Activity In Several Solid Tumors Research Articles

Clinical utility of circulating tumor DNA in patients with head and neck cancers.

e18003 Background: Globally, head and neck cancers (HNCs) account for over 900,000 cases annually with a meager overall survival rate of 50%. While early-stage HNCs may be amenable to surgery, advanced disease is treated with systemic therapy or chemoradiation. For localized disease, chemo-radiation is often curative, but is associated with severe toxicity. Assessment of systemic treatment in the era of immunotherapy is often challenging due to the pseudoprogression phenomenon. In general, surveillance is limited to clinical follow-up and radiological imaging due to the lack of a sensitive and specific biomarker to assess treatment response and disease progression. Circulating tumor DNA (ctDNA) has shown promise as a reliable marker of disease activity in several solid tumors. In this study we evaluated the clinical utility of ctDNA for monitoring of therapeutic response and disease progression in patients with HNCs. Methods: ctDNA analysis was performed utilizing a personalized, tumor-informed ctDNA assay (Signatera™ bespoke mPCR NGS assay) in patients with advanced stage (III, IV) HNC who underwent chemoradiation or systemic therapy. ctDNA levels were measured at diagnosis, throughout treatment and during remission. The primary endpoint was correlation of ctDNA kinetics with radiological response. The secondary endpoint was the rate of ctDNA positivity during remission. Additional data collected included patient demographics and tumor clinicopathologic characteristics. Analysis was conducted using descriptive statistics. Results: ctDNA kinetics from 15 patients with squamous HNCs were analyzed. Due to insufficient time points, 5 five patients were excluded from this analysis. At diagnosis, 9/10 (90%) patients were ctDNA-positive, with baseline ctDNA levels ranging from 0.2 to 8500 mean tumor molecules (MTM)/mL of plasma. Patients received either chemoradiation (7/10) or (chemo)immunotherapy (3/10). Among patients who received chemoradiation, 4 out of 7 cleared ctDNA in less than 40 days, while 2 out of 7 had persistent ctDNA after 40 days. Those who showed ctDNA clearance had a continued response at 3-6 month follow-up both by ctDNA and by standard of care imaging. The 2 patients that did not clear ctDNA by day 40 ultimately relapsed on imaging and had rising ctDNA levels within 3 months of completion of chemoradiation. The patient who was ctDNA negative at baseline remained negative throughout the treatment and follow up. Of the patients who received chemo(immunotherapy), 2/3 cleared ctDNA after 2 cycles of therapy and continued to be in remission. The remaining patient who did not show ctDNA clearance became refractory to treatment. Conclusions: Our study demonstrates the feasibility of personalized and tumor-informed ctDNA in patients with advanced HNCs. Monitoring of ctDNA kinetics during therapy may enable prediction of therapeutic response and early disease progression to guide clinical decision-making.

A novel HDAC1/2 inhibitor suppresses colorectal cancer through apoptosis induction and cell cycle regulation

Colorectal cancer (CRC) is one of the leading causes of death around the world, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as histone deacetylases (HADC) inhibitors, are under intensively studied. The target of HDAC involves in regulating critical cellular mechanisms and underpins the progression of anticancer therapy. However, little is known about the antitumor mechanisms of class I specific HDAC inhibitors in CRC. We structurally designed and synthesized benzamide-based compounds, examined their anticancer activity in several solid tumors, and identified compound 9 with high potential. Results from the in vitro enzyme and cell-based studies demonstrated that compound 9 as a selective HDAC1/2 inhibitor that possessed short-term and long-term suppression capacities against colorectal cancer cells. Investigation of molecular regulatory mechanisms of 9 in colorectal cancer cells by biological functional assays evidenced that treatment of compound 9 could activate apoptosis, induce cell cycle arrest, facilitate DNA damage process, and suppress cancer migration. A non-cancerous cell line and the in vivo zebrafish model were applied for safety evaluation. In summary, our results demonstrate that compound 9 is a promising lead drug worth further investigation for development of future cancer therapeutic agents.

