THERAPEUTIC FOCUS - Addressing the Unmet Need for Improved Treatments of Female Cancers

INTRODUCTION

Up to 70% of women with breast, ovarian, and endometrial cancer have hormone-dependent cancer.¹ The hormones estro­gen and progesterone drive cancer progression in these patients, but antiestrogens are the only antihormonal therapy approved by the US FDA and available to clinicians. Treatment of these pa­tients to date, therefore, has consisted of antiestrogens alone or in combination with drugs that enhance the antitumor activity of antiestrogens, including inhibitors of CDK4/6 or PI3Kα. Given the broad use of antiestrogens, antiestrogen resistance is now a major clinical challenge. Treatment options for antiestrogen re­sistance are limited, provide modest therapeutic benefit, and are associated with side effects.

Estrogen and progesterone are master regulators of normal female sex organ development and function, acting via estrogen receptors (ER) and progesterone receptors (PR). In hormone-de­pendent cancers, ER and PR are often hyperactive, constantly pushing breast, ovary, and endometrial tissues to grow, divide, and metastasize. To block this hormone-mediated growth, pa­tients are administered antiestrogen therapy (fulvestrant, letro­zole, anastrozole, or tamoxifen) alone or in combination with inhibitors of CDK4/6 or PI3Kα to block ER signaling. The cancer cells respond to this selective pressure of ER inhibition, however, by further activating progesterone signaling as a compensatory mechanism, along with other resistance mechanisms that can in­duce PR signaling, including ER ligand binding mutations (ESR1), growth factor signaling, and enrichment of cancer stem cells. Over time, all patients with advanced or metastatic disease even­tually become resistant to antiestrogens due to direct or indirect compensatory signaling mediated by the PR and other factors.^2-4 Therefore, PR and proteins that regulate PR represent ideal drug targets to address antiestrogen resistance.

Context^® Therapeutics (Context) is a clinical-stage biophar­maceutical company dedicated to improving the lives of women living with cancer. Our goal is to develop and commercialize in­novative and differentiated oncology products that address sig­nificant unmet medical needs in the field of female cancer. Context is building a portfolio of novel agents targeting multiple resistance mechanisms by leveraging our specialized expertise in hormone-dependent cancers, with a pipeline spearheaded by our clinical-stage lead program, onapristone extended release (ONA-XR), a selective and potentially potent antagonist of PR.

Our second program is CTIM-76, an anti-CD3 x anti-Claudin 6 antigen bispecific monoclonal antibody (CLDN6xCD3 bsAbs), is in preclinical development. CTIM-76 is intended to redi­rect T-cell-mediated lysis toward malignant cells expressing Claudin 6 (CLDN6). CLDN6 is a tight junction membrane protein target expressed in multiple cancers, including ovarian and en­dometrial tumors, that is absent from or expressed at very low levels in healthy adult tissues. CLDN6 is also expressed in lung, gastric, and testicular cancers, which broadens the therapeutic use potential.

COLLABORATION IS KEY TO SOLVING THE ISSUE

To attain our mission, Context has partnered with leading pharmaceutical companies and academic institutions to advance our programs forward, which Context has attempted to do in an expeditious and cost-efficient manner. Context has outstanding pharmaceutical partners, including The Menarini Group (Menarini) and Integral Molecular (Inte­gral). Through our partnership with Menarini, we are exploring the potential for complete hormone blockade in a Phase 1b/2 clinical proof-of-concept trial, referred to as the ELONA trial, by admin­istering the combination of ONA-XR and elacestrant, Menarini’s oral selective estro­gen receptor degrader (SERD). Through our partnership with Integral, Context li­censed the rights to Integral’s CLDN6 monoclonal antibody (mAb), and we have subsequently, in collaboration with Inte­gral, converted that mAb into CTIM-76, a CLDN6xCD3 bispecific antibody.

On the academic side, Context has established a network of Investigator-Sponsored Trials (ISTs) to broadly interro­gate the therapeutic potential of ONA-XR across breast, ovarian, and endometrial cancer. Through ISTs, we have been able to execute more trials than we otherwise would have given the inherent capital and bandwidth constraints that define a startup company. By partnering with leading aca­demic institutions and clinicians, we be­lieve we can unlock the full potential of ONA-XR.

