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Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.

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S1. Therapeutic strategies and corresponding laboratory tests.

S2. Policy and Infrastructure driven solutions noted for support of immunology work.

BackgroundThe MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20).MethodsIn 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety.ResultsIn MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred.ConclusionAtezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent’s known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Background : This phase 1b study investigated safety and activity of combined checkpoint inhibition (CPI) with programmed death-ligand 1 (PD-L1) antibody atezolizumab plus cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab in NSCLC. Patients and Methods : Eligible patients had previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) or melanoma. A standard 3+3 dose escalation investigated atezolizumab (600-1200 mg IV every 3 weeks) plus ipilimumab starting at 1 mg/kg, administered as a single dose or 4 doses, administered every 3 weeks. The expansion stage included a cohort previously treated with atezolizumab. Patients were monitored for safety and tolerability; response was evaluated every 6 weeks. Results : Twenty-seven patients were enrolled, 4 with melanoma and 23 with NSCLC; here, we focus on data for the NSCLC population. Three of 23 patients (13.0%) received prior CPI. No dose-limiting toxicities were reported during dose escalation; dose expansion occurred with atezolizumab 1200 mg plus 1 cycle of ipilimumab 1 mg/kg. Most common treatment-emergent adverse events (AEs) were dyspnea (39%) and cough (35%); treatment-related grade ≥3 AEs occurred in 11 patients (48%), most frequently pneumonitis (17%) and amylase or lipase elevation (9% each). Six of 23 NSCLC patients (26%) achieved confirmed responses, 5 of whom (25%) were CPI-naive. Median duration of response was 23.0 (95% CI, 3.2-36.9) months overall and 36.9 (95% CI, 2.9-36.9) months in CPI-naive patients. Conclusion : Preliminary efficacy of atezolizumab plus ipilimumab was observed in metastatic NSCLC. The combination had manageable toxicity, with a safety profile consistent with those of the individual agents. MicroAbstract : Dual checkpoint inhibitor therapy with atezolizumab (anti–PD-L1) and ipilimumab (anti–CTLA-4) may improve outcomes in locally advanced or metastatic NSCLC. This phase 1b study investigated atezolizumab plus ipilimumab in 23 patients with previously treated NSCLC. The combination had manageable toxicity and demonstrated preliminary clinical activity. Further elucidation of biomarkers to optimally select patients for checkpoint inhibitor therapy may be required.

ObjectivesEpigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.DesignAlternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.ResultsAPBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).ConclusionThese findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

