Relationship Between Best Tumor Shrinkage and Progression-Free Survival and Overall Survival in Patients With Progressive Midgut Neuroendocrine Tumors Treated With [177Lu]Lu-DOTA-TATE: Ad Hoc Analysis of the Phase III NETTER-1 Trial

Abstract

Background: In many solid tumors, early tumor shrinkage predicts the durability of treatment response. It is unclear whether this is the case for neuroendocrine tumors treated with peptide receptor radionuclide therapy (PRRT).

Methods: Data from the phase III NETTER-1 study of [¹⁷⁷Lu]Lu-DOTA-TATE (¹⁷⁷Lu-DOTATATE) for the treatment of advanced, well-differentiated, midgut NETs were used to investigate whether objective tumor shrinkage (local review) with ¹⁷⁷Lu-DOTATATE is associated with progression-free survival (PFS) and overall survival (OS) duration.

Results: Overall, 117 patients were treated with ¹⁷⁷Lu-DOTATATE (four cycles of 7.4 GBq every 8 weeks). In a landmark analysis, best tumor shrinkage from baseline until data cut-off (prior to first progression) was not associated with PFS (n = 102; hazard ratio: 1.002 [95% confidence interval (CI): 0.99-1.02]; nominal p = 0.7808). In further ad hoc analyses, patients on the ¹⁷⁷Lu-DOTATATE arm were dichotomized into ≥ 30% tumor shrinkage from baseline (18/117 [15.4%]) and < 30% shrinkage (99/117 [84.6%]). Median (95% CI) PFS was 17.6 (16.5-30.3) months in the ≥ 30% shrinkage group and 25.0 (19.4-31.0) months in the < 30% group. OS was not significantly different for the two tumor shrinkage groups (not estimable [31.0 months-not estimable] and 44.3 [34.9-53.8] months, respectively).

Conclusions: These results suggest the benefit of PRRT and the potential PFS and OS benefit of ¹⁷⁷Lu-DOTATATE should not be based on tumor shrinkage (objective response versus stable disease) and that lack of tumor shrinkage should not impact application of the approved four cycles of ¹⁷⁷Lu-DOTATATE.

Keywords: [177Lu]Lu‐DOTA‐TATE; neuroendocrine tumor; overall survival; progression‐free survival; tumor shrinkage.

FIGURE 1

Waterfall plot of best tumor shrinkage (local review) from baseline for (A) ¹⁷⁷Lu‐DOTATATE group (n = 102) and (B) control group (n = 86) (full analysis set). Seven patients in the control group had at least a 30% tumor reduction, but only four of these were considered a partial response due to censoring, progression of non‐target lesions, and progression at a later time point.

FIGURE 2

Forest plot showing the impact of a one‐unit increase in best tumor shrinkage on the hazard rate for PFS by time point (full analysis set). Best tumor shrinkage was calculated based on the best percentage change from baseline in the sum of target lesion diameters (based on local scan assessment) until each of the time points and on or before first progression. PFS was determined from the relevant time point to first disease progression or death from any cause. An HR < 1.0 suggests a one‐unit increase in best tumor shrinkage may be associated with a decreased hazard rate for PFS (i.e., prolonged PFS), while an HR > 1.0 suggests a one‐unit increase in best tumor shrinkage may be associated with an increased hazard rate for PFS (i.e., reduced PFS). Control: High‐dose octreotide LAR 60 mg every 4 weeks. CI, confidence interval; HR, hazard ratio; LAR, long‐acting repeatable; PFS, progression‐free survival.

FIGURE 3

Kaplan–Meier of PFS by tumor shrinkage (local review) up to study cut‐off for ¹⁷⁷Lu‐DOTATATE group (n = 117) (full analysis set). CI, confidence interval; PFS, progression‐free survival.

FIGURE 4

Kaplan–Meier of OS by tumor shrinkage (local review) up to study cut‐off for ¹⁷⁷Lu‐DOTATATE group (n = 117) (full analysis set). CI, confidence interval; NE, not estimable; OS, overall survival.