ONA-XR PROGRAM

Currently, there are no approved ther­apies that selectively target progesterone receptor positive (PR+) cancers. Context has chosen PR antagonism in breast can­cer as our initial therapeutic focus due to the well-documented biology of PR signal­ing as a mechanism of resistance to antie­strogen therapy in patients with hormone-dependent breast cancer. Hor­mone-dependent breast cancer cells ex­press ER and/or PR that allow the cells to grow in the presence of the hormones es­trogen and/or progesterone. Published data by D’Assoro et al suggests that PR sig­naling is predominantly required for breast cancer cell renewal (i.e., stemness) and metastatic spread, whereas ER is predom­inantly required for breast cancer cell pro­liferation.⁵ By combining antiprogestin and antiestrogen therapy, breast cancer cell growth, renewal, and spread can be mitigated. Based on these data, we believe ONA-XR, in combination with current standard-of-care antiestrogens, has the poten­tial to significantly improve clinical outcomes.

ONA-XR is currently being evaluated in three Phase 2 trials and one Phase 1b/2 trial in hormone-driven breast, ovarian, and endometrial cancers. These trials are intended to establish safety, pharmacoki­netics, pharmacodynamics, and anti-tumor activity at the recommended Phase 2 dose of ONA-XR to guide potential ad­vancement in Phase 3 development. The Phase 2 clinical trials of ONA-XR include second or third line (2L/3L) ER+, PR+, HER2- metastatic breast cancer (mBCa), PR+ recurrent granulosa cell tumor of the ovary, and PR+ recurrent endometrial cancer. Context reported preliminary data from all three Phase 2 trials in 2022.

To help inform which patients may be most suitable for treatment with ONA-XR, we are evaluating multiple biomarker as­says, including tools to monitor activated PR and ctDNA changes, both of which are being utilized in our ongoing clinical trials and may be used for patient selection in future clinical trials.

Context announced encouraging ONA-XR data in preclinical studies evalu­ating ONA-XR combination therapy in mouse models of cancer and the role of ONA-XR as an immunomodulatory agent at the American Association for Cancer Research Annual Meeting 2022. The pre­clinical data for ONA-XR support it is a po­tent, specific PR antagonist. The data further highlights the breadth of ONA-XR’s potential as a promising combination agent with standard-of-care therapies, as well as with emerging therapies for hor­mone-positive tumors, such as immune checkpoint inhibitors and inhibitors of the AURKA/STAT3 oncogenic axis. One partic­ularly exciting piece of data presented came from Lauryn Werner, MD, PhD can­didate, of the University of Kansas, wherein Dr. Werner showed that ONA-XR was able to induce complete tumor regres­sion in syngeneic mouse models of breast cancer and tumor response was driven by the activation of cytotoxic T cells by ONA-XR in the tumor microenvironment. While ONA-XR was found to be highly active in mice with full immune systems, it was less effective in mice that were immunocom­promised – thus, further underscoring the immunological activity of ONA-XR and why earlier studies of ONA-XR in immuno­compromised mice may have missed the full potential of the agent as a therapeu­tic.

Context also reported data as of Sep­tember 30, 2022, from an ongoing Phase 2 trial in collaboration with Jefferson Health investigating ONA-XR in combina­tion with the antiestrogen anastrozole in women with PR+ endometrial adenocar­cinoma who failed front-line therapy with a platinum/taxane-based chemotherapy regimen, the preliminary 4-month pro­gression free survival (PFS) rate was 77.7%, based on nine evaluable patients. Further, 33% of patients were alive and progression-free at 12 months. This data compares favorably to the data from the KEYNOTE-775 Phase 3 trial where similar patients by treatment background were administered chemotherapy, which re­sulted in a median PFS of 3.8 months. Data also showed that only 4% of patients were alive and progression-free at 12 months after chemotherapy treatment.⁶ There were no treatment-related serious adverse events reported. The trial has en­rolled 12 of 25 planned patients, three of which received treatment for greater than 12 months. Overall, seven patients remain in the trial. (ClinicalTrials.gov identi­fier:NCT04719273).

In collaboration with Memorial Sloan Kettering Cancer Center, an ongoing Phase 2 basket trial investigating ONA-XR 50mg BID as a single agent or in combi­nation with anastrozole 1 mg QD in women with PR+ recurrent GCT of the ovary, Context reported data from two co­horts from the trial. In cohort 1, which treats patients with PR+ recurrent GCT with ONA-XR as a single agent, completed accrual to stage 1 and has shown a 12-month PFS rate of 20.1% and a Clinical Benefit Rate (stable disease) of 35.7%. Two patients continued on active treatment for greater than 18 months. One patient re­mains on trial in cohort 1. Cohort 4, which treats patients with PR+ recurrent GCT with ONA-XR in combination with anastro­zole, enrolled 14 patients in stage 1 and will expand to stage 2 when greater than or equal to one response is observed. Seven patients remain on trial in cohort 4. There have been no treatment-related se­rious adverse events reported. (ClinicalTri­als.gov identifier: NCT03909152).