Uncovering the action mechanism of homoharringtonine against colorectal cancer by using network pharmacology and experimental evaluation

ABSTRACT Homoharringtonine (HHT), an Food and Drug Administration (FDA)-approved anti-leukemia drug, exerts anti-tumor activity in several solid tumors, including colorectal cancer (CRC). However, its mechanism of action in CRC progression has not been comprehensively elucidated. The drug-disease targets were obtained using publicly available databases. Protein–protein interaction (PPI) network, Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to reveal the core targets, biological processes and signaling pathways of HHT against CRC. Cell and animal experiments were performed to validate the inhibitory effects of HHT on CRC. A total of 98 overlapping target genes of HHT and CRC were predicted. Through PPI network and topology analysis, we screened out 23 hub genes. Enrichment assays showed 163 biological processes (BP), 18 cell components (CC), 35 molecular functions (MF), and 85 related pathways. Functionally, HHT inhibited CRC cell proliferation, cell cycle progression, colony formation, migration and invasion, and promoted apoptosis. HHT treatment resulted in the inactivation of PI3K/AKT/mTOR signaling in CRC cells. Moreover, activation of PI3K/AKT/mTOR signaling by 740Y-P abated the suppressive effects of HHT on cell malignant phenotypes. Furthermore, HHT repressed CRC tumor growth in nude mice. Our current study demonstrated that HHT repressed CRC progression at least partly by inactivating PI3K/AKT/mTOR signaling pathways, highlighting HHT as a potential therapeutic agent for CRC patients.

Resistance mechanisms to immune checkpointsblockade by monoclonal antibody drugs in cancer immunotherapy: Focuson myeloma.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death-1/programmed death-1 ligand and cytotoxic T-lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpointsblockade remains limited due to innate or primary resistance. Moreover, the malignanciesprogress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor-intrinsic and tumor-extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor-related factoreffects on immune checkpoints blockade in MM immunotherapy.

ACTR-33. INFIGRATINIB (BGJ398) IN PATIENTS WITH RECURRENT GLIOMAS WITH FIBROBLAST GROWTH FACTOR RECEPTOR (FGFR) ALTERATIONS: A MULTICENTER PHASE II STUDY

Abstract INTRODUCTION FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion is predictive of response to FGFR tyrosine kinase inhibitors pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor with anti-tumor activity in several solid tumors with FGFR genetic alterations. METHODS Open-label phase II trial of adults with recurrent high-grade gliomas following failure of initial therapy (NCT01975701). Tumors harbored FGFR1-TACC1 or FGFR3-TACC3 fusions, activating mutations in FGFR1, 2 or 3, or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg d1–21 q28d. Prophylaxis for hyperphosphatemia was recommended. Primary endpoint: 6-month progression-free survival (6mPFS) rate by RANO (locally assessed); goal of >40%. RESULTS As of Sep 2017, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥ 2 prior regimens) were treated; 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All had FGFR1 or FGFR3 gene alterations; 4 had >1 gene alteration. Estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). Best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. Most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions/reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes; analysis of biomarker data is ongoing.

OS10.6 Infigratinib (BGJ398) in patients with recurrent gliomas with fibroblast growth factor receptor (FGFR) alterations: a multicenter phase II study

Abstract BACKGROUND FGFR mutations and translocations occur in approximately 10% of glioblastomas (GBMs). FGFR3-TACC3 fusion has been reported as predictive of response to FGFR tyrosine kinase inhibitor therapy both pre-clinically and clinically. Infigratinib (BGJ398) is a selective small-molecule pan-FGFR kinase inhibitor that has demonstrated anti-tumor activity in several solid tumors with FGFR genetic alterations. Therefore, we conducted a phase II trial to test the efficacy of infigratinib in FGFR-altered recurrent GBM (NCT01975701). METHODS This open-label trial accrued adults with recurrent high-grade gliomas following failure of initial therapy that harbored FGFR1-TACC1 or FGFR3-TACC3 fusions; activating mutations in FGFR1, 2 or 3; or FGFR1, 2, 3, or 4 amplification. Oral infigratinib was administered 125 mg on days 1–21 every 28 days. Prophylaxis for hyperphosphatemia, a common toxicity, was recommended. The primary endpoint was the 6-month progression-free survival (6mPFS) rate by RANO (locally assessed, estimated by K-M method), with a goal of >40%. RESULTS As of the Sep 2017 data cut-off, 26 patients (16 men, 10 women; median age 55 years, range 20–76 years; 50% with ≥2 prior regimens) were treated, and 24 (92.3%) discontinued for disease progression (n=21) or other reasons (n=3). All patients had FGFR1 or FGFR3 gene alterations, and 4 had >1 gene alteration. The estimated 6mPFS rate was 16% (95% CI 5.0–32.5%); median PFS was 1.7 months (95% CI 1.1–2.8 months); median OS was 6.7 months (95% CI 4.2–11.7 months); ORR was 7.7% (95% CI 1.0–25.1%). The best overall response was: partial response 7.7% (FGFR1 mutation n=1; FGFR3 amplification n=1); stable disease 26.9%; progressive disease 50.0%; missing/unknown 15.3%. The most common (>15%) all-grade treatment-related adverse events (AEs) were hyperphosphatemia, fatigue, diarrhea, hyperlipasemia, and stomatitis. There were no grade 4 treatment-related AEs. Eleven patients (42.3%) had treatment-related AEs requiring dose interruptions or reductions (most commonly hyperphosphatemia). CONCLUSIONS Infigratinib induced partial response or stable disease in approximately one-third of patients with recurrent GBM and/or other glioma subtypes harboring FGFR alterations. Most AEs were reversible and manageable. Further potential combinations are being explored in patients with proven FGFR-TACC fusion genes and analysis of biomarker data is ongoing.

