The combination of SEA-CD40, gemcitabine, nab-paclitaxel (Abraxane), and pembrolizumab (Keytruda) demonstrated early efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to updated results from the phase 1 SGNS40-001 trial. (NCT02376699) presented evidence at the 2023 Gastrointestinal Cancers Symposium.1
As of August 16, 2022, with a median duration of exposure of 25.1 weeks, SEA-CD40 plus gemcitabine, nab-paclitaxel, and pembrolizumab combined was 44% (n = 27; 95% CI, 31.5%–57.6 %), with comparable response rates observed at both assessed dose levels of SEA-CD40. Patients receiving 10 μg/kg SEA-CD40 combination had a confirmed ORR of 48% (n = 19; 95% CI, 31.5%–63.9%) compared with 30 μg SEA-CD40 The confirmed ORR/kg of patients who received was 38% (n = 8; 95% CI, 18.1%-61.6%).
“Patients with pancreatic cancer need more and better treatments,” said study lead author Andrew L. Coveler, M.D., of the Fred Hutchinson Cancer Center in Seattle and the University of Washington School of Medicine. Stated. on live®“The combination of SEA-CD40, pembrolizumab, gemcitabine and nab-paclitaxel performed well compared to historical controls, indicating that immunotherapy may one day be a treatment for patients with pancreatic cancer.” I have.”
SEA-CD40 is a non-fucosylated, receptor-independent, humanized IgG1 CD40-directed monoclonal antibody that binds with increased affinity to FcγRIIIa, potentiates effector function and CD40 agonism, and regulates the PD-1 pathway. Potentially allows blockade and immunostimulatory amplification. Preclinical models indicate that CD40 agonists and chemotherapy can produce sustained antitumor activity.2
The ongoing single-arm SGNS40-001 trial is investigating SEA-CD40 alone and in combination with gemcitabine, nab-paclitaxel and pembrolizumab in patients with PDAC. Preliminary data in quadruplicates in this population show an acceptable side effect (AE) profile and evidence of immune activation.
Cohort L of SGNS40-001 enrolled 61 patients. 40 in the cohort where he received SEA-CD40 at 10 μg/kg and 21 in the cohort where he received SEA-CD40 at the recommended phase 2 dose of 30 μg/kg.
Eligible patients must have treatment-naïve cytologically or histologically confirmed metastatic PDAC measurable according to RECIST v1.1 criteria, ECOG performance status (PS) ≤1, liver, kidney, and Patients 18 years and older with adequate hematologic function are included. Patient may have received prior adjuvant or neoadjuvant therapy for non-metastatic PDAC if she had fully completed this treatment for >4 months before receiving SGNS40-001 treatment .
Patients received gemcitabine at 1000 mg/m2 and 125 mg/m2 nab-paclitaxel2 SEA-CD40 at 10 μg/kg or 30 μg/kg on days 1, 8, and 15 on day 3 of each 28-day cycle, plus 400 mg pembrolizumab every 6 weeks beginning on day 8 of the first cycle A total of 18 pembrolizumab treatments. Continued treatment was permitted in patients who experienced ongoing clinical benefit. During treatment, the investigator performed response assessments every two cycles of her from her Day 22 to her Day 28. Response assessments were also performed 30 to 37 days after the patient’s last dose of study treatment and every 12 weeks thereafter.
The primary endpoint of the study was confirmed ORR assessed by investigators according to RECIST v1.1 criteria. Secondary endpoints included investigator-assessed ORR according to iRECIST v1.1 criteria. disease control rate; duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety, including adverse events, dose-limiting toxicities and laboratory abnormalities. pharmacokinetic parameter estimation; and anti-therapeutic antibodies.
Overall, the median age of patients enrolled in this study was 66.0 years (range, 40-80 years). The median ages for the 10 μg/kg and 30 μg/kg cohorts were 66.0 (range 40-80) and 65.0 (range 41-76), respectively. A total of 48% (n = 29) of patients were male, 45% (n = 18) in the 10 μg/kg cohort and 52% (n = 11) in the 30 μg/kg cohort.
In the 10 μg/kg and 30 μg/kg cohorts, 40% (n = 16) and 62% (n = 13) had an ECOG PS of 1, 60% (n = 24) and 76% (n = 16), Each had liver lesions. Regarding prior therapy, 18% (n = 7) and 14% (n = 3) received radiotherapy and 23% (n = 9) and 24% (n = 9) received radiotherapy in the 10 μg/kg and 30 μg/kg cohorts, respectively. % (n = 5) had previous surgery, and 25% (n = 10) and 29% (n = 6) had previously received neoadjuvant or adjuvant therapy.
One patient in the 10 μg/kg cohort achieved a complete response as the best clinical response. Overall, 43% (n = 26) of the total study population achieved the best clinical response of partial response, compared with 45% (n = 18) in the 10 µg/kg cohort and 38% (n = 18) in the 30 µg/kg cohort. = 8) has been achieved. kg cohort. Additionally, 34% of the total population (n = 21) had stable disease as the best clinical response, compared to 30% of the 10 μg/kg cohort (n = 12) and 43% of the 30 μg/kg cohort (n = 9 ) was. cohort.
