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The focus of our educational theme on the Lymphoma Hub this quarter, is chemotherapy-free approaches for the treatment of patients with classical Hodgkin lymphoma (cHL). Historically, patients with relapsed/refractory (R/R) cHL who fail or are ineligible for high-dose chemotherapy and autologous hematopoietic stem cell transplant (HDT/ASCT) have a poor prognosis. A hallmark for cHL, is the copy number alterations of programmed death ligand 1 (PD-L1) on chromosome 9p24.1, resulting in the overexpression of PD-1 ligands on cancer cells. Therefore, the use of immune checkpoint inhibitors targeting PD-1, including nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab have drastically changed the treatment paradigm of adults with R/R cHL.1−3 Treatment with nivolumab and pembrolizumab are actively used in this setting and have demonstrated clinically meaningful activity in patients with cHL who relapse following HDT/ASCT. However, most patients do not achieve complete responses (CRs), and many progress within 18 months. Therefore, newer investigational anti-PD-1 agents, tislelizumab and camrelizumab, are being explored.3
During the 26th Congress of the European Hematology Association (EHA2021), Jianqiu Wu reported the extended follow-up data regarding the durability of response, survival benefit, and long-term safety of camrelizumab in Chinese patients with R/R cHL.1 Yuqin Song also presented at EHA2021, the long-term follow-up data of a phase II tislelizumab trial in Chinese patients with R/R cHL who were not eligible for HDT/ASCT.2 We provide a review of these results below.
Anti-PD-1 agents used as consolidation in R/R cHL have previously been covered by the Lymphoma Hub, and can be found here.
Camrelizumab was approved in China as treatment for patients with R/R cHL based on the primary results of a phase II (NCT03155425) multicohort study. Jianqiu Wu et al. reported the long-term, 36.2-month efficacy and safety of camrelizumab. The primary endpoint was objective response rate per Independent Review Committee (IRC) assessment.
A total of 75 heavily pretreated patients who relapsed after treatment with HDT/ASCT were enrolled in the study, between June 9, 2017 and September 18, 2017. The data cutoff for the primary analysis was September 18, 2018, and the current analysis cutoff was August 31, 2020 and lasted for a median follow-up duration of 36.2 months (range, 7.2−38.1 months).
A total of 47 patients discontinued treatment, 32 developed progressive disease (PD), and six had adverse events (AEs), resulting in only 28 patients continuing treatment. Camrelizumab was administered at a dose of 200 mg every 2 weeks until PD. Patient characteristics are shown in Table 1.
Table 1. Patient characteristics*
Characteristic |
Patients (N = 75) |
---|---|
Median age, years (range) |
34 (20−77) |
Male, % |
58.7 |
Pathological type, % |
|
Nodular sclerosis |
65.3 |
Mixed cellularity |
29.3 |
Lymphocyte-rich |
4 |
Missing |
1.3 |
ECOG performance status, % |
|
0 |
49.3 |
1 |
50.7 |
Median time from diagnosis to enrolment, months (range) |
35.4 (1.1−212.4) |
Previous therapies, % |
|
Brentuximab vedotin |
8 |
ASCT |
12 |
Radiotherapy |
48 |
Lines of therapy, median (range) |
3 (1−10) |
Time from completion of most recent regimen in months, % |
|
<3 |
46.7 |
3−6 |
18.7 |
>6 |
32 |
Missing |
2.7 |
Ann Arbor stage, % |
|
IIA |
8 |
IIB |
5.3 |
IIIA |
12 |
IIIB |
9.3 |
IVA |
30.7 |
IVB |
34.7 |
ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group. |
Table 2. Responses to treatment*
Response rate |
IRC assessment |
---|---|
Best overall response, % |
|
CR |
26.7 |
PR |
49.3 |
SD |
18.7 |
PD |
5.3 |
Overall response rate, % (95% CI) |
76 (65.7−85.1) |
CR, complete response; IRC, Independent Review Committee; PD, progressive disease; PR, partial response; SD, stable disease. |
Table 3. AEs*
Event, % |
All grades |
Grades 3/4 |
---|---|---|
AEs |
100 |
41.3 |
Serious AEs |
16 |
8 |
AEs leading to treatment interruption |
40 |
16 |
AEs leading to treatment discontinuation |
6.7 |
5.3 |
AE, adverse event. |
In a phase II single-arm multicenter study (NCT03209973), Yuqin Song et al.2 evaluated the 3-year efficacy and safety of tislelizumab in Chinese patients with R/R cHL who were not eligible for HDT/ASCT. Tislelizumab is a fully human IgG4 monoclonal antibody with high affinity for PD-1. Tislelizumab decreases Fc-γ binding on macrophages, thereby reducing antibody-dependent phagocytosis, which is thought to be linked with a potential T cell clearance and resistance to anti–PD-1 therapy.
