Table. Comparison of Study Characteristics (Enrollment Start 2000-2009 vs 2010-2020).
| Category | Enrollment period, No. (%) | Total (N = 117)a | P valueb | |
|---|---|---|---|---|
| 2000-2009 (n = 54) | 2010-2020 (n = 63) | |||
| Study design | ||||
| Phase | ||||
| II | 45 (83) | 54 (86) | 99 (85) | .72 |
| III | 9 (17) | 9 (14) | 18 (15) | |
| Designc | ||||
| Randomized | 12 (22) | 20 (32) | 32 (27) | .51 |
| Single arm | 34 (63) | 35 (56) | 69 (59) | |
| Parallel cohorts, non-randomized | 8 (15) | 8 (13) | 16 (14) | |
| Primary or coprimary end pointd | ||||
| Progression-free survival | 9 (18) | 22 (35) | 31 (27) | .04 |
| Objective response rate | 27 (53) | 19 (30) | 46 (40) | .01 |
| Overall survival | 1 (2) | 1 (2) | 2 (2) | .88 |
| Biomarker-enriched population | 10 (19) | 10 (16) | 20 (17) | .71 |
| Placebo-controlled | 4 (7) | 8 (13) | 12 (10) | .35 |
| Single agent | 31 (57) | 38 (60) | 69 (59) | .75 |
| Novel agent(s) | 22 (41) | 22 (35) | 44 (38) | .52 |
| Agent(s) licensed by a national regulatory body | 2 (4) | 12 (19) | 14 (12) | .01 |
| Agent classe | ||||
| Anti-VEGF | 15 (28) | 19 (30) | 34 (29) | .78 |
| Radioligand therapy | 9 (17) | 6 (10) | 15 (13) | .25 |
| Immune checkpoint inhibitor | 0 | 5 (8) | 5 (4) | .03 |
| Chemotherapy | 14 (26) | 12 (19) | 26 (22) | .37 |
| Non-VEGF receptor pathway inhibitor | 11 (20) | 22 (35) | 33 (28) | .08 |
| Cell cycle inhibitor | 0 | 1(2) | 1(1) | .35 |
| Somatostatin analog | 15 (28) | 16 (25) | 31 (26) | .77 |
| Other agents | 9 (16.6) | 6 (9.5) | 15 (12.8) | .25 |
| Defined primary end point | 51 (94) | 63 (100) | 114 (97) | .06 |
| Prespecified sample size | 40 (74) | 46 (74) | 86 (74) | .99 |
| Eligibility | ||||
| NEN types specified in inclusion criteria | ||||
| All NENsf | 34 (63) | 13 (21) | 47 (40) | <.001 |
| Gastrointestinal NETsg | 11 (20) | 25 (40) | 36 (31) | .02 |
| Limited to gastrointestinal NETs | 2 (4) | 2 (3) | 4 (3) | .88 |
| Pancreatic NETsg | 16 (30) | 32 (51) | 48 (41) | .02 |
| Limited to pancreatic NETs | 7 (13) | 16 (25) | 23 (20) | .09 |
| Lung NETsg | 4 (7) | 11 (17) | 15 (13) | .11 |
| Limited to lung NETs | 1 (2) | 1 (2) | 2 (2) | .91 |
| NECsg | 1 (2) | 11 (17) | 12 (10) | .006 |
| Limited to NECs | 0 | 7 (11) | 7 (6) | .01 |
| Treatment line | ||||
| First | 10 (19) | 8 (13) | 18 (16) | .32 |
| Later | 27 (50) | 39 (64) | 66 (57) | |
| Any | 17 (31) | 14 (23) | 31 (27) | |
| Disease progression required at baseline (among later line studies) | 18 (42) | 35 (67) | 53 (56) | .01 |
| Tumor differentiation reported in inclusion criteriah | 34 (63) | 59 (98) | 93 (82) | <.001 |
| Ki-67 Index reported in inclusion criteriai | 5 (9) | 23 (38) | 28 (25) | <.001 |
| Reported inclusion criteria | 53 (98) | 60 (98) | 113 (98) | .93 |
| Accrual and sponsorship | ||||
| Sponsorshipc | ||||
| Industry only | 24 (47) | 26 (43) | 50 (45) | .93 |
| National Cancer Institute only | 10 (20) | 13 (22) | 23 (21) | |
| Other only | 9 (18) | 13 (22) | 22 (20) | |
| Multiple | 8 (16) | 8 (13) | 16 (14) | |
| Any industry funding | 30 (59) | 32 (53) | 62 (56) | .56 |
| Study location | ||||
| United States only | 24 (44) | 17 (27) | 41 (35) | .26 |
| North America | 1 (2) | 3 (5) | 4 (3) | |
| Outside United States only | 20 (37) | 29 (47) | 49 (42) | |
| Global | 9 (17) | 13 (21) | 22 (20) | |
| Multicenter | 29 (60) | 41 (72) | 70 (67) | .21 |
| Slow accrual | 0 | 3 (5) | 3 (3) | .11 |
| Premature termination | 9 (17) | 14 (23) | 23 (20) | .40 |
| Reason for termination | ||||
| Poor accrualj | 1 (11) | 2 (14) | 3 (13) | .83 |
| Otherk | 8 (89) | 12 (86) | 20 (87) | |
| Sample size discrepancyl | 10 (24) | 16 (35) | 26 (30) | .29 |
| Outcomes | ||||
| Regulatory licensing for an agent | 3 (6) | 5 (8) | 8 (7) | .61 |
| Positive primary end point | 33 (65) | 37 (66) | 70 (65) | .88 |
| Objective response rate ≥10% | 25 (50) | 26 (57) | 51 (53) | .52 |
| Results reported as a published manuscript | 50 (93) | 42 (67) | 92 (79) | <.001 |
Abbreviations: NEC, neuroendocrine carcinoma; NEN, neuroendocrine neoplasm; NET, neuroendocrine tumor; VEGF, vascular endothelial growth factor.
Only 117 studies were included because 2 studies did not specify year of enrollment start.
Calculated using Pearson χ2 test.
Owing to rounding, the categories may add up to more than 100%.
Not mutually exclusive: if a study included coprimary end points, each primary end point was counted.
Not mutually exclusive: if a study included agents of different classes, each agent class was counted.
Studies that enrolled all NENs did not specify primary tumor site or tumor differentiation in inclusion criteria.
Not mutually exclusive: if a study specified the inclusion of several tumor types, each tumor type was counted.
Tumor differentiation was documented as being defined in study eligibility criteria if well-differentiated or poorly differentiated histological findings were explicitly stated. Low-, intermediate-, or high-grade was also accepted as a surrogate for this measure.
Ki-67 index was documented as being defined in study eligibility criteria if Ki-67 percentages were explicitly listed. Grade listings (grade 1, 2, or 3) were also accepted as a surrogate for this measure.
Poor accrual differs from slow accrual. A slow accruing study was defined as one that enrolled fewer than 2 patients per year. Poor accrual was used as a justification for terminating a study without a formal definition.
Of these studies, 15 were closed owing to lack of efficacy in an interim analysis while 5 were closed owing to meeting the efficacy threshold in an interim analysis.
Sample size discrepancy was denoted if the actual study sample size was at least 10 patients fewer than the predefined study sample size.