Ani Sarkis Balmanoukian

Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers

Meeting abstracts Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that is expressed in many cancers and induces immune tolerance by suppressing T cell responses. Epacadostat is a potent, selective oral inhibitor of IDO1. A dose-escalation study of epacadostat with

Abstract CT105: MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression

Background: MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has demonstrated durable antitumor activity in NSCLC and melanoma. Preliminary data presented at the 2013 World Congress of Lung Cancer showed a relationship between tumor PD-L1 expression and overall response to MK-3475. Here, we present updated data on tumor PD-L1 expression and its relationship with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Methods: In a phase I study, 38 previously treated NSCLC patients received MK-3475 10 mg/kg Q3W. Tumor response was assessed every 9 weeks by immune-related response criteria (irRC) per investigator review and by RECIST v1.1 per independent radiologic review. A new tumor biopsy performed within 60 days prior to the first dose of MK-3475 was required. Tumor PD-L1 expression was assessed by IHC. A potential cut point for PD-L1 expression was determined by the Youden Index from a receiver operating characterstics curve developed from the investigators’ irRC assessments. Results: Confirmed ORR for the entire cohort of 38 patients per investigators’ irRC assessments was 24%, median PFS was 9 weeks, and median OS was 51 weeks. PD-L1 IHC score was above a potential cut point in 9 patients and below a potential cut point in 22 patients; tumor was not submitted for or staining was not evaluable in 7 patients. Significant associations between tumor PD-L1 expression and ORR, PFS, and OS were observed (Table). Conclusions: Tumor PD-L1 expression levels were associated with tumor response, PFS, and OS in patients with NSCLC treated with MK-3475. The preliminary finding of minimal anti-tumor activity in patients whose tumors express low levels of PD-L1 suggests that PD-L1 is an important biomarker for patients with NSCLC treated with MK-3475. Citation Format: Leena Gandhi, Ani Balmanoukian, Rina Hui, Omid Hamid, Naiyer A. Rizvi, Natasha Leighl, Matthew Gubens, Jonathan W. Goldman, Gregory M. Lubiniecki, Kenneth Emancipator, Marisa Dolled-Filhart, Jared K. Lunceford, Michelle Niewood, Kevin Gergich, Edward B. Garon. MK-3475 (anti-PD-1 monoclonal antibody) for non-small cell lung cancer (NSCLC): Antitumor activity and association with tumor PD-L1 expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT105. doi:10.1158/1538-7445.AM2014-CT105

African American Women Who Receive Primary Anthracycline- and Taxane-Based Chemotherapy for Triple-Negative Breast Cancer Suffer Worse Outcomes Compared With White Women

