SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab, showed early evidence of efficacy in patients with metastatic pancreatic ductal adenocarcinoma.
The phase 1 SGNS40-001 study (NCT02376699) of SEA-CD40, gemcitabine, nab-paclitaxel (Abraxane), and pembrolizumab (Keytruda) showed early evidence of efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), according to updated results presented 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 showed a total confirmed objective response rate (ORR) of 44% (n = 27; 95% CI, 31.5%-57.6%), with comparable response rates observed at both evaluated dose levels of SEA-CD40. Patients who received the combination with SEA-CD40 at 10 µg/kg had a confirmed ORR of 48% (n = 19; 95% CI, 31.5%-63.9%), and those who received the combination with SEA-CD40 at 30 µg/kg had a confirmed ORR of 38% (n = 8; 95% CI, 18.1%-61.6%).
“Patients with pancreas cancer need more and better treatments,” lead study author, Andrew L. Coveler, MD, of Fred Hutchinson Cancer Center and the University of Washington School of Medicine, both in Seattle, said to OncLive®. “The combination of SEA-CD40, pembrolizumab, gemcitabine, and nab-paclitaxel compared favorably with historical controls, demonstrating that immunotherapy may 1 day be a treatment for patients with pancreas cancer.”
SEA-CD40 is a nonfucosylated, receptor-agnostic, humanized IgG1 CD40-directed monoclonal antibody that binds with increased affinity to FcγRIIIa, resulting in enhanced effector function and CD40 agonism and potentially allowing PD-1 pathway blockade and immune stimulation amplification. Preclinical models have shown that a CD40 agonist plus chemotherapy may produce durable 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 with the quadruplet in this population have demonstrated a tolerable adverse effect (AE) profile and evidence of immune activation.
Cohort L of SGNS40-001 enrolled 61 patients: 40 in the cohort that received SEA-CD40 at 10 µg/kg and 21 in the cohort that received SEA-CD40 at the recommended phase 2 dose of 30 µg/kg.
Eligible patients included those at least 18 years of age with an ECOG performance status (PS) of 1 or lower and adequate hepatic, renal, and hematologic function who had previously untreated cytologically or histologically confirmed metastatic PDAC measurable per RECIST v1.1 criteria. Patients could have received prior adjuvant or neoadjuvant therapy for nonmetastatic PDAC if they had fully completed this therapy over 4 months before receiving SGNS40-001 treatment.
Patients received gemcitabine at 1000 mg/m2 and nab-paclitaxel at 125 mg/m2 on days 1, 8, and 15 and SEA-CD40 at 10 µg/kg or 30 µg/kg on day 3 of each 28-day cycle, as well as 400 mg of pembrolizumab every 6 weeks starting on day 8 of the first cycle for a total of 18 pembrolizumab treatments. Continued treatment was allowed in patients who experienced ongoing clinical benefit. During treatment, the investigators performed response assessments every 2 cycles on days 22 through 28. Response assessments were also conducted 30 to 37 days after a patient’s last dose of study treatment and every 12 weeks thereafter.
The primary end point of this trial was investigator-assessed confirmed ORR per RECIST v1.1 criteria. Secondary end points included investigator-assessed ORR per iRECIST v1.1 criteria; disease control rate; duration of response (DOR); progression-free survival (PFS); overall survival (OS); safety, including AEs, dose-limiting toxicities, and laboratory abnormalities; pharmacokinetic parameter estimates; and antitherapeutic antibodies.
In total, the median age of the patients enrolled to this study was 66.0 years (range, 40-80). The 10 µg/kg and 30 µg/kg cohorts had respective median ages of 66.0 years (range, 40-80) and 65.0 years (range, 41-76). A total of 48% (n = 29) of the patients were male, 45% (n = 18) of the 10 µg/kg cohort and 52% (n = 11) of the 30 µg/kg cohort.
