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.

Circulating Tumor DNA Dynamics Fail to Predict Efficacy of Poly(ADP-ribose) Polymerase/VEGFR Inhibition in Patients With Heavily Pretreated Advanced Solid Tumors.

PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non-small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation-based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib.

Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All "BRCAness" Is Created Equal.

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.

NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors.

Purpose: Veliparib is a PARP inhibitor (PARPi) with activity in BRCA 1/2/PALB2-deficient tumors. Preclinical observations reveal topoisomerase inhibitors like irinotecan are synergistic with PARPi irrespective of homologous recombination deficiency (HRD), potentially expanding the role for PARPi. Experimental Design: NCI 7977 was a multicohort phase I clinical trial evaluating the safety and efficacy of multiple dose schedules of veliparib with irinotecan for solid tumors. In the intermittent veliparib cohort, escalating doses of veliparib were given twice daily at dose level (DL) 1 (50 mg) and DL 2 (100 mg) days 1-4 and 8-11 with irinotecan 100 mg/m2 days 3 and 10 in 21-day cycles. Results: Fifteen patients enrolled, 8 of 15 (53%) received ≥4 prior systemic treatments. At DL1, 1 of 6 patients experienced a dose-limiting toxicity (DLT) of diarrhea. At DL2, 9 patients were treated, with 3 unevaluable for DLT, and 2 of 6 evaluable patients experienced a DLT of grade 3 neutropenia. Irinotecan 100 mg/m2 and veliparib 50 mg twice daily was the MTD. No objective responses were observed, although 4 patients had progression-free survival >6 months. Conclusions: The MTD of intermittent veliparib is 50 mg twice daily days 1-4 and 8-11 with weekly irinotecan 100 mg/m2 days 3 and 10 every 21 days. Multiple patients experienced prolonged stable disease irrespective of HRD and prior irinotecan. However, due to the toxicities with higher dose intermittent veliparib and irinotecan, this schedule was determined too toxic for further development and the arm was closed prematurely. Significance: The combination of intermittent veliparib with weekly irinotecan was deemed too toxic for further development. Future PARPi combinations should focus on agents with nonoverlapping toxicities to improve tolerability. The treatment combination showed limited efficacy with prolonged stable disease observed in multiple heavily pretreated patients, but no objective responses were seen.

Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop.

Checkpoint inhibitors represent an effective treatment approach for a variety of cancers through their inhibition of immune regulatory pathways within the tumor microenvironment (TME). Unfortunately only a minority of patients with cancer achieve clinical benefit from immunotherapy, with the TME emerging as an important predictor of outcomes and sensitivity to therapy. The extent and pattern of T-cell infiltration can vary prominently within/across tumors and represents a biological continuum. Three immune profiles have been identified along this continuum: 'immune-desert' or 'T-cell cold' phenotype, 'immune-active', 'inflamed', or 'T-cell hot' phenotype, and 'immune excluded' phenotype. Of the three profiles, immune excluded remains the most ill-defined with no clear, universally accepted definition even though it is commonly associated with lack of response to immune checkpoint inhibitors and poor clinical outcomes. To address this, 16 multidisciplinary cancer experts from around the world were invited to participate in a symposium using a three-round modified Delphi approach. The first round was an open-ended questionnaire distributed via email and the second was an in-person discussion of the first round results that allowed for statements to be revised as necessary to achieve a maximum consensus (75% agreement) among the rating committee (RC). The final round questionnaire was distributed to the RC via email and had a 100% completion rate. The Delphi process resulted in moving us closer to a consensus definition for immune exclusion that is practical, clinically pertinent, and applicable across a wide range of cancer histologies. A general consensus of the role of immune exclusion in resistance to checkpoint therapy and five research priorities emerged from this process. Together, these tools could help efforts designed to address the underlying mechanisms of immune exclusion that span cancer types and, ultimately, aid in the development of treatments to target these mechanisms to improve patient outcomes.

BRCA2 BRC missense variants disrupt RAD51-dependent DNA repair.

