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Dose escalation and expansion (phase Ia/Ib) study of GLS-010, a recombinant fully human antiprogrammed death-1 monoclonal antibody for advanced solid tumors or lymphoma
1 These authors contributed equally to the study and publication.
Dan Liu
Footnotes
1 These authors contributed equally to the study and publication.
Affiliations
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology/Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The Department of Lymphoma, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
Thoracic Medicine Department I, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China
Department of Interventional Radiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China
Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China
Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, China
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology/Early Drug Development Center, Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, China
The PK, PD, and immunogenicity characteristics of GLS-010 were described.
•
DLT and MTD of GLS-010 were not found. The RP2D was 240 mg Q2w.
•
Anemia, leukopenia, and elevated alanine aminotransaminase/aspartate aminotransferase/bilirubin were commonly reported TEAEs.
•
GLS-010 showed considerable efficacy (ORR 23.6%), especially in Hodgkin lymphoma.
Abstract
Background
GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity.
Aim
This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors.
Methods
In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively.
Results
Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response.
Conclusion
GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.
Blocking PD-1 axis is a promising strategy to increase tumor-specific T-cell activation and antitumor activity in melanoma, lung cancer, lymphoma, hepatocellular carcinoma, urothelial cancer, gastric cancer, squamous cell carcinoma of head and neck, and esophageal squamous cell carcinoma [
KEYNOTE-045: randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer[J].
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial[J].
Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study[J].
]. As a novel and effective cancer immune-therapy, the efficacy of PD-1 blockade was also explored in other types of cancer lacking of effective therapy, such as neuroendocrine tumors and cholangiocarcinoma, to improve patients’ clinical outcomes [
GLS-010 is a novel engineered fully human immunoglobin G4 (IgG4) monoclonal antibody, with decreased likelihood of antidrug antibodies (ADAs) and allergic reactions. It could specifically bind to PD-1 and block the PD-1/PD-L1/2 pathway that is involved in tumor tolerance and reactivate the antitumor activity of T cells. The preclinical study in cynomolgus monkeys and mice showed that the drug activity, pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles are comparable with those of nivolumab and pembrolizumab, two existing PD-1 IgG4 monoclonal antibodies that showed promising antitumor activity [
]. Nevertheless, clinical trials in humans are needed to explore its value as cancer immunotherapy.
This phase Ia/Ib study (NCT 03713905) was to evaluate the safety, pharmacology, and efficacy of GLS-010 in patients with advanced solid tumors and lymphoma.
2. Methods
2.1 Study design and treatment
The design of this multiple-center, registered phase Ia/Ib study (NCT03713905) is detailed in Fig. 1. Phase Ia part was a dose-defining phase that followed a “3 + 3” design. Five dose levels (1 mg/kg, 4 mg/kg, 10 mg/kg, 240 mg Q2W, and 240 mg Q3W) were assessed for dose-limiting toxicity (DLT). A DLT was defined as an adverse event (AE) occurring in the first 28 days that met the predefined criteria. If a maximum tolerated dose (MTD) could not be established after evaluation of all dose levels, the dose for expansion would be determined based on safety and PK profile. Phase Ib part was a dose expansion phase to confirm the recommended phase II dose (RP2D) and explored efficacy in 9 specific tumors. All patients received GLS-010 injection via a 90-minute infusion, if tolerated, and the infusion was shortened to 45 minutes for all subsequent administrations. The patients could receive GLS-010 until confirmed disease progression, completion of 2-year treatment, death, intolerability, loss to follow-up, or withdrawal of informed consent.
Fig. 1Study design. ESCC, esophageal squamous cell cancer; HL, Hodgkin lymphoma; NPC, nasopharyngeal carcinoma; q2W, once every 2 weeks; q3W, once every 3 weeks.
In phase Ia, 3–6 patients were planned to be enrolled for dose escalation. Approximately 270 patients were enrolled for dose expansion in 9 specific cohorts in phase Ib.