TO THE EDITOR: We read with great interest the manuscript by Dawood et al from the M. D. Anderson Cancer Center (MDACC; Houston, TX) entitled, “Triple Receptor–Negative Breast Cancer: The Effect of Race on Response to Primary Systemic Treatment and Survival Outcomes.” We have also recently evaluated a data set of women with triple receptor–negative breast cancer who received primary systemic therapy (PST) at our institution and report our observations below. Breast cancer is a heterogeneous disease composed of a number of recognized biologic and pathologic subtypes. The so called “triple receptor–negative breast cancer,” used to describe all tumors that are estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative, may include basal-like and non– basal-like tumors. Chemotherapy is the only systemic treatment available for women with primary triple receptor–negative breast cancer to improve long-term outcomes. Triple receptor–negative breast cancer is more prevalent among premenopausal African American women and is associated with a shorter disease-free interval and overall survival than white women. This disparity has been often attributed to lack of access to healthcare, poor follow-up, low socioeconomic status, body mass index, and possibly lower doses of adjuvant therapy. Dawood et al have previously reported that African American women with metastatic breast cancer are at greater risk of death compared with white women. African American women with triple receptor–negative breast cancer often present with a stage II or III breast cancer and may be recommended PST. Although PST does not improve disease-free survival or overall survival, it may enhance breast conservation and provide prognostic information to individual women. Women with poor response to PST and a large residual disease are more likely to suffer a recurrence and die of their disease compared with women with a pathological complete response (pCR). Based on available evidence and anecdotal observations, we hypothesized that African American women with triple receptor– negative breast cancers have worse outcomes in part because of resistance to standard chemotherapy. To test our hypothesis, we compared pCR rate, recurrence-free and overall survival, in African American versus white and other women with triple receptor–negative breast cancer who received preoperative anthracyclineand/or taxane-based therapy. In 2002, members of the multidisciplinary breast cancer program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Hospital (Baltimore, MD) developed an algorithm for PST management used by the clinicians from all specialties, which led to uniform identification, staging, and treatment criteria. Briefly, women with a clinical stage II or III breast cancer appropriate for PST based on International Consensus Recommendations had nodal evaluation by a fine-needle aspiration or sentinel node mapping before initiating chemotherapy. The breast cancer program screens and collects demographics and key medical characteristics on all new patients to the medical oncology clinic. All patients with a clinical stage II or III breast cancer at the time of initial consultation who received PST are included in the database. Approximately 2 to 4 weeks following PST, women undergo breast-conserving surgery or a mastectomy at the Johns Hopkins at the discretion of the treating surgeon and patient preference. Women with a positive axillary lymph node before chemotherapy undergo axillary lymph node dissection at time of definitive surgery. We reviewed the breast cancer PST database from May 2002 to December 2007. Eligible subjects for the investigation included women with histologically confirmed, estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor 2–negative, clinical stage II or III, invasive breast cancer who received chemotherapy with doxorubicin and cyclophosphamide, with or without a taxane before or after the doxorubicin and cyclophosphamide combination. The Johns Hopkins Medicine institutional review board provided an exemption for this retrospective review. We studied patient and tumor characteristics including age, race, family history, menopausal status, initial clinical stage, initial clinical tumor size and nodal status. Study end points included pCR (no residual invasive cancer in the breast and lymph nodes), recurrencefree survival, and overall survival in African American versus white/ other women. Differences in patient and tumor characteristics across race were compared with Fisher’s exact test, exact 2 test, or Wilcoxon rank sum test, where appropriate. Survival outcomes including recurrence-free survival and overall survival were analyzed using the Kaplan-Meier method and compared between race groups by the log-rank test. We identified 38 women that met the predefined criteria; 15 were African American, 23 were white or other race (Table 1). Consistent with the literature, African American women were more likely to be younger than 50 years of age and be preor perimenopausal at the time of initial diagnosis. There was no statistically significant difference between initial clinical stage and type of chemotherapy administered to the groups. Following therapy, 13% of the African American women had a pCR compared with 52% in white/other women (P .034). Fewer white/other women had a stage III residual pathological stage compared with African American women (12% and 53%, respectively). With a median follow-up of 2.1 years (range, 0.6 to 6.5 years), Kaplan-Meier curves indicate a trend for shorter recurrence-free survival (P .045) and overall survival (P .028) for African American women compared with white/other women (Fig 1). The trends remained similar after controlling for patient and tumor characteristics. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 27 NUMBER 22 AUGUST 1 2009

Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status

Meeting abstracts As single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective

Abstract A047: Safety and clinical activity of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC)

