Julius Strauss

Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused to a TGFβ “trap.” Experimental Design: In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Results: Nineteen heavily pretreated patients with ECOG 0–1 have received M7824. Grade ≥3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFβ1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions: M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. Clin Cancer Res; 24(6); 1287–95. ©2018 AACR.

Considerations for the combination of anticancer vaccines and immune checkpoint inhibitors

ABSTRACT Introduction: Over the past few years, trials evaluating immunotherapies, particularly immune checkpoint inhibitors, have revolutionized the standard model of cancer treatment, demonstrating significant antitumor responses and improved clinical outcomes across a wide array of tumors types. Yet, despite these compelling data, a major limitation has been that only a fraction of patients mount a response to single-agent immune checkpoint inhibition. However, a growing amount of preclinical and clinical data suggests that combining immune checkpoint inhibition, either with other immune checkpoint inhibitors or with therapeutic cancer vaccines, has the potential to improve the proportion of patients seeing long-term durable responses with these therapies. Areas Covered: We have reviewed the reported data on immune checkpoint inhibition as monotherapy and as combination therapy with other immune checkpoint inhibitors or therapeutic cancer vaccines. Data is reviewed on agents with FDA approval or breakthrough designation as of the writing of this manuscript. Expert Opinion: Particular focus is given to the combination of immune checkpoint inhibitors and therapeutic cancer vaccines which has the potential to increase efficacy compared to single agent immune checkpoint inhibition with minimal added toxicity.

Anti–PD-L1 Treatment Induced Central Diabetes Insipidus

Context: Immune checkpoint inhibitors, including anti–programmed cell death protein 1 (PD-1), anti–programmed cell death protein ligand 1 (PD-L1), and anti–cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti–CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. Case Description: We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti–PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient’s symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. Conclusion: To our knowledge, this is the first report of central DI associated with anti–PD-L1 immunotherapy. The patient’s endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality.

Therapeutic vaccines for prostate cancer: recent advances and future directions

ABSTRACT In recent years, therapeutic cancer vaccines have emerged as a viable and promising treatment for prostate cancer. Beyond sipuleucel-T, phase III trials are evaluating multiple vaccine platforms in men with this disease. Growing data evaluating vaccine therapies suggests that these agents are more effective in patients with more indolent and possibly also earlier stages of disease. In addition, a wealth of preclinical data has shown that traditional prostate cancer treatments including anti androgens, cytotoxic and radiation therapies may provide immunologic synergy when given in combination with vaccine platforms. Building off this data, numerous clinical trials are evaluating therapeutic cancer vaccines in early stage prostate cancer and also in combination with traditional prostate cancer therapies. In addition, in order to optimize immune responses, ongoing trials are evaluating vaccines in combination with immune checkpoint inhibitors. Preliminary data from these trials have been promising and are offering an exciting glimpse at the future of immunotherapy for this disease.

Integrating Immunotherapies in Prostate Cancer.

In recent years, immunotherapy has emerged as a viable and promising treatment for prostate cancer. Beyond sipulecuel-T, phase III trials are evaluating multiple vaccine and immune-based therapies in men with this disease. Evidence suggests that many of these therapies are effective at augmenting immune responses and slowing tumor growth rates. Yet prospective data evaluating these responses as surrogates for survival are still needed. In the absence of validated intermediate markers of response, growing data suggests that patients with more indolent disease are more likely to benefit from immunotherapies. In order to further optimize immunotherapy use, ongoing trials are evaluating its combination with traditional as well as other immune-based treatments. Preliminary data from these trials are promising and are shedding new light on this area.

Evaluating immune responses after sipuleucel-T therapy

Following FDA approval of sipuleucel-T in 2010 for metastatic castration resistant prostate cancer (mCRPC), several studies have described the effect of sipuleucel-T on peripheral immune responses. Retrospective associations have also been made with immune responses and survival. A recently published study by Fong et al. was the first to characterize the immune response of sipuleucel-T in the tumor microenvironment. The findings of this study have been hypothesis generating, yet it remains unclear whether the peri-tumor immune response described is predictive of survival. Increasing evidence suggests that radiographic or PSA progression does not accurately reflect survival with sipuleucel-T and other immunotherapies. Finding an immune biomarker which can accurately reflect clinical benefit and validating it prospectively offers the potential for a predictive indicator of response in an area where none currently exists.

