1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
2Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
3Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
4Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Korea
5Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
6Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
7NKMAX Co., Ltd., Seongnam, Korea
8Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Copyright © 2022 by the Korean Cancer Association
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ethical Statement
This prospective clinical trial was approved by the institutional review board (IRB, 2018-1479) of Asan Medical Center (Seoul, South Korea) and registered at the Clinical Research Information Service (CRIS, KCT0003463). Informed consent was obtained from all participants prior to enrollment. The trial was designed and conducted in accordance with the Helsinki Declaration and the Ethical Guidelines for Clinical Studies.
Author Contributions
Conceived and designed the analysis: Kim EJ, Rho JK, Choi CM.
Collected the data: Kim EJ, Cho YH, Kim DH, Ko DH, Do EJ, Kim SY, Kim YM, Jung JS, Kang Y, Ji W, Lee JC, Rho JK, Choi CM.
Contributed data or analysis tools: Kim EJ, Cho YH, Kim YM, Jung JS, Kang Y, Rho JK, Choi CM.
Performed the analysis: Kim EJ, Cho YH, Kim DH, Ko DH, Do EJ, Kim SY, Ji W, Choi MG, Lee JC, Rho JK, Choi CM.
Wrote the paper: Kim EJ, Cho YH, Kim YM, Choi MG, Rho JK, Choi CM.
Provide NK cells: Kim YM, Jung JS, Kang Y.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Pembrolizumab monotherapy (n=6) | SNK combination (n=12a)) | p-valueb) | Cohort 1 SNK01 2×109 (n=6) | Cohort 2 SNK01 4×109 (n=6) | |
---|---|---|---|---|---|
ORR | 0/6 (0) | 5/12 (41.7) | 0.11 | 2/6 (33.3) | 3/6 (50.0) |
DCR | 1/6 (16.7) | 8/12 (66.7) | 0.13 | 4/6 (66.7) | 4/6 (66.7) |
PR | 0/6 | 5/12 | 2/6 | 3/6 | |
SD | 1/6 | 3/12 | 2/6 | 1/6 | |
PD | 5/6 | 4/12 | 2/6 | 2/6 | |
Median PFS (95% CI, mo) | 1.6 (0.6–4.7) | 6.2 (1.4) | 0.001 | 4.8 | 9.4 |
1-Year survival rate (%) | 50.0 | 66.7 | 0.39 | 50.0 | 83.3 |
Values are presented as number (%) unless otherwise indicated. CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
a) The efficacy outcomes were not evaluated in 2 patients who were scheduled to receive natural killer (NK) combination but received pembrolizumab monotherapy due to adverse event,
b) p-value for pembrolizumab monotherapy-administered patients vs. NK combination patients.
Baseline clinical characteristics of study patients (n=20)
Characteristic | Pembrolizumab monotherapy (n=6) | SNK combination (n=14) | p-value |
---|---|---|---|
Age (yr) | |||
Median (range) | 56.5 (49–70) | 62 (49–73) | |
≥ 65 | 1 (16.7) | 6 (42.9) | 0.35 |
Sex | |||
Male | 2 (33.3) | 11 (78.6) | 0.12 |
Female | 4 (66.7) | 3 (21.4) | |
Smoking status | |||
Current smoker | 0 | 0 | 0.12 |
Ex-smoker | 4 (66.7) | 11 (78.6) | |
Never smoker | 2 (33.3) | 3 (21.4) | |
ECOG performance status | |||
0 | 0 | 0( | |
1 | 6 (100) | 14 (100) | |
Histology | |||
Adenocarcinoma | 6 (100) | 13 (92.9) | 0.99 |
Squamous cell carcinoma | 0 | 0( | |
Pleomorphic carcinoma | 0 | 1 (7.1) | |
PD-L1 22c3 TPS | |||
Median (range, %) | 1 (1–15) | 25 (1–100) | |
≥ 50% | 0 | 6 (42.9) | 0.12 |
EGFR status | |||
Wild type | 1 (16.7) | 11 (78.6) | 0.02 |
Mutant | 5 (83.3) | 3 (21.4) | |
ALK translocation | |||
No | 6 (100) | 14 (100) | |
Yes | 0 | 0( | |
Previous lines of chemotherapy | |||
1 | 0 | 10 (71.4) | 0.01 |
2 | 2 (33.3) | 2 (14.3) | |
≥ | 3 | 4 (66.7) | 2 (14.3) |
NK cell activity (pg/mL) | |||
Median (range) | 972.4 (102.8–1,639.0) | 1570.5 (145.0–3,563.2) |
Values are presented as number (%) unless otherwise indicated. ALK, anaplastic lymphoma kinase; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; NK, natural killer; PD-L1, programmed death-ligand 1; TPS, tumor proportion score.
