Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non-Small Cell Lung Cancer

Abstract

Purpose: The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.

Patients and methods: In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.

Results: During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.

Conclusions: Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.

Trial registration: ClinicalTrials.gov NCT02403193.

Conflict of interest statement

Disclosure:

Alberto A. Chiappori reports grants from LUNGevity Foundation during the conduct of the study; personal fees outside the submitted work from Merck, Genentech, Takeda, Blue Print Medicines and Celgene for Speaker’s Bureaus; personal fees outside the submitted work from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Jazz, Novartis, and Pfizer for Advisory Boards; and research funding outside the submitted work from AstraZeneca, Bristol-Myers Squibb, and Novartis. Ben Creelan is an advisor/consultant with AbbVie, Achilles, Celgene, E.R. Squibb & Sons, Gilead Sciences, GlaxoSmithKline, KSQ Therapeutics, and Xilio Therapeutics; sits on the Speaker's Bureau for AstraZeneca, E.R. Squibb & Sons, Foundation Medicine, Hoffman-LaRoche, and Takeda; and reports contacted/support research grants from Adaptive Biotechnologies, Iovance Biotherapeutics, and Prometheus. Jhanelle E. Gray reports research grants outside the submitted work from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics, Merck, Novartis, Pfizer, and Ludwig Institute of Cancer Research; personal fees for consultant/advisory roles outside the submitted work from AstraZeneca, Blue Print Medicines, Bristol-Myers Squibb, EMB Serono-Merck, Inivata, Merck, and Novartis. Eric B. Haura reports personal fees for consultancy outside the submitted work from Janssen and Amgen. Amer A. Beg reports consulting roles outside the submitted work with Memgen. Julio Castro reports employment by Palobiofarma. Liza Morgan reports employment by Novartis. Mehreteab Aregay and Felipe K. Hurtado report employment with Novartis during the study period. Erick Morris and Luigi Manenti report employment by Novartis and holding Novartis stocks/shares. Scott Antonia reports institutional research funding from Novartis; consulting/advisory roles for Achilles Therapeutics, Amgen, AstraZeneca, Bristol-Myers Squibb, CBMG, Celsius, GlaxoSmithKline, Merck, Memgen, RAPT, Samyang Biopharma, and Venn; travel/accommodations/expenses from Achilles Therapeutics, Amgen, Bristol-Myers Squibb, Celsius, GlaxoSmithKline, Merck, and Rapt. Tawee Tanvetyanon, Ram Thapa, Margaret L. Barlow, Zhihua Chen, Dung Tsa Chen, and Theresa A. Boyle declare no conflict of interest.

©2022 American Association for Cancer Research.

Figures

Figure 1.. Geometric mean plasma concentration–time profiles of taminadenant, by visit and treatment group.

Data cut-off: January 15, 2020. Abbreviations: A2AR, adenosine 2A receptor.

Figure 2.. Tornado plot of adverse events, thought to be related to study treatment, reported in patients treated with taminadenant single agent

(A) and taminadenant in combination with spartalizumab (B). *Visual changes, shakiness; †Occasional indigestion; ‡Hypomotility of the gastrointestinal tract and intermittent gastrointestinal upset; §Elevated thyroid-stimulating hormone. Data cut-off: January 15, 2020. Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GE, gastro-esophageal; GGT, gamma-glutamyltransferase; GI, gastrointestinal.

Figure 3.. Best percentage change from baseline according to prior anti-PD-1/PD-L1 therapy in patients treated with taminadenant single agent

(A) and taminadenant in combination with spartalizumab (B). *CR does not revert to a 100% reduction in tumor size as the baseline target lesions were lymph nodes considered non-pathologic at best response; sizes decreased from 1.5 cm and 1.6 cm to 0.6 cm and 0.7 cm, respectively (any pathological lymph nodes are required to have a reduction in short axis to <10 mm to qualify for a CR). Data cut off: January 15, 2020. Abbreviations: CR, complete response; NA, not assessed; PD, progressive disease; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; PR, partial response; SD, stable disease.