Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Selection Criteria
2.3. Study Objectives
2.4. Data Extraction
2.5. Assessment of Study Quality
2.6. Outcome Measures and Statistical Analysis
3. Results
3.1. Search Strategy Results
3.2. Study Characteristics of Clinical Trials
3.3. Study Characteristics of Retrospective Studies
3.4. Nature of trAEs Reported in Retrospective Studies
3.5. Overall Incidence of trAEs
3.6. Incidence of Organ-Specific trAEs
3.7. Incidence of trAE Leading to Death and Drug Discontinuation
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Clinical Trial | Author | Phase | Key Eligibility Criteria | Treatment Arms | Primary Objective | Treatment Line | Median Age (Range), Years) | Sample Size (Female%) | Grade 3/4 trAE | Discontinuation Due to Adverse Events | ORR | PFS (Months) | DOR (Months) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
TATTON/NCT02143466 | Oxnard et al. | Ib | Advanced EGFR-mutant NSCLC and disease progression to a prior TKI | Arm 1: osimertinib 80 mg daily + durvalumab 3 mg/kg every 2 weeks (n = 10) Arm 2: osimertinib 80 mg daily + durvalumab 10 mg/kg every 2 weeks (dose escalation) | Safety, tolerability | ≥s | Arm 1: 67 (46–78) Arm 2: 58 (44–73) | Arm 1: 10 (70%) Arm 2: 13 (54%) | Arm 1: 60%, Arm 2: 38.5% | Arm 1: 30% a, 40% b Arm 2: 23.1% a, 38.5% b | Arm 1: 40%, Arm 2: 39% | NA | NA |
CheckMate012/NCT01454102 | Gettinger et al. | I | EGFR-mutant chemotherapy-naïve, EGFR-TKI naïve or TKI treated stage IIIB/IV NSCLC | Nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/d | Safety, tolerability | ≥s | 63 (41–80) | 21 (62%) | 24% | 10% | 15% | 48 | 5.1 c, 5.7 d |
CAURAL/NCT02454933 | Yang et al. | III | EGFR T790M-positive, TKI-treated NSCLC | Arm 1: Osimertinib (80 mg once daily) Arm 2: osimertinib (80 mg once daily) + durvalumab (10 mg/kg IV every 2 weeks) | Safety, tolerability | ≥s | Arm 1: 65 (41–80) Arm2: 56 (41–78) | Arm 1: 17 (76%) Arm 2: 12 (50%) | 34% | 17% | 80% a, 64% e | NA | NA |
Author | Year | Title | Study Design | Inclusion Criteria | EGFR Mutant (%) | Treatment Line | Treatment Arms | Time between ICI and TKI (Days) | Median Age (Range), Years | Sample Size (Female %) | Adverse Event Reported |
---|---|---|---|---|---|---|---|---|---|---|---|
Ito et al. | 2022 | Treatment with immune checkpoint inhibitors after EGFR-TKIs in EGFR-mutated lung cancer | Multiple institutions (Iwate Medical University Hospital, Iwate Prefectural Central Hospital, and Miyagi Cancer Center) retrospective study | EGFR mutant NSCLC previously treated with TKI | Ex19del/ L858R (25%) T790M (8%) | ≥s | G/E/Af/O followed by N/P/At | 139 (1–707) | 67 (38–80) | 25 (40%) | ILD |
Schoenfeld et al. | 2019 | Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib | Single institution (Memorial Sloan Kettering Cancer Center) retrospective study | EGFR mutant NSCLC treated with PD-(L)1 blockers and EGFR-TKI irrespective of drug sequence | NA | s | Arm 1: N/P/At/D followed by O Arm 2: sequential osimertinib followed by N/P/At/D | Arm 1: 61 (12–1446) Arm 2: 5 (1–256) | Arm 1: 61 (30–79) Arm 2: 56 (36–85) | Arm 1: 41 (66%)Arm 2: 29 (83% | Severe immune related adverse events (4 G3 pneumonitis, 1 G3 colitis, 1 G4 hepatitis) |