Cyclin-dependent kinase 4/6 inhibitors: what have we learnt across studies, therapy situations and substances.

Cyclin-dependent kinases (CDK) are key regulatory enzymes that control cell cycle and cell division. In the recent years, new therapeutic options selectively targeting CDK 4 and 6 have shown promising clinical activity in several solid tumors. Since 2015, three CDK 4/6 inhibitors have been approved for treatment of hormone receptor-positive HER2-negative metastatic breast cancer: palbociclib, ribociclib and abemaciclib. These drugs share a common mechanism of action and have been evaluated in studies with a similar design. The following review gives a clinical overview of the CDK 4/6 inhibitors in breast cancer therapy and highlight current study data with regard to their antitumor efficacy and toxicities. In clinical trials in the first-line and later-line setting, palbociclib, ribociclib and abemaciclib in combination with endocrine therapy significantly prolonged progression-free survival. The most common adverse events during treatment with CDK 4/6 inhibitors are neutropenia, fatigue and gastrointestinal symptoms. CDK 4/6 inhibitors represent a valuable treatment option for patients with metastatic hormone receptor-positive HER2-negative breast cancer. Although the clinical efficacy of the three agents seems similar, their toxicity profiles differ. Therefore, the choice of a CKD 4/6 inhibitor depends on patient's characteristics and individual preferences. In the video, the author describes the content of the review and present the main topics discussed in the article (http://links.lww.com/COOG/A44).

Abstract 1351: Inhibition of autophagy enhances dihydroartemisinin (DHA)-induced cytotoxicity through DR5 upregulation

Abstract Artemisinin (Qinghaosu) comes originally from Qinghao has been used against Plasmodium falciparum malaria for a long time. Dihydroartemisinin, an analogue of artemisinin, is also be listed by WHO to exhibit antimalarial and anticancer properties. In our study, DHA exhibits antiproliferative activity in several solid tumors, especially against colorectal cancer (CRC) HCT116 cells. Our current results show DHA suppresses cell proliferation and induces caspase-dependent apoptosis without inducing necrosis-like cell death in HCT116 cells. In addition, DHA interferes autophagy pathway by upregulating of LC3 II formation in HCT116 cells. Inhibition of autophagy with either autophagy inhibitor 3-methyladenine (3MA) or KD of ATG5 potentiated DHA-induced cell death. We found DHA increased expression level of DR5 while had no effect on DR4 expression level on surface of tumor cells. Further, cell-surface DR5 expression was significantly elevated in DHA-treated ATG5-KD cells. These findings suggest that inhibition of the autophagy enhances DHA-induced cytotoxicity through DR5 upregulation. Key words: Apooptsis, DR5 (Death Receptor 5), autophagy, colorectal cancer Citation Format: Chen Mei-Chuan. Inhibition of autophagy enhances dihydroartemisinin (DHA)-induced cytotoxicity through DR5 upregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1351.

