3D Rendering of Antibody Drug Conjugate Molecules
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By Scott Tomlins, MD, PhD, Co-Founder & Chief Medical Officer, Strata Oncology

 

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ADCs are part of the expression-based therapy revolution in cancer treatment

Oncology is seeing accelerated development of new expression-based therapy classes with the potential to deliver unprecedented improvements in patient outcomes. One class of particular interest are antibody-drug conjugates (ADCs), which comprise monoclonal antibodies directed toward a target antigen expressed on the cancer cell surface conjugated to a cytotoxic payload via a chemical linker.

Many ADCs are developed without biomarkers to guide their use, which represents a missed opportunity to optimize their use. When a biomarker is included in clinical development, as was the case for the breast cancer treatment fam-trastuzumab deruxtecan-nxki (also known as T-DXd or Enhertu®), the technology used is most often immunohistochemistry (IHC).

At ASCO 2022, results from the DESTINY-Breast04 trial were presented showing for the first time that patients with low HER2-expressing metastatic breast tumors, who currently are ineligible for HER2-targeted treatment, significantly benefited from T-Dxd1. The results have the potential to as much as quadruple the number of patients eligible for treatment with T-Dxd.

Excitement for the study was tempered, however, by the recognition that identifying “HER2-low” patients would be difficult due to variability and lack of sensitivity in current IHC biomarkers. Many experts noted the need for new, more sensitive and accurate tests in order to maximize eligibility for T-DXd.2,3

Precision use of ADCs requires efficient, quantitative gene expression biomarkers

We’ve seen the impact of comprehensive genomic profiling (CGP) on the use of mutation-based targeted therapies. It is now routine to test a single tumor sample and get genomic information that can guide the use of all approved and many investigational therapies in this class.

How can we repeat this success and enable multiplex, quantitative analysis of ADC targets?

At Strata Oncology we are leading the way by developing predictive treatment selection biomarkers based on quantitative, targeted RNA sequencing that can be analyzed in parallel with the genomic mutations assessed by CGP.

We simultaneously provide insights into potential targeted therapies and information on target expression for multiple approved and investigational expression-based therapies, including many ADCs. This maximizes the information available from often limited tumor tissue samples.

The sensitivity and quantitative nature of our predictive RNA biomarkers have the potential to define new populations of patients who may benefit from expression-based therapies, while also more reliably identifying those patients who will not. We’ve shown high correlation between our quantitative RNA biomarkers and expression by immunohistochemistry, the current gold standard for clinical target expression evaluation.

Bringing ADCs into the precision era with the Strata PATH™ trial

Multiple ADCs are now approved, all in tumor types that generally overexpress the ADC target protein. Even though many of these approved ADCs don’t currently require a biomarker to inform treatment, they are built to target overexpression of target proteins. We reason that subsets of other tumor types with target RNA expression above average levels in the approved indications as determined by our quantitative RNA biomarkers are likely to be highly responsive to these ADCs as well.

To test this hypothesis, and to validate our novel biomarkers, we are sponsoring a transformative clinical trial called Strata PATH. In this 700-patient prospective pan-tumor therapeutic trial we will evaluate the efficacy and safety of multiple FDA-approved cancer therapies in new biomarker-guided patient populations4.

Optimizing outcomes for more patients

We estimate that only around a quarter of patients will have a CGP-based molecular profile that matches them to a mutation-based targeted therapy. Expanding biomarker-matched treatment to expression-based therapies using our quantitative RNA biomarkers could more than double this number5.

Additionally, for most ADCs, the pan-tumor overexpressor sub-population is larger than the initial tumor type indication, meaning that with Strata’s biomarkers there is a potential opportunity to extend the benefit of these therapies to many more people.

Adding quantitative RNA biomarkers to the precision cancer care toolbox has the potential to optimize the use of a rapidly expanding class of cancer therapies and increase patient access to expression-based therapeutic approaches.

 

References
1. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA3-LBA3
2. Enhertu Benefit in HER2-Low Breast Cancer Wows at ASCO; Signals Shifting Therapy, Dx Paradigms; Precision Oncology News; June 6, 2022
3. ASCO: HER2 diagnostics need a revolution as AstraZeneca, Daiichi’s Enhertu looks to redefine breast cancer; Fierce Biotech; June 6, 2022.
4. Strata PATH™ (Precision Indications for Approved Therapies); ClinicalTrials.gov Identifier: NCT05097599
5. Strata Oncology internal data

 

For additional information: www.strataoncology.com

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