Background Talimogene laherparepvec (T-VEC) is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and to produce granulocyte-macrophage colony-stimulating factor to enhance systemic antitumor immune responses. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with the checkpoint inhibitors (CPI) pembrolizumab and ipilimumab. Additionally, T-VEC monotherapy has demonstrated tolerable safety for intrahepatic injection (Hecht GICS 2018). Atezolizumab (atezo) is a humanized monoclonal antibody that promotes antitumor immunity by targeting programmed cell death ligand-1 (PD-L1) and is approved for metastatic triple negative breast cancer (mTNBC). We hypothesize that T-VEC in combination with a CPI may be effective in mTNBC and CRC in addition to melanoma. This phase 1b, multicenter study (clinicaltrials.gov identifier: NCT03256344) evaluates the safety of intrahepatic injection of T-VEC in combination with intravenous (IV) atezo in patients (pts) with mTNBC or colorectal cancer (CRC) with liver metastases (LMs). Here we report early safety data in the TNBC cohort. Methods Key eligibility criteria included age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG PS 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable LM suitable for injection. T-VEC (≤ 4mL) was injected by image-guided intralesional injection: 106 PFU/mL day 1, 108 PFU/mL every 21 days thereafter; atezo 1,200 mg IV was given on day 1 and every 21 days thereafter. The primary objective of this study is to evaluate incidence of dose limiting toxicity (DLT) for safety of T-VEC injection into LMs in combination with IV atezo, by tumor type. The DLT analysis set included DLT-evaluable pts who were on treatment for at least 6 weeks from the initial dose of study treatment and received at least 2 doses of T-VEC and 2 doses of atezo in combination or have a DLT during the DLT evaluation period. Key secondary objectives include objective response rate, durable response rate, progression-free survival, and overall survival of the combination therapy, by tumor type. Results Thirty-two pts were enrolled in two parallel cohorts (8 TNBC, 24 CRC). Of the 8 TNBC pts, 4 were evaluable for DLT at the time of this analysis. Of the 4 pts that were not DLT-evaluable, 1 never received study drug, 1 received atezo monotherapy, and 2 received intrahepatic T-VEC and IV atezo but stopped study drugs for unconfirmed progression before the DLT evaluation period was completed. No DLTs were reported in the TNBC cohort. In the 7 TNBC pts who received at least one dose of the study drug, the most common treatment-emergent adverse events (TEAEs) in terms of the subject incidence were pyrexia (71.4%), chills (42.9%), and rash (42.9%). In the 7 TNBC pts who received at least one dose of study drug, T-VEC related AEs in more than one pt were pyrexia (n=3) and chills (n=2). Atezo related AEs in more than one pt were pyrexia (n=5), chills and rash (n=3 each), and fatigue, arthralgia, pain, and pruritus (n=2 each). Study drug-related serious adverse events (SAEs) occurred in 3 (42.9%) pts, including Grade (G) 3 hypersensitivity related to atezo, G3 orthostatic hypotension related to T-VEC and atezo, and G1 pyrexia related to T-VEC and atezo. Procedure-related SAEs occurred in 1 (14.3%) pt, of G3 hepatic hematoma and G3 abdominal infection, but these were not related to the study drugs. One confirmed partial response in the TNBC cohort has been seen thus far. Conclusion T-VEC intrahepatic injection in combination with IV atezo at standard doses has thus far been demonstrated as feasible and tolerable with no DLTs observed in the TNBC cohort to date. Citation Format: Joel Randolph Hecht, Arlene Chan, Jean-Francois Baurain, Miguel Martin, Federico Longo-Munoz, Kevin Kalinsky, Steven Raman, Chunxu Liu, Edward Cha, Emily Chan. Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-19.

BackgroundXL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases. In preclinical studies, oral dosing with XL092 resulted in pharmacodynamic inhibition of MET, TAM kinases (AXL, MER), and VEGFR2 phosphorylation and was associated with significant anti-tumor activity in xenograft tumor models. Drugs targeting TAM kinases may promote an immune-permissive environment, which may enhance response to immune checkpoint inhibitors (ICIs). The combination of XL092 and anti–PD-1 ICI exhibited greater anti-tumor activity in a syngeneic tumor model than either agent alone.[1] Preliminary XL092 pharmacokinetic data indicate a median terminal half-life of 21 hours, suitable for daily dosing.MethodsThis multi-center, phase 1, open-label study aims to enroll approximately 800 patients total in dose-escalation and cohort-expansion stages (NCT03845166). The dose-escalation stage will enroll patients with inoperable locally advanced or metastatic solid tumors in a 3+3 design (monotherapy cohorts) or rolling 6 design (combination cohorts). Patients will receive escalating doses of XL092 alone or in combination with ICIs (atezolizumab 1200mg Q3W or avelumab 800mg Q2W). Following identification of the maximum tolerated dose (MTD) and/or recommended dose (RD) of XL092 monotherapy, the expansion stage will enroll XL092 monotherapy cohorts in 3 tumor-specific indications (renal cell carcinoma [RCC], metastatic castration-resistant prostate carcinoma [mCRPC], and hormone-receptor positive breast carcinoma [HR+ BC]) using a Simon’s optimal 2-stage design. Once the MTDs/RDs are identified for XL092 in combination with each ICI, the expansion stage will also enroll patients in tumor-specific cohorts for XL092+atezolizumab (RCC, mCRPC, HR+ BC, and colorectal carcinoma) and XL092+avelumab (urothelial carcinoma) using Simon’s optimal 2-stage design or a Precision-Based design. A limited number of patients will be enrolled in dedicated biomarker cohorts, with tumor and blood samples collected, to evaluate the pharmacodynamic effects of XL092 alone and in combination with ICIs. Key eligibility criteria include unresectable or metastatic solid tumors; measurable disease per RECIST 1.1 (expansion cohorts only); available tumor tissue (archival or fresh biopsy); and ECOG 0-1. The primary objective of the dose-escalation stage is to determine MTDs/RDs of XL092 when administered alone or in combination with ICIs, and the primary objective of the expansion stage is to evaluate objective response rate and progression-free survival rate by investigator per RECIST 1.1 of XL092 as monotherapy or in combination with ICIs. Secondary objectives include evaluation of the safety of XL092 alone and in combination with ICIs and evaluation of plasma pharmacokinetics of XL092 and its potential metabolites. The study is open for enrollment.AcknowledgementsMedical writing support provided by Griselda Zuccarino-Catania, PhD (Exelixis, Inc.)Trial RegistrationNCT03845166ReferencesHsu J, Chong C, Goon L, et al. XL092, a Multi-targeted Inhibitor of MET, VEGFR2, AXL and MER with an Optimized Pharmacokinetic Profile. European Journal of Cancer [abstract 33] 2020;138 Suppl 2:S16.Ethics ApprovalStudy approved by institutional Review Boards at each investigational site.

