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An end-to-end approach to precision medicine: MET exon 14 skipping mutations in non-small cell lung cancer (NSCLC)

Earlier this month, FoundationOne CDx was approved to identify mutations that lead to MET exon 14 skipping in advanced non-small cell lung cancer (NSCLC) and match patients with a new targeted therapy, which was approved in parallel. This simultaneous approval presents a new treatment option for the 2-3% of lung cancer patients with cancers driven by METex14. It is another significant step forward on the path of progress in lung cancer treatment, which demonstrates the power of cancer precision medicine in action and the role that comprehensive genomic profiling plays.

For me personally, this approval represents a journey that started nearly a decade ago. At the time, Foundation Medicine was a relatively new organization, with a team driven by a collective belief in the great potential of comprehensive genomic profiling (CGP) to help cancer patients. CGP gave us the possibility of targeting less common oncogenic drivers that had been overlooked due to their low frequency or molecular diversity.

Our growing database, which was unprecedented in its size at the time, presented a unique opportunity; the ability to look for patterns or signals in previously unappreciated driver mutations with clinical and therapeutic relevance.

The role and diversity of MET alterations in NSCLC

One of the first ”hits” from our early data mining efforts was that variants affecting splicing of the MET gene were occurring much more frequently in lung cancer than any other tumor type. The receptor tyrosine kinase encoded by the MET gene plays a fundamental role in regulating development and cell growth. Activation of MET is a well-characterized oncogenic driver, promoting tumor proliferation, invasive growth and angiogenesis. A number of MET-targeting therapies have been explored over time, but the results had been mixed and the diversity and frequency of MET genomic alterations had led to doubt about MET being a viable therapeutic target.

We examined all genomic alterations found through CGP of the 38,000 patients in our database at the time and found 224 alterations that affected MET exon 14 splicing, almost all in lung cancers. Alterations that affected splicing of exon 14 had been reported previously, but this was by far the largest characterization of their frequency, diversity, and co-occurring genomic alterations. The results indicated that METex14 mutations were clinically and therapeutically relevant oncogenic drivers in ~3% of NSCLC samples. These findings were published in 2015 and presented at ASCO that year, reigniting broader interest in the role of METex14 mutations in lung cancer.

Stimulating the race to bring METex14 therapeutics to the clinic

But what next? We were a long way from translating this new knowledge into improved outcomes in the clinic. What followed was, for us, treading new ground. We continued to work with various collaborators in order to build further evidence that would stimulate the comprehensive exploration of METex14 as a therapeutic target in NSCLC. A key element of that was improving the identification of patients bearing METex14 mutations through updates to clinical guidelines and further classification of this diverse class of alterations.

One of those early collaborators later initiated a clinical study to systematically assess the effectiveness of its tyrosine kinase inhibitor in this new subset of patients.

While my focus shifted back to harnessing the expanding wealth of genomic data that we were building through CGP, the role of Foundation Medicine in the METex14 story had only just begun.

The power of partnership in precision medicine

In 2018, Foundation Medicine entered into a strategic collaboration with one of our biopharma partners for the development of a companion diagnostic for a new targeted therapy for NSCLC with METex14. This far-reaching partnership has helped accelerate understanding of METex14 alterations for both organizations and allowed us to rapidly push the oncology forward in order to bring these advances to patients.

From that initial mining of our genomic database and the early work with collaborators, we are now able to identify patients with METex14 mutated NSCLC and match them with a potentially beneficial treatment option, using our FDA-approved diagnostic platform, FoundationOne CDx.

This is the ultimate reward for me, that we are in the unique position to be able to come full circle and bring the benefits of new approaches to treatment and testing to the very patients who play a fundamental role in advancing the science. That is the power of comprehensive genomic profiling as part of an end-to-end approach to precision medicine in oncology.