Uchida et al. | 2019 | Different incidence of interstitial lung disease according to different kinds of EGFR-tyrosine kinase inhibitors administered immediately before and/or after anti-PD-1 antibodies in lung cancer | Single institution (Saitama medical university international medical center) retrospective study | Advanced EGFR mutant patients who receive TKI immediately before and/or after N or P | Ex19del/ L858R (100%) | ≥s | O or Af before or after N or P | NA | 69 (44–80) | 26 (62%) | ILD |
Oshima et al. | 2018 | EGFR–TKI-associated interstitial pneumonitis in nivolumab-treated patients with non–small cell lung cancer | Database study of US FDA Adverse Event Reporting System | EGFR mutant NSCLC | NA | NA | N/P/At in combination with Af/E/G/O | NA | Without N and TKI: 63 (NA) Without N, with TKI: 69 (NA). With N, without TKI: 66 (NA) With N and TKI: 64 (NA) | 20516 | ILD |
Kotake et al. | 2017 | High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy | Single institution (Shizuoka Cancer center) retrospective study | Advanced EGFR mutant NSCLC and disease progression on or after EGFR TKI | T790M (100%) | ≥s | N followed by O | In patients with ILD: 14 (7–28) In patients without ILD: 49 (28–119) | Median age NA In patients with ILD: 4 < 70 In patients without ILD: 10 < 70, 5 > 70 | 19 | ILD |
trAEs | Combination of TKI and ICI | TKI Monotherapy | Odds Ratio (Combined vs. Monotherapy) | p |
---|---|---|---|---|
Overall | ||||
Any grade | 100.0 (96.3, 100.0) a,b | 87.7 (68.1, 99.0) b,c | 1.27 (0.75, 1.66) | 0.077 |
Grade ≥ 3 | 30.0 (12.0, 51.6) b,c | 13.8 (0.1, 40.4) b,c | 1.23 (0.85, 1.76) | 0.271 |
Skin | ||||
Any grade | 61.1 (47.3, 74.1) a | 42.6 (25.5, 61.2) c | 1.19 (0.95, 1.49) | 0.012 |
Grade ≥ 3 | 1.7 (0.0, 8.5) a | 0.2 (0.0, 0.9) a | 1.13 (0.96, 1.29) | 0.082 |
Gastrointestinal | ||||
Any grade | 44.0 (21.2, 68.1) c | 40.3 (22.5, 59.5) c | 1.04 (0.77, 1.40) | 0.790 |
Grade ≥ 3 | 3.6 (0.0, 11.6) a | 1.0 (0.2, 2.1) a | 1.13 (0.99, 1.02) | 0.076 |
Interstitial lung disease (ILD) | ||||
Any grade | 16.3 (6.7, 28.6) a | 2.8 (1.5, 4.3) a | 1.28 (1.11, 1.48) | 0.001 |
Grade ≥ 3 | 4.4 (0.8, 9.8) a | 0.5 (0.0, 1.5) a | 1.16 (1.05, 1.28) | 0.003 |
Sensitivity analysis (on studies of sample size >40) | ||||
Any grade | 30.5 (23.1, 38.3) a | 3.4 (2.0, 5.0) a | 1.48 (1.34, 1.62) | < 0.001 |
Grade ≥ 3 | 9.6 (2.7, 23.1) a | 1.0 (0.3, 2.1) a | 1.24 (1.06, 1.45) | 0.007 |
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Chan, D.W.-K.; Choi, H.C.-W.; Lee, V.H.-F. Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cancers 2022, 14, 2157. https://doi.org/10.3390/cancers14092157
Chan DW-K, Choi HC-W, Lee VH-F. Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cancers. 2022; 14(9):2157. https://doi.org/10.3390/cancers14092157
Chicago/Turabian StyleChan, Daisy Wai-Ka, Horace Cheuk-Wai Choi, and Victor Ho-Fun Lee. 2022. "Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis" Cancers 14, no. 9: 2157. https://doi.org/10.3390/cancers14092157