Bisialidase/Fc Fusion Protein E-602 Shows Preliminary Activity and Tolerability in Advanced Solid Tumors

Jason Luke, MD, FACP

Proof of mechanism and safety has been established for the first-in-class bisialidase and Fc fusion protein E-602 in advanced solid tumors, supporting its continued investigation and viability of harnessing glycan-mediated immune regulation as a novel therapeutic approach in this population, according to Jason Luke, MD, FACP.

Data from the dose-escalation portion of the first-in-human phase 1 GLIMMER-01 trial (NCT05259696) were presented at the 2023 AACR Annual Meeting. Results demonstrated that E-602 produced a dose-dependent increase in pro-inflammatory cytokines in peripheral blood. Patients also experienced sustained, biologically meaningful desialylation in peripheral CD8+ T cells 24 to 48 hours after treatment with E-602 at 10 mg/kg, 20 mg/kg, and 30 mg/kg. These immunomodulatory effects were consistent with preclinical data.

Moreover, E-602 was deemed safe and tolerable up to doses of 30 mg/kg, and no dose-limiting toxicities were observed. In the overall population (n = 40), 19 patients experienced a grade 1/2 infusion-related adverse effect (AE), while 1 patient reported a grade 3 infusion-related AE. Other AEs included decreased lymphocyte count, fatigue, abdominal pain, myalgia, tachycardia, vomiting, and nausea.¹

Based on these results, the phase 2 dose-expansion portion of GLIMMER-01 will evaluate the clinical activity of E-602 monotherapy in patients with checkpoint inhibitor–resistant non–small cell lung cancer and melanoma. The safety of E-602 plus cemiplimab-rwlc (Libtayo) will also be investigated in the phase 1 portion of the trial.

“[As we investigate this drug in] future populations that may have a better chance of responding to treatment, we’re hopeful that these biomarker observations will turn into true responses in the clinic,” said Luke, who is an associate professor of medicine in the Division of Hematology/Oncology, and director of the Cancer Immunotherapeutic Center, Immunology and Immunotherapy Program at UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania.

In an interview with OncLive®, Luke emphasized the significance of this novel therapeutic class of glyco-immune checkpoint inhibitors for advanced solid tumors, the safety and preliminary activity of E-602, and next steps for its investigation.

OncLive: What was the rationale for conducting the phase 1 GLIMMER-01 trial of E-602 in advanced solid tumors?

Luke: We’re giving the first presentation [of data from] the GLIMMER-01 clinical trial. This portion is the dose escalation of the novel bispecific sialidase enzyme, E-602. This is a novel area of cancer drug development, and it takes advantage of our new understanding of [how] glycosylation patterns on tumor cells affect tumor immunity. People may or may not be aware that Carolyn Bertozzi, PhD, of Stanford University, won the Nobel Prize in chemistry for deciphering some of this biology this past year. This is the first attempt to try to harness that [biology] as a therapeutic approach in cancer.

Could you discuss the key methods and objectives of the dose-escalation portion of this study? What will be examined in continued investigations of E-602?

This clinical trial recruited patients with advanced solid tumors that are unfortunately no longer benefiting from standard therapies. In the dose-escalation [portion, dose levels for E-602 ranged] from 1 mg/kg to 30 mg/kg, and we demonstrated the safety of this new molecule.

In addition, we’re pursuing biomarker and translational investigations looking at the effect of this therapy on desialylation of the tumor and immune cells. We [aim to] show that in the peripheral blood, the pharmacodynamic effect of activating some immune subsets with the drug [is consistent with what] was observed in the preclinical mouse models.

How could the unique biological mechanisms targeted by E-602 explain and potentially address poor outcomes with immunotherapy in patients expressing biomarkers that are associated with a favorable response? 

