CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials.

Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC.

Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma.

IMPORTANCE: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses. OBJECTIVE: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial. DESIGN, SETTING, AND PARTICIPANTS: IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020. INTERVENTIONS: Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off). MAIN OUTCOMES AND MEASURES: The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety. RESULTS: The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98). CONCLUSIONS AND RELEVANCE: The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti-PD-L1 and anti-VEGF therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420821.

cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole based scaffolds: design rationale, synthesis and cysteinyl proteinase inhibition.

The 5,5-bicycles cis-6-oxo-hexahydro-2-oxa-1,4-diazapentalene 3 and cis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole 4 were designed as rotationally restricted templates towards the preparation of inhibitors of CAC1 cysteinyl proteinases. The design strategy was exemplified through the solution and solid phase preparation of potent inhibitors of human cathepsin K and may potentially be applied to inhibitors of other CAC1 proteinases.

Synthesis and evaluation of cis-hexahydropyrrolo[3,2-b]pyrrol-3-one peptidomimetic inhibitors of CAC1 cysteinyl proteinases.

A stereoselective synthesis of functionalised cis-hexahydropyrrolo[3,2-b]pyrrol-3-ones has been developed through Fmoc and Cbz-protected intermediates 5 and 6. Building blocks 5 and 6 were prepared via the intramolecular cyclisation of anti-epoxide 17. The intramolecular reaction occurred exclusively through the anti-epoxide to provide the 5,5-cis-fused bicycle, whereas the syn-epoxide, which theoretically would provide the 5,5-trans-fused bicycle, remained unchanged. These experimental observations are consistent with a key design element that we have introduced within this novel bicyclic ketone scaffold. Our bicyclic design strategy provides chiral stability to the bridgehead stereocentre that is situated alpha to the ketone because the cis-fused geometry is both thermodynamically and kinetically stable. Building blocks 5 and 6 have been utilised in both solid phase and solution phase syntheses of peptidomimetics 22, 36-40, which exhibit potent in vitro inhibition against a range of CAC1 cysteinyl proteinases. Compound 22, a potent and selective inhibitor of human cathepsin K exhibited good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption.

Bicyclic peptidomimetic tetrahydrofuro[3,2-b]pyrrol-3-one and hexahydrofuro[3,2-b]pyridine-3-one based scaffolds: synthesis and cysteinyl proteinase inhibition.

A stereoselective synthesis of (3aS,6aR)-tetrahydrofuro[3,2-b]pyrrol-3-ones and (3aS,7aR)-hexahydrofuro[3,2-b]pyridine-3-ones has been developed through Fmoc protected scaffolds 12 and 13. A key design element within these novel bicyclic scaffolds, in particular the 5,5-fused system, was the inherent stability of the cis-fused geometry in comparison to that of the corresponding trans-fused. Since the bridgehead stereocentre situated beta to the ketone was of a fixed and stable configuration, the fact that cis ring fusion is both kinetically and thermodynamically stable with respect to trans ring fusion provides chiral stability to the bridgehead stereocentre that is situated alpha to the ketone. To exemplify this principle, building blocks 12 and 13 were designed, prepared and utilised in a solid phase combinatorial synthesis of peptidomimetic inhibitors 10, 45a-e, 11 and 46. Both series were chirally stable with 5,5-series 10 and 45a-e exhibiting potent in vitro activity against a range of CAC1 cysteinyl proteinases. Compound 10, a potent and selective inhibitor of cathepsin K, possessed good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption.

Functionalised 2,3-dimethyl-3-aminotetrahydrofuran-4-one and N-(3-oxo-hexahydrocyclopenta[b]furan-3a-yl)acylamide based scaffolds: synthesis and cysteinyl proteinase inhibition.

A stereoselective synthesis of functionalised (2R,3R)-2,3-dimethyl-3-amidotetrahydrofuran-4-one, its (2S,3R)-epimer and (3aR,6aR)-N-(3-oxo-hexahydrocyclopenta[b]furan-3a-yl)acylamide cysteinyl proteinase inhibitors has been developed using Fmoc-protected scaffolds 6-8 in a solid-phase combinatorial strategy. Within these scaffolds, the introduction of an alkyl substituent alpha to the ketone affords chiral stability to an otherwise configurationally labile molecule. Preparation of scaffolds 6-8 required stereoselective syntheses of suitably protected alpha-diazomethylketone intermediates 9-11, derived from appropriately protected alpha-methylthreonines (2R,3R)-12, (2R,3S)-13 and a protected analogue of (1R,2R)-1-amino-2-hydroxycyclopentanecarboxylic acid 14. Application of standard methods for the preparation of amino acid alpha-diazomethylketones, through treatment of the mixed anhydride or pre-formed acyl fluorides of intermediates 12-14 with diazomethane, proved troublesome giving complex mixtures. However, the desired alpha-diazomethylketones were isolated and following a lithium chloride/acetic acid promoted insertion reaction provided scaffolds 6-8. Elaboration of 6-8 on the solid phase gave alpha,beta-dimethyl monocyclic ketone based inhibitors 38a-f, 39a,b,d,e,f and bicyclic inhibitors 40a-e that exhibited low micromolar activity against a variety of cysteinyl proteinases.