Rixe, Olivier

Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10–30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.

9004 Background: Despite advances in first-line (1L) immunotherapy ± CT, most patients (pts) with aNSCLC experience disease progression, necessitating novel strategies. Dato-DXd is an antibody drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a plasma-stable tetrapeptide-based cleavable linker. Dato-DXd had encouraging efficacy and manageable safety in heavily pretreated aNSCLC. Dato-DXd + immunotherapy yielded greater preclinical activity than either agent alone. Methods: TROPION-Lung02 (NCT04526691) is a phase 1b, global, dose-escalation and -expansion study evaluating Dato-DXd (4 or 6 mg/kg) + pembro 200 mg ± Pt-CT (cisplatin 75 mg/m2 or carboplatin AUC 5) every 21 days across 6 cohorts. Pts in escalation may have received ≤2 prior lines of therapy for aNSCLC. Pts in expansion were primarily treatment (tx) naive (pts receiving Dato-DXd + pembro may have ≤1 prior Pt-based tx). The primary objective is to assess safety and tolerability, including dose-limiting toxicities (DLTs). Secondary objectives include evaluation of efficacy, pharmacokinetics, and immunogenicity. Results: As of the Oct 31, 2022, data cutoff (DCO), 120 pts were treated. All cohorts met DLT criteria to move to escalation. Median age was 65 years. PD-L1 expression was <1%, 1%-49%, and ≥50% in 40%, 33%, and 26% of pts, respectively. Median tx duration was 4.6 mo, with 55% receiving tx at DCO. The most frequent any-grade (gr) tx-emergent adverse events (TEAEs) were nausea (45%) and stomatitis (45%). Gr ≥3 TEAEs occurred in 61% of pts; most frequent were neutrophil count decreased (8%) and amylase increased (8%). TEAEs that were serious, associated with discontinuation, or associated with death occurred in 31%, 24% (16% associated with Dato-DXd), and 6% of pts, respectively. Dose reductions due to TEAEs associated with Dato-DXd occurred in 17%. Drug-related interstitial lung disease occurred in 12 pts (10%; 9 gr 1/2; 3 gr 3). The objective response rate (ORR) with 1L Dato-DXd + pembro doublet and Dato-DXd + pembro + Pt-CT triplet tx was 60% (95% CI, 36%-81%; 12 [2 unconfirmed]/20) and 55% (95% CI, 39%-70%; 23 [5 unconfirmed]/42), respectively. The ORR for any line of therapy was 38% (95% CI, 25%-54%; 18 [2 unconfirmed]/47) with doublet and 47% (95% CI, 34%-60%; 28 [5 unconfirmed]/60) with triplet tx. In both subsets, the disease control rate was 85% and median duration of response was not reached. Responses were observed in all 3 PD-L1 expression level subgroups. Although immature, median progression-free survival (95% CI) was 10.8 (8.3-15.2) and 7.8 mo (5.5-NE) with doublet and triplet tx, respectively. Conclusions: Dato-DXd + pembro ± Pt-CT demonstrated tolerable safety with notable 1L activity in this first and largest dataset with an ADC + immunotherapy ± Pt-CT in aNSCLC pts. Clinical trial information: NCT04526691 .

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.