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Dramatic improvement in progression-free survival (PFS) for progressive midgut neuroendocrine tumors (NETs) failed to translate into significantly better overall survival (OS), according to a randomized trial.

Patients treated with the radionuclide agent ¹⁷⁷Lu-dotatate (Lutathera) had a median OS of 48.0 months compared with 36.3 months for patients who received the somatostatin analog octreotide (Sandostatin). Nonetheless, the difference did not achieve statistical significance (P=0.30). As previously reported, the primary analysis of the showed almost a fivefold increase in median PFS, from 8.4 to 40 months.

The relatively small size of the trial (231 patients), historically long survival compared with other tumors, and the 36% rate of crossover from octreotide to ¹⁷⁷Lu-dotatate all could have contributed to the lack of significant difference in OS, reported Jonathan R. Strosberg, MD, of Moffitt Cancer Center in Tampa, Florida, during the virtual .

The OS outcome continues a pattern observed in prior randomized trials in midgut NETs.

"If we look at previous phase III studies in this population, for example the which looked at octreotide versus placebo, we see significant improvement in PFS but absolutely no difference in overall survival," said Strosberg. "Again, that is almost certainly related to crossover. Similarly with we have a very strong trend toward improved PFS with everolimus (Afinitor) [plus octreotide versus octreotide-placebo], actually significantly improved on local investigator review, but when it comes to overall survival, everolimus fell short compared to placebo."

Despite failing to achieve significant improvement in OS, the 12-month difference shown with ¹⁷⁷Lu-dotatate "could be considered clinically meaningful," he added.

Midgut NETs are the most common subtype of advanced well-differentiated gastropancreatic-NETs, most of which express somatostatin receptors. ¹⁷⁷Lu-dotatate of a beta-emitting radionuclide coupled to a high-affinity somatostatin analog.

The phase III randomized NETTER-1 trial compared ¹⁷⁷Lu-dotatate and standard-of-care octreotide in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut NETs. The primary endpoint was PFS, and the results showed that treatment with the radionuclide agent was associated with an 82% reduction in the hazard for progression or death (95% CI 0.11-0.29, P<0.0001).

OS was a key secondary endpoint of the trial, and a prespecified final OS analysis was to occur after a total of 158 deaths or 5 years after the last patient was randomized. Strosberg reported findings after a median follow-up of 76 months, at which time 142 patients had died. The analysis showed that the ¹⁷⁷Lu-dotatate group had a 16% reduction in the survival hazard (95% CI 0.60-1.17).

Landmark survival analyses favored ¹⁷⁷Lu-dotatate from 12 months (91% vs 79.7%) through 60 months (37.1% vs 35.4%).

Strosberg pointed out that 36% of patients in the control arm crossed over to ¹⁷⁷Lu-dotatate, and 26.3% received other systemic therapies. In contrast, 12% of patients in the ¹⁷⁷Lu-dotatate arm received additional treatment with the radionuclide at progression, and 21.4% received other systemic therapy.

Investigators performed a post-hoc survival analysis that accounted for the effect of crossover from octreotide to ¹⁷⁷Lu-dotatate (rank-preserving structural failure time). The results showed an even larger difference in favor of ¹⁷⁷Lu-dotatate (48.0 vs 30.9 months), which nonetheless remained nonsignificant (HR 0.73, 95% CI 0.40-1.34).

The safety analysis showed no new or concerning signals, according to Strosberg. ¹⁷⁷Lu-dotatate is associated with a small risk of myelodysplastic syndrome (MDS)/acute leukemia. The primary report from NETTER investigators showed two cases of MDS in 111 (1.8%) patients treated with ¹⁷⁷Lu-dotatate (lower than historical estimates of about 3%), and no additional cases were reported with longer follow-up.

Nephrotoxicity is another potential risk with the radionuclide therapy. Rates of grade ≥3 nephrotoxicity were low in both groups and similar -- 5.4% with ¹⁷⁷Lu-dotatate and 3.6% with octreotide.

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