Background: Durvalumab (D) is a human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to programmed cell death-1 (PD-1) and CD80 with high affinity and selectivity. PD-L1 is expressed in NSCLC tumors and may be associated with response to anti-PD-L1 treatment. This ongoing Phase 1/2, multicenter, open-label study (NCT01693562) evaluates the safety and clinical activity of D in patients (pts) with multiple solid tumor types including NSCLC. Methods: D is administered at 10 mg/kg IV every 2 weeks (wks) (q2w) until unacceptable toxicity, disease progression, or for up to 12 months. Safety evaluations occur prior to each dose (toxicities graded by CTCAE v4.0). Response is based on investigator assessment (RECIST v1.1; includes confirmed/unconfirmed responses) at 6, 12, and 16 wks, then every 8 wks. Retreatment is permitted upon disease progression after 12 months of therapy. PD-L1 expression within the pre-treatment tumor is assessed using Ventana PD-L1 immunohistochemistry (IHC) (SP263). Results: As of February 27, 2015, 228 pts (126 non-squamous and 102 squamous histology; mean age 64 [range 26 – 87]; Eastern Cooperative Oncology Group Performance Status 0 [25%] or 1 [74%]; 83% current/prior smokers; 0 [12%], 1 [29%], or ≥2 [56%] prior lines of therapy) have been treated with D 10 mg/kg q2w (median 6 doses; range 1 – 27). Drug-related adverse events (AEs) were reported in 50% of pts; most frequently fatigue (15%), decreased appetite (9%), and nausea (8%). Grade ≥3 drug-related AEs were reported in 8% of pts. Drug-related AEs led to study discontinuation in 5% of pts with no treatment-related deaths. Pneumonitis occurred in 3 (1%) pts; none were Grade ≥3. In all, 200 pts were evaluable for response with ≥12 wks of follow-up; objective response rate (ORR) was 16% (27% in PD-L1+), and disease control rate at 12 wks was 42%. ORR was higher in squamous (21%) than non-squamous pts (13%). Responses were durable with 66% ongoing (duration of response range 0.1+ – 54.4+ wks). Data from translational studies will be presented. Conclusions: With longer follow-up, the safety profile of D in NSCLC is manageable and consistent with our previous reports. Responses are durable; ORR appears to be higher in squamous NSCLC and PD-L1+ pts. A broad development program of D alone and in combination with other treatments in NSCLC is underway. Citation Format: Scott Antonia, Naiyer Rizvi, Julie Brahmer, Sai-Hong Ou, Samir N. Khleif, Wen-Jen Hwu, Martin Gutierrez, Patrick Schoffski, Omid Hamid, Jared Weiss, Jose Lutzky, Michele Maio, John Nemunaitis, Dirk Jaeger, Ani Balmanoukian, Marlon C. Rebelatto, Keith E. Steele, Xiaoping Jin, Paul B. Robbins, John A. Blake-Haskins, Neil H. Segal. Safety and clinical activity of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A047.

Development of MEDI4736, an anti-programmed cell death ligand 1 (PD-L1) antibody, as monotherapy or in combination with other therapies in the treatment of non-small cell lung cancer (NSCLC)

Meeting abstracts MEDI4736 is an engineered human IgG1 that blocks PD-L1 binding to PD-1 and allows T-cells to recognize and kill tumor. MEDI4736 has single-agent activity and potential for further increased activity in combination. A comprehensive development programme is underway in NSCLC, as

Abstract CT104: Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001)

Background: Preliminary KEYNOTE-001 data showed that the PD-1 inhibitor pembro has manageable safety and antitumor activity in previously treated and treatment-naive advanced non-small cell lung cancer (NSCLC). In a training set of 182 pts, 129 of whom had measurable disease and tumor evaluable by an IHC clinical trial assay (CTA) for PD-L1 expression, ORR was higher in pts with membranous PD-L1 expression in ≥50% of tumor cells (proportion score [PS] ≥50%) vs PS Methods: Advanced or metastatic NSCLC pts received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed every 9 wk. Treatment decisions were managed per investigator-assessed irRC. Efficacy evaluation was per centrally assessed RECIST v1.1. PD-L1 expression was determined by the CTA. Before analysis, ORR and PD-L1 data from the validation set were merged in pts with measurable disease and CTA-evaluable tumors. Duration of response (DOR), PFS, and OS were assessed in all treated pts from the training and validation sets with CTA-evaluable tumors. Results: In all 495 pts from the training and validation sets, irrespective of PD-L1 expression, ORR was 19.4%, median DOR was 12.4 mo, median PFS was 3.7 mo, and median OS was 12.0 mo. 9% experienced grade 3-5 treatment-related AEs; 4% discontinued due to a treatment-related AE. There was 1 treatment-related death (pneumonitis). Of the 313 pts in the validation set, ORR in the 204 pts evaluable by the CTA was 45.2% in those with PS ≥50% (Table). The relationship between ORR and PD-L1 expression was observed in previously treated and treatment-naive pts (Table). In the 356 pts evaluable by the CTA in the total population, PFS and OS were longer in pts with PS ≥50% (Table). Median OS was not reached in pts with PS ≥50%, regardless of prior treatment. Median (range) DOR was similar in pts with PS ≥50% (12.4 mo [2+ to 22.8+]), 1-49% (10.3 mo [1.4+ to 10.3]), and Conclusion: Pembro provides durable antitumor efficacy and safety in pts with treatment-naive and previously treated NSCLC. These data validate that membranous PD-L1 expression in ≥50% of tumor cells identifies pts with advanced NSCLC who are particularly likely to obtain clinical benefit from pembro. Citation Format: Edward B. Garon, Naiyer Rizvi, Rina Hui, Natasha B. Leighl, Ani S. Balmanoukian, Joseph P. Eder, Amita Patnaik, Charu Aggarwal, Matthew A. Gubens, Leora Horn, Enric Carcereny, Myung-Ju Ahn, Enriqueta Felip, Jong-Seok Lee, Jin Zhang, Reshma A. Rangwala, Gregory M. Lubiniecki, Charlotte M. Roach, Kenneth Emancipator, Leena Gandhi. Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2015-CT104

