Lutathera-Based PRRT Retreatment Shows OS Benefit With Acceptable Safety in NETs

Jonathan Strosberg, MD

Retreatment with Lutathera (lutetium Lu 177 dotatate)–based peptide receptor radionuclide therapy (PRRT) has been shown to have an encouraging survival benefit with an acceptable safety in patients with neuroendocrine tumors, according to results from a real-world retrospective analysis, as well as a systemic literature review and meta-analysis presented during the 2020 NANETs Virtual Symposium.

In a multicenter, real-world experience, results showed that the median progression-free survival (PFS) following retreatment was 16.7 months (95% CI, 14.5-18.6) in a total of 224 evaluable patients across 3 different sites.¹ The median overall survival (OS) from the start of initial PRRT was 83.1 months (95% CI, 68.4-93.9). Moreover, the short-term hematological toxicity profile of Lutathera-based PRRT retreatment was comparable with initial PRRT, and myeloproliferative toxicity remained within the expected range.

Results from the systematic literature review and random-effects meta-analyses which included 7 studies with 414 patients demonstrated an estimated median PFS of 12.52 months (95% CI, 9.82-15.22) with moderate heterogeneity observed across the studies analyzed (I² = 50.5%).² In random-effects meta-analyses of 2 studies with 194 patients, the estimated mean OS was 26.78 months (95% CI, 18.73-34.83) from the start of retreatment, with high heterogeneity (P = 57.2%). Again, retreatment with Lutathera-based PRRT was not found to have a worsened toxicity profile compared with initial PRRT.

In January 2018, Lutathera was approved for the treatment of patients with somatostatin receptor–positive gastroenteropancreatic NETs based on data from the phase 3 NETTER-1 trial, in which it resulted in a 79% reduction in the risk of progression or death versus octreotide.³ Because options remain limited for those who progress on initial PRRT, retreatment with PRRT has become an active area of investigation.

Lutathera-Based PRRT Retreatment in a Multicenter Real-World Analysis

To examine the safety and efficacy of PRRT retreatment with 2 extra cycles of Lutathera for a total of 400 mCI +/- 10%), investigators conducted a retrospective analysis of real-world data from patients who had progressive somatostatin receptor–positive NETs from 3 different study sites in different countries. The study sites included Eramus Medical Center in Rotterdam, Netherlands; Royal Free London NHS Foundation Trust, in London, United Kingdom; and Universitätsklinikum Bonn in Bonn, Germany.

To be eligible for inclusion, patients had to have had at least 18 moths of PFS following initial treatment with PRRT, with 4 intended cycles of Lutathera. Of those who received initial PRRT, a little more than half, or 57% (n = 127) were men. Moreover, 8% (n = 18) had bronchial NETs, 29% (n = 66) had pancreatic NETs, 36% (n = 80) had midgut NETs, and 27% (n = 60) had other. Sixty-four percent of patients had baseline progression.

Additionally, 67% of patients (n = 149) had moderate extent of disease, while 23% (n = 51) had extensive disease, and 11% (n = 24) had limited disease. Thirty-seven percent of patients (n = 82) had bone lesions, while 92% (n = 207) had liver lesions.

The median age of patients who underwent PRRT retreatment was 64 years. Forty-five percent (n = 101) had moderate extent of disease, 44% (n = 98) had extensive disease, and 10% (n = 23) had limited disease. Additionally, 51% (n = 115) had bone lesions and 97% (n = 218) had liver lesions.

A total of 224 patients with NETs who received PRRT retreatment with were included in the efficacy set; 168 patients were from the Rotterdam site, 26 were from London, and 30 were from Bonn. Thirteen additional patients from Rotterdam were included in the safety set. Notably, the proportion of those who had bone lesions at the start of initial PRRT was found to differ across the study sites. The mean cumulative dose of Lutathera was 29.1 GBq and 15.0 GBq for initial PRRT and PRRT retreatment, respectively, across the sites.

The mean follow-up from the start of initial PRRT was 83.4 months. Additional data from the analysis revealed that grade 3 or 4 bone marrow toxicity was reported in 9% of patients (n = 21/237) following PRRT retreatment. Moreover, 1.7% (n = 4/237) of patients experienced acute myeloid leukemia (AML) (n = 2) or myelodysplastic syndrome (n = 2) during follow-up. Grade 3/4 nephrotoxicity effects associated with PRRT had not been reported at the Rotterdam or London sites; results are still pending for Bonn.

