Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20×CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell/major histocompatibility complex interaction. Phase I results in patients with R/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1; NCT02290951). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab. METHODS: Patients with R/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4×21 day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing. RESULTS: Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here. CONCLUSIONS: This biomarker analysis expands on clinical findings of odronextamab in patients with R/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.

Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies.

Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first-in-human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half-maximal effective concentration values from in vitro cytokine release assays (range: 0.05-0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1-10 mg/L) were useful to predict efficacious concentrations in patients and inform dose-escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.

Pre-operative opioid use in gynecologic oncology: a common comorbidity relevant to the peri-operative period.

OBJECTIVES: Pre-operative opioid use is common and should be considered a comorbidity among surgical candidates. Our objective was to describe the rate of pre-operative opioid use and patterns of post-operative outpatient opioid prescribing in a cohort of gynecologic oncology patients. METHODS: A retrospective cohort study was conducted with 448 gynecologic oncology surgical patients undergoing surgery for a suspected or known cancer diagnosis from January 2016 to December 2016. Pre-operative opioid users (n=97) were identified. Patient and surgical characteristics were abstracted, as was post-operative opioid prescription (type of opioid, oral morphine equivalents amount) and length of stay. For pre-operative opioid users, the type of opioid prescribed post-operatively was compared with the type of pre-operative opioid. Pre-operative opioid users were compared with non-users, stratified by surgery type. Descriptive statistics were analyzed using χ2 statistic, and medians were compared using a Mann-Whitney U statistic. RESULTS: Pre-operative opioid prescriptions were noted in 21% of patients, and 24% of these had two or more opioid prescriptions before surgery. The majority of pre-operative opioid users (51%) were maintained on the same agent post-operatively at the time of discharge, but 36% were switched to a different opioid and 7% were prescribed an additional opioid. Overall and in laparotomies, pre-operative opioid users received higher volume post-operative prescriptions than non-users. There was no difference in post-operative prescription volume for minimally invasive surgeries or in length of stay between pre-operative users and non-users. CONCLUSIONS: Pre-operative opioid use is common in gynecologic oncology patients and should be considered during pre-operative planning. Pre-operative opioid use was associated with a higher volume and wider range of post-operative prescription. Over 40% of opioid users were discharged with either an additional opioid or a new opioid, highlighting a potential missed opportunity to optimize opioid safety. Further research is needed to characterize the relationship between pre-operative opioid use and peri-operative outcomes and to develop strategies to manage pain effectively in this population without compromising opioid safety.

Priorities in Fertility Decisions for Reproductive-Aged Cancer Patients: Fertility Attitudes and Cancer Treatment Study.

PURPOSE: The Fertility Attitudes and Cancer Treatment Study (FACTS) aims at better understanding the reasons and priorities of young adult cancer patients making decisions for fertility preservation (FP). Identifying the factors that center around a patient's fertility decisions will support the development of educational tools for providers and improve clinical care to meet patients' reproductive needs. METHODS: An exploratory qualitative study was conducted of 27 newly diagnosed male and female cancer patients who had presented for an oncofertility consultation. Interviews lasted ∼30 minutes and were transcribed verbatim. A thematic analysis was conducted to explore the factors driving decisions for future fertility. Themes were grouped to address the following topics: reasons for/against FP, patient priorities, informational needs, support, wellness, and satisfaction with information. Strength of the theme was determined by examining the frequency of a response. RESULTS: Patients who chose FP versus those who did not choose FP and men versus women proved to be more similar than different in their reasoning, priorities, and informational needs for FP decisions. Patients who chose FP identified a "concern for future fertility" as a top reason to do so and "parenthood" as a top priority. For those who did not choose FP, "cancer treatment" was identified as their top priority. For patients identifying financial barriers, 50% of them were able to overcome this to pursue FP. CONCLUSIONS: Reproductive-aged patients diagnosed with a new cancer should be referred to a reproductive specialist and provided the opportunity to come to a fertility decision on their own before initiating cancer treatment.

Sexual and Marital Dysfunction in Women With Gynecologic Cancer.

