0.59–2.62); p = 0.570
CR	42.3%	56.8%	1.66 (1.14–2.44); p = 0.008	35.1%	42.1%	1.66 (1.14–2.44); p = 0.008

• The key secondary outcomes are shown in Table 4. In summary, there were no statistically significant differences between the groups in terms of malignancy relapse, malignancy relapse death rates, OS, failure-free survival or 6-month NRM

Table 4. Key secondary outcomes of GRAVITAS-301¹

cGvHD, chronic GvHD; CI, confidence interval; DoR, duration of response; FFS, failure-free survival; GvHD, graft-versus-host disease; NRM, non-relapse mortality; OS, overall survival *Median follow-up of 267 days for both arms †Median follow-up was 130 days for the placebo arm and 148 days for itacitinib
Outcome	Placebo arm	Itacitinib arm	p value
6-month NRM, % (95% CI)	18.9 (14–25)	18.3 (13–24)	0.7952
Malignancy relapse, % Leading to death, %	10.9 7.3	12.4 4.6	—
Median OS, % (95% CI)*	NE (520 days–NE)	NE (NE–NE)	—
One-year OS, % (95% CI)	66 (58–72)	70 (62–76)	0.7414
One-year FFS, % (95% CI)†	0.27 (0.21–0.34)	0.30 (0.23–0.37)	0.3560
Signs/symptoms of cGvHD, %	22.3	13.7	—
Median DoR (range), days	174 (1–633)	180 (1–587)	—

• Median duration of corticosteroids use was 44 days in the placebo and 47 days in the itacitinib group
• The main reason for treatment discontinuation in both arms was adverse events (22.7% in the placebo arm vs 35.6% in the itacitinib arm) with similar discontinuation rates:
  • Placebo arm: 90.5% (n = 199)
  • Itacitinib arm: 93.6% (n = 205)
• Interestingly, patient discontinuation rates due to GvHD progression or inadequate response therapy were higher in the placebo (14.1%; 12.3%) than the itacitinib arm (4.1%; 7.3%)

Safety

• Treatment-related adverse event (TEAE) rates were similar across the two arms with the most common Grade ≥ 3 events shown below in Table 5
• Fatal adverse events occurred in 13.4% of patients in the placebo group compared with 10.2% in the itacitinib arm, and were mainly due to infections/infestations in both arms

Table 5. Most common (> 5%) Grade ≥ 3 TEAEs observed in GRAVITAS-301¹

Grade ≥ 3 TEAEs	Placebo arm (n = 216)	Itacitinib arm (n = 215)
ALT, alanine aminotransferase; CMV, cytomegalovirus; TEAEs, treatment-related adverse events
All, %	82.4	86.0
Thrombocytopenia, %	31.5	36.3
CMV infections, %	7.4	8.4
Anemia, %	12.0	18.6
Neutropenia, %	20.8	22.8
Hyperglycemia, %	13.0	12.1
Diarrhea, %	10.2	6.5
Pyrexia, %	3.2	5.1
Hypertension, %	6.5	7.9
Hypokalemia, %	5.1	4.7
Hypertriglyceridemia, %	4.2	9.8
ALT increase, %	1.9	7.0
Pneumonia, %	6.9	5.1
Febrile neutropenia, %	6.0	5.1

Conclusions

GRAVITAS-301 did not meet its primary endpoint of ORR improvement at Day 28 with itacitinib addition to corticosteroids vs placebo. Moreover, no statistical differences were found in terms of OS or 6-month NRM rates. Nevertheless, post-hoc patient stratification by aGvHD risk revealed that itacitinib addition to corticosteroids improves complete response rates by Day 28 in both standard and high-risk patients. Moreover, fewer patients in the itacitinib group discontinued treatment due to GvHD progression or the need of additional therapy from inadequate response. Further analyses of the GRAVITAS-301 data and more studies are needed to provide an explanation and validate these results.