Multivariate Analysis Provides Additional Insight on Efficacy of 177Lu-Dotatate in GEP-NETs

Marianne E. Pavel, MD

Efficacy benefits provided by lutetium Lu 177 dotatate (177Lu-Dotatate; Lutathera) over high-dose octreotide as first-line treatment in patients with advanced, well-differentiated, grade 2 or 3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) proved to be consistent after adjustment for baseline covariates, according to data from a post-hoc, multivariate analysis of the phase 3 NETTER-2 trial (NCT03972488) presented during the 2024 ESMO Congress.¹

The key objectives of the analysis were to examine the effect of the therapy when adjusted for baseline covariates, including disease spread, and to determine potential prognostic factors, Marianne E. Pavel, MD, of the Department of Medicine 1, Uniklinikum Erlangen, Friedrich-Alexander University Erlangen-Nümberg, in Erlangen, Germany, said in an oral presentation of the data.

Pavel and colleagues applied a multivariate Cox regression model for progression-free survival (PFS) and a logistic regression model for overall response rate (ORR) to select baseline covariates of age (<65 vs ≥65 years), sex (male vs female), primary disease site (pancreas vs small intestine vs other), NET grade (G2 vs G3 low [Ki67 ≤30%] vs G3 high [Ki67 >30%]), Ki67 as a continuous variable, metastatic spread (liver metastases only with or without lymph nodes vs other metastases), chromogranin A (CgA; ≤2 x upper limit of normal [ULN] vs >2 x ULN), somatostatin receptor (SSTR) uptake score (3 [>liver, <spleen] vs 4 [>spleen]).

When adjusted for covariates, they found that effects on PFS and ORR were minimally affected. With regard to PFS, the hazard ratio (HR) for PFS in the primary analysis with 177Lu-Dotatate vs high-dose octreotide was 0.276 (95% CI, 0.182-0.418; P < .0001). In the exploratory analysis, the HR was 0.212 (95% CI, 0.134-0.337; P < .0001). With regard to ORR, in the primary analysis, the odds ratio (OR) was 7.81 (95% CI, 3.32-18.40; P < .0001). In the exploratory analysis, the OR was 10.43 (95% CI, 3.98-27.29; P <.0001).

“Treatment benefit of Lu 177 dotatate [in terms of PFS and ORR] was consistent across all prespecified subgroups in the primary PFS analysis,” Pavel said. “Nevertheless, there were potential prognostic factors identified for PFS/response regardless of study treatment in this post-hoc analysis.”

NETTER-2: Delving Into Design and Prior Data

The trial enrolled patients with histologically confirmed, advanced G2 (Ki67 ≥10% and ≤20%) and G3 (Ki67 >20% and ≤55%), SSTR-positive GEP-NETs who received a diagnosis within 6 months of enrollment. They needed to be at least 15 years old and could not have previously received chemotherapy or targeted therapy in over 1 month.

Patients were randomly assigned 2:1 to receive 177Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 cycles plus octreotide at 30 mg long-acting repeatable (LAR) every 8 weeks during treatment with 177Lu-Dotatate and then every 4 weeks or high-dose octreotide at 60 mg LAR every 4 weeks.

Patients who experienced progressive disease were able to enter into an optional treatment extension period where they would be retreated with 177Lu-Dotatate at the same dose with octreotide LAR if decided by the investigator every 8 weeks for 2 to 4 cycles, or crossover treatment with 177Lu-Dotatate at the same dose also every 8 weeks for 4 cycles plus octreotide at 30 mg LAR. They then entered into a follow-up period with visits happening every 6 months for the duration of 3 years.

Stratification factors included NET grade (G2 vs G3) and tumor origin (pancreatic NET vs other).

Prior data related to the primary end point showed that the median PFS in the 177Lu-Dotatate group was 22.8 months vs 8.5 months in the high-dose octreotide group (stratified HR, 0.276; 95% CI, 0.182-0.418; P < .0001). In the subgroup of patients with G2 NETs, the HR for PFS was 0.306 (95% CI, 0.176-0.530); in the subgroup of patients with G3 NETs, the HR was 0.266 (95% CI, 0.145-0.489).

Previous findings regarding the secondary end point of ORR indicated that the 177Lu-Dotatate regimen elicited an ORR of 43.0% vs 9.3% with the control regimen (stratified OR, 7.81; 95% CI, 3.32-18.40; P < .0001). In the subgroups of patients with G2 or G3 NETs, the respective ORs were 5.83 (95% CI, 2.12-16.00) and 11.57 (95% CI, 2.48-53.97), respectively.

Breaking Down the Baseline Characteristics

In the 177Lu-Dotatate arm (n = 151), the median patient age was 61 years (range, 23-88); the median age was 60 years (range, 34-82) in the high-dose octreotide arm. Across the arms, most patients were female (54% vs 53%), had a primary tumor located in the pancreas (54% vs 55%), had G2 NET grade at diagnosis (66% vs 64%), CgA above 2 x ULN (70% vs 65%), and SSTR uptake score of 4 (63% vs 67%). In the 177Lu-Dotatate arm, 56% of patients did not have metastases in the liver only vs 48% of those in the high-dose octreotide arm. The median Ki67 index in the respective arms was 17 (range, 10-50) and 16 (range, 10-50).

Post-Hoc Analysis Reveals Potential Prognostic Factors

Investigators were able to identify possible prognostic factors with regard to PFS or ORR, irrespective of study treatment. They found that having a small intestine NET origin (small intestine vs pancreas: HR, 0.499; 95% CI, 0.275-0.906; P = .0222), lower CgA (>2 x ULN vs ≤2 x ULN: HR, 1.905; 95% CI, 1.127-3.222; P = .0162), lower Ki67 score (continuous variable: HR, 1.064; 95% CI, 1.009-1.123; P = .0228), and higher SSTR uptake score (4 vs 3: HR, 0.560; 95% CI, 0.296-1.058; P = .0739) led to varying improvements in PFS.

Moreover, pancreatic NET origin (small intestine vs pancreas: HR, 0.315; 95% CI, 0.133-0.747; P = .0087) and lower CgA (>2 x ULN vs ≤2 x ULN: HR, 0.427; 95% CI, 0.196-0.926; P = .0312) were linked with varying improvements in objective response. “Disease spread had limited impact on PFS and ORR,” Pavel concluded.

Disclosures: Pavel disclosed receiving consulting fees from Advanced Accelerator Applications (a Novartis company), Novartis, Ipsen, Riemser, and Hutchmed. She also received honoraria from Ipsen, Advanced Accelerator Applications, Novartis, Boehringer, MSD, Lilly, Recordati, Sanofi, and Serb. She also participates on the advisory board for Crinetics, Advanced Accelerator Applications, and Ipsen.

Reference

Pavel M, Ferone D, Halperin D, et al. A multivariate efficacy analysis of [177Lu]Lu-DOTA-TATE in the NETTER 2 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 114MO.