Search

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.

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.

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.

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 (

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.

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]

Treatment for advanced prostate cancer has and will continue to grow increasingly complex, owing to the introduction of multiple new therapeutic approaches with the potential to substantially improve outcomes for this disease. Agents that modulate the patient's immune system to fight prostate cancer - immunotherapeutics - are among the most exciting of these new approaches. The addition of antigen-specific immunotherapy to the treatment of castration-resistant prostate cancer (CRPC) has paved the way for additional research that seeks to augment the activity of the immune system itself. The monoclonal antibody ipilimumab, approved in over 40 countries to treat advanced melanoma and currently under phase 2 and 3 investigation in prostate cancer, is thought to act by augmenting immune responses to tumors through blockade of cytotoxic T-lymphocyte antigen 4, an inhibitory immune checkpoint molecule. Ipilimumab has been studied in seven phase 1 and 2 clinical trials that evaluated various doses, schedules, and combinations across the spectrum of patients with advanced prostate cancer. The CRPC studies of ipilimumab to date suggest that the agent is active in prostate cancer as monotherapy or in combination with radiotherapy, docetaxel, or other immunotherapeutics, and that the adverse event profile is as expected given the safety data in advanced melanoma. The ongoing phase 3 program will further characterize the risk/benefit profile of ipilimumab in chemotherapy-naïve and -pretreated CRPC.

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...

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.

742 Background: The anatomical side of the colon where a tumor arises has been shown to be prognostic in patients treated with first-line therapy; patients with tumors that arise from the left side of the colon have significantly longer survival compared with patients whose tumors arise from the right side of the colon. However, there is little evidence of whether this factor is prognostic in later lines of treatment. The objective of this study was to determine the impact of tumor side on the survival of metastatic colorectal cancer patients who received second line (2L) or third line (3L) therapy. Methods: Metastatic (stage IV) colorectal cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims diagnosed 2001-2005 who received 2L (n = 921) or 3L (n = 502) therapy were included in the study. Overall survival (OS) was determined from the start of the indicated line of therapy and was estimated using the Kaplan-Meier method; statistical differences were tested using the log-rank tests. Results: The distribution of tumor sites was similar for 2L and 3L treated patients (right: 36%; left: 58%; transverse: 6%; for 2L). The median follow up time from start of therapy was 11 months (mo) for 2L and 10 mo for 3L patients. Median OS for left-sided tumors receiving 2L+ therapy was 13.6 mo (95%CI: 11.9, 14.8) compared with 8.7 mo (95%CI: 7.5, 9.9) for right-sided tumors (log-rank p < 0.001). Similar results were seen in patients receiving 3L+ therapy, although the difference was of lesser magnitude. The median OS for patients with left-sided tumors was 10.8 mo (95%CI: 9.6, 12.9) compared with 7.6 mo (95%CI: 5.7, 9.4) for right-sided tumors (log-rank p = 0.002). Conclusions: These results suggest that side of tumor origin remains a prognostic factor for colorectal cancer patients treated in later lines of therapy (2L+).

Background: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. Methods: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0–1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1–14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m−2) was administered on day 1 starting with cycle 2. 3′-Deoxy-3′-18F-fluorothymidine (18F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. Results: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing 18F-FLT-PET scans showed increases (23–92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAFV600E/K patients had significantly worse PFS than patients without these mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3′-Deoxy-3′-18F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