2.2 Patients
Patients (aged 18–75 years) with refractory pathologically confirmed advanced solid tumors or lymphoma with measurable disease (as defined by RESCIST V.1.1 or Lugano 2014), an Eastern Cooperative Oncology Group score ≤1, adequate organ functions, and life expectancy ≥3 months were eligible for enrollment. All patients were advised to provide tissue samples before treatment. Patients were excluded if they had meningeal or symptomatic central nervous system metastases; a history of, or active, autoimmune disease requiring systemic corticosteroids (≥10 mg/d prednisone) or immunosuppressants within 2 weeks before or during the study; prior vaccine therapy or PD-1/PD-L1/CTLA4 antibody; allergy to study drug; a prior malignancy within 5 years expect for cured locally cancers, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix; a history of hepatitis B (HBV-DNA > 103 copies/ml), hepatitis C, syphilis, or HIV infection; uncontrolled cardiac disease and infection; a history of alcohol, drug, or substance abuse within 1 year; or prior organ transplantation.
2.3 End points
The primary endpoints were to assess DLT (phase Ia) of GLS-010, as well as efficacy (phase Ib). Secondary endpoints included determining the RP2D and MTD, evaluating the PK and PD profile, assessing the host immunogenicity, and exploring biomarkers (PD-L1 expression or tumor mutation burden [TMB] level) of efficacy.
2.4 Safety assessment
Safety assessment was across the entire study. All AEs were recorded and categorized according to severity (NCI-CTCAE V.4.03) and relationship with GLS-010. DLT criteria included any grade ≥4 nonhematological toxicity, grade 3 nonlaboratory anomaly duration >3 days with supportive care, or grade 3 laboratory anomaly with hospitalization, medical interventions, or duration >1 week. Hematological toxicities meeting DLT criteria included grade 3–4 (G3-4) febrile neutropenia, G4 thrombocytopenia, G4 anemia, or G4 neutropenia lasting >7 days.
2.5 Pharmacokinetics and pharmacodynamics assessments
The PK parameters were estimated using noncompartmental analysis (Phoenix WinNonlin 7.0; Certara, Princeton, NJ). The PK parameters of multiple doses were adopted through concentration for drug accumulation analysis. The serum concentration of GLS-010 was determined by a validated electrochemical luminescence assay. The quantitative range of the assay was 7.813–800 ng/ml. Blood samples were collected as described in Appendix P1.
As an indication of target engagement, receptor occupancy assessment was also profiled from the selected patients. The occupancy rate of the CD3+, CD4+, and CD8+ receptors in peripheral blood was determined by validated flow cytometry. Blood samples were collected as follows: cycle 1, predose (within 1 h before administration) and postdose (5 min, 24, 336 h [only in Q2w cohort] after the end of infusion) on day 1, 2, and 15; and cycle 2 to 5, within 1 h before administration. In subsequent cycles, within 1 h before administration for every 2 cycles.
2.6 Immunogenicity
A validated bridging-electrochemical luminescence immunoassay based on the Meso Scale Discovery platform was used to detect serum ADA. Blood samples were collected as follows: cycle 1 and 2, within 1 h before administration on day 1 and 15 (only in Q2W cohort); cycle 3 to 5, within 1 h before administration on day 1. Thereafter, within 1 h before administration on day 1 for every 2 cycles.
2.7 Antitumor efficacy assessment
Imaging assessments were performed at screening and every 8 (Q2W) or 9 (Q3W) weeks for the first 12 months and every 12 weeks thereafter. The response was evaluated by RECIST 1.1/irRECIST 1.1 for solid tumors and Lugano 2014 for lymphoma.
2.8 Biomarker analysis
PD-L1 expression and TMB were examined in patients with solid tumors. PD-L1 expression was examined by immunohistochemistry with PD-L1 (SP263) Assay (Ventana Medical Systems, Tucson, AZ). PD-L1 status was recorded by tumor proportion score. Definition of PD-L1 positively was different from tumor types based on previously reported cutoffs. The cutoff value was 25% in lung cancer and nasopharyngeal cancer, while 1% in other solid tumors [
Development of a programmed cell death ligand-1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma[J].
Re: safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer[J].
Safety and efficacy of durvalumab and tremelimumab alone or in combination in patients with advanced gastric and gastroesophageal junction adenocarcinoma[J].
Clin Canc Res: an official journal of the American Association for Cancer Research.2020; 26: 846
TMB was determined by somatic mutations per mega-base (Mb). Tissue TMB (t-TMB) was examined by whole-exome sequencing with tumor samples and matched peripheral blood samples. Blood TMB (b-TMB) was analyzed by 620 gene panel of Glorious Med (The details are shown in Appendix P2). The positive cutoff value was 4.3 mutations/Mb for t-TMB, and 34.8 mutations/Mb for b-TMB.