“The study has shown that PRRT retreatment, which includes 2 additional cycles of Lutathera, has a similar hematologic safety profile as the initial 4 cycles of Lutathera,” said Shaunak Navalkissoor, MRCP, MSc, consultant in nuclear medicine, at Royal Free London, in a presentation during the meeting. “Myeloproliferative toxicity was within the expected range. PRRT retreatment showed excellent treatment efficacy consistent across the 3 sits, with an appreciable OS benefit.”

Lutathera-Based PRRT Retreatment in Progressive NETs

Investigators conducted a systemic review and meta-analysis to examine the safety and efficacy of Lutathera-based PRRT retreatment in patients with advanced NETs. To identify published evidence pertaining to the clinical safety and efficacy of PRRT retreatment in this patient population, investigators utilized Embase, MEDLINE, MEDLINE In-Process, and Cochrane CENTRAL databases. They included any studies with initial PRRT, as well as those with PRRT retreatment with either Lutathera alone or 90Y-dotatate.

First, investigators evaluated how feasible it would be to combine the studies selected to compute pooled safety and efficacy from time to PRRT retreatment. Then, they pooled the data using medians and variance for time-to-event outcomes, as well as inverse-variance weighted

proportions, for binary outcomes. Using Stata Version 14, investigators conducted their analyses.

A total of 567 citations were screened and investigators identified 27 publications that included a total of 18 studies that examined PRRT retreatment with either Lutathera or ⁹⁰Y-dotatate. Ten studies looked specifically at PRRT retreatment in those with progressive disease following previous treatment with Lutathera (n = 523 patients); they were evaluated for feasibility. Eight studies examined PRRT retreatment following previous treatment with ¹¹¹In-octreotide–based PRRT (n = 2 studies), ⁹⁰Y-dotatate–based PRRT (n = 4 studies), and ⁹⁰Y-dotatate/Lutathera-based PRRT (n = 2); these were also examined for feasibility.

Of the 18 studies selected, 14 were found to examine retreatment efficacy outcomes of interest, such as PFS, OS, and disease control rate (DCR); as such, they were included in the meta-analyses. With regard to patient characteristics, age and sex were found to be similar across the studies included. The median age ranged from 54 years to 63 years, while the mean age ranged from 58 years to 61 years. Over 50% of participants were male in 5 of 6 studies that had those data available.

Retreatment ranged from 1 to 6 doses. In 7 of the 8 studies with Lutathera-based PRRT, the dose was 7.4 GBq for both the initial PRRT and PRRT retreatment. In 1 study, however, the Lutathera dose was 3.7 GBq during retreatment.

Additional results showed that in 5 studies that only had Lutathera-based PRRT as both initial treatment and retreatment, the median PFS was 12.26 months (95% CI, 9.06-15.47) in 272 patients. Moreover, the median PFS was 12.92 months (95% CI, 10.40-15.47) in those who received either Lutathera-based PRRT or ⁹⁰Y-dotatate-based PRRT as either initial treatment or retreatment (n = 8 studies; 815 patients). Notably, the extent of pretreatment and the number of doses administered was not found to impact PFS following PRRT retreatment. The pooled DCR was 60% (95% CI, 45%-74%) across all response criteria from random-effects meta-analyses, and evidence for high heterogeneity (I² = 83.5%).

With regard to safety, grade 3 or 4 toxicities were reported in 5% of patients (95% CI, 2%-8%) who received Lutathera-based PRRT retreatment (n = 5 studies; 271 patients), and few renal toxicities that were grade 3 or 4 in severity were experienced (95% CI, 0%-1%). The incidence of secondary malignancies also proved to be low (95% CI, 0%-1%; n = 4 studies; 262 patients).

“We conclude that retreatment with Lutathera-based PRRT provided an encouraging median PFS in a relatively refractory setting among patients with advanced NETs and it wasn’t really associated with a worsened safety profile compared with initial PRRT,” Jonathan Strosberg, MD, a professor at Moffitt Cancer Center, concluded in another presentation during the meeting.

References:

1. Navalkissoor S, Essler M, Caplin M, et al. Retreatment with ¹⁷⁷Lu-DOTATATE in patients with neuroendocrine tumors: multicenter real-world experience. Presented at: 2020 NANETs Symposium; October 2-3, 2020; Virtual. Poster 119.
2. Strosberg J, Leeuwenkamp O, Siddiqui MK, et al. 177Lu-DOTATATE/DOTATOC re-treatment in patients with progressive neuroendocrine tumors (NETs): a systematic review and meta-analysis. Presented at: 2020 NANETs Symposium; October 2-3, 2020; Virtual. Abstract 43.
3. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. J Clin Oncol. 2016;34:4005. https://bit.ly/33oTTgD.