OBJECTIVE: Sexual dysfunction can be a long-term issue for women with gynecologic cancer. This study assesses the extent of sexual and marital dysfunction women face following treatment of a gynecologic cancer. METHODS: A cross-sectional study of women with gynecologic cancer was conducted using a 181-item survey. Sexual dysfunction was measured by change in the Female Sexual Function Index score; marital dysfunction was measured by change in Intimate Bond Measure from prediagnosis to posttreatment. Paired t tests and Fisher exact test were used to compare women with dysfunction to those without dysfunction. RESULTS: Three hundred twenty women were enrolled (mean age, 56.0 [SD, 12.0] years). Among all women, sexual function declined from a score of 21.3 (SD, 10.4) prior to 15.3 (SD, 10.2) (P < 0.001), and sexual activity decreased from 6.1 (SD, 6.8) to 2.6 (SD, 4.9) times per month following treatment (P < 0.001). Among the 208 women who were sexually active at the time of study, sexual dysfunction after treatment was associated with younger age (50.9 [SD, 11.7] years to 57.3 [SD, 12.3] years), ovarian (40.7% vs 30.7%) or cervical (21.0% vs 10.2%) cancer diagnosis, chemotherapy treatment (72.8% vs 50.4%), and being in a relationship (97.3% vs 82.7%). Among women in relationships, 27% experienced marital dysfunction. CONCLUSIONS: Women who are younger, have an ovarian or cervical cancer diagnosis, receive chemotherapy, or are in a committed relationship are at particularly high risk of sexual dysfunction. These women should be provided information about the risks associated with their cancer treatment.

A Review of the Oncology Patient's Challenges for Utilizing Fertility Preservation Services.

PURPOSE: The American Society of Clinical Oncology issued practice guidelines in 2006 to provide critical information about fertility impact to adolescents and young adults (AYA) at the time of cancer diagnosis. Survivors continue to express concerns about their long-term reproductive health after cancer therapy even as treatment options for fertility preservation evolve. An underutilization of fertility preservation methods by cancer patients continues to persist. A review of the literature cites barriers and challenges that limit fertility information and preservation options for AYA cancer patients. METHODS: A review of medical literature was conducted to examine current practice for patients receiving fertility information and the barriers to patients receiving fertility preservation services. RESULTS: A total of 69 publications were included in this review. The review summarizes (1) patient experiences with receiving fertility information and (2) patient desires, barriers, and challenges to utilizing fertility preservation services. CONCLUSIONS: Despite advances in fertility preservation, there are challenges for patients to utilizing fertility preservation services. Barriers include the following: urgency to initiate treatment, inadequate information, clinic time constraints, and perceptions around patients' gender, age, cost, parity, race, relationship, and sociodemographic status influence whether patients receive fertility preservation consultation. Patients report a lack of adequate information to make informed fertility decisions.

Do Patient Characteristics Decide if Young Adult Cancer Patients Undergo Fertility Preservation?

PURPOSE: The Fertility Attitudes and Cancer Treatment Study (FACTS) is a two-phase research initiative aimed to understand factors involved with decision making for future fertility. The FACTS will improve services and utilization of fertility preservation (FP) before cancer treatment. Phase-I examined patient characteristics as associated with FP decision. METHODS: A retrospective cohort study of 108 reproductive-aged (18-45 years) males and females who received a fertility consultation before cancer treatment from January 1, 2012 to April 30, 2014 was conducted. Chi-square, student's t-test, and logistic regression were conducted to examine associations with FP decision. RESULTS: The utilization rate of FP following fertility consultation was 49%. Gender was the most significant factor contributing to FP decision; 74% of those who choose FP were male (odds ratio = 12.5; 95% confidence interval 5.1-31.4). Those who opted for FP were more likely to be Caucasian (p = 0.042), have a solid tumor (p = 0.03), and have a shorter time from diagnosis to fertility consultation (29.5 vs. 58.8 days; p = 0.017). Age, relationship, tumor location, treatment plan, and parity were not significant predictors of FP. CONCLUSIONS: Current perceptions about patient demographics do not predict FP utilization by young adult cancer patients. Providing patients an informed fertility consultation has demonstrated an increase in FP utilization to nearly one-half of patients. Despite gender being a significant factor in choosing FP, the study did not provide reasons as to why. The phase-II study will explore patients' reasons for FP decision in a qualitative design to understand these differences.