On December 12, 2024 iTeos Therapeutics, Inc. (Nasdaq: ITOS), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients, reported the presentation of clinical, translational, and preclinical data from its adenosine A2A receptor (A2AR) antagonist program, inupadenant, including interim data from the dose escalation portion of A2A-005, the Phase 2 trial assessing inupadenant and platinum-doublet chemotherapy in post-immunotherapy metastatic non-small cell lung cancer (NSCLC) patients, at the European Society for Medical Oncology Immuno-Oncology (ESMO IO) Congress 2024 (Press release, iTeos Therapeutics, DEC 12, 2024, View Source [SID1234649083]).

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"We believe our presentations at ESMO (Free ESMO Whitepaper) IO on the adenosine pathway demonstrate the strong efforts our research and discovery team have put into understanding this immunosuppressive mechanism," said Michel Detheux, Ph.D., president and chief executive officer of iTeos. "While the initial signal for inupadenant’s RP2D in the A2A-005 trial compared to chemotherapy alone is encouraging and supports its differentiated, insurmountable profile, we as well as our scientific and clinical advisory boards believe it does not meet sufficient level of clinical activity to warrant further investment. We remain committed to focusing our resources on developing differentiated, first- or best-in-class therapies and look forward to providing updates on our pipeline in 2025."

Mini Oral Sessions
Title: Inupadenant Combined with Chemotherapy in Patients with Non-Squamous NSCLC Progressing On or After Immune Checkpoint Inhibitor Therapy: Results from Dose-Finding Part of the A2A-005 Trial
Summary: As of the October 29, 2024 data cutoff, the topline data from the dose escalation portion of A2A-005 presented at the ESMO (Free ESMO Whitepaper) IO Congress were based on 36 patients eligible for safety and efficacy evaluation. Patients received inupadenant at 40mg, 60mg, or 80mg twice daily (BID) in combination with carboplatin/pemetrexed. All patients had a minimum follow-up of 6 months. Patient baseline characteristics were balanced across arms, with a slight imbalance of more patients with brain metastases in the 40mg and 80mg cohorts and ECOG status 0 favoring the 80mg cohort.

The primary endpoint of the safety of inupadenant in combination with carboplatin/pemetrexed was observed to be manageable and tolerable, with no dose dependent toxicities.
The secondary endpoint of ORR was 63.9% across all patients (53.3% at 40mg, 66.7% at 60mg, and 73.3% at 80mg).
The secondary endpoint of mPFS was 7.7 months across all patients (5.6 months at 40mg and 6.6 months at 60mg; mPFS remains unreached at 80mg).
The exploratory biomarker of CXCL13, a B-cell chemokine and lymphoid structure marker associated with clinical activity, was observed to be restored by inupadenant after depletion by chemotherapy, with quicker restoration kinetics in patients with PFS greater than 6 months.
As of the data cutoff, 8 patients remained on treatment (1 at 40mg, 1 at 60mg, and 6 at 80mg). The median follow-up was 9.7 months (10.6 months at 40mg, 13.1 months at 60mg, and 8.2 months at 80mg).

Response Measure Inupadenant 40mg + carboplatin / pemetrexed BID Inupadenant 60mg + carboplatin / pemetrexed BID Inupadenant 80mg + carboplatin / pemetrexed BID Overall
(N=15) (N=6) (N=15) (N=36)
ORR, % 53.3% 66.7% 73.3% 63.9%
n
(95% CI) n=8
(26.6–78.7) n=6
(22.3–95.7) n=15
(44.9–92.2) n=36
(46.2–79.2)
Complete response, n (%) 0 0 2 (13.3%) 2 (5.6%)
Partial response, n (%) 8 (53.3%) 4 (66.7%) 9 (60.0%) 21 (58.3%)
Stable disease, n (%) 7 (46.7%) 1 (16.7%) 3 (20.0%) 11 (30.6%)
Progressive disease, n (%) 0 0 1 (6.7%) 1 (2.8%)
Not evaluable/no assessment, n (%) 0 1 (16.7%) 0 1 (2.8%)
mPFS, months 5.6 6.6 NC 7.7
Event n (%)
(95% CI) 13 (86.7%)
(4.1-8.3) 5 (83.3%)
(0.4-NC) 6 (40.0%)
(4.9-NC) 24 (66.7%)
(5.1-11.0)
Landmark 6-Month PFS % 46.7%
(21.2-68.7) 50.0%
(11.1-80.4) 64.6%
(34.7-83.5) 54.5%
(36.8-69.1)
CI, confidence interval; NC, not calculable

Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Patients
Summary: Based on monotherapy clinical and translational data, inupadenant demonstrated modulation of humoral responses in patient blood and tumor tissue, supporting our previous finding that expression of antibody-secreting cells (ASCs) in tumor tissue is associated with non-progression in patient disease. Furthermore, CXCL13 expression, a protein involved in immune cell recruitment, activation, and adaptive immune response regulation, increased in patients treated with inupadenant and more rapidly and extensively in non-progressors compared to progressors. These findings confirm inupadenant plays a key role in B cell maturation restoration and may play a substantial role in delaying progression in end-stage patients.

Poster Sessions
Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Preclinical Models
Summary: In preclinical models, inupadenant counteracted the A2AR-mediated inhibition of B cell maturation into ASCs and immunoglobulin production in both in vitro and ex vivo systems by modulating B cells at the level of the germinal center (GC). These findings suggest that inupadenant restores or even enhances B cell maturation towards ASCs and GC reactions in both secondary lymphoid organs as well as the tumor in the presence of A2AR signaling. Furthermore, this process is essential for producing high-affinity antibodies and potentially for sustained anti-tumor immunity.

Title: A Novel Tumor Adenosine Signature to Guide Indication Selection for Adenosine Pathway inhibitor
Summary: Based on the spatial quantification of adenosine in human tumors, we developed the first adenosine gene signature, demonstrating its potential for indication selection. This new signature, derived from 249 differentially expressed genes (DEGs) associated with metabolism and immune activation, showed high predictive power across tumor types. Furthermore, the adenosine signature was higher in tumors compared to healthy tissue and exhibited variable expression and prognostic value across tumor subtypes. These findings suggest that the adenosine signature represents a powerful tool for prioritizing tumor types which may benefit most from adenosine-targeting therapies and for understanding the mechanisms of adenosine-mediated immunosuppression.