Despite the variability in definitions of DLL3 positivity and the tumor heterogeneity among the 30 identified studies, most patients with SCLC were found to be DLL3-positive. |
This SLR demonstrates that DLL3 is expressed in most patients with SCLC and presents a potentially impactful therapeutic target. |
Future investigations should explore the impact of DLL3 expression using large populations with validated tests for DLL3 expression to better understand the dynamics of DLL3 as a therapeutic target for SCLC. |
1 Introduction
2 Methods
2.1 Study Eligibility
2.2 Study Identification and Screening
2.3 Data Abstraction
2.4 Risk of Bias Evaluation
3 Results
3.1 Study Identification
3.2 Study Characteristics
3.3 Risk of Bias
3.4 Patient and Treatment Characteristics
3.5 Prevalence of DLL3 Expression in SCLC
3.5.1 Positive Versus Negative DLL3 Expression
Author, year | study design (cohort name or NCT number, if applicable); population inclusion details | Geographic location (year) | N patients | DLL3 positivity threshold (proportion of positive cells), N (%) | DLL3 expression (definition), N (%) | H-score threshold, N (%) | ||
---|---|---|---|---|---|---|---|---|
Positive | Negative | High | Low | |||||
Ali [15], 2021 | Retrospective cohort; chemo- and radiation-naïve surgical specimens | Italy (2007–2019) | 32 | NR | NR | ≥ 50%: 24 (75) | < 50%: 8 (25) | High (≥ 150): 15 (53.1) Low (< 150): 17 (46.9) |
Brcic [16], 2019 | Cross-sectional; chemo-naïve surgical specimens | Germany (1996–2012) | 24 | ≥ 25%: 14 (58.3) | < 25%: 10 (41.7) | ≥ 75%: 5 (20.8) ≥ 50%: 11 (45.8) | < 50%: 13 (54.2) | NR |
Furuta [17], 2019 | Retrospective cohort; surgical resections of primary tumors | Japan (2003–2013) | 93a | ≥ 1%: 77 (82.8) | 0%: 16 (17.2) | ≥ 75%: 44 (47.3) | < 75%: 49 (52.7) | NR |
Huang [24], 2019b | Cross-sectional; primary and metastatic SCLC samples | USA (NR) | 1362 | Reactivity (> 0%): 1040 (76.4) | Non-reactive (0%): 322 (23.6) | NR | NR | NR |
Johnson [18], 2021 | Randomized controlled trial (MERU; NCT03033511); patients with ES–SCLC that did not progress after 1L platinum-based chemotherapy | Multicountry (2017–2019) | Intervention: 365b | NR | NR | ≥ 75%: 217 (59.5) | < 75%: 148 (40.5) | NR |
Placebo: 360b | NR | NR | ≥ 75%: 240 (66.7) | < 75%: 120 (33.3) | NR | |||
Kuempers [10], 2021 | Retrospective cohort; paired chemo-naïve and recurrent SCLC post-chemotherapy | Germany (NR) | Chemo-naïve: 30c | ≥ 1%: 26 (86.7) | 0%: 4 (13.3) | ≥ 50%: 16 (53.3) | 1–49%: 10 (33.3) | High (≥ 150): 10 (33.3%) Low (< 150): 16 (53.3%) Negative (0): 4 (13.3%) |
Chemo-relapsed: 30c | ≥ 1%: 24 (80.0) | 0%: 6 (20.0) | ≥ 50%: 19 (63.3) | 1–49%: 5 (16.7) | High (≥ 150): 16 (53.3) Low (< 150): 8 (26.7) Negative (0): 6 (20.0) | |||
Messaritakis, 2019[19] | Prospective cohort; SCLC samples from pre-chemotherapy, after a single cycle, or at progression | Greece (NR) | 20d | NR | NR | ≥ 50%: 14 (70.0) | < 50%: 6 (30.0) | NR |
Morgensztern [20], 2019 | Single-arm clinical trial (TRINITY; NCT02674568); relapsed/ refractory SCLC | Multicountry (2016–2017) | 315e | ≥ 25%: 287 (91.1) | < 25%: 28 (8.9) | ≥ 75%: 238 (75.6) | < 75%: 77 (24.4) | NR |
Odashiro [21], 2020 | Cross-sectional; SCLC samples | Canada (NR) | 39 | ≥ 1%: 36 (92.3) | < 1%: 3 (7.7) | > 75%: 25 (64.1) 50–74%: 2 (5.1) | 1–49%: 9 (23.1) | NR |
Rojo [6], 2020 | Retrospective cohort; SCLC samples | Multi-country (2008–2017) | 1050f | ≥ 25%: 895 (85.2) | 0–24%: 155 (14.8) | High positive (≥ 75%): 719 (68.5) | Non-high positive (25–74%): 176 (16.8) | NR |
