Combination of everolimus and lu-177 PRRT in treatment of G1-2 neuroendocrine tumors (NET): Phase 1-2 study.

Abstract

386 Background: Everolimus and Lutetium-177 PRRT were approved as monotherapy. However, animal model research showed synergistic effect of the combination. The goal of this study is to assess the safety and efficacy of the combination in treatment of unresectable G1-2 NETs of all gastrointestinal, lung and pancreatic origins. Methods: This is a phase 1-2 study. Phase 1 part involves finding the maximum tolerating dose (MTD) of everolimus and accordingly to recommend dose for phase II part. Starting everolimus dose was 5 mg OD. Patients were treated concurrently with Lu-177 DOTATOC therapy at intervals of 8 weeks (+/-1 week) with average of 4 sessions. Sample size calculation was based on the expected response of the combination to be 30% with power of 80 and type 1 of .05, compared to the known response rate of everolimus alone of 5%. Primary end point is safety. Other end points include response rate, PFS and OS. Results: Eleven patients, with progressive disease, were enrolled. Characteristics are summarized in the table. Everolimus MTD was 10 mg once daily. However, dose was reduced to 5 mg OD in 3 patients and to 5 mg once every other day in 2 patients. Median number of sessions of Lu-177: 3 sessions, and median cumulative dose: 300 mci. Most common G1-2 toxicities: stomatitis (90.9%), Nausea (72.7%), Fatigue (63.6%), anorexia (36.4%), diarrhea (36.4%) and skin and nail changes (36.4%). G3 toxicities (36%) were infection, fatigue, pneumonitis and neutropenia. No grade 4 toxicities. Reasons of discontinuation were toxicity in 3 patients, progression in 3, stroke in 1 and due to interruption of therapy in 4 patients. ORR: 1 PD, 1 PR and 9 SD. At median FU of 18.9 months, 7 patients are still alive, 3 died, and 1 lost to FU. Median PFS: 23.3 months. Conclusions: Combination of Everolimus and the Lu-177 PRRT appear to be safe and effective. Four patients, due to strict compliance criteria in the study protocol, were removed from the study prematurely resulting in undertreatment. Larger and randomized studies are required to confirm such findings.[Table: see text]

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors

“…Improved treatment options are needed, as a third of GEP-NET patients do not respond to current regimens [2,3,18]. Radiotherapy and mTOR inhibition are two promising therapies that have improved treatment outcomes, such as progression-free survival [4,5,16,19,22]. PRRT is a form of targeted radiotherapy, coupled with either an alpha-emitter or a beta-emitter and a somatostatin analog to induce DNA damage in targeted GEP-NETs overexpressing somatostatin receptors [4,9].…”

“…Of particular interest, mTOR inhibitors have been tested in vitro as radiosensitizers in combination with PRRT [21]. Recently, PRRT combination therapy with everolimus has entered phase I/II clinical trials [22,23]. Although this combination therapy has demonstrated an improved treatment response rate of 44%, serious side effects, such as neutropenia and renal function impairment, occurred in 8 out of 11 patients in one study, requiring dose reduction [22,23].…”

“…Recently, PRRT combination therapy with everolimus has entered phase I/II clinical trials [22,23]. Although this combination therapy has demonstrated an improved treatment response rate of 44%, serious side effects, such as neutropenia and renal function impairment, occurred in 8 out of 11 patients in one study, requiring dose reduction [22,23]. New combination strategies may improve patient tolerance to PI3K/mTOR, such as inhibiting PI3K/mTOR pathway only when cancer cells experience radiation-induced stress, which may offer short-term synergistic effects combined with radiotherapy.…”

Targeted radionuclide therapy in endocrine-related cancers: advances in the last decade

“…Other avenues being explored in primarily the GEP-NET population are combinations with mTOR inhibitors, radiation sensitizers (such as cell signaling inhibitors, DNA damage repair inhibitors, and DNA damage inducers), and tandem PRRT with multiple radioisotopes ( 121 – 127 ). The majority of research thus far has been preclinical in mouse models and xenografts, however a few clinical trials have recently begun enrollment and are exploring the combinations of radiosensitizers and DNA-damage-repair inhibitors in combination with PRRT.…”

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

“…Results from phase I/II study of everolimus in combination with 177 Lu-Edotreotide in patients with GEP NETs and lung NETs were reported. 39 The rationale for this study stemmed from lung NET xenograft data where the combination of everolimus and 177 Lu-Dotatate elicited improved tumor shrinkage compared with monotherapy with either agent, and early clinical data in patients with GEP NETs where the combination appeared to be cytoreductive (ORR of 44%). 40 In the study, 11 patients (10 GEP NET) patients received four doses of 177 Lu-Edotreotide (3.7 GBq per dose) concurrently with everolimus in the trial.…”