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The tumor microenvironment of classical Hodgkin lymphoma (cHL) is composed of Hodgkin Reed-Sternberg cells, which constitute < 1% of the tumor volume, and the stroma. These primary lymphoma tumor cells overexpress programmed cell death ligand 1 and 2 (PD-L1 and PD-L2), which facilitate evasion of immune surveillance and survival within the tumor microenvironment. Approximately 15% of patients with cHL have chromosomal rearrangements of CIITA, the master regulator of MHC class II expression, which result in its down regulation. There are also high numbers of CD4+ cells, with an expansion of regulatory T cells. Therapies targeting the tumor alone are inadequate to induce a high complete remission rate in patients with relapsed/refractory (R/R) cHL.1
Therefore, Catherine Diefenbach and colleagues investigated a novel approach of combining the use of the checkpoint inhibitors ipilimumab and nivolumab, to potentiate the peritumoral T cells, with the CD30-specific antibody-drug conjugate brentuximab vedotin, to target the Hodgkin Reed-Sternberg cells. Results of the phase I portion of this clinical trial (NCT01896999) were recently published in The Lancet Haematology.1
BV, brentuximab vedotin.
*Patients were excluded due to ineligibility.
Table 1. Baseline patient characteristics1
BV, brentuximab vedotin; ECOG, Eastern Cooperative Oncology Group; N/A, not available |
|||
Characteristic |
Ipilimumab group (n = 21) |
Nivolumab group (n =18) |
Triplet group (n = 22) |
---|---|---|---|
Age, years (range) |
33 (30–40) |
40 (26–51) |
35 (27–40) |
Women/men, % |
48/52 |
50/50 |
50/50 |
Stage, % |
|
|
|
I |
0 |
6 |
9 |
II |
48 |
39 |
55 |
III |
29 |
22 |
14 |
IV |
24 |
33 |
23 |
ECOG performance status, % |
|
|
|
0 |
76 |
56 |
55 |
1–2 |
24 |
44 |
45 |
Number of extra nodal sites, % |
|
|
|
0–1 |
86 |
89 |
91 |
≥ 2 |
14 |
6 |
9 |
Bulky disease (≥ 7cm), % |
0 |
11 |
9 |
No. of previous therapies, % |
|
|
|
1 |
43 |
50 |
36 |
2 |
24 |
17 |
41 |
3 |
10 |
22 |
18 |
≥ 4 |
24 |
11 |
5 |
Previous BV |
14 |
22 |
5 |
Median time since last BV, years (range) |
1.20 (1.14–2.94) |
1.27 (0.85–1.78) |
1.34 (N/A) |
Response to last therapy, % |
|
|
|
Refractory |
48 |
50 |
73 |
≥ 6 months ≤ 1 year |
19 |
22 |
9 |
Response ≥ 1 year |
24 |
28 |
14 |
Unevaluable |
10 |
0 |
5 |
Five DLTs were reported during dose escalation and one DLT was reported during dose expansion.
The MTDs of each therapy in the respective treatment groups are summarized in Table 2. Once the MTDs were established, patients were enrolled in the expansion cohorts with these schedules.
Table 2. Maximum tolerated dose of each therapy1
BV, brentuximab vedotin |
|||
Maximum tolerated dose |
Ipilimumab group |
Nivolumab group |
Triplet group |
---|---|---|---|
BV dose, mg/kg |
1.8 |
1.8 |
1.8 |
Ipilimumab dose, mg/kg |
3.0 |
— |
1.0 |
Nivolumab dose, mg/kg |
— |
3.0 |
3.0 |
Table 3. Grade ≥ 3 toxicities1
WBC, white blood cell |
|||
Grade ≥ 3 toxicity in > 5% of patients |
Ipilimumab group (n = 23) |
Nivolumab group (n =19) |
Triplet group (n = 22) |
---|---|---|---|
Fatigue, % |
0 |
0 |
9 |
Increased lipase, % |
0 |
0 |
9 |
Pneumonitis, % |
0 |
11 |
0 |
Maculopapular rash, % |
22 |
5 |
9 |
Vomiting, % |
4 |
0 |
9 |
Decreased WBC count, % |
0 |
0 |
9 |
Table 4. Response data1
CI, confidence interval; CR, complete response; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. |
|||
Response |
Ipilimumab group |
Nivolumab group (n =18) |
Triplet group (n = 22) |
---|---|---|---|
ORR, % (95% CI) |
76 (53–92) |
89 (65–99) |
82 (60–95) |
CR, % (95% CI) |
57 (34–78) |
61 (36–83) |
73 (50–89) |
1-year PFS, % (95% CI) |
61 (43–86) |
70 (50–96) |
80 (64–100) |
Median PFS, years (95% CI) |
1.2 (0.74–NR) |
NR |
NR |
Median OS |
NR |
NR |
NR |
The combination of brentuximab vedotin with ipilimumab, nivolumab, or both, was safe and well tolerated in adult patients with R/R cHL. However, the incidence of toxicities was higher in the triplet regimen, raising a possible concern for potentially higher immune activation related toxicity. Although the study may have been limited by the heterogeneity of the patient population, such as the number of previous treatments, and a small sample size, each treatment regimen also had a complete remission rate significantly higher than expected for the individual monotherapies. The nivolumab and triplet group had a higher response rate and better PFS than the ipilimumab regimen. Therefore, going forward, the phase II portion of the study will evaluate the tolerability and activity of nivolumab and brentuximab vedotin, and the triplet therapy.
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