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1–9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10–20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1–85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6–25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway. Treatment with BRAF and/or MEK inhibitors followed by addition of anti-PD-L1 in BRAF-mutant melanoma patients is safe and shows promising anti-tumor activity.

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge. To address this unmet need, the Society for Immunotherapy of Cancer convened a multistakeholder taskforce—consisting of experts in cancer immunotherapy from academia, industry, and government—to generate consensus clinical definitions for resistance to PD-(L)1 inhibitors in three distinct scenarios: primary resistance, secondary resistance, and progression after treatment discontinuation. The taskforce generated consensus on several key issues such as the timeframes that delineate each type of resistance, the necessity for confirmatory scans, and identified caveats for each specific resistance classification. The goal of this effort is to provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance.

Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO1). Here we report results from the open‐label, dose‐escalation, Phase 1b ECHO‐110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum‐based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose‐limiting toxicities (DLTs). Twenty‐nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty‐three patients (79%) had treatment‐related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment‐related AEs. No fatal treatment‐related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD‐L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD‐L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited., What's new? There has been considerable interest in investigating combination treatment strategies that target separate but complementary immune‐evasion pathways, in patients with advanced non‐small‐cell lung cancer (NSCLC). The goal is to enhance the efficacy of immune checkpoint inhibitors. In this study, the authors found that combining the IDO1 enzyme inhibitor epacadostat with the PD‐L1 checkpoint inhibitor atezolizumab was generally well tolerated. However, clinical activity was limited. These results provide important insights into the challenges associated with developing combination immunotherapies in NSCLC.

TPS401 Background: XL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases MET, VEGFR2, and TAM kinases (AXL, MER), which are important in tumor growth, neovascularization, and immune modulation of the tumor microenvironment. XL092 as a single-agent and in combination with an anti-PD-1 antibody showed antitumor activity in xenograft tumor models (Hsu et al. 2020). This first-in-human study is evaluating safety, pharmacokinetics (PK), and preliminary antitumor activity of XL092 with or without (w/wo) ICIs in pts with advanced solid tumors. Presented here are the trial design and details of GU cohorts. Methods: In this phase 1, multicenter, open-label, dose-escalation and expansion study (NCT03845166), pts will receive escalating doses of XL092 w/wo atezolizumab (ATEZO) 1200 mg Q3W or avelumab (AVE) 800 mg Q2W. The dose-escalation stage is enrolling pts with inoperable locally advanced or metastatic solid tumors using a 3+3 (single-agent) or rolling 6 (combination) design; the primary objective is to determine maximum tolerated dose and/or recommended dose of XL092 for further evaluation when administered w/wo ICIs; secondary objective is to evaluate plasma PK of XL092 and its metabolites alone and in combination with ICIs. Primary objectives for the expansion stage are to evaluate preliminary efficacy of XL092 w/wo ICIs by estimating objective response rate (ORR) by investigator (Inv) per RECIST 1.1 and for specific cohorts by estimating the % of pts with PFS at 6 months by Inv per RECIST 1.1; secondary objective is safety of XL092 w/wo ICIs via monitoring nonserious and serious adverse events (AEs) including immune related AEs and AEs of special interest. For GU cohorts in expansion stage, single-agent XL092 will be tested in: (i) previously treated advanced clear cell (cc) renal cell carcinoma (RCC; progression on 1-3 prior systemic regimens w/wo a sarcomatoid component); (ii) previously treated advanced non-cc RCC (progression on 1-3 prior systemic regimens); (iii) metastatic castration resistant prostate cancer (mCRPC; prior treatment with ≥1 novel hormonal therapy and taxane-based chemotherapy, ≤4 prior systemic regimens). XL092 + ATEZO will be tested in non-cc RCC and mCRPC cohorts. Pts with advanced urothelial carcinoma will be enrolled in 3 cohorts: (i) pts with ongoing CR/PR/SD after 4-6 cycles of first-line chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) will receive XL092 + AVE; (ii) pts with progression on/after prior ICI therapy (≤2 prior systemic therapies) will be randomized 1:1 to XL092 + AVE or single-agent XL092; (iii) pts with progression on/after first-line platinum-based chemotherapy will receive XL092 + AVE. The study is currently enrolling pts. Clinical trial information: NCT03845166.

Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.

BACKGROUND: Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors. PATIENTS AND METHODS: This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21 days on, 7 days off. Atezolizumab was dosed at 800 mg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival. RESULTS: Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n = 84), melanoma (n = 22), non-small-cell lung cancer (NSCLC; n = 28), and other solid tumors (n = 16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF

3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers. Here, atezo (anti-PD-L1) was tested with Imprime and bev (anti-VEGF) for MSS mCRC, a poorly immunogenic cancer generally resistant to checkpoint inhibitors. Imprime acts as a pathogen-associated molecular pattern that, when bound to anti-β glucan antibodies (ABA), activates the innate immune system with the potential to 1) promote priming and expansion of tumor-specific T cells, 2) promote M2-M1 macrophage polarization and 3) enhance the immunomodulatory effects of atezo and bev. Therefore, we hypothesized that atezo + Imprime + bev would induce an antitumor response beyond that of rego, a standard-of-care multikinase inhibitor, in patients (pts) with MSS mCRC. Methods: Pts with MSS mCRC unselected for the Imprime-specific biomarker (ABA) and refractory to 1-2 prior lines of standard therapy received atezo (1200 mg IV every 3 weeks [q3w]) + Imprime (4 mg/kg IV on Days 1, 8, 15) + bev (7.5 mg/kg IV q3w) or control tx with rego (160 mg orally days 1-21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included disease control rate (DCR; response or stable disease ≥ 12 weeks), progression-free survival (PFS), overall survival (OS) and safety. Results: Pts were followed-up for ≥18 wk. 15 pts received atezo + Imprime + bev and 13 received rego. Grade (Gr) 3/4 tx-related adverse events (TRAEs) were seen in 13% of atezo + Imprime + bev and 62% of rego pts. No Gr 5 AEs occurred in atezo + Imprime + bev pts and 1 (8%) was reported in a rego pt. One pt in each arm (7% vs 8%, respectively) withdrew from tx due to a TRAE. No radiological responses were seen in either arm. Five pts (33%) receiving atezo + Imprime + bev and 8 (62%) receiving rego had stable disease as best response. DCR was 13% with atezo + Imprime + bev and 23% with rego. Median PFS was 1.5 mo (95% CI: 1.4, 2.8) and 2.8 mo (95% CI: 1.6, 3.1), and median OS was 5.7 mo (95% CI: 4.4, 10.5) and 10.2 mo (95% CI: 4.8, NE) with atezo + Imprime + bev and rego, respectively. There was no apparent correlation between baseline PD-L1 expression or CD8+ lymphocyte tumor infiltration and clinical benefit. Further, the systemic exposure of atezo, Imprime and bev and immunogenicity of atezo and bev are in line with previous clinical experience. Additional biomarker, pharmacokinetics and anti-drug antibody data will be shown. Conclusions: Atezo + Imprime + bev was well tolerated; toxicities were consistent with the safety profiles of the individual agents. No efficacy signal was identified with atezo + Imprime + bev in pts with MSS refractory mCRC. Clinical trial information: NCT03555149.