We know that with immunotherapy, biomarkers like PD-L1 and tumor mutational burden predict outcomes, but they do not do so perfectly. Even patients who have perfect biomarkers sometimes do not respond to treatment. How can we explain that? Clearly, there’s more that needs to be understood. One [potential explanation] could be the glycosylation patterns of the tumor cells and of the immune cells. To harness our new understanding of this [biology], we now have therapeutics that we are trying to apply in that setting. Going after this new biology with both this and other agents will be exciting [in the] future.

What would you like to emphasize regarding the safety results presented from this trial?

The important thing is that [this] novel therapeutic approach in cancer was safe. We shouldn’t dismiss that. In oncology, we do a lot of things that otherwise wouldn’t be tolerated in medicine. We give patients drugs that can make them sick. Whenever we try a new therapeutic modality, we need to be cautious that we’re not going to hurt anyone. [The fact that targeting] this new biology didn’t hurt anyone is an important caveat. More than that, we can see immunological effects from the peripheral blood that we would associate with a good outcome. In this population of patients, it’s unfortunately very difficult to see treatment responses.

If research on E-602 continues to be positive, how could this agent affect the treatment landscape in advanced solid tumors?

We’ve demonstrated safety in the current portion of the study. The next portion will be a dedicated study in patients with melanoma and lung cancer, where we know [patients] have high levels of glycosylation. We hope to see monotherapy activity that’s immune activating. There’s also a portion of the study that will investigate E-602 in combination with an anti–PD-1 antibody. If we can see some signs of treatment effect, [we] will quickly try to move [this agent] into earlier lines of treatment.

What is a main message to impart to colleagues regarding this research?

[We need to] start learning about this area of glyco-time biology as it’s sometimes called by Dr Bertozzi. This is a new area of what we’re calling glyco-immune checkpoints. We hope that this will expand the ability of immunology to [improve] clinical medicine for patients with cancer. [I’d like] to emphasize that this is new biology. Only a few years ago, we couldn’t study [these targets] because we didn’t have the tools to do so. [These data are] very exciting, but [there’s] even more for us to learn and be cognizant of as the field moves forward.

Will any other presentations at this year’s meeting be particularly practice-changing for advanced solid tumors?

Results from the phase 2b [KEYNOTE-942 trial (NCT03897881) of] the neoantigen cancer vaccine [mRNA-4157/V940] from Moderna in combination with the anti–PD-1 [inhibitor pembrolizumab (Keytruda)] really have the potential to be transformative, both in melanoma and more broadly in cancer. This is the first demonstration of a cancer vaccine having a major therapeutic effect, and it’s the first example of a neoantigen targeting strategy [that] shows benefit in clinic. That is a big deal [for the field of] melanoma, because this is the first study to show an increase [in benefit] beyond what adjuvant PD-1 monotherapy [provides]. Conceptually, this approach should be applicable anywhere in cancer. Watch this space very closely, because a very similar approach will presumably be imminent in lung cancer, head [and] neck cancer, [and] bladder cancer.

Disclosures: Dr Luke reports working in an advisory role or as a paid consultant for 7 Hills, Abbvie, Actym, Agenus, Alnylam, Atomwise, Affivant, Alphamab Oncology, Arch Oncology, BioCytics, Bright Peak, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Duke Street Bio, Eisai, EMD Serono, Endeavor, Exo, Evaxion, Fstar, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Ikena, Inzen, Immatics, Immunocore, Immutep, Incyte, Instil, IO Biotech, Janssen, Kanaph, KSQ, Macrogenics, Mavu, Merck, Mersana, Mavu, Nektar, Novartis, NeoTx, Onc.AI, OncoNano, Partner, Pfizer, Pioneering Medicines, PsiOxus, physIQ, Pyxis, RefleXion, Xilio (stock), Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine, Saros, STipe, Tempest; he reports receiving research support from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; he reports the following patents (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Ant–iPD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)

Reference

1. Luke, JJ, Johnson M, Tolcher A, et al. GLIMMER-01: Initial results for dose escalation of a phase 1/2 trial demonstrating proof of mechanism of a novel, first-in-class bi-sialidase (E-602) in solid tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, Florida. Abstract CT034.