Tendler [25], 2020 | Cross-sectional; patients with SCLC completing ≥ 1 cycle of platinum-doublet chemotherapy | Sweden (2008–2015) | 46 | ≥ 1%: 43 (93.5) | 0%: 3 (6.5) | Undefined: 38 (82.6) > 75%: 19 (41.3) 51–75%: 9 (19.6) 26-50%: 9 (19.6) | Undefined: 8 (17.4) 1–25%: 6 (13.0) | NR |
Udagawa [22], 2019 | Single-arm clinical trial (NCT03086239); advanced recurrent SCLC that progressed after ≥ 2 chemotherapy regimens | Japan (2017–2018) | 28g | ≥ 25%: 24 (82.3) | < 25%: 4 (13.8) | ≥ 75%: 18 (64.3) | < 75%: 10 (35.7) | NR |
Xie [23], 2019 | Retrospective cohort; SCLC resection samples | USA (1995–2017) | 44 | NR | NR | ≥ 50%: 35 (79.5) | < 50%: 9 (20.5) | NR |
3.5.2 High Versus Low DLL3 Expression
3.5.3 H-Score Categorization of DLL3 Expression
3.6 Factors Significantly Associated with DLL3 Expression
Author, year | DLL3 expression (definition) | N patients | Age | Sex | Smoking status | Stage |
---|---|---|---|---|---|---|
Furuta [17], 2019 | High (≥ 75%) | 44 | < 65: 38.6% ≥ 65: 61.4% | Male: 79.5% Female: 20.5% | Pack-years ≥ 20: 84.1% < 20: 9.1% Unknown: 6.8% | TNM stage I–II: 79.5% III–IV: 20.5% |
Low (< 75%) | 49 | < 65: 26.5% ≥ 65:73.5% | Male: 75.5% Female: 24.5% | Pack-years ≥ 20: 77.6% < 20: 14.3% Unknown: 8.2% | TNM stage I–II: 95.9% III–IV: 4.1% | |
p value (univariate; high versus low) | 0.268 | 0.805 | 0.526 | 0.022 | ||
Kuempers [10], 2021 | High (≥ 50%) | 16 chemo-naïve | Median (IQR): 57.0 (65.0, 88.0) | Male: 78.6% Female: 21.4% | NR | TNM stage < IV: 14.3% IV: 28.6% Missing: 57.1% |
Low (< 50%) | 14 chemo-naïve | Median (IQR): 67.0 (61.0, 75.0) | Male: 56.2% Female: 43.8% | NR | TNM stage < IV: 12.5% IV: 37.5% Missing: 50.0% | |
p value (univariate; high versus low in chemo-naïve) | 0.024 | 0.26 | NR | 1.0 | ||
High (≥ 50%) | 19 chemo-relapsed | NR | NR | NR | NR | |
Low (< 50%) | 11 chemo-relapsed | NR | NR | NR | NR | |
p value (univariate; high versus low in chemo-relapsed) | > 0.05 | > 0.05 | NR | > 0.05 | ||
Rojo [6], 2020 | Positive (≥ 25%) | 895 | < 65: 44.5% ≥ 65: 55.2% Missing: 0.3% | Male: 65.1% Female: 34.9% | NR | Limited: 31.1% Extensive: 64.2% Missing: 4.7% |
Negative (< 24%) | 155 | < 65: 40.0% ≥ 65: 60.0% Missing: 0% | Male: 60.6% Female: 39.4% | NR | Limited: 36.8% Extensive: 59.4% Missing: 3.9% | |
p value (multivariate, positive versusnegative) | NR (p > 0.05 on univariate analyses) | NR (p > 0.05 on univariate analyses) | NR | 0.1995; OR 0.767 (95% CI 0.511, 1.151) | ||
High positive (≥ 75%) | 719 | NR | NR | NR | NR | |
p value (multivariate, high positive versus negative + non-high positive) | NR (p > 0.05 on univariate analyses) | NR (p > 0.05 on univariate analyses) | NR | 0.0835; OR 0.752 (95% CI 0.545, 1.039) | ||
Non-high positive (25–74%) | 176 | NR | NR | NR | NR | |
p value (multivariate, high positive versus non-high positive) | NR (p > 0.05 on univariate analyses) | 0.0580; OR 1.450 (95% CI: 0.987, 2.129) | NR | 0.1061; OR 1.357 (95% CI: 0.937, 1.965) | ||
Tendler [25], 2020 | High (undefined) | 38 | < 70: 34.2% ≥ 70: 65.6% | Male: 47.4% Female: 52.6% | NR | Limited disease: 44.7% Extensive disease: 55.3% |
Low (undefined) | 8 | < 70: 50.0% ≥ 70: 50.0% | Male: 25.0% Female: 75.0% | NR | Limited disease: 25.0% Extensive disease: 75.0% | |
p value (univariate; high versus low) | < 0.05 | > 0.05 | NR | > 0.05 | ||
Xie [23], 2019 | High (≥ 50%) | 35 | Median (range): 69.5 (53.2–81.8) | Male: 34.3% Female: 65.7% | NR | TNM stage I: 46.4% II: 10.7% III/IV: 42.9% |