2.9 Statistical analysis
Statistical analysis was performed by SAS Enterprise Guide 7.1 (SAS Institute, Cary, NY). The safety was assessed in the safety analysis set (SS; patients who received ≥1 dose of GLS-010). Patients' characters and efficacy were assessed in the full analysis set (FAS; patients who met all included criteria and received ≥1 dose of GLS-010). The Clopper-Pearson method was used to calculate the 95% confidence interval (CI) of objective response rate (ORR) and disease control rate (DCR). The Kaplan-Meier method was used to estimate duration of response (DOR), overall survival (OS), progress free survival (PFS), and time-to-progression, and the 95% CI of median time was calculated using the Brookmeyer and Crowley method.
3. Results
3.1 Patient characteristics
From July 2017 to April 2020, all sites totally enrolled 291 patients (phase Ia, n = 26; phase Ib, n = 265). In phase Ia part, 24 patients received one of five doses of GLS-010 (1 mg/kg Q2W [n = 3], 4 mg/kg Q2W [n = 3], 10 mg/kg Q2W [n = 4], 240 mg Q2W [n = 8], 240 mg Q3W [n = 6]) and included in FAS, as well as SS. Another 2 patients failed to receive study drug for AE or other reasons. In phase Ib part, out of 380 screening patients, 265 patients enrolled and received GLS-010. All enrolled patients were included in SS, while 260 patients were included in FAS, with 5 patients excluded for violation of inclusion criteria.
The patients’ characteristics are shown in Table 1. The median age was 56.0 years, with 72.2% being male. Most patients (91.2%) received at least 1 prior anticancer therapy.
Table 1Patient demographics and baseline characteristics (FAS).
The safety data are shown in Table 2. No DLT was observed. MTD could not be found in the dose escalation cohorts. Of the 289 patients in SS (phase Ia, n = 24; phase Ib, n = 265), 275 patients (95.2%) suffered ≥1 treatment-emergent AE (TEAE). A total of 89 patients suffered immune-related AE (irAE). About 6% of patients dropped out (n = 18) and died (n = 19) because of TEAEs. Commonly reported AEs were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. Hypothyroidism was the most common irAE, with an incidence of 16.3%.
Table 2Treatment-emergent adverse events (SS).
Phase Ia (n = 24)
Phase Ib (n = 265)
Overall (n = 289)
Any treatment-emergent adverse event (TEAE)
23 (96%)
252 (95.1%)
275 (95.2%)
≥G3 TEAE
12 (50%)
103 (38.5%)
115 (39.8%)
TESAE
8 (33%)
73 (27.5%)
81 (28.0%)
Immune-related adverse event (irAE)
0
89 (33.6%)
89 (30.8%)
≥G3 irAE
0
13 (4.9%)
13 (4.5%)
Drug-related TEAE
21 (88%)
210 (79.2%)
231 (79.9%)
Drug-related TESAE
0
55 (20.8%)
55 (19.0%)
TEAE leading to drop out
1 (4%)
17 (6.4%)
18 (6.2%)
TEAE leading to death
2 (8%)
17 (6.4%)
19 (6.6%)
Dose-limiting toxicity
0
0
0
TEAE occurring in ≥10% patients
Anemia
16 (63%)
72 (27.2%)
88(30.4%)