To gain a better understanding of the impact of dose and other prognostic factors on safety and efficacy of docetaxel in second-line non-small-cell lung cancer patients.A model-based meta-analysis (MBMA) of a published docetaxel monotherapy data in 6085 second-line non-small-cell lung cancer patients from 46 trials was conducted.The logit of grade 3/4 neutropenia incidence was a linear function of dose, with a 5% increase in the odds of neutropenia per mg/m(2) increase in dose [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.04-1.06], and a Japanese study effect (OR 17.1, 95% CI 6.05-48.4). The logit of overall response rate (ORR) was a linear function of cumulative dose (0.4% increase in the odds of response per mg/m(2) increase; OR 1.004, 95% CI 1.001-1.008) and median population age (OR 1.08 per year, 95% CI 1.02-1.15). A Japanese study effect was identified for overall survival (OS) in addition to prognostic factors identified by a previous meta-analysis.This current MBMA identified docetaxel dose-response relationships for both neutropenia and ORR, an effect of age on ORR, and Japanese study effects on both neutropenia and OS.

Background: The MORPHEUS platform comprises multiple Phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Within MORPHEUS, atezolizumab (atezo), a PD-L1 inhibitor, was tested in combination with cobimetinib (cobi), a MEK1/2 inhibitor, in patients with advanced/metastatic (m) NSCLC, PDAC or GC. Methods: MORPHEUS-NSCLC (NCT03337698) enrolled patients who had disease progression during or after receiving a platinum-based regimen and a PD-L1/PD-1 checkpoint inhibitor. MORPHEUS-PDAC (NCT03193190) enrolled patients who had received 1 prior line of systematic therapy. MORPHEUS-GC (NCT03281369) enrolled HER2-negative patients who had not received prior chemotherapy. Patients enrolled in the atezo + cobi arms received atezo 840 mg q2w and cobi 40 mg daily on days 1-21 of each 28-day cycle. In MORPHEUS-GC, patients in the atezo + cobi arm also received mFOLFOX6. This arm started with a safety run-in during which cobi 40 mg could be dose escalated to 60 mg. Control treatments were docetaxel (75 mg/m2) in MORPHEUS-NSCLC and mFOLFOX6 or gemcitabine (100 mg/m2) plus nab-paclitaxel (125 mg/m2) in MORPHEUS-PDAC. The MORPHEUS-GC safety run-in did not have a control. Primary endpoints were objective response rate (ORR; investigator-assessed RECIST 1.1) and safety. Results: MORPHEUS-NSCLC (data cutoff, April 10, 2019): 15 patients received atezo + cobi, and 14 patients received control treatment. No responses were observed, and 7 patients had stable disease (SD) as best response in the treatment arm. In the control arm, 3 patients had partial response (PR), and 5 patients had SD as confirmed best response. All treated patients were evaluable for safety, with 67% of atezo + cobi and 93% of control patients experiencing a treatment-related adverse event (TRAE). Updated data from MORPHEUS-NSCLC will be presented. MORPHEUS-PDAC (data cutoff, September 7, 2018): 14 patients received atezo + cobi, and 15 patients received control treatment. There were no responses in either study arm, but 6 patients in the control arm had SD as confirmed best response. All treated patients were evaluable for safety, with 79% of atezo + cobi and 87% of control patients experiencing a TRAE. MORPHEUS-GC (data cutoff, July 11, 2019): 5 patients received atezo + cobi + mFOLFOX6 in the safety run-in after which this arm was terminated (due to internal re-prioritization, no safety concerns identified). Two patients had PR, and 3 patients had SD as confirmed best response. All 5 patients had a TRAE. Biomarker data will also be presented. Conclusions: No superior efficacy signals were identified with atezo + cobi in NSCLC, PDAC or GC. The safety of atezo + cobi was consistent with each agent's known safety profile, with no new safety signals identified. Citation Format: Byoung Chul Cho, Nathan Bahary, Johanna Bendell, Enriqueta Felip, Melissa Johnson, Yoon-Koo Kang, Farah Louise Lim, Teresa Macarulla, Gulam Manji, Do-Youn Oh, Osama Rahma, Simon Allen, Edward Cha, Denise Cotting, Hans-Joachim Helms, Jan Pintoffl, Pakeeza Sayyed, Xiaosong Zhang, Kyu-pyo Kim. Phase Ib/II open-label, randomized evaluation of atezolizumab + cobimetinib vs control in MORPHEUS-NSCLC (non-small cell lung cancer), MORPHEUS-PDAC (pancreatic ductal adenocarcinoma) and MORPHEUS-GC (gastric 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 CT201.