Watch Yuqin Song discuss the early data for tislelizumab in R/R cHL, here.
A total of 70 patients with R/R cHL were enrolled. Patients were eligible if they had no response or progressed following ASCT, or previously received ≥2 lines of chemotherapy and were not eligible for ASCT. Patients received 200 mg of intravenous tislelizumab every 3 weeks until PD or unacceptable toxicity. The median time of follow-up was 33.8 months (range, 3.4−38.6).
Endpoints
Table 4. Patient characteristics*
Characteristic |
Total (N = 70) |
---|---|
Median age, years (range) |
32.5 (18-69) |
Male, % |
57.1 |
ECOG performance status, % |
|
0 |
68.6 |
1 |
31.4 |
Stage IV at study entry, % |
60 |
Bulky disease, % |
11.4 |
Bone marrow involvement, % |
31.4 |
B-symptoms, % |
37.1 |
Median time from initial diagnosis, months |
25.33 |
Prior lines of systemic therapy, median |
3 |
Type of prior therapy, % |
|
Chemotherapy |
100 |
ASCT |
18.6 |
Immunotherapy |
21.4 |
Brentuximab vedotin |
5.7 |
Ineligible for prior ASCT, % |
81.4 |
Prior radiation therapy, % |
30 |
ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group. |
Table 5. Response to treatment*
Response |
Total (N = 70) |
95% CI |
ORR, % |
87.1 |
77−93.9 |
CR, % |
67.1 |
54.9−77.9 |
Median DoR, months |
31.3 |
20.73−not reached |
Median PFS, months |
31.5 |
16.53−not reached |
PFS, % |
||
At 24 months |
55.4 |
42.2−66.8 |
At 36 months |
40.8 |
25.2−55.8 |
Median OS, months |
Not reached |
Not reached |
OS, % |
||
At 24 months |
93.9 |
84.5−97.7 |
At 36 months |
84.8 |
70.5−92.6 |
CR, complete response; DoR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. |
The most frequent TRAEs, occurring in 97.1% of patients, were pyrexia and upper respiratory tract infection. Grade 3 TRAEs were reported in 41.4% of patients, and six out of the 70 patients discontinued due to treatment toxicity. The most common immune-related AEs were hypothyroidism (28.6%), and skin adverse reaction (8.6%).
The results from the extended follow-up study by Jianqiu Wu et al. have demonstrated that camrelizumab monotherapy is of clinical benefit for patients with R/R cHL. With an extended 36.2-month follow-up, responses were durable, PFS and OS rates were favorable, and the safety profile was manageable. Similarly, with a 33.85-month follow-up, Yuqin Song et al. showed that tislelizumab is highly active, with an ORR of 87.1% regardless of patient subgroups. There was also evidence of a continued PFS benefit, and no additional safety concerns. Overall, both of these PD-1 therapies showed clinical benefit with a low safety risk profile and may represent an alternative treatment option for this population.
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