Median DOR was 5.7 months (95% CI 3.9 to 7.4) and 5.7 months (95% CI 2.3 to 9.2) in the 10 μg/kg and 30 μg/kg cohorts, respectively.
Median follow-up was 6.7 months (range, 0–23.4) in the 10 µg/kg cohort and 7.4 months (range, 0.7–19.9) in the 30 µg/kg cohort, with a median total follow-up of 6.9. bottom. months (range, 0–23.4), median PFS for both cohorts combined was 7.4 months (95% CI, 5.6–9.0), with 49 PFS events observed.
Median follow-up was 14.9 months (range, 0.8-25.1) in the 10 μg/kg cohort and 9.4 months (range, 0.7-25.7) in the 30 μg/kg cohort, with a median total follow-up of 11.9 months. bottom. months (range, 0.7–25.7), median OS for both cohorts combined was 13.8 months (95% CI, 7.8–16.2) with 47 OS events observed.
Patients had transient increases in circulating cytokines and chemokines in peripheral blood associated with post-treatment immune activation and trafficking. It also increased activation of peripheral natural killer (NK) cells and her T cells. The researchers observed a similar incidence of cytokine induction in a patient who received SEA-CD40 monotherapy 4 hours after her SEA-CD40 infusion.
Evaluation of changes in peripheral blood immune subsets after treatment showed no differences in peripheral blood immune subset activation markers between the two dose levels.In both cohorts, the researchers noted a transient decrease in circulating monocytes, NK cells, CD4 and CD8 positive T cells 24 hours after his SEA-CD40 infusion (modified P. < .05) and increased expression of CD69 activation and Ki67 proliferation markers in circulating CD4- and CD8-positive T cells (corrected P. < .05). Furthermore, this analysis showed that there was no significant change in circulating regulatory T cell levels after SEA-CD40 infusion (P. > .10).
Regarding safety, infusion-related reactions were the most common SEA-CD40-related AEs (Grade 1-2, 56%; Grade ≥3, 8%). All patients received mandatory her H1 and H2 antihistamines, ibuprofen, acetaminophen, and investigator-selected antiemetics before starting study therapy. All patients had a controlled infusion rate.
In both study cohorts, other treatment-related AEs (TRAEs) of grade 1–2 and grade ≥3, respectively, included fatigue (16%; 5%), nausea (grades 1–2, 30%), neutrophil Hypochondriasis (3%) was included. 8%), chills (52%; 2%), fever (grades 1-2, 25%), and diarrhea (grades 1-2, 10%). Across both cohorts, treatment-emergent AEs of grade 1–2 and grade ≥3, respectively, were fatigue (66%; 18%), nausea (70%; 3%), neutropenia (7%; 61%), were infusions. Associated reactions (56%; 8%), chills (61%; 2%), fever (56%; 5%), and diarrhea (44%; 15%).
The 10 μg/kg cohort tended to be better tolerated. Specifically, in this cohort, grade 3 or higher TRAEs were neutropenia (5%) and infusion-related reactions (19%). In the 30 μg/kg cohort, grade 3 or greater TRAEs were fatigue (14%), neutropenia (14%), infusion-related reactions (5%), and chills (5%).
Adverse events leading to treatment discontinuation included immune-mediated lung disease (8%, n = 3) and septic shock (3%, n = 1), 10 μg/kg SEA-CD40 and colitis (5%). , n = 1) were included. Portal vein thrombosis with 30 μg/kg SEA-CD40 (5%, n = 1).
“SEA-CD40 in combination with gemcitabine, nab-paclitaxel, and pembrolizumab has an acceptable safety profile. The evidence of immune activation in this study was consistent with the proposed SEA-CD40 mechanism of action.” ,” the study authors concluded in a poster.
Editor’s Note: Dr. Coveler has held consulting or advisory roles at Abbvie, Halozyme, Merrimack, and Seattle Genetics. AbGenomics International (Inst), Actuate Therapeutics (Inst), Amgen (Inst), Amgen (Inst), Genentech (Inst), Gilead Sciences (Inst), Halozyme (Inst), Immunomedics (Inst), Lilly ( Inst), MedImmune ( Inst), Newlink Genetics (Inst), Nextrast (Inst), Novocure (Inst), Nucana (Inst), Onconova Therapeutics (Inst), Seattle Genetics (Inst), Surface Oncology (Inst), Taiho Pharmaceutical (Inst), and XBiotech (Inst); received travel or accommodation funding from Abbvie, Halozyme, and Nucana.
- Coveler AL, Gutierrez M, Vaccaro GM, et al. Updated results from phase 1 trial of SEA-CD40, gemcitabine, nab-paclitaxel and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) (SGNS40-001). J Clin Oncol. 2023;41(suppl 4):708.doi:10.1200/JCO.2023.41.3_suppl.708
- Byrne KT, Vonderheide RH. CD40 stimulation disarms innate sensors and promotes her T-cell immunity to cancer. cell rep2016;15(12):2719-2732. doi:10.1016/j.celrep.2016.05.058