Abstract 3421: Epidemiology and survival in patients with extragastric signet ring carcinoma

Background: Signet ring carcinoma (SRC) is a distinct histological phenotype of adenocarcinoma. There are only a few published studies specifying the epidemiology of SRC with extragastric presentation. The purpose of our study was to define the most common primary sites of extragastric SRC, determine the incidence, and to compare survival by primary site and disease stage. Methods: The Surveillance Epidemiology and End Result (SEER) database was examined from 2000 to 2012 in order to identify SRC histology (8490) and determine its most common primary sites, incidence, and survival by site and stage. The five most common primary extragastric sites were identified by utilizing ICD-0-3/WHO 2008 classification. Age-adjusted incidence rates for extragastric SRC were calculated and compared to gastric SRC. Relative survival (RS) and overall survival (OS) at 1 and 3 years were analyzed by primary site and stage using Kaplan-Meier method. Chi-square test was used for categorical variables. Results: A total of 24,522 histologically confirmed cases of SRC were identified, and SRC comprised 0.5% of all malignant neoplasms. Among cases with known histological grade, 89.7% had poorly differentiated tumors. Overall, digestive system origin was recorded for 90% of SRC cases. Approximately half (44.2%) of primary SRC tumors were detected outside of the stomach. The most common primary sites for extragastric SRC were colon (40.5%), esophagus (11.9%), rectum (9.8%), lung/bronchus (7.3%), and pancreas (4.7%). The incidence rates for common extragastric SRC were much lower than for gastric SRC, and were higher for males than females (p Conclusion: Our study indicated that extragastric SRC most commonly occurs in the colorectum, esophagus and lung/bronchus. We confirmed that the primary site substantially impacts survival. Thus, development of unique molecular or histologic markers may help to identify the organ of origin and thereby determine prognosis in these phenotypically similar neoplasms. Citation Format: Chul Kim, Susanna Ulahannan, Julius Strauss, Jaydira Del Rivero, Austin Duffy, Tim F. Greten, Oxana V. Makarova-Rusher. Epidemiology and survival in patients with extragastric signet ring 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 3421.

Abstract 5015: Pretreatment carcinoembryonic antigen levels predict survival in patients with rectal adenocarcinoma

Background: Population-based studies have reported elevated Carcinoembryonic Antigen (CEA) level as an independent prognostic factor in patients with colon cancer, thus supporting inclusion of CEA-based C stage in classical TNM staging for colon cancer. However, the effect of C-stage incorporation on outcomes for patients with rectal adenocarcinoma is unknown. Methods: The Surveillance, Epidemiology and End Result (SEER) database was used to collect data from 2004 to 2007 for patients with rectal adenocarcinoma by topography code C20.9 and histology codes 8140-8144, 8210-8211, 8220-8221, 8260-8263, 8440, 8480-8481, and 8490. CEA stage C0 = normal CEA or C1 = elevated CEA was assigned to patients with known pretreatment CEA levels. Observed survival (OS) by American Joint Committee on Cancer (AJCC) stages I-IV and CEA stage C0 or 1 was determined using Kaplan Meier method. Relative survival (RS) as a net measure of cancer survival adjusted for sex, race, age and date was calculated in addition to observed survival (OS). Log-rank was used to compare observed survival. Z-test with corresponding p values was used to compare 5-year relative survival. Results: We identified 25,241 patients with a record of histologically confirmed invasive rectal adenocarcinoma. Approximately half (N = 13,151) of these patients had records of pretreatment CEA levels: N = 6,360 stage C1, N = 6,690 stage C0 and a small number (101) with borderline CEA levels. Mean age at diagnosis was similar in both groups, 64.2 for C0 and 64.7 for C1. Among patients with C1 disease the leading AJCC stage was distant metastatic, stage IV (33.8%) followed by 25.8% stage III, 20.7% stage II, 13.8% stage I, and 5.9% unknown stage. In contrast to CI disease, the most common stage for C0 was stage I (35.2%), and only 6.3% of patients with C0 were diagnosed with stage IV disease. Observed survival by each of I-IV AJCC TNM stages was decreased for C1 stage relative to C0, p Conclusion: Our study suggests that pretreatment CEA levels predict survival in patients with rectal adenocarcinoma, in accordance with previous data in colon cancer. Therefore, our study supports C-stage inclusion in AJCC TNM staging for this neoplasm. Further prospective confirmatory studies are warranted. Citation Format: Oxana V. Makarova-Rusher, Julius Strauss, Susanna Ulahannan, Chul Kim, Jaydira Del Rivero, Austin Duffy, Tim F. Greten. Pretreatment carcinoembryonic antigen levels predict survival in patients with rectal adenocarcinoma. [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 5015.