Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung

Abstract

Background: Lutathera is a 177Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung.

Methods: Patients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks).

Results: Nine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2.

Conclusions: Lutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration.

Trial registration number: NCT03325816.

Keywords: drug therapy, combination; immunotherapy; lung neoplasms; radioimmunotherapy.

Conflict of interest statement

Competing interests: CK has received research grants (to institution) from AstraZeneca, BMS, Novartis, Regeneron, Tesaro, Karyopharm, Debiopharm, and Altor Bioscience, and has served on the advisory board of Novartis. SVL has received research grants (to institution) from Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Ignyta, Lilly, Lycera, Merck, Merus, Molecular Partners, Pfizer, Rain Therapeutics, RAPT, Spectrum, and Turning Point Therapeutics. He has served on the advisory board of AstraZeneca, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Ignyta, Janssen, Lilly, LOXO, PharmaMar, Regeneron, and Takeda. DSS is an employee of AstraZeneca and has stock options with AstraZeneca starting July 29, 2019. DSS was on the speaker’s bureau of AstraZeneca, Genentech, and Takeda Oncology, and was on the advisory board of AstraZeneca. GE is on the speaker’s bureau of Advanced Accelerator Applications. The other authors declare no potential conflicts of interest.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study schema.

Figure 2

In patient 1, there is increased gallium-68 DOTATATE (SUVmax=9.3) and fluorodeoxyglucose (FDG) uptake (SUVmax=19.8) in the right hepatic lobe lesion (A, B). A lesion in the left upper lobe shows faint activity on gallium-68 DOTATATE positron emission tomography (PET) (C) and mild activity on FDG PET (D). In patient 2, the left upper lobe mass exhibits higher uptake on gallium-68 DOTATATE PET (SUVmax=46.8) compared with FDG PET (SUVmax=10.0) (E, F). In patient 3, abnormal radiotracer uptake in the right lower lobe mass was noted on both gallium-68 DOTATATE and FDG PET (SUVmax=20.0 and 11.5, respectively) (G, H). Similarly, the right hepatic lesion was avid on both scans (SUVmax=20.0 and 14.9, respectively) (I, J). In patient 5, left hilar lymphadenopathy had uptake of gallium-68 DOTATATE (SUVmax=16.31) and FDG (SUVmax=5.5) (K, L). In patient 6, left lung mass had faint activity on gallium-68 DOTATATE PET (SUVmax=7.9), while FDG PET demonstrated high uptake (SUVmax=29.9) (M, N).

Figure 3

In a patient who achieved a partial response (study ID #2), baseline gallium-68 DOTATATE positron emission tomography (PET) shows avid uptake in tumors (A). The target lesion (right perihilar mass) was decreased in size with study treatment (A, B) and the uptake of gallium-68 DOTATATE was reduced (C, D).