Tumor-Agnostic Therapies Advance Precision Oncology Through Comprehensive Biomarker Testing

Clinical Summary:

• Vivek Subbiah, MD, examines the expanding role of tumor-agnostic precision oncology, including comprehensive molecular profiling, biomarker interpretation, and the integration of targeted therapies, immunotherapies, and antibody-drug conjugates across cancer types.

• Tumor-agnostic treatment strategies target actionable molecular alterations such as NTRK and RET fusions, BRAF V600 mutations, microsatellite instability, and HER2 overexpression, although treatment selection must account for tumor-specific biology, supporting evidence, and prior therapies.

• These developments highlight the importance of distinguishing detected, actionable, and druggable alterations through comprehensive genomic and immunohistochemical testing to identify eligible patients and optimize precision treatment selection.

Vivek Subbiah, MD, NYU Perlmutter Cancer Center, New York, New York, discusses the expanding role of tumor-agnostic precision oncology and the importance of comprehensive biomarker testing in identifying patients for targeted therapies, immunotherapies, and antibody-drug conjugates following his plenary presentation at Great Debates in Solid Tumors in New York, New York.

Dr Subbiah reviews how clinicians can distinguish detected molecular alterations from clinically actionable and druggable targets, emphasizing the importance of tumor context, molecular testing platforms, and supporting clinical evidence. He also discusses tumor-agnostic treatment opportunities involving BRAF, NTRK, RET, MSI-high/dMMR, and HER2 biomarkers, highlighting the integration of next-generation sequencing and immunohistochemistry to guide individualized cancer treatment.

Transcript: 

Hello, I'm Vivek Subbiah, medical oncologist, precision oncologist, clinical trialist, and an expert in tumor-agnostic precision medicine. At Great Debates, I just spoke in the plenary session on "Biomarkers Beyond Boundaries: Tumor-Agnostic Drug Development and Tumor-Agnostic Drugs."

We are in an unprecedented era where we have sequenced a human genome, and we have an explosion of new therapies that include targeted therapies, immunotherapies, and antibody-drug conjugates that can deliver these precision medicines to these patients.

But how do we match these precision medicines, what is the central mantra of precision medicine? Matching the right patient to the right therapy at the right time.

So the first question is, how to determine whether an identified biomarker is clinically actionable?

When we receive these molecular reports and next-generation sequencing reports, we have 20 different alterations, and I would say it would be easy if we have a guide to look into those alterations.

The first question is, detected molecular alteration, the second question is, is it actionable, and the third is, is it druggable. Detected means we detect 20 different alterations, it doesn't mean that it is actionable and druggable, so we need to sift those 3 different aspects in our test.

Also, we need to look into the next-generation sequencing profile and see if it's from tissue, is it from plasma?

We need to also see if the variant is somatic versus germline versus clonal hematopoiesis. So again, these are the ones that help us make decisions if we have a drug to target that particular alteration.

So the next question is, how disease context, supporting evidence, and prior treatment influence this interpretation?

Again, that's a great question because let's take, for instance, BRAF V600E. BRAF V600E is a tissue-agnostic target with a combination of tumor-agnostic drugs, BRAF and MEK combination, dabrafenib and trametinib, approved across all indications with the exception of colorectal cancer.

So here, the disease context plays an importance because the BRAF and MEK combination is actionable in all cancers beyond colorectal cancer. In colorectal cancer, this is also actionable with the addition of an EGFR inhibitor. Here, the disease context, supporting evidence, and prior treatment definitely influence the interpretation here.

And again, we have a host of 10 other tumor-agnostic therapies based on biomarkers, starting from MSI-high and dMMR for pembrolizumab, tumor mutational burden-high for pembrolizumab, larotrectinib, entrectinib, and repotrectinib for NTRK fusion-positive cancers, selpercatinib for RET fusion-positive cancers, and we live in an antibody-drug conjugate era. So we have trastuzumab deruxtecan (Enhertu) approved in a tissue-agnostic manner across all cancers that overexpress HER2. So this is HER2 by immunohistochemistry 3+.

The next question I've been asked is to focus on practical considerations for connecting eligible patients with matched therapies. As I said, we live in a precision oncology era. In order for our patients to benefit from these precision medicines, we need to do the right testing, we need to do comprehensive testing.

Today, it includes comprehensive next-generation sequencing that includes the fusion testing for RET fusions and NTRK fusions, and also immunohistochemistry (IHC) testing for HER2 because if they overexpress HER2, IHC 3+, they are candidates for this antibody-drug conjugate.

The first thing is we need to do comprehensive testing, we cannot guess, we have to do NGS plus this IHC testing. That's what I would say.

Then based on the tests, as I said, we go back to this algorithm. Is it detected? Is it actionable? Is it druggable? Do we have a drug for that? And what is the evidence for the drug for this particular alteration?

These are the questions that we need to ask in clinic so that we can deliver precision medicine to our patients so that we can tackle this beast, the emperor of all maladies.