Low (< 50%) | 9 | Median (range): 71.7 (41.9–88.1) | Male: 77.8% Female: 22.2% | NR | TNM stage I: 28.6% II: 14.3% III/IV: 57.1% | |
p value (univariate; high versus low) | 0.49 | 0.03 | NR | 0.73 |
3.7 Overall Survival
Author, year | Geographic location (dates) | DLL3 expression (definition) | N patients | Response | Overall survival | Progression-free survival or disease-free survival |
---|---|---|---|---|---|---|
Median or % (95% CI) | Median (95% CI) or % by milestone | Median (95% CI) or % by milestone | ||||
Furuta [17], 2019 | Japan (2003–2013) | High (≥ 75%) | 44 | NR | Overall: 24.4 months (16.8–32.7) Stage I/II: 25.8 months (18.1–39.4) Stage III/IV: 10.8 months (1.1–61.1) | NR |
Low (< 75%) | 49 | NR | Overall: 33.3 months (23.5–N/A) Stage I/II: 40.2 months (24.1–N/A) Stage III/IV: 11.2 months (3.1–19.3) | NR | ||
p value (univariate; high versus low) | NR | Overall: p = 0.16 Stage I/II: p = 0.182 Stage III/IV: p = 0.641 | NR | |||
Johnson [18], 2021 | Multicountry (2017–2019) | High (≥ 75%) | Intervention: 217 | ORR: 10.0% (6.2–15.3) CBR: 72.0% (65.5–78.7) CR: 0.0% PR: 10.0% | 8.5 months (7.3–10.2) | PFS: 4.0 months (3.2–4.1) |
Placebo: 240 | ORR: 5.0% (2.6–9.0) CBR: 30.0% (24.3–37.0) CR: 0.0% PR: 5.0% | 9.8 months (8.4–10.9) | PFS: 1.4 months (1.4–1.5) | |||
Low (< 75%) | Intervention: 148 | NR | 9.0 months (8.1–10.1) | PFS: 2.8 months (2.6–4.0) | ||
Placebo: 120 | NR | 11.3 months (8.3–13.0) | PFS: 1.5 months (1.4–1.7) | |||
p value (univariate, low versus high) | NR | Intervention: p > 0.05 Placebo: p > 0.05 | NR | |||
Kuempers [10], 2021 | Germany (NR) | High (≥ 50%) | Chemo-naïve: 14 | NR | NR | NR |
Chemo-relapsed: 19 | NR | NR | NR | |||
Low (< 50% | Chemo-naïve: 16 | NR | NR | NR | ||
Chemo-relapsed: 11 | NR | NR | NR | |||
p value (univariate, high versus low) | NR | Chemo-naïve: p = 0.42 Chemo-relapsed: 0.57 | NR | |||
Morgensztern [20], 2019 | Multicountry (2016–2017) | High (≥ 75%) | 238 | ORR: 14.3% (10.1–19.4) DCR: 73.5% (67.4–79.0) DOR: 3.7 months (2.9–4.2) | 5.7 months (4.9–6.7) | PFS: 3.8 months (3.2–4.1) |
Positive (≥ 25%) | 287 | ORR: 13.2% (9.5, 17.7) DCR: 71.8% (66.2–76.9) DOR: 3.7 months (2.9 4.2) | 5.8 months (5.1–6.7) | PFS: 3.8 months (3.2–4.0) | ||
HR (95% CI), p value | NR | NR | NR | |||
Rojo [6], 2020 | Multicountry (2008–2017) | High positive (≥ 75%) | 719 | NR | 9.5 months | NR |
Non-high positive (25–74%) | 176 | NR | 9.5 months | NR | ||
Positive (≥ 25%) | 895 | NR | 9.5 months | NR | ||
Negative (0–24%): | 155 | NR | 9.5 months | NR | ||
p value (univariate, positive versus negative) | NR | p > 0.05 | NR | |||
Tendler [25], 2020 | Sweden (2008–2015) | High (undefined) | 38 | NR | 11.5 months (9.2–13.7) | PFS: 7.4 months (6.1–8.7) |
Low (undefined) | 8 | NR | 10.6 months (8.9–12.4) | PFS: 5.6 months (2.5–8.7) | ||
p value (univariate, low versus high) | NR | p > 0.05 | p > 0.05 | |||
Udagawa [22], 2019 | Japan (2017–2018) | High (≥ 75%) | 18 | ORR: 16.7% DCR: 55.6% DOR: 3.0 months (2.9-4.1) | 7.4 months (4.1–11.9) | PFS: 2.9 months (1.2–3.6) |
Low (< 75%) | 10 | ORR: 0.0% DCR: 60.0% DOR: NR | 5.1 months (1.8–7.8) | PFS: 2.0 months (0.7–2.7) | ||
p value (univariate, low versus high) | NR | p = 0.346 | PFS: p = 0.082 (investigator); 0.157 (central review) | |||
Xie [23], 2019 | USA (1995–2017) | High (≥ 50%) | 35 | NR | 5-year survival: 33.0% | DFS: NR |
Low (< 50%) | 9 | NR | 5-year survival: 0.0% | DFS: NR | ||
HR (95% CI), p value [low versus high; multivariate (OS) or univariate (DFS)] | NR | 1.0 month (0.985–1.008), p = 0.49 | DFS: p = 0.27 |