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Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity.Significance:This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1

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Purpose: Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non–small cell lung cancer (NSCLC).Experimental Design: Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab. Peripheral blood was analyzed for CTC enumeration, EGFR expression in CTCs, and detection of oncogenic mutations in CTCs and ctDNA. Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-d-glucose–positron emission tomographic (FDG-PET) and computed tomographic (CT) imaging and survival endpoints.Results: CTCs were detected (≥1 CTC) at baseline in 78% of patients. Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor. Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST, P = 0.009) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response (P = 0.014 and P = 0.019) and longer progression-free survival (P = 0.050).Conclusion: These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC. These findings require prospective validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood. Clin Cancer Res; 18(8); 2391–401. ©2012 AACR.

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib.Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined.Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders.Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res; 17(10); 3304–15. ©2011 AACR.

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Supplementary Figure S1; Supplementary Table S1.

Background: Metastases remains the major cause of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) that are shed from primary and metastatic sites and circulate in patients' peripheral blood, represent an important window into disease status. Minimally invasive techniques are required to identify at time of diagnosis, which patients will have worse prognosis due to distant relapse. Method: We collected bloods from treatment naïve, locoregionally advanced HNC patients (n=72) at the time of diagnosis, and CTCs were isolated using a spiral microfluidic device. CTCs were then immobilised onto glass slides and identified by using immunofluorescence staining (Cytokeratin/CD45/DAPI). We then correlated the CTC numbers of each patient to their clinical outcome based on either PET/CT scan and/or clinical assessment after definitive treatment. Results: CTCs were detected in 39/72 (54%) of patients (ranging from 1-18 CTCs/10 mL blood) at diagnosis. CTC numbers were correlated to TNM staging (p Conclusion: We were able to predict disease progression based on CTC numbers, thus providing potential additional prognostic information for locally advanced HNC patients. The ability to detect CTCs at diagnosis allows us to stratify the risk in patients as well as to understand the fundamental mechanisms by which CTCs spread. The clinical benefit of establishing the use of CTCs in HNC is likely to translate into better patient selection for treatment intensification and/or de-intensification strategies. Citation Format: Xi Zhang, Kai Tang, Brett Hughes, Sarj Vasani, Zhen Liu, Majid Warkiani, Gunter Hartel, Rahul Ladwa, Liz Kenny, Chamindie Punyadeera. Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 602.

