Dataset Information

¹⁷⁷Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

ABSTRACT:

Introduction

Neuroendocrine tumors (NETs) are rare malignancies with different prognoses. At least 25% of metastatic patients have functioning neuroendocrine tumors (F-NETs) that secrete bioactive peptides, causing specific debilitating and occasionally life-threatening symptoms such as diarrhea and flushing. Somatostatin analogs (SSAs) are usually effective but beyond them few treatment options are available. We evaluated the clinical efficacy of 177 Lu-DOTATATE in patients with progressive metastatic F-NETs and SSA-refractory syndrome.

Patients and methods

A non-pre-planned joint analysis was conducted in patients enrolled in phase II clinical trials on metastatic NETs. We extrapolated data from F-NET patients with ≥1 refractory sign/symptom to octreotide, and ≥1 measurable lesion. Syndrome response (SR), overall survival (OS), progression-free survival (PFS), tolerance and disease response were analyzed.

Results

Sixty-eight patients were enrolled, the majority (88.1%) with a SR. According to RECIST criteria, 1 (1.5%) patient showed a CR, 21 (32.3%) had a PR and 40 (61.5%) SD. At a median follow-up of 28.9 months (range 2.2-63.2) median PFS was 33.0 months (95%CI: 27.1-48.2). Median OS (mOS) had not been reached at the time of the analysis; the 2-year OS was 87.8% (95%CI: 76.1-94.1). Syndromic responders showed better survival than non-responders, with a 2-year OS of 93.9% (95%CI: 92.2-98.0) vs. 40.0% (95%CI: 6.6-73.4), respectively. A total of 233 adverse events were recorded. Grade 1-2 hematological toxicity was the most frequent.

Conclusion

The 177 Lu-DOTATATE improved symptoms and disease control in patients with F-NETs. Treatment was well tolerated. The syndrome had an impact on both quality of life and OS.

SUBMITTER: Bongiovanni A

PROVIDER: S-EPMC9776442 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

<sup>177</sup>Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

Bongiovanni Alberto A Nicolini Silvia S Ibrahim Toni T Foca Flavia F Sansovini Maddalena M Di Paolo Arianna A Grassi Ilaria I Liverani Chiara C Calabrese Chiara C Ranallo Nicoletta N Matteucci Federica F Paganelli Giovanni G Severi Stefano S

Cancers 20221207 24

<h4>Introduction</h4>Neuroendocrine tumors (NETs) are rare malignancies with different prognoses. At least 25% of metastatic patients have functioning neuroendocrine tumors (F-NETs) that secrete bioactive peptides, causing specific debilitating and occasionally life-threatening symptoms such as diarrhea and flushing. Somatostatin analogs (SSAs) are usually effective but beyond them few treatment options are available. We evaluated the clinical efficacy of 177 Lu-DOTATATE in patients with progres ...[more]

PMID: 36551507

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Project description:BackgroundPatients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.MethodsWe randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.ResultsAt the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.ConclusionsTreatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Project description:Tumor dosimetry was performed for 177Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. Methods: The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18) who had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving a total of 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semiautomatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes in tumor ADs over cycles, absorbed-dose rates and activity concentrations on day 1, effective half-times, and tumor volumes. Tumors smaller than 8 cm3 were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average, the AD decreased over the cycles, with significantly different rates (P < 0.05) of 6% and 14% per cycle for grade 1 and 2 NETs, respectively. The absorbed-dose rates and activity concentrations on day 1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than for grade 1 (P < 0.001). For grade 2 NETs, the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate, and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTATATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.

Project description:BackgroundGastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland.MethodsCost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes.ResultsFor unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus.ConclusionsCost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Dataset Information

¹⁷⁷Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

Introduction

Patients and methods

Results

Conclusion

Publications

<sup>177</sup>Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

177Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

Introduction

Patients and methods

Results

Conclusion

Publications

<sup>177</sup>Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

¹⁷⁷Lu-DOTATATE Efficacy and Safety in Functioning Neuroendocrine Tumors: A Joint Analysis of Phase II Prospective Clinical Trials.