<div>AbstractPurpose:<p>To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC).</p>Patients and Methods:<p>This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis–related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined.</p>Results:<p>Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47–77]. ORR was 17% (95% CI, 7–32), comprising of seven PRs. Median duration of response was 20 months (range, 10–48 months). Median PFS was 8.4 months and median OS 31.4 months. Grade 1–2 peripheral edema and joint-related symptoms were common. Overall incidence of grade 3–4 adverse events (AE) of any type was 33% (<i>n</i> = 15). Expected AEs of bevacizumab treatment did not appear to be increased by the addition of trebananib.</p>Conclusions:<p>In a first-line mCRC population, the dual antiangiogenic combination, bevacizumab plus trebananib, without chemotherapy, was efficacious with durable responses. The toxicity profile of the combination was manageable and did not exceed that expected with bevacizumab +/− chemotherapy. Exploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.</p></div>
<p>Supplementary Fig 3. Hierarchical clustering of plasma antibody profiles after 6 weeks of study treatment, using the Spearman rank correlation method with average linkage. Patient ID (0n) at the 6-week time point (best tumour response, PFS).</p>
Abstract Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway by activating caspases. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody to human DR5 created by CDR grafting of the murine antibody TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in patients with mCRC. Methods: Pts with mCRC who had received at least 1 course of chemotherapy (CT) were treated with weekly IV CS-1008 infusions in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (Co 1: 0.2 and 6 mg/kg; Co 2: 1 and 6 mg/kg; Co 3: 2 and 6 mg/kg; Co 4: 4 and 4mg/kg; Co 5: 6 and 2 mg/kg), followed by a weekly CS-1008 dose of 2 mg/kg. Cycle 1 encompassed 7 wks of therapy (D1 and D36 doses trace-labeled with 111In); additional weekly CS-1008 was scheduled as 4-wk cycles. Primary endpoints were to determine (1) the influence of CS-1008 dose on initial biodistribution, pharmacokinetic (PK) and tumor uptake of 111In-CS-1008 following single infusion; (2) changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints were to determine (1) anti-tumor response; (2) changes in tumor metabolism; (3) serum apoptosis biomarkers and serum tumor response markers. Results: Nineteen pts with a median age of 64 years and 2-6 prior CT lines were enrolled as follows: Co 1, 2 pts; Co 2, 4 pts; Co 3, 5 pts; Co 4, 3 pts; and Co 5, 5 pts. Twelve pts showed tumor uptake of 111In-CS-1008, 3 at each of the 1, 2, 4 and 6 mg/kg D1 dose levels. 111In-CS-1008 uptake in tumor was variable: some pts showed no uptake, in others uptake was observed in all measurable lesions. Liver metastases showed poor uptake of CS-1008. No significant differences were observed in tumor uptake between D1 and D36, and no effect of dose on tumor uptake was seen. DR5 expression in archived samples did not correlate with 111In-CS-1008 uptake, nor with clinical outcome. 111In-CS-1008 biodistribution showed gradual blood pool clearance and no discernible abnormal uptake in normal tissue. CS-1008 PK was not affected by dose or repeated drug administration. At restaging, there were 8 SD, 1 PR and 10 PD. The duration of PR was 3.7 months (mos). The mean duration of SD was 4 mos (range, 2.6-6.7 mos). Among the group of pts who showed CS-1008 uptake in tumor, 58% had clinical benefit (SD or PR), compared with 28% of pts in the group with no tumor uptake. The lesions that showed CS-1008 uptake were less likely to progress even in pts with overall PD at restaging. Conclusions: 111In-CS-1008 uptake in tumor predicts SD or PR. Tumor DR5 expression, assessed by 111In-CS-1008 imaging, reveals real-time heterogeneous DR5 expression, both on a per pt and on a lesion by lesion basis, and appears to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Citation Format: Marika Ciprotti, Niall C. Tebbutt, Fook T. Lee, Sze T. Lee, Dave C. McKee, Graeme J. O'Keefe, Sylvia J. Gong, Geoffrey Chong, Hui K. Gan, Wendie Hopkins, Bridget Chappell, Nancy Y. Guo, Fiona E. Smyth, Archie N. Tse, Mendel Jansen, Manabu Matsumura, Rira Watanabe, Robert A. Beckman, Jon Greenberg, Andrew M. Scott. A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). [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 1174. doi:10.1158/1538-7445.AM2013-1174