Background: In the multicenter, open-label, nonrandomized, phase 2 KEYNOTE-629 trial, pembro has demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile for R/M cSCC based on the first interim analysis (IA). Here, we present the second IA of KEYNOTE-629, which reports the initial efficacy and safety data for the LA cohort and updated data for the R/M cohort in cSCC.Methods: Eligible patients (pts) were ≥18 years old, had histologically confirmed cSCC (LA or R/M) with measurable disease per RECIST 1.1 by blinded independent central review (BICR), an ECOG PS score of 0 or 1, and adequate organ function. Pts received intravenous pembro 200 mg every 3 weeks for up to 35 infusions (~ 2 years) or until protocol-specified treatment discontinuation criteria were met. The primary endpoint was ORR per RECIST 1.1 by BICR. Secondary endpoints were DOR, DCR, and PFS, all per RECIST 1.1 by BICR; OS; and safety and tolerability. Results: A total of 159 pts were enrolled and treated with pembro (LA, n=54; R/M, n=105). The median time from the first dose to data cutoff (July 29, 2020) was 14.9 (range, 10.1-19.4) mo for the LA cohort and 27.2 (range, 24.6-32.0) mo for the R/M cohort. In the LA cohort, 22.2% of pts were treated with prior systemic therapy with curative intent. In the R/M cohort, 86.7% of pts received ≥1 prior systemic therapy. Updated efficacy outcomes are summarized in the table. Across cohorts, grade 3-5 treatment-related AEs occurred in 11.9% of pts. Grade 3-5 immune-related AEs occurred in 8.2% of pts. Conclusions: Pembro confirmed robust and durable antitumor activity, with promising survival in LA and R/M cSCC. AEs with pembro in this study were generally consistent with its established safety profile. These data support the use of pembro for cSCC. LA cSCC(N=54)R/M cSCC(N=105)Total(N=159)ORR, % (95% CI)50.0 (36.1-63.9)35.2 (26.2-45.2)40.3 (32.6-48.3)DCR (SD ≥12 wks + ORR), % (95% CI)64.8 (50.6-77.3)52.4 (42.4-62.2)56.6 (48.5-64.4)Best overall response, n (%)CR9 (16.7)11 (10.5)20 (12.6)PR18 (33.3)26 (24.8)44 (27.7)SD13 (24.1)30 (28.6)43 (27.0)SD≥12 wks8 (14.8)18 (17.1)26 (16.4)PD9 (16.7)28 (26.7)37 (23.3)NE1 (1.9)2 (1.9)3 (1.9)No assessment4 (7.4)8 (7.6)12 (7.5)DOR, median (range), moNR (1.0+-17.2+)NR (2.7-30.4+)NR (1.0+-30.4+)Patients with extended responses≥12 months, n (%)10 (84.1)25 (77.8)35 (80.3)PFS, median (95% CI), moNR (5.5-NR)5.7 (3.1-8.5)7.8 (5.3-12.3)12-mo PFS rate, % (95% CI)54.4 (39.6-67.0)36.4 (27.0- 45.9)42.4 (34.3-50.2)OS, median (95% CI), moNR (NR-NR)23.8 (13.4-29.8)26.4 (19.5-NR)12-mo OS rate, % (95% CI)73.6 (59.5-83.4)61.0 (50.9-69.5)65.1 (57.1-72.0) Citation Format: Brett G.M. Hughes, Eva Munoz-Couselo, Laurent Mortier, Åse Bratland, Ralf Gutzmer, Osama Roshdy, Rene González Mendoza, Jacob Schachter, Ana Arance, Florent Grange, Nicolas Meyer, Abhishek Joshi, Salem Billan, Pingye Zhang, Burak Gumuscu, Ramona F. Swaby, Jean-Jacques Grob. Phase 2 study of pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): KEYNOTE-629 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT006.

Introduction: In the phase 3 KEYNOTE-048 trial (NCT02358031) in R/M HNSCC, first-line pembrolizumab (P) monotherapy vs EXTREME (E; chemotherapy [C] + cetuximab) improved overall survival (OS) in PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 populations and led to noninferior OS in the total population with favorable safety; first-line P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety. Outcomes in CPS Table.Efficacy in subgroups of patients with PD-L1 CPS Citation Format: Barbara Burtness, Danny Rischin, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, Åse Bratland, Thorsten Fuereder, Brett G. Hughes, Ricard Mesia, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Joy Ge, Ramona Swaby, Burak Gumuscu, Kevin Harrington. Efficacy of first-line (1L) pembrolizumab by PD-L1 combined positive score

Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predictive of outcome to immunotherapy. Comprehensive characterization of the tumor microenvironment and liquid biopsy allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies. Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Brett Hughes, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera. Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3384.

Background: Findings from Phase I and II clinical trials suggest that treatment with an anti-programmed death 1 (PD-1) antibody is well tolerated and provides durable antitumor activity in patients with local/regionally advanced or metastatic cutaneous squamous cell carcinoma (cSCC). Encouraging efficacy and safety findings have also been reported from an expansion cohort in the phase 1 KEYNOTE-012 trial with the PD-1 inhibitor pembrolizumab. KEYNOTE-012 demonstrated that pembrolizumab 200 mg administered once every 3 weeks was well tolerated and yielded a clinically meaningful overall response rate with evidence of durable responses in patients with recurrent and/or metastatic head and neck cSCC. To test the clinical activity of pembrolizumab, the open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be carried out in patients with locally advanced, unresectable, and recurrent or metastatic cSCC. Trial design: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC that is ineligible for surgical resection or radiotherapy (RT) or that previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing study treatment administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by computed tomography or magnetic resonance imaging 6 weeks after treatment initiation, every 6 weeks through year 1, then every 9 weeks thereafter or more frequently if clinically indicted. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study treatment and for 30 days after treatment end and for 90 days for serious adverse events after the end of treatment. The primary end point is objective response rate (RECIST v1.1). Secondary end points include duration of response, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced unresectable cSCC are enrolled. Citation Format: Jean-Jacques Grob, Rene Gonzalez Mendoza, Nicole Basset-Seguin, Jacob Schachter, Olga Vornicova, Jessica Bauman, Florent Grange, Nicolas Meyer, Josep Piulats, Pingye (Eric) Zhang, Burak Gumuscu, Ramona Swaby, Brett GM Hughes. KEYNOTE-629: Phase II study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT170.

