Unprecedented PFS in Midgut NETs Shown With Lu-Dotatate

Results from NETTER-1 trial showed an unprecedented 79% reduction in the risk of progression or death with the radiopharmaceutical Lu-Dotatate (¹⁷⁷Lutetium DOTATATE; Lutathera) compared with high-dose octreotide LAR (60 mg) in patients with progressive, metastatic midgut neuroendocrine tumors (NETs).

“The findings were, in my opinion, extraordinarily impressive, the median progression-free survival improved by nearly 80%, which is fairly unprecedented in oncologic studies,” said presenter and medical oncologist Jonathan Strosberg, MD, Moffitt Cancer Center, at the 2015 NANETS Symposium. “The finding is important because limited therapeutic options exist for such patients, who comprise 20% to 45% of neuroendocrine tumor cases.”

The NETTER-1 trial is the first prospective, randomized, phase III study for patients with midgut NETs, specifically those in the ileum and cecum. Patients in the trial had progressed on prior therapy with octreotide at 30 mg and had inoperable, somatostatin receptor-positive tumors.

Those randomized to the Lu-Dotatate arm received the therapy at 7.4 GBq in 4 doses over 8 weeks in combination with 30 mg of octreotide LAR every 28 days. In the comparator arm, octreotide LAR was administered alone at 60 mg every 4 weeks. Patient in the Lu-Dotatate arm also received renal protection via amino acid solution infusion.

Interim results showed the median PFS had not been reached for Lu-Dotatate compared with 8.4 months for octreotide (HR, 0.21; 95% CI, 0.13-0.34;P<.0001). The objective response rate with Lu-Dotatate was 19% compared with 3%. One patient in the radiopharmaceutical arm achieved a complete response compared with none in the octreotide arm. Disease progression had occurred in 4% of patients in the Lu-Dotatate group and 24% of the octreotide group. Stable disease was almost the same for both groups.

&ldquo;The median time to progression was 8.7 months with high-dose octreotide, which was the control arm, and was not yet reached in the Lutetium arm, with a median follow-up of nearly a year and a half,&rdquo; Strosberg said. "It is looking like the ultimate outcome, median progression-free survival, will probably be around the 40-month range."

For the secondary endpoint of overall survival (OS), 13 patients had died in the Lu-Dotatate arm compared with 22 in the octreotide group. ThePvalue for this trend toward improvement in OS was .018; however, the threshold for statistical significant at the preliminary analysis was less than .001, according to Strosberg.

&ldquo;As far as OS, which was the secondary endpoint, there was a very strong trend toward improvement in OS,&rdquo; he toldTargeted Oncology. &ldquo;The results are extremely encouraging for survival, not quite meeting the exacting threshold for preliminary survival.&rdquo;

Safety data from the NETTER-1 trial confirmed favorable results of the preceding phase I/II studies. Serious adverse events (AEs) related to treatment were 9% for Lu-Dotatate and 1% for octreotide. Withdrawals due to AEs were 5% for Lu-Dotatate and did not occur in patients treated with octreotide, according to Strosberg.

The ongoing study includes an 18-month accrual period (completed) plus a 5-year follow-up starting from the last patient&rsquo;s randomization date, which was in February 2015. Every 12 weeks, evaluators use the RECIST 1.1 criteria to assess tumor response in both arms. Patients remain under treatment until disease progression, unacceptable toxicity or inability/unwillingness to comply with study requirements.

The first patient was enrolled in July 2012. The analysis of primary endpoint started after 74 evaluable and centrally confirmed events. Main secondary endpoints are objective response rate, overall progression, time to progression, safety, tolerability and health-related quality of life, which will continue to be assessed. In a subset of patients, dosimetry, pharmacokinetics, and ECG evaluations are also performed.

The drug&rsquo;s maker, Advanced Accelerator Applications, called Lu-Dotatate the most advanced candidate in development of peptide receptor radionuclide therapy (PRRTs), which target tumors with radiolabeled somatostatin analogue peptides. In April 2015, the FDA granted a fast track designation to Lutathera for the treatment of inoperable progressive midgut NETs. This designation is meant to facilitate the development of novel therapies.

A diagnostic for identifying patients who are likely to respond to Lutathera, SomaKit-TATE, was granted a priority review designation in early September 2015. The kit is designed to facilitate 68Ga-DOTATATE for injection, which can be used to detect somatostatin receptor-positive NETs by PET scan.

References

1. Strosberg J, Wolin E, Chasen B, et al. 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumors: Results of the phase III NETTER-1 trial. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract C39.