TPS591 Background: Although CIT has efficacy against multiple cancers, only subsets of patients (pts) have durable responses with monotherapy. CIT combination treatment (tx) targets multiple immune-evasion mechanisms and may thus be more likely to improve outcomes. However, a large number of potential combinations need to be tested to identify effective combinations. The MORPHEUS platform comprises multiple global, open-label, randomized Phase Ib/II trials to identify early efficacy signals and safety of tx combinations in pts with different cancers. MORPHEUS-mUC is a randomized study of 6 CIT combinations compared with a single CIT control in pts with locally advanced UC/mUC who progressed during or after a platinum-containing regimen. The PD-L1 inhibitor atezolizumab will be combined with agents targeting different mechanisms (via nectin-4, PARP, CD47, CD38, DPP-4 and IL-6R) to simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells. To accelerate the clinical development of novel combinations, MORPHEUS has the flexibility, via amendment, to allow for the modification of eligibility criteria or the opening of new tx arms to replace arms that demonstrate no signs of clinical activity/unacceptable toxicity. Methods: MORPHEUS-mUC (NCT03869190) has 2 stages. In Stage 1, approximately 130-305 pts with histologically documented, locally advanced inoperable UC/mUC will be randomized to atezolizumab monotherapy (control) or experimental arms: atezolizumab + either enfortumab vedotin, niraparib, magrolimab (Hu5F9-G4), isatuximab, linagliptin or tocilizumab. Safety will be monitored for potential overlapping toxicities. Stage 2 arms will be atezolizumab + either enfortumab vedotin or linagliptin arms, unless these combinations show no activity in Stage 1. Eligible pts who experience unacceptable toxicity or loss of clinical benefit in Stage 1 may enroll in Stage 2 within 3 months. The primary study endpoint is investigator-assessed ORR per RECIST 1.1; secondary endpoints include PFS, OS, DOR, DCR and safety. Biomarkers will also be explored. Clinical trial information: NCT03869190.

CTLA-4 inhibition produces durable T cell–driven antitumor responses, but understanding which patients achieve a long-term benefit remains unclear. Deep sequencing of rearranged T cell receptor β (TCRβ) genes can monitor the effects of CTLA-4 inhibition and potentially identify patients with long-term survival.

This report is a summary of ‘New Cancer Immunotherapy Agents in Development’ program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.

TPS467 Background: CIT has significant survival benefits across multiple tumor types, but durable response is experienced by only subsets of patients (pts). To extend clinical benefit to more pts, efficacious CIT combinations (combos) targeting multiple cancer immune escape mechanisms need to be identified. The MORPHEUS platform includes multiple ph Ib/II trials designed to identify early signals of safety and efficacy of CIT combos. Using a randomized trial design, multiple treatment (tx) arms are compared with a single control arm in each pt cohort. We present three GI-specific MORPHEUS trials, each assessing CIT combos that could concurrently enhance multiple aspects of the cancer immune response. Methods: The MORPHEUS trials described here are global, open-label, randomized, Ph Ib/II trials enrolling pts with pancreatic ductal adenocarcinoma (PDAC), gastric or gastroesophageal junction cancers or colorectal cancer (CRC). New arms with novel CIT combos (table) are opened as new txs become available, and arms with minimal efficacy or unacceptable toxicity are closed. Studies include multiple cohorts for pts receiving different lines of tx (1L and 2L PDAC and gastric; 3L CRC). Pts with loss of clinical benefit or unacceptable toxicity may be eligible to enroll in a different CIT combo arm. Primary endpoints include safety and investigator-assessed ORR (RECIST v1.1); secondary endpoints: PFS, OS, DCR and DOR. Clinical trial information: NCT03193190, NCT03281369, NCT03555149. [Table: see text]

Intratumoral gene electroporation uses electric charges to facilitate entry of plasmid DNA into cells in a reproducible and highly efficient manner, especially to accessible sites such as cutaneous and subcutaneous melanomas. Effective for locally treated disease, electroporation of plasmid DNA encoding interleukin-12 can also induce responses in untreated distant disease, suggesting that adaptive immune responses are being elicited that can target melanoma-associated antigens. In vivo electroporation with immunomodulatory cytokine DNA is a promising approach that can trigger systemic anti-tumor immune responses without the systemic toxicity associated with intravenous cytokine delivery and potentially offer complete long-term tumor regression.

Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.

TPS4134Background: Multiple cancers have been treated successfully with CIT; nonetheless, only subsets of pts experience durable response with CIT monotherapy. CIT combinations may therefore be nee...

TPS9105Background: CIT has demonstrated a significant survival benefit in multiple cancers. Despite this, only subsets of pts experience durable response with CIT monotherapy. Thus, CIT combination...

560 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation of combined anti–PD-L1 (A) plus MEKi (C) in pts with mCRC. Methods: Pts with chemotherapy-refractory or locally advanced mCRC were evaluated. A was administered IV q2w at 800 mg. C was dosed PO daily at 20 to 60 mg during dose escalation and 60 mg during dose expansion (14/14 or 21/7 d on/off schedule). Primary endpoints were safety and tolerability. Investigator-assessed ORR and PFS by RECIST v1.1 and OS were secondary endpoints. Microsatellite instability (MSI) status was locally reported and centrally confirmed by NGS-based scoring. Results: As of May 10, 2017, 84 pts (57 KRASmt, 25 KRASwt, 2 unknown) were enrolled and evaluable. 66 pts had received 5+ prior therapies; 38 had known MSI status at baseline (MSS [n = 29], MSI-low [n = 8], MSI-H [n = 1]). A + C combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 37%, respectively. The most frequent related Gr 3-4 AEs were increased blood CPK, rash, diarrhea and fatigue (5% each). No treatment-related Gr 5 AEs occurred. 13% and 24% of pts experienced AEs leading to A and C withdrawal, respectively. Median follow-up was 14.3 mo (range, 0.5-29.8). Confirmed PR was observed in 7 pts (8%; locally reported MSS [n = 3], MSI-low [n = 1], MSI unknown [n = 3]). Median DOR was 14.8 mo (95% CI: 6.0, NE); DCR (PR + SD) was 31%. Median PFS was 1.9 mo (95% CI: 1.8, 2.3); median OS was 10.0 mo (95% CI: 6.2, 14.1). The 6-mo and 1-y OS rates were 65% (95% CI: 54, 76) and 46% (95% CI: 34, 58), respectively. Molecular determinants and immune biomarkers of response will be presented. Conclusions: A + C demonstrated a tolerable safety profile and improvements in OS vs those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts with MSS/MSI-low mCRC were durable, suggesting benefit of this novel combination in a pt population refractory to immune therapies. Clinical trial information: NCT01988896.

TPS530 Background: CIT has demonstrated significant survival benefits across multiple cancers. Despite remarkable success, only subsets of pts derive clinical benefit from CIT monotherapy. Thus, CIT combinations may be needed to address the mechanisms that allow cancers to escape antitumor immunity. However, a large number of potential combinations would have to be tested to identify an effective CIT combination regimen. The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to assess the impact of CIT combination therapies in pts with different tumor types. The randomized trial designs allow comparison of a single control arm vs multiple CIT combination arms. The trials will aid development of CIT combinations by identifying early signals and have the flexibility to open arms with new CIT combinations and close arms that show minimal clinical activity or unacceptable toxicity. Various CIT combinations that simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells for elimination will be evaluated. Here, we will describe Phase Ib/II trials in pts with gastric or gastroesophageal junction cancer (GC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), both of which represent populations with high unmet medical need. Methods: MORPHEUS-GC (NCT03281369) will enroll 2 cohorts including pts with advanced unresectable or metastatic GC who have not received prior chemotherapy (chemo) or have progressed on platinum- or fluoropyrimidine-based chemo. MORPHEUS-PDAC (NCT03193190) will enroll pts with mPDAC who have progressed on prior chemo. Further eligibility criteria details will be provided. Pts will be randomized to one of the CIT combination arms or a control arm (up to 8 arms across 2 cohorts in GC; 4 arms in PDAC). Pts experiencing loss of clinical benefit or unacceptable toxicity may be eligible to continue on a different CIT combination arm. Primary endpoints are investigator-assessed ORR per RECIST v1.1 and safety. Secondary endpoints include PFS, OS, DCR and DOR. Multiple exploratory biomarkers will also be examined. Clinical trial information: NCT03281369, NCT03193190.