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Purpose Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Patients and Methods Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Blood–Brain Barrier and CNS Malignancy

Improving treatment outcomes for patients with central nervous system (CNS) malignancies is associated with a series of difficult challenges. The use of enzyme-inducing antiepileptic drugs and glucocorticoids significantly affects the pharmacology of many systemically administered anticancer agents. The blood–brain barrier plays a major role in restricting the delivery of drugs to the CNS and there are a host of drug resistance mechanisms within the blood–brain barrier and brain tumors which further limit the effectiveness of therapeutic agents. This chapter reviews important characteristics of CNS malignancies and focuses on unique aspects of care for neurologic cancers, characteristics of the blood–brain barrier (BBB), drug resistance mechanisms, important drug interactions, and novel approaches to increase drug delivery to the brain tumor tissue.

Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy. Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (<500 cells/mm3). Results: The findings in each patient cohort are similar: 1) About 40% of patients develop severe TRL two months after initiating radiation and this persists for many months, 2) There is an association between TRL at two months and shorter survival from tumor progression, and 3) The hazard ratio for reduced survival is high after adjusting for known prognostic factors. Lung cancer patients treated with neoadjuvant chemotherapy did not experience TRL until after radiation was initiated. Conclusions: Severe TRL is common, severe, long-lasting and associated with earlier death from tumor progression in patients with solid tumors receiving radiation and chemotherapy. These studies suggest that radiation likely plays a major role in the development of TRL and that novel approaches to protect and/or restore immunologic function in patients with solid tumors are critical. | Neoplasm | Total number patients | Patients developing grade III-IV TRL | Median Survival 500 lymphocytes (months) | Multivariate association with reduced survival:HR, (CI), pvalue | |:----------------------- | --------------------- | ------------------------------------ | ------------------------------------------------- | --------------------------------------------------------------- | | High grade glioma | 96 | 40% | 13 vs 19.7 (p = 0.002) | OS: 1.66, (1.05–2.64), 0.03 | | Pancreatic resected | 53 | 45% | 14 vs 20 (p = 0.048) | OS: 2.2, (1.17–4.12), 0.01 | | Pancreatic unresectable | 120 | 74% | 9.2 vs 14.6 (p = 0.013) | OS: 1.34, (0.09–2.0), 0.15 | | | | | | | | NSCLC Stage III | 47 | 50% | 21.8 vs 28.3 (p = 0.38) | OS: 1.7, (0.8–3.6), 0.17 | | HEENT (HPV) | 22 | 36% | PFS only | PFS: 6.2, (1.1–35.2), 0.04 | Citation Format: Stuart A. Grossman, Susannah Yovino, Jian Campian, Aaron Wild, Joseph Herman, Daniel Laheru, Malcolm Brock, Shanthi Marur, Ani Balmanoukian, Xiaobu Ye. The association between treatment-related lymphopenia and survival in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2013-1242