Purpose: Elevated levels or increases in circulating tumor cells (CTC) portend poor prognosis in patients with epithelial cancers. Less is known about CTCs as surrogate endpoints or their use for predictive biomarker evaluation. This study investigated the utility of CTC enumeration and characterization using the CellSearch platform, as well as mutation detection in circulating tumor DNA (ctDNA), in patients with advanced non–small cell lung cancer (NSCLC). Experimental Design: Forty-one patients were enrolled in a single-arm phase II clinical trial of erlotinib and pertuzumab. Peripheral blood was analyzed for CTC enumeration, EGFR expression in CTCs, and detection of oncogenic mutations in CTCs and ctDNA. Changes in CTC levels were correlated with 2[18F]fluoro-2-deoxy-d-glucose–positron emission tomographic (FDG-PET) and computed tomographic (CT) imaging and survival endpoints. Results: CTCs were detected (≥1 CTC) at baseline in 78% of patients. Greater sensitivity for mutation detection was observed in ctDNA than in CTCs and detected mutations were strongly concordant with mutation status in matched tumor. Higher baseline CTC counts were associated with response to treatment by Response Evaluation Criteria in Solid Tumors (RECIST, P = 0.009) and decreased CTC counts upon treatment were associated with FDG-PET and RECIST response (P = 0.014 and P = 0.019) and longer progression-free survival (P = 0.050). Conclusion: These data provide evidence of a correlation between decreases in CTC counts and radiographic response by either FDG-PET or RECIST in patients with advanced NSCLC. These findings require prospective validation but suggest a potential role for using CTC decreases as an early indication of response to therapy and ctDNA for real-time assessment of mutation status from blood. Clin Cancer Res; 18(8); 2391–401. ©2012 AACR.

Purpose: Assessing clinical activity of molecularly targeted anticancer agents, especially in the absence of tumor shrinkage, is challenging. To evaluate on-treatment 18F-fluorodeoxyglucose (FDG) and/or 18F-fluorodeoxythymidine (FLT) positron emission tomography (PET) for this purpose, we conducted a prospective multicenter trial assessing PET response rates and associations with progression-free (PFS) and overall survival (OS) in 2nd/3rd-line non–small-cell lung cancer patients treated with erlotinib. Experimental Design: PET/computed tomography (CT) scans were conducted at baseline, day (d)14 and d56 after the first daily erlotinib dose, with diagnostic CT at baseline and d56 (all scans centrally reviewed). PET partial metabolic response (PMR) was defined as a mean decrease (in ≤5 lesions/patient) of 15% or more maximum standardized uptake value. PFS was investigator-determined. Results: Of 74 erlotinib-treated patients, 51 completed all imaging assessments through d56; 13 of 51 (26%) FDG-evaluable patients had PMR at d14, as did 9 of 50 (18%) FLT-evaluable patients. Four (7.8%) showed partial responses (PR) by d56 CT; all 4 had PMR by d14 FDG-PET with 3 PMRs by d14 FLT-PET. Three of the 4 patients with CT PR had evaluable archival tumor tissue; all 3 had epidermal growth factor receptor mutations. D14 and d56 PMRs by FDG or FLT were associated with improved PFS; HRs for PET responders versus nonresponders were 0.3 to 0.4. D14 FDG-PET PMR was associated with improved OS (P = 0.03) compared with FDG-PET nonresponders. Conclusion: Early (d14) FDG-PET PMR is associated with improved PFS and OS, even in the absence of subsequent Response Evaluation Criteria in Solid Tumors response. These data support inclusion of FDG-PET imaging in clinical trials testing novel targeted therapies, particularly those with anticipated cytostatic effects. Clin Cancer Res; 17(10); 3304–15. ©2011 AACR.

