Educational theme | The long-term efficacy and safety outcomes of anti-PD-1 inhibitors for the treatment of R/R cHL

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.

Camrelizumab¹

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.

Patient characteristics and study design

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*

ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group. *Adapted from Wu et al.1
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

Results

• Among the responders, the median time to response from the IRC assessment was 2 months (range, 1.7–5.7)
• At data cutoff, 50.7% of patients had PD or died
• The median time to CR was 3.8 months (range, 1.8−11.2)
• The median duration of response (DoR) was 31.7 months (95% CI, 16.7−not reached)

• At 24 months, 53.3% of patients (95% CI, 38.1−66.4) were in response
• A total of 54.4% of patients maintained an ongoing response at the data cutoff

• Progression-free survival (PFS) was reached by 49.5% (95% CI, 36.5−61.2) of patients at 24 months
• The median PFS was 22.5 months (95% CI, 14.7−not reached)
• The overall survival (OS) at 24 months was 90.7% (95% CI, 81.4−95.4)

• The OS at 36 months was 82.7% (95% CI, 72−89.5)
• The median OS was not reached

Table 2. Responses to treatment*

CR, complete response; IRC, Independent Review Committee; PD, progressive disease; PR, partial response; SD, stable disease. *Adapted from Wu et al.1
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)

Safety

• No new toxicities or AEs leading to death were reported
• The most common treatment-related adverse events (TRAEs) were reactive capillary endothelial proliferation (RCEP, 97.3%), pyrexia (44.%), upper respiratory tract infection (36%), and hypothyroidism (32%)
• Although the incidence of RCEP was high, the severity was either Grade 1 (80.8%) or 2 (19.2%), and 67.1% of patients were able to achieve a complete resolution in a median of 8.2 months
• Most RCEP cases spontaneously resolved without the need of systemic corticosteroid use

Table 3. AEs*

AE, adverse event. *Adapted from Wu et al.1
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

Tislelizumab²

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.

Patient characteristics and study design

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

• The primary endpoint was overall response rate (ORR) based on a positron emission tomography/computed tomography (PET/CT) scan assessed by an IRC per Lugano criteria
• Secondary endpoints were PFS, DoR, CR rate, time to response, safety, and tolerability

Table 4. Patient characteristics*

ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group. *Adapted from Song et al.2
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

Results

• Partial response (PR) was reached by 20% of patients
• Stable disease (SD) was reached by 5.9% of patients
• A total of 8.6% of patients had PD
• Among the patients who previously received ASCT, 84.6% achieved CR and one reached a PR
• The median time to reach a response was approximately 12 weeks; 17.2% of CR patients achieved a CR within the first time of tumor evaluation
• At the data cutoff, the PFS subgroup analysis showed the following:

• median PFS of patients who had a PR and SD (n = 16) was 13.2 months vs not reached (NR) by patients who had a CR (n = 47)
• median PFS of patients who had no prior ASCT (n = 57) was 27.6 months vs NR by patients who had prior ASCT (n = 13)
• median PFS of patients who had more than three lines of therapy (n = 42) was 34 months vs patients who had <3 prior lines of therapy (n = 28) who had 29.5 months

Table 5. Response to treatment*

Response	Total (N = 70)	95% CI
CR, complete response; DoR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. *Adapted from Song et al.2
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

Safety

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%).

Conclusion

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.