Leukopenia
7 (29%)
48 (18.1.%)
55 (19.0%)
Elevated bilirubin
10 (41.7%)
43 (16.2%)
53 (18.3%)
Proteinuria
6 (25%)
28 (10.6%)
34 (11.8%)
Weight loss
6 (25%)
28 (10.6%)
34 (11.8%)
Elevated alanine aminotransaminase
4 (16.7%)
44 (16.6%)
48 (16.6%)
Elevated aspartate aminotransferase
4 (16.7%)
51 (19.2%)
55 (19.0%)
Vomiting
4 (16.7%)
18 (6.8%)
22 (7.6%)
Fever
4 (16.7%)
42 (15.8%)
46 (15.9%)
Hypothyroidism
4 (16.7%)
43 (16.2%)
47 (16.3%)
Upper respiratory tract infection
4 (16.7%)
30 (11.3%)
34 (11.8%)
Elevated CK
3 (12.5%)
4 (1.5%)
7 (2.4%)
Neutropenia
3 (12.5%)
27 (10.2%)
30 (10.4%)
Diarrhea
3 (12.5%)
18 (6.8%)
21 (7.3%)
Abdominal pain
3 (12.5%)
17 (6.4%)
20 (6.9%)
Fatigue
3 (12.5%)
17 (6.4%)
20 (6.9%)
Hypoproteinemia
3(12.5%)
33 (12.5%)
36 (12.5%)
Decreased platelet
0
28 (10.6%）
28 (9.7%)
Grade≥3 TEAE
Anemia
5 (20.7%)
14 (5.3%)
19 (6.6%)
Hyponatremia
3 (12.4%)
11 (4.2%)
14 (4.8%)
Pneumonia
1 (4.2%)
10 (3.8%)
11 (3.8%)
Liver injury
0
7 (2.7%)
7 (2.4%)
Decreased platelet
0
6 (2.2%)
6 (2.0%)
Elevated bilirubin
0
5 (1.9%)
5 (1.7%)
Neutropenia
0
4 (1.5%)
4 (1.4%)
Leukopenia
0
3 (1.1%)
3 (1.0%)
Rash
0
3 (1.1%)
3 (1.0%)
Cerebral injury
0
3 (1.1%)
3 (1.0%)
Hyperglycemia
0
3 (1.1%)
3 (1.0%)
Hypermagnesemia
0
3 (1.1%)
3 (1.0%)
This table shows AEs of all grades occurring in ≥10% of patients and grade 3–5 AEs occurring in ≥3 patients.
TEAEs of ≥grade 3 severity, regardless of attribution, were reported in 115 patients. These AEs were reported across the study. TEAEs of ≥grade 3 occurring in ≥2% of patients included anemia (n = 19, 6.6%), hyponatremia (n = 14, 4.8%), pneumonia (n = 11, 3.8%), liver injury (n = 7, 2.4%), and decreased platelet (n = 6, 2.0%). Thirteen patients (n = 4.5%) suffered ≥G3 irAE. Pneumonitis was the most commonly reported ≥G3 irAE.
3.3 Pharmacokinetics and pharmacodynamics characteristics
Fifty-six patients (phase Ia: n = 24, phase Ib: n = 32) received PK and PD evaluation. The serum concentrations and PK data are shown in Fig. 2 and Table 3a, Table 3ba,b , respectively. After single and multiple doses of GLS-010, the highest AUCs and Cmax were achieved in 10 mg/kg Q2W cohort. The T1/2, clearance (CL), clearance at steady state (CLss), volume of distribution (Vd), and volume of distribution at steady state (Vss) were similar among all dose groups and tumor types. Based on the safety, PK, and PD data, the dose of 240 mg Q2w was chosen for expansion in phase Ib.
Fig. 2Serum concentration. (A) Serum concentration-time curve of a single dose in the different dose groups in cycle 1. (B) Serum concentration-time curve of a single dose in the different tumor types in cycle 1. ESCC, esophageal squamous cell cancer; HL, Hodgkin lymphoma; UC, urothelial cancer; GC, gastric cancer.
Table 3bPharmacokinetics parameters in different tumor types of phase Ib (240 mg Q2W).