In the 10 µg/kg and 30 µg/kg cohorts, 40% (n = 16) and 62% (n = 13), respectively, had an ECOG PS of 1, and 60% (n = 24) and 76% (n = 16), respectively, had liver lesions. Regarding prior therapies, in the 10 µg/kg and 30 µg/kg cohorts, respectively, 18% (n = 7) and 14% (n = 3) had received radiation therapy, 23% (n = 9) and 24% (n = 5) had received prior surgery, and 25% (n = 10) and 29% (n = 6) had received prior neoadjuvant or adjuvant therapy.
One patient from the 10 µg/kg cohort achieved complete response as their best clinical response. Overall, 43% (n = 26) of the total study population achieved a best clinical response of partial response, 45% (n = 18) of the 10 µg/kg cohort and 38% (n = 8) of the 30 µg/kg cohort. Additionally, 34% (n = 21) of the total population had stable disease as their best clinical response, 30% (n = 12) of the 10 µg/kg cohort and 43% (n = 9) of the 30 µg/kg cohort.
The median DOR was 5.7 months (95% CI, 3.9-7.4) and 5.7 months (95% CI, 2.3-9.2) in the 10 µg/kg and 30 µg/kg cohorts, respectively.
At a median follow-up of 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, for a total median follow-up of 6.9 months (range, 0-23.4), the median PFS for both cohorts combined was 7.4 months (95% CI, 5.6-9.0), with 49 PFS events observed.
At a median follow-up of 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, for a total median follow-up of 11.9 months (range, 0.7-25.7), the 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 the peripheral blood associated with immune activation and trafficking after treatment. They also had increased activation on peripheral natural killer (NK) cells and T cells. The investigators observed a similar incidence of cytokine induction 4 hours after SEA-CD40 infusion in patients who had received SEA-CD40 monotherapy.
An evaluation of the changes in peripheral blood immune subsets after treatment showed no difference in the activation markers of peripheral immune subsets between the 2 dose levels. Across both cohorts, the investigators noted a transient decrease in circulating monocytes, NK cells, and CD4- and CD8-positive T cells 24 hours after SEA-CD40 infusion (corrected P < .05) and an increased expression of CD69 activation and Ki67 proliferation markers on circulating CD4- and CD8-positive T cells (corrected P < .05). Additionally, this analysis showed 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%). Prior to initiating study therapy, all patients received mandatory H1 and H2 antihistamines, ibuprofen, acetaminophen, and an anti-emetic of investigator’s choice. All patients had a controlled infusion rate.
Other treatment-related AEs (TRAEs) of grade 1 to 2 and grade 3 or higher, respectively, across both study cohorts included fatigue (16%; 5%), nausea (grade 1-2, 30%), neutropenia (3%; 8%), chills (52%; 2%), pyrexia (grade 1-2, 25%), and diarrhea (grade 1-2, 10%). Across both cohorts, treatment-emergent AEs of grade 1 to 2 and grade 3 or higher, respectively, were fatigue (66%; 18%), nausea (70%; 3%), neutropenia (7%; 61%), infusion-related reactions (56%; 8%), chills (61%; 2%), pyrexia (56%; 5%), and diarrhea (44%; 15%).
The 10 µg/kg cohort trended toward greater tolerability. Specifically, in this cohort, the TRAEs of grade 3 or higher were neutropenia (5%) and infusion-related reactions (19%). In the 30 µg/kg cohort, the TRAEs of grade 3 or higher were fatigue (14%), neutropenia (14%), infusion-related reactions (5%), and chills (5%).
AEs leading to treatment discontinuation included immune-mediated lung disease (8%, n = 3) and septic shock (3%, n = 1) with SEA-CD40 at 10 µg/kg and colitis (5%, n = 1) and portal vein thrombosis (5%, n = 1) with SEA-CD40 at 30 µg/kg.
“SEA-CD40 in combination with gemcitabine, nab-paclitaxel, and pembrolizumab has an acceptable safety profile. Evidence of immune activation in this study was consistent with the proposed SEA-CD40 mechanism of action,” the study authors concluded on the poster.