Genetic and epigenetic alterations can distinguish cancer cells from their normal counterparts, allowing tumors to be recognized as foreign by the immune system. The immune system's ability to detect and destroy these abnormal cells is the foundation of cancer immunotherapy. In order for this to occur immune cells must traffic and persist in the tumors. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and tumor-infiltrating immune cells, plays an important part in blocking immune-mediated tumor cell destruction by binding B7.1 (CD80) and programmed death-1 (PD-1), which is a negative regulator of T-lymphocyte activation. PD-L1 blockade has previously been shown to increase CD8+ T cell infiltration and PD-L1 protein levels, as well as the expression levels of immune genes in tumors. Vascular endothelial growth factor A (VEGF-A) is a secreted factor that specifically acts on endothelial cells to stimulate angiogenesis and has also been shown to exert immunosuppressive effects. Although some cytotoxic agents have been proposed to induce immunogenic cell death, the effects of chemotherapy and anti-angiogenic therapy on the tumor immune milieu have not been extensively studied. This study was designed to evaluate the safety, activity and biomarkers of combined FOLFOX treatment combined with PD-L1 and VEGF-A inhibition in 1L colorectal (CRC) patients using the humanized antibodies atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF-A), respectively. RECIST (v1.1) responses by the cutoff date of 09/01/2015 were observed in 52% (95% CI 30.6-73.2) of the patients (n = 23) with a median progression free survival of 14.1 months (95% CI 8.7-17.1) and a median duration of response of 11.4 months (95% CI 7.6-15.9). No unexpected toxicities were observed. We found that CD8+ T cells and PD-L1 expression by IHC were increased in tumors following administration of FOLFOX alone as well as after combined administration of FOLFOX, atezolizumab and bevacizumab. Elevations in cytotoxic T-cell signatures (e.g. CD8A, IFNγ, GZMB, EOMES) with treatment were also noted in several of the patient tumors. Patients with elevations in tumor-infiltrating CD8+ T cells consistent with increased expression of cytotoxic T-cell signatures and PD-L1 exhibited sustained responses or prolonged disease control. These data suggest that the combination of FOLFOX, atezolizumab, and bevacizumab promote immune-related activity in CRC potentially resulting in enhanced efficacy. Citation Format: Jeffrey Wallin, Michael J. Pishvaian, Genevive Hernandez, Mahesh Yadav, Suchit Jhunjhunwala, Lelia Delamarre, Xian He, John Powderly, Christopher Lieu, S Gail Eckhardt, Herbert Hurwitz, Howard S. Hochster, Janet Murphy, Vincent Leveque, Edward Cha, Roel Funke, Daniel Waterkamp, Priti Hegde, Johanna Bendell. Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab (anti-PDL1) in combination with FOLFOX and bevacizumab (anti-VEGF) in metastatic colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2651.

We conducted a phase II clinical trial of anti-CTLA-4 antibody (ipilimumab) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 22 patients with metastatic melanoma and determined clinical outcomes and immunologic responses. The treatment consisted of a 3-mo induction with ipilimumab at 10mg/kg administered every 3weeks for four doses in combination with GM-CSF at 125µg/m2 for 14d beginning on the day of the ipilimumab infusion and then GM-CSF for 3mo on the same schedule without ipilimumab. This was followed by maintenance therapy with the combination every 3mo for up to 2y or until disease progression or unacceptable toxicity. Blood samples for determination of immune subsets were obtained before treatment, at week 3 (end of cycle 1) and at week 6 (end of cycle 2). Blood samples were also obtained from seven subjects who were cancer-free. The immune response disease control (irDC) rate at 24weeks was 41% and the overall response rate (ORR) was 32%. The median progression free-survival (PFS) was 3.5mo and the median overall survival (OS) was 21.1mo. 41% of the patients experienced Grade 3 to 4 adverse events. We conclude that this combination is safe and the results suggest the combination may be more effective than ipilimumab monotherapy. Further, the results suggest that lower levels of CD4+ effector T cells but higher levels of CD8+ T cells expressing PD-1 at pre-treatment could be a potential biomarker for disease control in patients who receive immunotherapy with ipilimumab and GM-CSF. Further trials of this combination are warranted.

3016 Background: While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, the immunobiology and biomarkers associated with improved clinical outcomes is ...

8580 Background: Several clinical trials adding VEGF signaling inhibitors to chemotherapy have not demonstrated any benefit over chemotherapy alone in advanced melanoma potentially due to decreased tumor cell proliferation induced by VEGF blockade. We tested the hypothesis that sequential administration of axitinib followed by carboplatin and paclitaxel may be more effective than chemotherapy alone in metastatic melanoma. Methods: We conducted a prospective phase II trial of this combination in previously treated metastatic melanoma patients. Patients had an ECOG PS 0-1, and normal organ function. Axitinib 5 mg PO bid was taken on days 1 through 14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg/m2) was administered on day 1 starting with cycle 2. FLT-PET scans were performed on 6 patients to assess tumor cell proliferation on days 1, 14, 17, and 20 of cycle 1. Results: Treatment has been well tolerated. The most common grade 3 AEs have been neutropenia, hypertension, and gastrointestinal events. Grade 4 non-hematologic AEs have not been observed. 4 of 5 patients completing FLT-PET scans to date showed increases (23% to 92%) in SUV values during the axitinib holiday. The fifth patient had a single, minimally FLT avid lesion at baseline (SUV=1.9). In 30 evaluable patients, there have been 4 confirmed PRs, 2 unconfirmed PRs, and 3 patients with 28.6, 29.3, and 29.5% decreases in tumor size by RECIST. Overall, 19 patients have had SD and 5 have had PD as the best response. With a median follow-up of 8.3 months and 17 patients still active, the median PFS is 6.9 months, and 23 patients (77%) are still alive. 26 of 30 evaluable patients have been wild type for BRAF-V600E/K mutations. Conclusions: Axitinib followed by carboplatin and paclitaxel has been well tolerated and effective in a largely BRAF wild-type metastatic melanoma population. Given the urgent need for effective therapies in this population, this regimen warrants phase III testing.