At the 2022 San Antonio Breast Can­cer Symposium^®, data from the Phase 2 SMILE trial were presented. Being con­ducted in collaboration with the Wisconsin Oncology Network, the clinical trial is evaluating ONA-XR in combination with the antiestrogen fulvestrant in patients with ER+, HER2- advanced or mBCa who pro­gressed on prior CDK4/6 inhibitor ther­apy. Preliminary Phase 2 findings highlighted a 4-month PFS rate of 44%, and favorable safety and tolerability. Con­text believes this initial data is encouraging based upon the EMERALD Phase 3 study in which fulvestrant monotherapy in a sim­ilar treatment population resulted in a me­dian PFS of 2.0 months.

We are particularly excited about our partnership with Menarini established in August 2022. We entered into a Clinical Trial Collaboration and Supply Agreement with Menarini and initiated the Phase 1b/2 clinical proof-of-concept ELONA trial eval­uating ONA-XR in combination with elacestrant in patients with ER+, PR+, HER2- mBCa who have previously been treated with a CDK4/6 inhibitor in Novem­ber 2022. Context is sponsoring the clini­cal trial and Menarini is supplying elacestrant at no cost.

According to the American Cancer Society, breast cancer is the second most common cancer among women occurring in one in eight women (13%) over the course of her lifetime, with ~280,000 new cases of invasive breast cancer and 51,400 cases of non-invasive breast can­cer expected in 2022. Elacestrant is the first oral SERD to demonstrate a statistically significant and clinically meaningful im­provement in PFS versus standard-of-care (SOC) endocrine therapy in a Phase 3 trial in patients with ER+, HER2- mBCa, with 30% reduction in the risk of progression or death in all patients. Data also showed 22% of patients were alive and progres­sion-free at 12 months after elacestrant treatment initiation versus 9% with SOC in the overall population.⁷ Therefore, elaces­trant may become the new backbone en­docrine therapy for ER+, HER2- mBCa. However, emergence of resistance to elacestrant is a major therapeutic barrier to long-term clinical benefit. Context is ex­ploring whether PR inhibition with ONA-XR in combination with elacestrant can reduce the emergence of resistance and further improve treatment benefit for patients with ER+, PR+, HER2- mBCa. Context antici­pates Phase 1b data from the ELONA trial in the fourth quarter of 2023.

CLDN6 X CD3 PROGRAM

There is growing interest in applying antibody modalities, including bispecifics, antibody-drug conjugates, and CAR-T cell therapies to solid tumors. However, iden­tifying appropriate tumor-specific targets that avoid adverse effects in healthy tissue has been challenging. The tight junction protein CLDN6 is a validated therapeutic target for many solid tumor types, includ­ing ovarian, endometrial, testicular, and gastric. It is differentially expressed on can­cer cells with no reported expression in normal, healthy tissue. Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. There are 27 human CLDN family members, and most are broadly expressed and highly conserved. The extracellular region of CLDN6 closely resembles the widely ex­pressed CLDN9, which differs by only 3 amino acids. The few CLDN6 MAbs that have advanced to clinical development have all demonstrated significant binding to other CLDN family members, and most have now been halted from development. Using Integral’s Membrane Protein Solu­tions antibody discovery platform, we have been able to isolate and optimize rare an­tibodies against CLDN6 that do not cross-react with other CLDN family members.

The specificity of our CLDN6 antibod­ies makes them amenable to use as the tumor-targeting arm of bispecific T-Cell Engagers. Starting with highly specific CLDN6 antibodies with a range of affini­ties, we engineered a large set (> 50) of CLDN6xCD3 bispecific antibodies (CLDN6 bispecifics) using multiple bispe­cific formats and CD3 arms that encom­pass different valencies and geometries. We designed the CLND6 arms to include antibody moieties with different affinities and stoichiometries, as these factors are expected to play a critical role in the po­tency of these molecules both in in vitro and in vivo. The full panel of bispecifics has been functionally tested in in vitro T cell cytotoxicity assays and has demon­strated potent killing of CLDN6-expressing cells with minimal killing of cells express­ing other closely related Claudin family members. We have also extensively char­acterized this panel of bispecific antibodies for detailed binding to both CD3 and CLDN6, selectivity against closely related Claudin family members, and developa­bility. The bispecifics were also screened for specificity against ~6,000 membrane proteins, representing > 95% of the entire human membrane proteome.

