oleclumab (MEDI9447)

P2, N=147, Active, not recruiting, Jules Bordet Institute | Trial primary completion date: Sep 2024 --> May 2025

P1/2, N=129, Active, not recruiting, Jules Bordet Institute | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Mar 2025

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P2, N=13, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=30 --> 13

Background Neo-CheckRay (NCT03875573) demonstrated high rates of pathological complete response (pCR) after immune-modulating stereotactic body radiation therapy (iSBRT) to the primary BC in combination with the anti-PD-L1 durvalumab (durva) in high-risk early-stage luminal BC...Pts were randomized 1:1:1 to ARM 1: paclitaxel q1w x12 with iSBRT at week 4 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; ARM 2 : arm 1 + durva q4w x5; and ARM 3 : arm 1 + durva + oleclumab (anti-CD73) q2w x4 then q4w x3...Table: 2O All Arm 1 Arm 2 Arm 3 n 135 45 45 45 pts, % B: PD-L1 negative* 58.5 57.8 57.8 60.0 W6: no tumor 32.2 13.5 46.3 34.9 W6: TILs increase 14.0 16.2 12.2 14.0 W6: PD-L1 IC increase 42.7 31 48 48 pCR rate, % All pts 28.9 17.8 33.3 35.6 B: PD-L1 negative* 24.0 3.8 34.6 33.3 W6: no tumor 48.7 40.0 47.4 53.3 W6: TILs increased 17.6 0.0 20.0 33.3 W6: PD-L1 IC increased 24.0 0.0 46.0 40.0 TILs: pts, % B: TILs ≥ 1% 51.5 51.2 50.0 53.3 W6: TILs ≥ 1% 26.8 28.1 27.3 25.0 PD-L1: pts, % B: PD-L1 IC ≥ 1% 57.0 57.8 57.8 55.6 W6: PD-L1 IC ≥ 1% 70.5 48.3 85.7 82.1 B: PD-L1 TC ≥ 1% 22.2 24.4 17.8 24.4 W6: PD-L1 TC ≥ 1% 29.9 13.8 42.9 37.0 B: PD-L1 CPS ≥ 1% 39.3 37.8 40.0 40.0 W6: PD-L1 CPS ≥ 1% 54.5 37.9 66.7 63.0 B, baseline; pts, patients; W6, week 6. *Stratification factor.Conclusions In pts treated with iSBRT+durva, PD-L1 increase or absence of tumor at W6 is associated with higher pCR rate at surgery.

P2, N=30, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1; Recruiting --> Suspended

P2, N=490, Recruiting, AstraZeneca | Trial completion date: Dec 2029 --> May 2030 | Trial primary completion date: Dec 2029 --> May 2030

P2, N=30, Not yet recruiting, AstraZeneca

P2, N=490, Recruiting, AstraZeneca | Trial completion date: Dec 2028 --> Dec 2029 | Trial primary completion date: Dec 2028 --> Dec 2029

Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Both agents demonstrated antitumor activity in early-phase trials. PACIFIC-9 (NCT05221840) is an international, double-blind, randomized, placebo-controlled, Phase III trial comparing durvalumab plus either oleclumab or monalizumab with durvalumab plus placebo in patients with unresectable, stage III NSCLC and no disease progression following cCRT.Clinical Trial Registration: NCT05221840 (ClinicalTrials.gov).

Neo-CheckRay (NCT03875573) is the first prospective, international, phase 2, randomized trial investigating this treatment. Eligible patients (pts) with newly diagnosed cT1c-3 (≥ 2 cm) cN0 or cT1c-3 (≥ 1.5 cm) cN1-3, grade 2 (Ki67 ≥ 15%) or grade 3, MammaPrint (MP) high risk, invasive ER+/HER2- BC were randomized 1:1:1 to arm 1: neo-adjuvant paclitaxel q1w x12 with SBRT at week 5 (3x8 Gy targeting the primary tumour, avoiding lymph nodes and normal breast tissue), followed by dose-dense epirubicin/cyclophosphamide q2w x4; arm 2: arm 1 + durva 1500mg q4w x5; and arm 3: arm 2 + ole 3000 mg q2w x4 then q4w x3. The addition of durva+/- ole numerically increases pCR and RCB 0/1 rates compared to NACT+SBRT. Final statistical analysis will be presented at the conference. Ongoing translational research will shed light on the mechanisms of response.

P1/2, N=243, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P2, N=75, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

P1/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2025 --> Jul 2025

P2, N=114, Active, not recruiting, Assistance Publique Hopitaux De Marseille | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Oct 2023 --> Oct 2024

P1/2, N=240, Recruiting, AstraZeneca | Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Aug 2024 --> Nov 2024

P2; Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Sep 2029 | Trial primary completion date: Jan 2024 --> Sep 2024

P1, N=175, Active, not recruiting, AstraZeneca | Trial completion date: May 2023 --> Mar 2026

P2, N=490, Recruiting, AstraZeneca | N=350 --> 490

A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

P1/2, N=43, Active, not recruiting, MedImmune LLC | Phase classification: P1b/2 --> P1/2 | Trial completion date: Sep 2024 --> Jan 2025

Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade...This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP)...Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

P1; Suspended --> Recruiting

P2, N=22, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

P1; N=24 --> 48

P2, N=188, Completed, MedImmune LLC | Active, not recruiting --> Completed

P2; This novel treatment combination was considered safe and is worth further investigation in a randomized phase II trial.

P1/2, N=61, Terminated, MedImmune LLC | Phase classification: P1b/2 --> P1/2 | Completed --> Terminated; On 17 February 2022, the decision was made to terminate the clinical study because superior efficacy was not observed for the novel study drug combinations under investigation.

Eighty-three patients received a single cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab (anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense oligonucleotide). Safety profiles for the combinations were similar to that of durvalumab alone. Multiplatform immune profiling suggested improved MPR rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were associated with enhanced effector immune infiltration of tumors, interferon responses and markers of tertiary lymphoid structure formation, and systemic functional immune-cell activation.

P2, N=350, Recruiting, AstraZeneca | Trial completion date: Mar 2026 --> Dec 2028 | Trial primary completion date: Mar 2026 --> Dec 2028

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Oct 2023 --> Oct 2024

BsAb CD73xEGFR outperforms oleclumab as it inhibits the CD73/ADO immune checkpoint in an EGFR-directed manner and concurrently counteracts several oncogenic activities of EGFR and CD73. Therefore, bsAb CD73xEGFR may be of significant clinical potential for various forms of difficult-to-treat solid cancer types.

Thus far, conventional CD73-blocking antibodies such as oleclumab show limited clinical efficacy, probably due to the fact that it indiscriminately binds to and blocks CD73 on a massive surplus of normal cells...Additionally, treatment with bsAb CD73xEpCAM potently inhibited the proliferative capacity of OC cells and enhanced their sensitivity to cisplatin, doxorubicin, 5FU, and ionizing radiation. BsAb CD73xEpCAM may be useful in the development of tumor-directed immunotherapeutic approaches to overcome the CD73-mediated immunosuppression in patients with refractory OC.

P1, N=192, Completed, MedImmune LLC | Trial completion date: Jun 2023 --> Mar 2023 | Active, not recruiting --> Completed

P1b/2, N=43, Active, not recruiting, MedImmune LLC | Trial completion date: Jan 2024 --> Sep 2024

P1/2, N=203, Recruiting, AstraZeneca | Active, not recruiting --> Recruiting

P1/2, N=129, Active, not recruiting, Jules Bordet Institute | Trial completion date: Oct 2023 --> Apr 2025 | Trial primary completion date: Jul 2023 --> Aug 2024

Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant.