Abstract #3092: A Phase 1 Study of mRNA-2752, a Lipid Nanoparticle Encapsulating mRNAs Encoding Human OX40L, IL-23, and IL-36γ, for Intratumoral ...
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Abstract #3092: A Phase 1 Study of mRNA-2752, a Lipid Nanoparticle Encapsulating
mRNAs Encoding Human OX40L, IL-23, and IL-36γ, for Intratumoral (iTu) Injection
Alone and in Combination with Durvalumab
Manish R. Patel1, Todd Michael Bauer2, Antonio Jimeno3, Ding Wang4, Patricia Mucci LoRusso5,
Khanh Do6, Salomon M Stemmer7, Corinne Maurice-Dror8, Ravit Geva9, Sima J. Zacharek10,
Andressa S. Laino10, Jing Sun10, Josh Frederick 10, Honghong Zhou10, Baoyu Ding10, William
Randolph10, Lisa Johansen10, Pamela S. Cohen10, Robert S. Meehan10, Ryan J Sullivan11
1Sarah Cannon Research Institute / Florida Cancer Specialists, Sarasota, FL; 2Sarah Cannon Research Institute / Tennessee Onc ology, PLLC,
Nashville, TN; 3University of Colorado Cancer Center, Aurora, CO; 4Henry Ford Hospital, Detroit, MI; 5Yale School of Medicine, New Haven, CT;
6Dana Farber Cancer Institute, Boston, MA; 7Rabin Medical Center, Tel Aviv, Israel; 8Rambam Health Care Center, Haifa, Israel; 9Sourasky Medical
Center, Tel Aviv, Israel; 10Moderna Therapeutics, Cambridge, MA; 11 Massachusetts General Hospital, Boston, MA
NCT03739931
mRNA-2752-P101 Background
Recent outcomes of immune-mediated therapies have created a paradigm shift in the
treatment of cancer. Significant survival improvements in metastatic diseases with clear
unmet medical need have been demonstrated most impactfully by systemic
administration of check point inhibitor (CPI) antibodies, but not all patients benefit from
these therapies.
mRNA-2752 is a novel mRNA-based therapeutic encoding OX40L T cell co-stimulator, IL-
23 and IL-36γ pro-inflammatory cytokines. Preclinical data (Hewitt et al., 2019)
demonstrate robust activity in syngeneic murine tumor models as a single agent and in
combination with PD-L1 blockade, as well as induced regression of uninjected lesions.
Here we present findings from a first-in-human study of iTu mRNA-2752 in solid tumor
patients as monotherapy or in combination with durvalumab. As of 08-Apr-2020, 29
patients were evaluable for safety and 23 patients evaluable for efficacy.
It is hypothesized that the expression of pro-inflammatory cytokines within a treated
tumor along with T-cell co-stimulation may serve to ignite a response or transform an
otherwise non-productive tumor microenvironment (TME) into one permissive of a more
robust immune response. Based on pre-clinical studies (Hewitt et al., 2019), mRNA-
2752 treatment may result in systemic immune recognition of tumor antigens and
regressions of metastatic lesions.
mRNA-2752-P101 study design
Patient characteristics
Primary Diagnosis
Arm A (n=17) Arm B (n=12)
Breast 5 Breast 4
Melanoma 5 Sarcoma 2
Demographics
Colon 2 Bladder 1
Arm A (n=17) Arm B (n=12)
Head and Neck 1 Endometrial 1
Age(y) Age(y)
Ovarian 1 Esophageal 1
Range: 43-79 Range: 37-79
Pancreatic 1 Head and Neck 1
Median: 63 Median: 61.5
Other 2 Ovarian 1
Sex Sex
Other 1
Male: 6 Male: 1
Prior Systemic Therapy Female: 11 Female: 11
Number of Prior Systemic Race: Race:
Arm A (%) Arm B (%)
Therapies Caucasian 14 Caucasian 10
0 - - Black 2 Black 1
1 4 (23.5) 4 (33.3) Other 1 Other 1
2 4 (23.5)
3 2 (11.8) 2 (16.7)
3+ 7 (41.2) 6 (50)
Patients who Received
Prior Checkpoint Inhibitors 7 (41) 6 (50)
Safety & efficacy
Related Adverse Events*
Arm A (n=17) Grade 1 - 2 Grade 3
Injection site erythema 6 -
Injection site pain 6 -
Pyrexia 5 1** Responses in evaluable patients per RECIST 1.1
Chills 3 1** Arm A (N=15)
Fatigue 3 1** Best Overall Response
Alanine aminotransferase Stable Disease (SD) 5
2 - Progressive Disease (PD) 10
increased
Aspartate aminotransferase
2 - Arm B (N=8)
increased
Back pain 2 - Best Overall Response
Rash maculo-popular 2 - Partial Response (PR) 1
Injection site reaction - 1** Stable Disease (SD) 4
Malaise - 1** Progressive Disease (PD) 3
Arm B (n=12)
Injection site erythema 3 -
Injection site pain 2 -
*Treatment-related AEs reported once per patient. **All Gr 3 events observed in 1 patient @ 4mg
dose
AEs: ≥ 2 patients (grade 1-2), ≥ 1 patient (grade 3), No Gr 4 or 5 AEs were reported
mRNA-2752-P101 swimmer plot: per RECIST 1.1
17 patients on Arm A with duration on study up to 16 weeks. 12 patients on Arm B up to 28 weeks
on study and continuing at time of data cutoff.
mRNA-2752-P101 Waterfall Plot of Maximum %Change from Baseline in Sum of Diameters of Target Lesions Based on Investigator Assessment per RECIST 1.1 Tumor shrinkage in both injected and un-injected target lesions in both monotherapy and in combination with the partial response and greatest reduction being noted in a patient in the combination arm (images shown in figure 2-1.)
Expression of protein from introduced mRNAs and modulation of immune response after treatment with mRNA-2572 +/- durvalumab
Expression of protein from introduced mRNAs and modulation of immune response after treatment with mRNA-2572 +/- durvalumab
Partial Response: Patient 106-0001
A partial response with 81% shrinkage of
target lesions was observed in a PD-L1
low squamous-cell bladder (αPD-1/L1
naïve) patient receiving 0.5 mg mRNA-
2752 Q4W in combination with
durvalumab. Of note, squamous-cell
C1D1 C3D1 bladder cancer is a distinct subtype with
unknown checkpoint inhibitor response
rate, as it does not fall under the
classification of urothelial bladder cancer
(approved indication for durvalumab).
The patient remains on study in the 8th
cycle of treatment.
C1D1 C3D1Biomarker evaluation, Patient 106-0001
Elevated PD-L1 and T cell populations
post-treatment in partial responder patient.
Representative pre- and post- treatment
biopsies at timepoints as indicated from
squamous-cell bladder cancer patient with
partial response by RECIST 1.1. (A)
SP263 PD-L1 IHC; semi-quantitative PD-
L1 scores: Pre: TC=1%, IC=0%; C1D15:
TC=30%, IC=25%; C2D1: TC=15%,
IC=20%. (B) Fluorescence-IHC for CD3
(cyan, T cells), CD8 (yellow, cytotoxic T
cells), Ki67 (red, proliferation), and DAPI
(blue, nuclei).Conclusions • iTu mRNA-2752 given as monotherapy and in combination with durvalumab is tolerable at all dose levels studied with no DLTs reported and the majority of related AE's being grade 1 or 2 • Administration of iTu mRNA-2752 is associated with tumor shrinkage in both injected and non-injected lesions in both monotherapy and in combination, with 1 PR in a PD-L1 low squamous-cell bladder patient • Increased IL-23 and IL-36γ protein expression after 6-24 hours in tumor and/or plasma, and increased levels of downstream cytokines IL-22 and IL-6, respectively, were observed • Analyses of tumor and plasma biomarkers suggest a sustained immunomodulatory effect of treatment that includes elevated IFN-γ, TNF-α, and PD-L1 levels • All post-treatment plasma cytokine levels evaluated (including IL-6, TNF-α, IFN-γ, IL-8, IL-2, IL-10) were well below what has been suggested as clinically toxic levels for these cytokines in cytokine release syndrome (Yiu et al., 2012) • These data support the ongoing testing of the mRNA-2752/durvalumab combination in Arm B of the study
Acknowledgements
• To all patients who participated in this study and their families
• To all study personnel involved at study sites
• Durvalumab supplied by AstraZeneca
Thank You!
Study supported by Moderna
Further inquiries: robert.meehan@modernatx.comYou can also read