Anti-PD-1 therapy in patients with end-stage renal disease on dialysis: A single-center case series.

e14553 Background: Anti-PD-1 monoclonal antibodies (PD1) have clinical activity in several solid tumors. However, experience treating dialysis pts with PD1 is limited. Dosage adjustments are not recommended for renal impairment but PK studies did not include pts with ESRD on dialysis. Two case reports have described objective responses and a tolerable AE profile. We sought to explore the safety and efficacy of PD1 in such pts. Methods: In this single-center case series, we identified 4 pts with ESRD on dialysis who were treated with PD1 between 10/2014 to 11/2016. Data regarding clinical history, PD1 dosing, dialysis regimen, treatment (tx) response, and toxicity were collected. Results: Four pts were evaluable for data collection. Two pts had metastatic renal cell carcinoma (mRCC) and 2 others had unresectable cutaneous squamous cell carcinoma (cuSCC). Age at tx ranged from 66 to 71; all 4 pts were male. Number of doses ranged from 4 to 8. Two pts with mRCC received nivo 3 mg/kg q2wk after dialysis. Two pts with cuSCC received pembro 2 mg/kg q3wk after dialysis; dosing was extended to q4wk for 1 pt due to persistent grade (G) 2 fatigue. Three pts were on hemodialysis 3 times a wk and 1 pt was on peritoneal dialysis. Time to progression was 3 months for 1 mRCC pt and could not be determined for the other mRCC pt who had a PR but died from possible tx-related causes. Two cuSCC pts are still receiving pembro with PR at time of analysis. Immune-related AEs were seen in all 4 pts, including 2 incidences of G2 fatigue and 1 incidence each of G2 rash and G3 pneumonitis.One pt developed acute encephalitis after 4 doses of nivo that improved with steroids but was ultimately fatal. Conclusions: This single-center case series highlights the efficacy and AE profile of PD1 for pts with ESRD on dialysis. While this is a small series, there was significant anti-tumor activity in this group of pts. Despite the reported favorable AE profile of PD1, one pt had a serious and mortal AE that may have been related to tx. This should be considered in future studies. High molecular weight of PD1 suggests these agents are not removed by dialysis but we were limited by lack of PK data. Our experience adds to the 2 cases in the literature. Further studies are warranted in larger cohorts.

New Approaches for Immune Directed Treatment for Ovarian Cancer.

The immune system plays an active role in the pathogenesis of ovarian cancer (OC), as well as in the mechanisms of disease progression and overall survival (OS). Immunotherapy in gynecological cancers could help to revert immunosuppression and lymphocyte depletion due to prior treatments. Current immunotherapies for ovarian cancer, like all cancer immunotherapy, are based on either stimulating the immune system or reverting immune suppression. Several approaches have been used, including therapeutic vaccines, monoclonal antibodies; checkpoint inhibitors and adoptive T cell transfer. Most of these therapies are still in early-phase testing (phase I and II) for ovarian cancer, but the initial data in ovarian cancer and successful use in other types of cancers suggests some of these approaches may ultimately prove useful for ovarian cancer as well. Ovarian cancer vaccines have shown only a modest benefit in ovarian cancer when used as monotherapy, but these agents may be able to enhance antitumor activity when combined with chemotherapy, checkpoint inhibitors, or other immunotherapies. Monoclonal antibodies have been explored in ovarian cancer but despite encouraging phase II data, randomized studies failed to demonstrate significant clinical benefit. Check point inhibitors have promising activity in several solid tumors and have demonstrated a favorable toxicity profile. Data from early clinical trials utilizing PD1 and PD-L1 inhibitors showed encouraging results. Ongoing clinical trials are evaluating the role of check point inhibitors in combination with chemotherapy. Adoptive T cell transfer involves the infusion of ex vivo activated and expanded tumor specific T cells, using various sources and types of T cells. While this approach has been explored in several hematologic malignancies, it constitutes early research in ovarian cancer. Immunotherapy remains investigational in ovarian cancer and the benefit of this approach in improving progression-free survival (PFS) or OS is unknown. Previous clinical trials have not selected patients based on biomarkers and this may explain the negative results. We expect to discover that tumor response will relate to the patient's immune features and specific tumor characteristics. We are only beginning to realize the potential of immunotherapy for ovarian cancer patients, and one goal of future clinical trials will be to identify subsets of patient based on histologic, molecular, and immune characteristics.

PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment

PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment

Pembrolizumab in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM): Keynote-023

Pembrolizumab in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma (RRMM): Keynote-023

Phase 1b Study of PD-1 Blockade with Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Introduction: Like classical Hodgkin lymphoma (cHL), PMBCL frequently harbors genetic alterations of the 9p24.1 locus, leading to overexpression of the PD-1 ligands, PD-L1 and PD-L2. This provides a possible mechanism of immune evasion and suggests that PMBCL could have a genetically determined vulnerability to PD-1 blockade. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands. Pembrolizumab has already demonstrated robust antitumor activity in advanced solid tumors and in cHL. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b trial testing the safety and preliminary efficacy of pembrolizumab in patients with hematologic malignancies. Based on its genetics, PMBCL was included as an independent cohort in this trial. Here we report the preliminary results in this patient population.Methods: The PMBCL cohort of KEYNOTE-013 is enrolling patients with relapsed/refractory (R/R) disease who have relapsed after or are ineligible for autologous stem cell transplant (ASCT). Pembrolizumab is administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed disease progression or unacceptable toxicity. The primary end points are safety and antitumor activity. Response is being evaluated using computed tomography (CT) and positron emission tomography (PET) at week 12 and every 8 weeks thereafter, using IHP 2007 criteria. Other end points include complete remission (CR) rate, duration of response (DOR), and exploratory biomarker analyses.Results: As of July 23, 2015, 10 patients with R/R PMBCL with a median age of 28 (23-62) years have been enrolled in this cohort. Patients were heavily pretreated: 40% had ≥4 prior lines of therapy, and 60% had prior radiation. Six patients (60%) experienced at least 1 adverse event (AE) of any grade related to study treatment. These treatment-related AEs, all grade 1/2, were: hypothyroidism and decreased appetite (2 patients each), and diarrhea, nausea, vomiting, fatigue, edema, weight loss, and arthralgia (1 patient each). There were no grade 3-5 treatment-related AEs. Two patients experienced a serious AE (grade 3 infectious pneumonia) unrelated to study drug. No patient discontinued for toxicity.Nine patients were evaluable for response (1 discontinued treatment based on clinical progression before week 12). The objective response rate (ORR) was 44% (4/9), with 1 patient achieving a CR and 3 patients achieving a partial response. The intent-to-treat ORR was 40%. With a median follow-up of 144 days, the median DOR has not been reached (1+ to 291+) days, with all 4 responses ongoing at the time of data cutoff. Six of 10 patients have discontinued study treatment because of disease progression, and 4 patients remain on study.Conclusion: The preliminary results of KEYNOTE-013 indicate that PD-1 blockade with pembrolizumab is associated with a tolerable safety profile and a promising response rate in heavily pretreated patients with R/R PMBCL. Those patients often have a very poor outcome with conventional therapy, justifying further studies of pembrolizumab in this population. DisclosuresZinzani:Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Off Label Use: The PD-1 pathway is an important mechanism of immune evasion for many tumors. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2 on the tumor cell surface and, based upon pembrolizumab's antitumor immune activity in several solid tumors, it may be an effective option for treating hematological malignancies.. Ribrag:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Moskowitz:Genentech: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Research Funding; Pharmacyclics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Karyopharm: Honoraria. Balakumaran:Merck: Employment, Equity Ownership; Amgen: Equity Ownership. Snyder:Merck: Employment, Equity Ownership. Marinello:Merck: Employment, Equity Ownership. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Armand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; BMS: Research Funding.

First-line nivolumab (anti-PD-1) monotherapy in advanced NSCLC: the story of immune checkpoint inhibitors and "the sorcerers apprentice".

Non-small cell lung cancer (NSCLC) has usually been thought to be a non-immunogenic tumor, because early studies with Bacillus Calmette-Guerin, interleukin-2, or interferon have failed to demonstrate any benefit in NSCLC. Recently, some studies indicated that immune mechanisms play a vital role in the origin and development of lung cancer, and the abnormality of immune checkpoints would be the chief culprit. Immune checkpoint-inhibitors have shown promising activity in several solid tumors, including NSCLC. But interfering with the complex immune system in tumor immunosurveillance can trigger not only long lasting responses, but also severe and sometimes irreversible immunological side effects, as seen with the first approved cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab. This reminds one of a famous German poem written by Johann Wolfgang von Goethe in the year 1797, where an apprentice takes the opportunity to “play a little” with some magic when his master wizard had gone out of the house. But the apprentice summoned some powerful spirits he couldn’t actually control.

Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma.