e19046 Background: Pyrexia (fever) is a common adverse event associated with combined BRAF and MEK inhibition (dabrafenib and trametinib). Although the mechanism of fever is unclear, we explore pyrexia as a pharmacodynamic marker for clinical response. Methods: A phase II international trial with dabrafenib and trametinib in metastatic melanoma (MM) and colorectal cancers (CRC) harboring BRAF mutations is ongoing. Twenty-nine patients (pts) were enrolled at UCSF between January 2011 and January 2012. Fevers were graded based on temperature and coinciding symptoms, and an episode of pyrexia was defined as a temperature of >100 °F at least once a day for one or more consecutive days. Tumor assessments were performed every 8 weeks (wks). Results: To date, 13 pts with MM and 5 with CRC had tumor assessments up to 24 wks. In MM, pyrexia was reported 2 or more times in 7 pts; 5 had none, and 1 reported one episode of Grade 1 pyrexia. Episodes occurred 2-4 wks after starting treatment, and time between subsequent recurrences ranged from 1 to 25 wks. Neutrophil counts showed early fluctuations, but none had neutropenia. Of the 7 pts with recurring fevers, 5 had partial responses and 2 had stable disease at 8 wks. Of the 6 pts with nonrecurring or no fevers, 2 had partial responses at 8 wks, and 1 progressed. At 24 wks, all 7 pts with ≥ 2 fever episodes remained progression-free, whereas 0/6 pts with < 2 fever episodes were progression-free (p < 0.001). Pts without progression continued to have recurring fevers (median = 4). There were no differences by disease stage (12 of 13 with M1c) or mutation status (10 with V600E; 2 with V600K; 1 with V600E + V601I). While pts with CRC had pyrexia, no association between pyrexia and response was noted; however, only 5 pts are included in this analysis. Conclusions: In this limited analysis of pts with MM, recurrent fevers were associated with durable response (≥ 24 wks). These results suggest that pyrexia could be a marker for inflammation and antitumor activity. Further studies are underway to characterize cytokine profiles and immune responses. [Table: see text]

Background: Axitinib is a potent VEGFR inhibitor. We tested the hypothesis that axitinib could increase the effectiveness of carboplatin/paclitaxel in specific subtypes of advanced melanoma. Methods: A prospective single arm phase I/II trial of this combination was initiated August 2010 in metastatic melanoma (NCT01174238) at UCSF. Twenty seven patients have been enrolled, 16 are evaluable for response to date. Patients had an ECOG PS 0–1, and normal organ function. Axitinib 5 mg PO bid was taken days 1 − 14 of each 21-day cycle, and carboplatin/paclitaxel was administered on day 21. Biopsy specimens were sequenced for mutations in BRAF, NRAS, c-KIT, GNAQ and G11 and FLT-PET scans were done in selected patients to on days 1, 14, 17, and 20 of cycle 1. Results: This regimen was well tolerated with adverse events including GI toxicity, musculoskeletal pain, fatigue, hypertension, and mild sensory neuropathy. Grade 3 adverse events have been uncommon, and grade 4 adverse events have not been observed. Four of 13 WT/NRAS patients have had a PR by RECIST, 7/13 have had some shrinkage of tumor while only 2/13 have had PD. Of the 3 patients with BRAF V600 E/K mutations, all have had PD. In the overall study population, median OS and PFS have not been reached. Conclusions: Striking activity was seen in patients whose tumors are WT for BRAF including those with NRAS mutation. Given the urgent need for effective therapies in this population, this combination warrants further study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A3.