Pathogenic mutations in the BRCA2 tumor suppressor gene predispose to breast, ovarian, pancreatic, prostate, and other cancers. BRCA2 maintains genome stability through homology-directed repair (HDR) of DNA double-strand breaks (DSBs) and replication fork protection. Nonsense or frameshift mutations leading to truncation of the BRCA2 protein are typically considered pathogenic; however, missense mutations resulting in single amino acid substitutions can be challenging to functionally interpret. The majority of missense mutations in BRCA2 have been classified as Variants of Uncertain Significance (VUS) with unknown functional consequences. In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine their impact on canonical HDR and fork protection functions. We provide evidence that S1221P and T1980I, which map to conserved residues in the BRC2 and BRC7 repeats, compromise the cellular response to chemotherapeutics and ionizing radiation, and display deficits in fork protection. We further demonstrate biochemically that S1221P and T1980I disrupt RAD51 binding and diminish the ability of BRCA2 to stabilize RAD51-ssDNA complexes. The third variant, T1346I, located within the spacer region between BRC2 and BRC3 repeats, is fully functional. We conclude that T1346I is a benign allele, whereas S1221P and T1980I are hypomorphic disrupting the ability of BRCA2 to fully engage and stabilize RAD51 nucleoprotein filaments. Our results underscore the importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer risk and guide therapy selection during cancer treatment.

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade.

BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma.

BACKGROUND: To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. METHODS: Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). RESULTS: TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=-0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% Ò¡=0.573) among patients whose HPV results were available using both methods. CONCLUSIONS: TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. TRIAL REGISTRATION NUMBER: NCT01848834.

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations).

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination-directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA-mutated PARP inhibitor-resistant high-grade serous ovarian cancer (HGSOC). PATIENTS AND METHODS: Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks). RESULTS: Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor-resistant HGSOC, one achieved PR (-90%) and five had SD ranging 16-72 weeks (CBR 86%). CONCLUSION: Olaparib with ceralasertib demonstrated preliminary activity in ATM-mutated tumors and in PARP inhibitor-resistant BRCA1/2-mutated HGSOC. These data warrant additional studies to further confirm activity in these settings.

A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation.

PURPOSE: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. PATIENTS AND METHODS: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. RESULTS: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0-12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. CONCLUSIONS: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure-toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.

Phase I Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844).

PURPOSE: Epigenetic modulators improve immune checkpoint inhibitor (ICI) efficacy and increase CD8+ effector:FoxP3+ regulatory T cell ratios in preclinical models. We conducted a multicenter phase I clinical trial combining the histone deacetylase inhibitor entinostat with nivolumab ± ipilimumab in advanced solid tumors. PATIENTS AND METHODS: Patients received an entinostat run-in (5 mg, weekly × 2) prior to the addition of ICIs. Dose escalation followed a modified 3+3 design [dose level (DL)1/2: entinostat + nivolumab; DL 3/4: entinostat + nivolumab + ipilimumab]. Blood and tissue samples were collected at baseline, after entinostat run-in, and after 8 weeks of combination therapy. Primary endpoints included safety and tolerability, and the recommended phase II dose (RP2D). Secondary endpoints included antitumor activity and change in tumor CD8/FoxP3 ratio pre- and post-therapy. RESULTS: Thirty-three patients were treated across four dose levels. Treatment-related adverse events (AE) included fatigue (65%), nausea (41%), anemia (38%), diarrhea (26%), and anorexia (26%). Grade 3/4 AEs included fatigue (n = 7, 21%), anemia (n = 9, 27%), and neutropenia (n = 4, 12%). The RP2D was 3 mg entinostat weekly, 3 mg/kg every 2 weeks nivolumab, and 1 mg/kg every 6 weeks ipilimumab (max four doses). The objective response rate by RECIST 1.1 was 16%, including a complete response in triple-negative breast cancer. A statistically significant increase in CD8/FoxP3 ratio was seen following the addition of ICIs to entinostat, but not post-entinostat alone. CONCLUSIONS: The combination of entinostat with nivolumab ± ipilimumab was safe and tolerable with expected rates of immune-related AEs. Preliminary evidence of both clinical efficacy and immune modulation supports further investigation.

Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas.

PURPOSE: Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points. METHODS: Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily. RESULTS: Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma. CONCLUSION: These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.

A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. METHODS: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. RESULTS: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. CONCLUSIONS: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. CLINICAL TRIALS REGISTRATION: NCT01987362.

Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors.

BACKGROUND: M4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors. METHODS: In preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects. RESULTS: In mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%). CONCLUSIONS: There were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration number NCT03306420.