295 Background: Patients (pts) with metastatic urothelial carcinoma (UC) progressing after first-line chemotherapy have limited treatment options. Ramucirumab (Ram), a human VEGFR2-targeted mAb, has demonstrated clinical activity in several solid tumors. Preclinical testing supports a role for Ram-taxane combinations in UC. Study JCDC is an open-label, multicenter, randomized phase 2 study of docetaxel (Doc) alone or combined with Ram or icrucumab (Icr) in locally advanced or metastatic platinum-resistant UC. We report on a planned interim analysis for Doc + Ram vs Doc; Icr results will be reported later. Methods: Eligible pts with advanced UC and ECOG PS 0-1 who relapsed ≤ 1 year from a platinum-regimen were randomized to receive Doc 75 mg/m2IV alone or with Ram 10mg/kg IV on Day 1 of repeating 21-day cycles. A sample size of 46 pts per arm enabled 71% power to demonstrate statistical significance of 4.5 mo (Doc + Ram) vs 3 mo (Doc) at a 1-sided α= 0.1. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed PFS with RECIST v1.1, analyzed by K-M methods. A planned interim analysis was performed after 75% of the PFS events. Results: 44 pts received Doc and 46 received Doc + Ram. Study arms were well matched with a mean age of 67 yr (29-84), and a 4:1 male to female ratio. 58.7% (Doc + Ram) vs 61.4% (Doc) had ECOG PS 1. 58.7% (Doc + Ram) vs 52.3% (Doc) had visceral metastases. Doc + Ram reduced the risk of disease progression, stratified HR = 0.388; 95% CI: 0.222, 0.677; log-rank p = 0.0005, improving median PFS (5.1 vs 2.4 mo). The ORR for Doc + Ram was 19.6 vs 4.5% for Doc (p= 0.0502), and the disease control rate was 67.4 vs 43.2%. OS maturity is pending. The most common adverse events in the Doc + Ram arm (all grades) were fatigue (80.4% Doc + Ram v 75.0% Doc), decreased appetite (54.3 v 43.2%), nausea (54.3 v 25.0%), and neuropathy (50.0 v 38.6%). Grade (G) ≥3 febrile neutropenia (19.6 v 11.4%), pneumonia (13 v 9.1%), hypertension (4.3 v 0%) were higher with Doc + Ram. One G3 hematuria was observed in each arm. Conclusions: Results support a statistically significant improvement in PFS for Doc + Ram in second-line UC. Final results are expected in 2015. Clinical trial information: NCT01282463.

A Phase Ib Study of Pembrolizumab (Pembro; Mk-3475) in Patients (Pts) with Human Papiilloma Virus (Hpv)-Positive and Negative Head and Neck Cancer (Hnc)

ABSTRACT Aim: Background: The highly selective, anti-PD-1 humanized monoclonal antibody pembro has shown antitumor activity in several solid tumors, including HNC. We present updated safety, tolerability, and antitumor activity of pembro for recurrent/metastatic HNC (Clinicaltrials.gov: NCT01848834). Methods: During screening, PD-L1 expression in archival or newly obtained tumor samples was assessed using a prototype immunohistochemistry assay; PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pembro 10 mg/kg was given every 2 wk until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events (AEs) were recorded throughout the study. Response was assessed every 8 wk. Primary end point was overall response rate (ORR) per RECIST v1.1. Results: Out of 104 HNC pts screened, 81 (78%) were PD-L1-positive, 61 enrolled, and 60 received ≥1 pembro dose: 23 HPV+, 37 HPV-. After a median follow-up of 10.2 mo, 15 pts (25%) remain on pembro. ORR (confirmed + unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). 9 of 11 responders had a smaller target lesion burden (ie, sum below the median) at baseline. ORR was similar in HPV+ and HPV- pts, whereas PFS and OS were longer in HPV+ pts (Table). PD-L1 expression was positively correlated with ORR (P = 0.018) and PFS (P = 0.024). ORR was 50% in the 12 pts with high PD-L1 expression. Drug-related AEs of any grade occurred in 58% of pts (grade ≥3 in 17%). The most common drug-related AEs were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths. Conclusions: Pembro is safe and tolerable and shows antitumor activity in both HPV+ and HPV- advanced HNC. These findings support further development of pembro in advanced HNC. Overall N = 61* HPV+ n = 23* HPV– n = 38* ORR, n (%) 11 (20) 4 (20) 7 (19) Median PFS (95% CI), wk 9.3 (8.0-20.1) 17.2 (8.0-41.7) 8.1 (7.9-15.6) Median OS (95% CI), mo 12.6 (8.2-12.6) NR (9.6-NR) 9.5 (3.9-12.6) *ORR and PFS were evaluated in the 56 pts (20 HPV+, 36 HPV-) who received ≥1 pembro dose and had measurable disease per RECIST v1.1 by investigator review. Disclosure: L.Q. Chow: Advisory Board Member for Bristol Myers Squibb, Novartis, Celgene; Research funding from Bristol Myers Squibb, Novartis, AstraZeneca/Medimmune, Genentech/Roche, VentiRx, Pfizer, Lily/Imclone; B. Burtness: Advisory board membership for VentiRx and Novartis; Research funding from Merck, Genentech, Boehringer Ingelheim, and Pfizer; E.J. Gonzalez, J.K. Lunceford, C. Gause and J.D. Cheng: Employee of and stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; J. Pulini, J. Johnson, M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; T. Seiwert: Advisory board membership for Novartis and Onyx/Bayer; Research funding from Boehringer Ingelheim and Genentech; Honoraria from Merck. All other authors have declared no conflicts of interest.