TPS7093 Background: Approximately 30–40% of patients (pts) with high-risk, aggressive B-NHL are refractory to or relapse after first-line chemoimmunotherapy. Although autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapies are available in the second line, access, eligibility, tolerability, and cost pose limitations for pts, and there remains a need for well-tolerated, effective off-the-shelf therapies in this setting. Odronextamab, a CD20×CD3 bispecific antibody, demonstrated encouraging clinical activity (complete response [CR] rate 31.5%; median duration of CR 17.9 months) and a generally manageable safety profile as monotherapy in pts with heavily pretreated R/R diffuse large B-cell lymphoma (DLBCL) in the Phase 2 ELM-2 study (Ayyappan, et al. ASH 2023). This study will evaluate odronextamab versus SOC treatment in pts with DLBCL who have relapsed early (within 1 year) or were refractory to first-line therapy. Methods: OLYMPIA-4 (EudraCT 2022-502783-21-00) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus SOC in pts with previously treated aggressive B-NHL. Odronextamab will be administered intravenously in 21-day cycles, with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, at 160 mg on Days 1, 8, and 15 of C2–4, then as maintenance at 320 mg Q2W until one year from the start of treatment, progressive disease, or death. Treatment in the SOC arm consists of physician’s choice of salvage therapy with intent to proceed to ASCT. SOC regimens are: ifosfamide, carboplatin, and etoposide (ICE); dexamethasone, cisplatin, and cytarabine (DHAP); or gemcitabine, dexamethasone, and cisplatin (GDP), ± rituximab. Pts will receive up to three 21-day cycles of salvage therapy, followed by ASCT. Pts without an optimal response to salvage therapy or ASCT may cross over to receive one year of odronextamab treatment. Key inclusion criteria: ≥18 years of age; aggressive B-NHL that is primary refractory or relapsed within one year of first-line treatment initiation; intent to proceed to ASCT; measurable disease; ECOG performance status 0–1; and adequate organ and hematologic function. Pts with central nervous system lymphoma or active infection are excluded. The primary endpoint is event-free survival, as assessed by independent central review. Key secondary endpoints are progression-free survival, best overall response, and change from baseline in physical function, as measured by EORTC QLQ-C30. Other secondary endpoints include CR rate, duration of response, overall survival, minimal residual disease, pharmacokinetics, and incidence and severity of treatment-emergent adverse events. The trial is currently recruiting and is expected to enroll ~216 pts at ~200 global sites. Clinical trial information: 2022-502783-21-00.
Odronextamab, a CD20×CD3 bispecific antibody that engages cytotoxic T cells to destroy malignant B cells, has demonstrated encouraging activity across multiple subtypes of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma.
Patients and methods
This phase II study (ELM-2; NCT03888105) evaluated odronextamab in patients with R/R follicular lymphoma after two or more lines of systemic therapy. Patients received intravenous odronextamab in 21-day cycles, with step-up dosing in cycle 1 to help mitigate the risk of cytokine release syndrome, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate by independent central review.
Results
Among 128 patients evaluated, 95% completed cycle 1, and 85% completed four or more cycles. At 20.1 months' efficacy follow-up, objective response rate was 80.0% and complete response rate was 73.4%. Median duration of complete response was 25.1 months. Median progression-free survival was 20.7 months, and median overall survival was not reached. Discontinuation of odronextamab due to adverse events occurred in 16% of patients. The most common treatment-emergent adverse events were cytokine release syndrome [56%; grade ≥3 1.7% (1/60) with 0.7/4/20 mg step-up], neutropenia (39%), and pyrexia (38%).
Conclusions
Odronextamab achieved high complete response rates with generally manageable safety in patients with heavily pretreated R/R follicular lymphoma.
The chimeric monoclonal antibody cG250 recognizes the CAIX/MN antigen. cG250 induces antibody-dependent cellular cytotoxicity (ADCC) responses in vitro that can be enhanced by IL-2. We studied the effects of adding daily low-dose subcutaneous IL-2 to cG250 for treatment of clear cell renal cell carcinoma (RCC). The primary endpoints of the trial were toxicity and immunological effects (human anti-chimeric antibodies [HACA], ADCC, natural killer [NK] and lymphokine-activated killer cell [LAK] activity); secondary endpoints were cG250 biodistribution and pharmacokinetics (PK) and tumour response rates. Eligible patients had unresectable metastatic or locally advanced clear cell RCC with measurable or evaluable disease. Nine patients were treated with six doses of cG250 (10 mg/m(2)/week, first and fifth doses trace-labelled with (131)I), and 1.25 x 10(6) IU/m(2)/day IL-2 for six weeks. Treatment was generally well tolerated with no adverse events attributable to cG250. Two patients required a 50% dose reduction of IL-2 due to toxicity. No HACA was detected. (131)I-labeled cG250 showed excellent targeting of tumour deposits. (131)I cG250 PK: T(1/2)alpha 20.16 +/- 6.59 h, T(1/2)beta 126.21 +/- 34.04 h, CL 39.67 +/- 23.06 mL/h, Cmax 5.12 +/- 0.86 microg/mL, V(1) 3.88 +/- 1.05 L. IL-2 did not affect cG250 PK. A trend for increased percentage of circulating CD3-/CD16+CD56+ NK cells was observed. Some patients showed enhanced ADCC or LAK activity. No antitumour responses were observed. In conclusion, weekly cG250 with daily low-dose subcutaneous IL-2 is well tolerated. IL-2 does not influence cG250 biodistribution or increase HACA.
Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.
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