Introduction: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway, which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown using an in vivo tumorigenicity limiting dilution assay to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels, resulting in an antiangiogenic effect. Data from a phase 1b study of carboplatin (C), pemetrexed (P), and demcizumab (D) in patients with 1st-line metastatic non-squamous NSCLC led to this double-blind randomized 3-arm placebo (Pl)-controlled phase 2 study. Methods: Patients with non-squamous NSCLC were randomized (1:1:1) to 1st-line therapy with either Arm 1 -CPPl, Arm 2 -CPD with a single 70-day truncated course of demcizumab or Arm 3 - CPD with two 70-day truncated courses of demcizumab (second course starting on Day 168). CP were given at usual dose and schedule; P/D was given IV on days 1 and 15 in cycles 1-3 and 7-9. The primary endpoint was response rate and secondary endpoints included progression-free survival, survival, safety, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles, and tumor cells. The primary study analyses compared CPPl to the two pooled CPD arms. Results: 82 patients were randomized and all 82 were treated. The median age was 61, the male/female ratio was 40/42, 80 pts had adenocarcinoma, 0 pts harbored EGFR mutation or ALK rearrangement, and 15 were KRAS mutated. The response/clinical benefit rates were 52%/92% and 28%/79% in the CPPl and pooled CPD arms, respectively (response p value = 0.04). The median progression-free survival (PFS) was 8.7 months (95% CI: 5.4-12.5) in the CPPl arm and 5.5 months (95% CI: 4.1-6.9) in the pooled CPD arms (HR = 2.3; 95%CI: 1.1-4.8). The interim median overall survival (OS) for the CPPl and pooled CPD arms was not reached (95% CI: 16.0—NR) and 15.5 months (95% CI: 8.3-NR) (HR= 2.4; 95% CI: 0.94-6.1), respectively. CPD was generally well tolerated with nausea, fatigue, constipation, anemia, and hypertension being the most common reported toxicities. The incidences of the Grade 3 or greater toxicities of special interest with demcizumab therapy were hypertension (8% vs 25%), pulmonary hypertension (0% vs 0%), heart failure (0% vs. 0%), and bleeding (0% vs. 3.4%) in the CPPl and pooled CPD arms, respectively. Conclusions: The addition of either 1 or 2 truncated courses of demcizumab to 1st-line carboplatin and pemetrexed did not improve the efficacy compared to CPPl in patients with 1st-line metastatic NSCLC. CPD therapy was generally well tolerated. Citation Format: Brett Hughes, Andrew Dean, Ben Markman, Luke Dreisbach, Mariano Provencio, Libero Ciuffreda, Rachel Dear, Peter Graze, Alforia Nadal, Baerin Houghton, Teresa Moran, Rachel Roberts, Grace Dy, Taus Alvaro, Alex Martinez Marti, Rainer Brachmann, Robert Stagg, Ramaswamy Govindan. DENALI: a 3-arm double-blind randomized phase 2 study of carboplatin, pemetrexed, and placebo (CPP) versus carboplatin, pemetrexed, and either 1 or 2 truncated courses of demcizumab (CPD) in patients with non-squamous non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A084.