Parameter
Gastric cancer (N = 8)
ESCC (N = 8)
Hodgkin lymphoma (N = 8)
Urothelial cancer (N = 8)
n
Mean ± SD (CV%)/median (range)
n
Mean ± SD (CV%)/median (range)
n
Mean ± SD (CV%)/median (range)
n
Mean ± SD (CV%)/median (range)
Single dose
AUC0-∞ (μg/mL × h)
8
24,688 ± 14,288(58)
8
18,556 ± 4962 (27)
8
24,696 ± 4255 (17)
8
23,774 ± 6712 (28)
AUC0-t (μg/mL × h)
8
13,848 ± 4840 (35)
8
13,340 ± 2789 (21)
8
15,476 ± 2903 (19)
8
14,223 ± 2444 (17)
AUC0–336h (μg/mL × h)
8
13,984 ± 4299 (31)
8
13,018 ± 3691 (28)
8
14,796 ± 2398 (16)
8
14,216 ± 2441 (17)
AUC0–504h (μg/mL × h)
8
–
8
–
8
–
8
–
Cmax (μg/mL)
8
142.1 ± 137.0 (96)
8
82.1 ± 24.5 (30)
8
92.0 ± 24.7 (27)
8
100.7 ± 19.9 (20)
T1/2 (h)
8
253.0 ± 123.3 (49)
8
196.1 ± 46.6 (24)
8
246.6 ± 37.3 (15)
8
231.7 ± 83.6 (36)
Tmax (h)
8
1.9 (0.9, 2.9)
8
2.8 (1.0, 6.8)
8
1.1 (0.8, 3.1)
8
1.2 (0.9, 49.2)
CL (L/h)
8
0.012 ± 0.006 (48)
8
0.014 ± 0.004 (28)
8
0.010 ± 0.002 (16)
8
0.011 ± 0.005 (42)
Vd (L)
8
3.8 ± 0.7 (20)
8
4.0 ± 1.9 (49)
8
3.5 ± 0.6 (17)
8
3.3 ± 0.8 (23)
Vss (L)
8
3.8 ± 0.8 (21)
8
4.0 ± 1.9 (47)
8
3.6 ± 0.6 (15)
8
3.3 ± 0.7 (20)
Multiple dose
AUC0-∞ (μg/mL × h)
1
131,122(−)
3
65,660 ± 24,726(38)
8
75,111 ± 24,568(33)
4
62,655 ± 27,281 (44)
AUC0-t (μg/mL × h)
2
16,917 ± 178,486 (103)
4
15,994 ± 8099(51)
8
18984.3 ± 3413 (18)
4
18,082 ± 2789 (15)
Cmax (μg/mL)
2
163.4 ± 62.5 (38)
4
149.7 ± 331.1(22)
8
158.0 ± 36.9 (23)
4
153.0 ± 25.6 (17)
T1/2 (h)
1
468.9(−)
3
326.6 ± 103.0(32)
8
397.9 ± 118.6(30)
4
334.1 ± 139.5 (42)
Tmax (h)
2
6.9 (6.8, 6.9)
4
5.0 (1.0–48.4)
8
2.8(0.9, 6.7)
4
2.9 (0.9, 6.9)
CLss (L/h)
1
0.005 (−)
3
0.008 ± 0.002(20)
8
0.008 ± 0.002(20)
4
0.008 ± 0.002 (20)
Vd (L)
1
3.143 (−)
3
3.5 ± 1.0 (30)
8
4.2 ± 1.2(27)
4
3.7 ± 0.1 (30)
Vss (L)
1
3.113 (−)
3
3.5 ± 1.1 (32)
8
4.3 ± 1.2(27)
4
3.7 ± 0.1 (30)
AUC0–336h (μg/mL × h)
1
51657.3(−)
3
32,945 ± 7287(22)
8
32,746 ± 6134(19)
4
30,405 ± 5837(19)
Rac (Cmax)
2
1.0 ± 1.1 (108)
4
1.9 ± 0.5(27)
8
1.8 ± 0.4 (24)
4
1.8 ± 0.3 (16)
Rac (AUC0–336h)
1
2.7(−)
3
2.1 ± 0.2 (9)
8
2.2 ± 0.2 (8)
4
2.4 ± 0.2 (9)
DF (%)
1
71.2 (−)
3
93.6 ± 2.4(3)
8
93.7 ± 9.8 (10)
4
102.8 ± 0.2 (9)
Cmin (μg/mL)
2
66.1 ± 45.4 (69)
4
62.2 ± 15.1 (24)
8
67.1 ± 20.1 (30)
4
61.3 ± 14.9 (24)
Cavg (μg/mL)
1
153.7 (−)
3
98.1 ± 21.7 (22)
8
97.5 ± 18.3 (19)
4
90.5 ± 17.4 (19)
AUC, area under the curve; Cmax, maximal concentration; T1/2, half-life; Tmax, time to reach the maximal concentration; CL, clearance; Vd, apparent volume of distribution; Vss, volume of distribution at steady state; CLss, clearance at steady state; Rac, accumulation ratio; DF, coefficient of fluctuation; Cmin, minimal concentration; Cavg, average concentration.