Solid tumors lead to 580,000 deaths annually in the US, and safe and effective therapeutics for many late-stage solid tu­mors are lacking. Ovarian cancer alone kills 14,000 people each year, according to the American Cancer Society, and many patients do not respond to currently avail­able treatments. The specificity of our CLDN6xCD3 bispecifics suggests their po­tential to address the need for potent ther­apeutic modalities for CLDN6 positive ovarian and other cancers without com­promising patient safety.

In November 2022, Context an­nounced the selection of CTIM-76, a T cell-engaging bispecific antibody, as its lead clinical development candidate to tar­get CLDN6 positive tumors. CTIM-76, is a CLDN6 x CD3 bispecific antibody that in­corporates a highly selective CLDN6 bind­ing arm and a CD3 binding single-chain Fv domain in an IgG format with a si­lenced Fc that is designed to be function­ally monovalent to avoid aberrant T-cell activation and to enhance the safety pro­file. Research has demonstrated that CTIM-76 is potent with specific lysis of CLDN6+ cancer cells over normal cells and can activate cytotoxic T cells without concomitant activation of free cytokines – critical determinants of immunotherapy safety and activity. Preclinical studies sug­gest the potential for convenient dosing with low immunogenicity risk and manu­facturing can be scalable to address the significant number of patients who are po­tentially eligible for CTIM-76 therapy. Con­text initiated Investigational New Drug Application (IND)-enabling studies and ex­pects to submit an IND for CTIM-76 to the US FDA in the first quarter of 2024.

FUTURE & NEXT STEPS

Context believes it is growing in a pragmatic, stepwise fashion. Over time, Context aspires to become a fully inte­grated pharmaceutical company; how­ever, it is our belief that being encumbered by large capital expenditure commitments, including research laboratories and com­mercial infrastructure, is currently a poor use of investor capital. Instead, Context re­tains a small footprint focusing on late preclinical through Phase 2 development. Pipeline assets have been externally sourced and development subsequently advanced through collaborations with other parties, including clinical research organizations and academic research cen­ters. As the assets mature to commercial­ization, Context will consider whether to partner with large pharmaceuticals that have existing commercial in­frastructures as a means to potentially en­able Context to achieve economies of scale and a flexible cost model to navigate the ups and downs of drug development.

Context’s mission is to become a leading company in the women’s oncology space, to prolong the lives of women living with these devastating cancers, and to provide women with a high quality of life while on treatment. To realize this mission, Context is advancing a pipeline of innovative products designed to ad­dress treatment resistance in breast, ovarian, and endometrial cancer, which, if approved, could provide patients with a much-needed new treatment options.

This article contains forward-looking statements (FLS), which involve risks and un­certainties and do not guarantee future performance, as actual results or develop­ments may be substantially different. Further information concerning risks and uncertainties associated with these FLS and Context’s business can be found in our public disclosures with the SEC on EDGAR (www.sec.gov).

REFERENCES

1. American Cancer Society. Hormone therapy for breast cancer. https://www.cancer.org/cancer/breast-cancer/treat­ment/hormone-therapy-for-breast-cancer.html, 2019.
2. Chandarlapaty S, D Chen, W He, et al. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metasta­tic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. 2016. JAMA Oncol. 2(10):1310-1315.
3. Nardone A, C De Angelis, MV Trivedi, et al. 2015. The changing role of ER in endocrine resistance. Breast. 24 Suppl 2(0 2):S60-6.
4. Kumar M, K Salem, JJ Jeffery, et al. 2021. Longitudinal Molecular Imaging of Progesterone Receptor Reveals Early Differential Response to Endocrine Therapy in Breast Cancer with an Activating ESR1 Mutation. J Nucl Med. 62(4):500-506.
5. Antonino B. D’Assoro. PR/STAT3 nuclear transcriptional complexes mediate aurora-A kinase-induced stemness plasticity in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl): Abstract nr 3163.
6. Makker V, et al.; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022 Feb 3;386(5):437-448.
7. Bidard FC, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256.

Martin Lehr is the Co-founder and CEO of Context Therapeutics. In addition, Mr. Lehr serves on the Boards of Praesidia Biologics and CureDuchenne Ventures. Previously, he was part of the founding team at Osage University Partners, a venture capital fund focused on academic spinouts from leading research institutions. Prior to Osage, he conducted research at the Sloan Kettering Institute in DNA repair and at the Children’s Hospital of Philadelphia in thrombosis and hemostasis. He is a Director of BioBreak, a biotech executive peer networking group with over 2,500 active members across the US, and an Advisory Board Member of Life Science Cares and Life Science Leader magazines. Mr. Lehr earned his MA in Biotechnology from Columbia University and his BA in Economics from the University of Pennsylvania.