Background: Accumulation of extracellular adenosine in the tumor microenvironment activates A2aR suppressing anti-tumor immunity. CPI-444 is an oral, selective A2aR antagonist with single agent (SA) antitumor efficacy in mouse models, and the addition of anti-PD-1/PD-L1 antibodies leads to synergistic anti-tumor activity. CPI-444 was well-tolerated in previous clinical trials in the non-oncology setting. This phase 1/1b open-label clinical trial uses a 2-step adaptive design to evaluate CPI-444 alone and in combination with atezolizumab (atezo, Tecentriq®) in patients(pts) with advanced cancers. Preliminary efficacy and safety results in the dose selection phase (Step 1) are reported. This is the first report of adenosine inhibition as a treatment for cancer. Methods: Adult pts who have failed up to 5 standard therapies with advanced solid tumors were enrolled. In Step 1, pts were randomized 1:1:1:1 to 1 of 4 dose cohorts (28 days/cycle) including 3 SA cohorts (100mg BID x 14 days(d), 100mg BID x 28d and 200 mg QD x 14d) or combined with atezo (CPI-444 50mg or 100 mg BID x 14d + atezo 840mg IV q2 weeks). Primary objectives: safety and efficacy and defining the optimal dose and schedule of CPI-444. Results: 48 pts were enrolled in Step 1; 47 received treatment. Median age was 65 years (range, 36-84).Tumor types enrolled were: non- small cell lung cancer(NSCLC, n=10), triple negative breast cancer (TNBC,n=10),melanoma(MEL,n=7), urothelial bladder cancer(UBC,n=6), renal cell cancer(RCC,n=5), MSI-H colorectal cancer(CRC,n=4), head and neck cancer (SCCHN, n=3)and prostate cancer (n=2). Median number of prior systemic regimens was 4(range, 1-5). Twenty-four pts received prior anti PD-1/PD-L1 therapy. One pt in the combination cohort had reversible grade 3 autoimmune hemolytic anemia which was the only DLT observed. Biomarker analyses defined the optimal dose of CPI-444 as 100 mg bid x 28 days. With a median follow-up time of 12 weeks(range, 2-32), the overall disease control rate (DC defined as CR, PR or SD) was 45% per RECIST. Nineteen pts had SD;15 pts received SA CPI-444. Two pts had a PR; both received SA. Of 5 RCC pts enrolled, 4 had DC (1 PR, 3 SD). Of these 4 RCC pts, 3 are receiving SA CPI-444 including the patient with PR. These 4 RCC pts remain on treatment with 2 pts on treatment for > 30 weeks. Of 7 MEL pts, 1 pt receiving SA had a PR and 2 had SD. SD was observed in 5/10 NSCLC pts, 4/10 TNBC pts, as well as 2/6 UBC pts and 1 pt each with CRC, SCCHN and prostate cancer. The proportion of pts with DC were similar for pts treated with CPI-444 alone and for pts treated with CPI-444 combined with atezo. 9/18(50%) pts who were naïve to anti-PD-1/PD-L1 treatment achieved DC as well as 10/24(42%) of pts who were resistant/ refractory to anti-PD1/PDL1 therapy. The most common (≥ 10% of pts) adverse events related to study drug were Grade 1 or 2 nausea (13%) and fatigue (19%). Conclusion: Inhibition of adenosine signaling through the A2aR results in anti-tumor activity in pts with advanced solid tumors. Responses are observed in multiple histologies both as a SA and in combination with atezo and in pts naïve or resistant/refractory to anti-PD-1/PD-L1 therapy. The optimal dose is 100 mg bid continuous. Enrollment in Step 2, evaluating disease-specific cohorts, is ongoing. Citation Format: Leisha Emens, John Powderly, Lawrence Fong, Joshua Brody, Patrick Forde, Matthew Hellmann, Brett Hughes, Shivaani Kummar, Sherene Loi, Jason Luke, Daruka Mahadevan, Benjamin Markman, Ian McCaffery, Richard Miller, Ginna Laport. CPI-444, an oral adenosine A2a receptor (A2aR) antagonist, demonstrates clinical activity in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT119. doi:10.1158/1538-7445.AM2017-CT119

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material and Methods: Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Results: Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in ≥10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 167 and 183, respectively. As a result, the duration of DEM was limited to 63 days in the 7.5 mg/kg dose cohort. The pharmacokinetics and immunogenicity specimens are being analyzed and these data will be presented. Nine of the 23 (39%) evaluable patients had a RECIST partial response and 11 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.3 months. Conclusion: DEM, pemetrexed and carboplatin was generally well tolerated with nausea, fatigue and hypertension being the most common drug related toxicities. The duration of demcizumab therapy is being limited to 63 days in subsequent cohorts due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Enrollment is ongoing and updated results will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A71. Citation Format: Mark McKeage, Dusan Kotasek, Ben Markman, Michael Millward, Manuel Hildalgo, Michael Jameson, Dean Harris, Robert Stagg, Jakob Dupont, Brett Hughes. A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A71.