Add-on radioligand therapy improves PFS in SSTR+ G2/G3 GEP-NETs

Adding lutetium-177 (¹⁷⁷Lu)–Dotatate radioligand therapy (RLT) to long-acting octreotide as first-line therapy significantly improves progression-free survival (PFS) in patients with newly diagnosed somatostatin receptor-positive (SSTR+), grade 2 and 3 (G2 and G3), well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NETs) compared with high-dose long-acting octreotide alone, according to the NETTER-2 trial presented at ASCO GI 2024.

“¹⁷⁷Lu–Dotatate RLT, sometimes known as peptide receptor radionuclide therapy, is a rapidly emerging, promising way of treating cancer,” said lead author Dr Simron Singh from the University of Toronto in Ontario, Canada.

In the NETTER-1 trial, which was a pivotal trial for RLT, ¹⁷⁷Lu-Dotatate was established as a treatment for progressive SSTR+, G1 and G2 midgut NETs, after progression on somatostatin analogues, he noted.

The phase III, open-label, multicentre trial enrolled 226 patients diagnosed with SSTR+ high G2 or G3 (Ki-67 ≥10 percent to ≤55 percent) advanced GEP-NETs within 6 months prior to randomization. They were randomized in a 2:1 ratio to receive ¹⁷⁷Lu-Dotatate (4 x 7.4 GBq) every 8 weeks in addition to octreotide LAR* 30 mg (n=151) or high-dose octreotide LAR 60 mg alone (n=75) every 4 weeks.

Patients who received the combination of ¹⁷⁷Lu-Dotatate and octreotide had a significantly longer PFS than those who received high-dose octreotide alone (median 22.8 vs 8.5 months; stratified hazard ratio, 0.276; p<0.0001), translating to a 72-percent reduction in the risk of disease progression or death. [ASCO GI 2024, abstract LBA588]

In addition, the PFS benefit observed with ¹⁷⁷Lu-Dotatate + octreotide vs high-dose octreotide alone was consistent across all prespecified subgroups, regardless of age, gender, and race, as well as tumour grade (G2 and G3), tumour origin (pancreas, all nonpancreas, and small intestine), and SSTR uptake per central review (G3 and G4).

The ¹⁷⁷Lu-Dotatate arm also showed a significantly higher objective response rate (complete response and partial response) compared to the high-dose octreotide alone arm (stratified odds ratio, 7.81; p<0.0001). According to Singh, this was one of the highest response rates reported in neuroendocrine malignancies to date.

With regard to global health status, the time to deterioration (TTD) in quality of life (QoL) remained similar between the two treatment arms. “The fact that we did not see any differences in TTD in QoL was considered a positive outcome,” said Singh.

In terms of safety, the most common adverse events of any grade were diarrhoea, abdominal pain, and nausea, which was slightly higher in the ¹⁷⁷Lu-Dotatate arm than in the control arm (27.2 percent vs 17.8 percent). However, Singh emphasized that this was significantly less than that observed in the NETTER-1 trial.

There was one case of haematological malignancy reported in the ¹⁷⁷Lu-Dotatate group, while none occurred in the control group.

The safety findings were consistent with the known safety profile of ¹⁷⁷Lu-Dotatate, noted Singh.

“Overall, the NETTER-2 trial met its primary endpoint,” said Singh. “NETTER-2 is the first randomized trial to evaluate an RLT in the first line for any metastatic solid tumour … These data have clinical practice-changing implications and support the use of first-line ¹⁷⁷Lu-Dotatate in high G2 and G3 GEP-NETs.”

“Further investigations of RLT as a therapeutic option in other settings are warranted,” he added.