AEs reported in study patients (n=20)
Type of adverse event | Pembrolizumab monotherapy (n=8) | SNK combination (n=12) | ||
---|---|---|---|---|
|
| |||
Any grade | Grade 3–5 | Any grade | Grade 3–5 | |
All AEs | 8 (100) | 2 (25.0) | 12 (100) | 1 (8.3) |
| ||||
Treatment-related AEs | ||||
Pembrolizumab-related AEs | 6 (75.0) | 1 (12.5) | 11 (91.7) | 0 |
| ||||
SNK01-related AEs | 0 | 0 | 0 | 0 |
| ||||
Common AEs occurring in ≥ 2 patients | ||||
| ||||
Anorexia | 3 (37.5) | 0 | 4 (33.3) | 0 |
| ||||
Myalgia | 2 (25.0) | 1 (12.5) | 1 (8.3) | 0 |
| ||||
Arthralgia | 1 (12.5) | 1 (12.5) | 2 (16.7) | 0 |
| ||||
Pneumonia | 0 | 0 | 3 (25.0) | 0 |
| ||||
Back pain | 1 (12.5) | 0 | 2 (16.7) | 0 |
| ||||
Hyperkalemia | 0 | 0 | 3 (25.0) | 0 |
| ||||
Fatigue | 2 (25.0) | 0 | 0 | 0 |
| ||||
Insomnia | 0 | 0 | 2 (16.7) | 0 |
| ||||
Urticaria | 0 | 0 | 2 (16.7) | 0 |
| ||||
Headache | 0 | 0 | 2 (16.7) | 0 |
| ||||
Immune-related AEs | 0 | 0 | 5 (41.7) | 0 |
| ||||
Hyperthyroidism | 0 | 0 | 3 (25.0) | 0 |
| ||||
Hypothyroidism | 0 | 0 | 3 (25.0) | 0 |
| ||||
Pneumonitis | 0 | 0 | 1 (8.3) | 0 |
Values are presented as number (%). AE, adverse event.
Comparison of efficacy outcomes between two treatment groups (n=18)
Pembrolizumab monotherapy (n=6) | SNK combination (n=12 |
p-value |
Cohort 1 SNK01 2×109 (n=6) | Cohort 2 SNK01 4×109 (n=6) | |
---|---|---|---|---|---|
ORR | 0/6 (0) | 5/12 (41.7) | 0.11 | 2/6 (33.3) | 3/6 (50.0) |
DCR | 1/6 (16.7) | 8/12 (66.7) | 0.13 | 4/6 (66.7) | 4/6 (66.7) |
PR | 0/6 | 5/12 | 2/6 | 3/6 | |
SD | 1/6 | 3/12 | 2/6 | 1/6 | |
PD | 5/6 | 4/12 | 2/6 | 2/6 | |
Median PFS (95% CI, mo) | 1.6 (0.6–4.7) | 6.2 (1.4) | 0.001 | 4.8 | 9.4 |
1-Year survival rate (%) | 50.0 | 66.7 | 0.39 | 50.0 | 83.3 |
Values are presented as number (%) unless otherwise indicated. CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
a)The efficacy outcomes were not evaluated in 2 patients who were scheduled to receive natural killer (NK) combination but received pembrolizumab monotherapy due to adverse event,
b)p-value for pembrolizumab monotherapy-administered patients vs. NK combination patients.
Values are presented as number (%) unless otherwise indicated. ALK, anaplastic lymphoma kinase; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; NK, natural killer; PD-L1, programmed death-ligand 1; TPS, tumor proportion score.
Values are presented as number (%). AE, adverse event.
Values are presented as number (%) unless otherwise indicated. CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. The efficacy outcomes were not evaluated in 2 patients who were scheduled to receive natural killer (NK) combination but received pembrolizumab monotherapy due to adverse event, p-value for pembrolizumab monotherapy-administered patients vs. NK combination patients.