Ramucirumab and its use in gastric cancer treatment.

The inhibition of the mechanisms of tumor neo-angiogenesis represents a milestone that in the last 10 years has seen the advent of numerous molecules to target action against the vascular endothelial growth factor (VEGF). More recently, new molecules have been developed that inhibit tumor spread by the blockade of specific VEGF receptors (VEGFRs), thereby preventing the binding of a ligand to its receptor and the cascade of proliferative events downstream. Ramucirumab is a fully humanized IgG1 monoclonal antibody that performs its action by blocking the isoform 2 of the VEGF receptor (VEGFR-2). Numerous preclinical and clinical studies have demonstrated its activity in several solid tumors, demonstrating a remarkable efficacy in terms of progression-free survival and overall survival in addition to a favorable toxicity profile. This review analyzes in detail the role of ramucirumab in the treatment of advanced gastric and gastroesophageal junction cancers.

Investigation of a novel irreversible pan-HER inhibitor combined with chemotherapy in bladder cancer models.

4545 Background: Human Epidermal Receptors (HER) play an important role in bladder cancer (BCa) progression and may mediate chemotherapy resistance. Dacomitinib (Dac) is a novel, potent, irreversible pan-HER inhibitor with activity in several solid tumors, currently in phase III trials in NSCLC. We showed that Dac has single agent anti-tumor activity in human BCa models in vitro and in vivo, inducing apoptosis and G1 arrest. We hypothesized that Dac has additive effects with Gemcitabine (G) and Cisplatin (C) in BCa xenografts. Methods: UM-UC-6 (UC6) or UM-UC-9 (UC9) xenografts were established in age-matched NOD/SCID mice. A week after injection, mice had small tumors, were randomized and treated with i. G 50mg/kg + C 2mg/kg via 3 weekly intra-peritoneal injections (IPI) + daily p.o. buffer for 3 weeks; ii. Dac 6mg/kg p.o. daily for 3 weeks + 3 weekly IPI (saline); iii. GC (same dose/schedule) + Dac starting 1 day after GC (based on cell cycle effect and kinetics); iv. no treatment (control). Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors were weighed. 3 tumors/group were stained for EGFR, HER2, Ki67, E-cadherin, ALDH, p-EGFR, p-ERK, p-Akt. 3rd GC dose in UC6 model was given at 50% due to weight loss; all GC doses were given at 50% in UC9 model. Mann-Whitney test with multiple comparison adjustments was used for analysis. Results: Dac- and GC+Dac-treated mice had no significant weight loss. UC6 tumor weights were significantly lower in Dac and GC+Dac vs control (p<0.0001) or GC (p<0.0001), corresponding to decreased p-ERK %cell expression and staining intensity. GC and control had similar tumor weights (p=0.19). 5 Dac and 3 GC+Dac UC6-injected mice had no tumor at 4 weeks. UC9 tumor weights were significantly lower in Dac (p=0.002, 6x reduction) or GC (p=0.0006; 7x reduction) vs control. GC+Dac had significantly lower tumor weights vs GC (p=0.005), Dac (p=0.06) or control (p<0.0001; 17x reduction). Conclusions: Dac had dramatic singe-agent activity in UC6 xenograft that was GC-resistant. Dac+GC was superior to GC in UC9 xenograft, supporting clinical evaluation. Further investigation of Dac anti-tumor activity and predictive biomarker discovery in additional bladder cancer models is pursued.

Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors.

2569 Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were >18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.

Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma

9026 Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003. [Table: see text] No significant financial relationships to disclose.