Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host’s immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop ‘off-the-shelf’ anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.

Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy demonstrated greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA demonstrated encouraging clinical activity in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who had received previous treatment. This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) vs. placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary endpoint was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. Based on the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary endpoint). A total of 153 patients were randomized to either BA (n=75) or durvalumab groups (n=78). Median PFS was 12.8 months vs. 14.6 months (stratified hazard ratio: 1.48 [95% confidence interval, 0.69-3.17], in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% vs. 32.1%) and disease control rate (66.7% vs. 70.5%) were similar between the two groups. Any grade treatment-emergent adverse events occurred in 94.6% vs. 96.1% of patients in the BA vs. durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). BA with cCRT followed by BA demonstrated no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1^T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

The population of cancer survivors is on the rise due to an increase in cancer incidence and a decline in cancer mortality. This growing survivor population creates a number of challenges. Although there have been improvements in care planning for cancer survivors, our healthcare system still lacks the delivery of coordinated care between primary care physicians and specialists. Understanding the needs of cancer survivors can help improve the current care models. In this review we describe existing survivorship care models. We also describe emerging models using some programs at the Cleveland Clinic to highlight various potential approaches.

Ang et al. show that a widely studied biomarker for immunotherapy varies based on patient demographics, and that it may only predict outcomes in certain populations.