Eighty-six patients (phase Ia: n = 24, phase Ib: n = 62) achieved evaluation of receptor occupancy rate on CD3+, CD4+, and CD8+ T cells. The data are shown in Table 4. The receptor occupancy rate could achieve saturation state (≥80%) in all dose groups at 5 min after GLS-010 infusion and maintained at all time points during the study period. It indicated that GLS-010 could continuously and effectively block the PD-1/PD-L1 axis to show antitumor activity.
One hundred and seven patients finished immunogenicity evaluation. Only 1 patient had positive serum ADA on the baseline. But after GLS-010 infusion, the serum ADA was negative. The serum ADA of the rest 106 patients was all negative.
3.5 Antitumor activity
There were 284 patients in FAS who achieved efficacy evaluation (Table 5). Overall, the ORR was 23.6%, including 10 patients who achieved complete response (nasopharyngeal cancer, n = 2; Hodgkin lymphoma, n = 7; peripheral/NK-T cell lymphoma, n = 1) and 57 patients who achieved partial response. The DCR was 45.4%. GLS-010 showed extremely high antitumor activity in Hodgkin lymphoma (ORR, 87.5%). In phase Ia, median TTF and PFS was 6.6 (95% CI: 1.6-NE) months and 1.9 (95% CI: 1.4–3.2) months, respectively. In phase Ib, median TTF and PFS was 3.68 (95% CI: 3.48–5.45) months and 2.86 (95% CI: 1.4–3.2) months, respectively. The median OS was 13.01 (95% CI: 10.38, 15.61) months.
Table 5Confirmed clinical response by phase and tumor types in phase Ia/Ib (FAS).
A total of 193 patients achieved valid PD-L1 expression results. Of all, 40.9% patients (n = 79) were PD-L1 high-expression, especially in nasopharyngeal cancer (71.8%) and esophageal squamous cell cancer (48.3%) cohorts. Patients with PD-L1 high-expression responded significantly better than those with PD-L1 low-expression (31.1% Versus. 13.7%, p = 0.012). PD-L1 high-expression also contributed to longer median PFS (3.68 m Versus. 1.87 m, p = 0.0032) and OS (13.84 m Versus. 8.74 m, p = 0.019) (Fig. 3).
Fig. 3Kaplan-Meier plots of median (A) PFS and (B) OS of PD-L1 high-expression versus PD-L1 low-expression patients.
A total of 97 patients achieved valid t-TMB results, with 48 patients presenting a high t-TMB level. Results showed that a high t-TMB level is associated with better ORR (31.3% Versus. 5.6%, p = 0.009) than a low t-TMB level. The high t-TMB level also had better median PFS (3.71 m Versus. 1.84 m, p < 0.0001) and OS (13.47 m Versus. 8.08 m, p = 0.013) (Fig. 4).
Fig. 4Kaplan-Meier plots of median (A) PFS and (B) OS of high tissue TMB level versus low tissue TMB level patients.
A total of 164 patients achieved valid b-TMB results, with 35 patients presenting a high b-TMB level. More than half of these patients (n = 18) came from the gastric cancer and esophageal cancer cohorts. Results showed that high b-TMB patients have better ORR (40.0% Versus. 16.1%, p = 0.010) than those with a low b-TMB level. The high b-TMB level patients had potentially longer PFS (p = 0.038) but similar OS (13.7 Versus. 10.2 m, p = 0.33) (Fig. 5).
Fig. 5Kaplan-Meier plots of median (A) PFS and (B) OS of high tissue TMB level Versus. low tissue TMB level patients.
This phase Ia/Ib study was conducted to explore the safety, PK/PD profile, and efficacy of GLS-010. DLT and MTD were not reached in all dose cohorts, indicating a relatively low incidence of DLT compared with tislelizumab, a PD-1 blockade with 1 DLT (grade 3 colitis) in 5 mg/kg Q2W [
]. No clear dose-related TEAEs were observed in different dose cohorts. Most drug-related AEs were of grade 1–2. Grade ≥3 irAEs occurred uncommon (<5%), and a minority of patients dropped out or died of treatment. Toxicity profiles were largely similar to those of previously reported studies [
Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD1 antibody in phase Ib/II clinical trial NCT02915432[J].
], indicating GLS-010 having a manageable safety profile. However, GLS-010 presented relative high incidence of anemia compared with other PD-1/PD-L1 blockades [
Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
], which could be explained by more than half of gastrointestinal cancer and lymphoma patients enrolling in this study.
In the PK analysis, after a single dose of GLS-010, the mean Cmax and AUC0–336h were escalated by dose escalation. After multiple doses, the exposure degree of GLS-010 in each dose group was slightly increased. Vd and Vss of the single dose were similar to those of multiple doses in each dose group, indicating that GLS-010 was mainly distributed in the serum. CLss of multiple doses was slightly lower than that of single dose, while T1/2 of multiple doses was slightly higher than that of single dose, indicating that multiple doses had a certain but small influence on the volume of distribution and clearance.
In immunogenicity assessment, only 1 patient had positive ADA on the baseline. While after receiving GLS-010, the ADA was negative, indicating the baseline ADA could be false-positive. The incidence of ADA was 0% after receiving GLS-010. As previous data reported, 0.7–48% patients treated with the previous humanized antibodies such as nivolumab, cemiplimab, ipilimumab, and avelumab, all generated ADA [
]. Our fully engineered human characteristic of GLS-010 reduces the likelihood of ADAs and allergic reactions. It might contribute to the low incidence of Rash related to GLS-010.
The ORR was 23.6% across the study. As a single agent, the antitumor efficacy was relatively comparable with that of other PD-1 blockades among unselective patients [
Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD1 antibody in phase Ib/II clinical trial NCT02915432[J].
Nivolumab in patients with advanced gastric or gastroesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a ran-domized, double blind, placebo-controlled, phase 3 trial.
]. Patients with Hodgkin lymphoma showed wonderful response to GLS-010, which was valuable to explore further studies. As previously reported, high PD-L1 expression and TMB-H were promising biomarkers to predict favorable efficacy to PD-1 blockades [
]. Our results also showed this potential, especially in cancers of digestive system including gastric cancer, esophageal squamous cancer, and cholangiocarcinoma. Among patients with digestive systems cancers, none of them with a low TMB level responded to GLS-010. While 5 patients with low PD-L1 expression showed response, suggesting PD-L1 expression might not be sufficient to identify patients likely to benefit from PD-1 blockade. In practice, tumor tissues were always hard to be obtained. As in this study, less than 40% patients achieved the tissue TMB examination; therefore, liquid biopsy may be an optional method to resolve this problem. Our results also showed that patients with a high b-TMB level showed higher ORR and potentially longer PFS than those with a low b-TMB level. It seemed that a high b-TMB level has the potential for identifying patients responding to GLS-010 when sufficient tumor tissues are infeasible.
In conclusion, GLS-010 demonstrated favorable safety and clinical response in refractory population of lymphoma and solid tumors.
Funding
This work was supported by the National Key Research and Development Program of China (no. 2017YFC1308900). This clinical trial (NCT03713905) was sponsored by Guangzhou Gloria Biosciences Co., Ltd.
Author contributions
Dan Liu: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Chunguang Ma: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Ping Lu: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Dingwei Ye: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Siyang Wang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Peijian Peng: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Yuxian Bai: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Yuqin Song: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Jianhua Chen: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Ou Jiang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Guojun Zhang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Yi Ba: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Li Chen: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Jianji Pan: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Qi Li: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Liling Zhang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Shanzhi Gu: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Xianli Yin: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Bangwei Cao: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Weiqing Han: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Haiying Dong: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Jianming Guo: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Huilai Zhang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Hang Su: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Yongsheng Jiang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Weiwei Ouyang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Lulin Ma: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Yan Sun: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Feng Zhang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Jun Lv: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Yabing Guo: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Chongyuan Xu: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Junyuan Qi: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Li Wang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Xiang Wang: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Zhen Liu: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Supervision, Project administration, Jifang Gong: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration, Lin Shen: Conceptualization, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – review & editing, Visualization, Supervision, Project administration, Funding acquisition.
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Zhen Liu declared employment by Guangzhou Gloria Biosciences Co., Ltd. All the other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial.
Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD1 antibody in phase Ib/II clinical trial NCT02915432[J].
Nivolumab in patients with advanced gastric or gastroesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a ran-domized, double blind, placebo-controlled, phase 3 trial.
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