Bryan Schneider, MD, clinical professor, service chief, Department of Internal Medicine, Division of Hematology/Oncology, associate medical director, Office of Research, service chief member, Rogel Cancer Center, University of Michigan Health, discusses agents available for use in the targeting of 

 exon 14 mutations in non–small cell lung cancer (NSCLC).

 exon 14 mutations are considered a rare oncogenic driver mutation, occurring in approximately 3% of patients with NSCLC, Schneider begins. These mutations result in the skipping of exon 14 during protein translation, leading to stage-dependent MET genomic amplification and c-MET overexpression that drives the oncogenic process, Schneider explains.

The MET-targeted kinase inhibitors capmatinib (Tabrecta) and tepotinib (Tepmetko) are both approved for this indication, Schneider continues. 

Tepotinib was granted accelerated approval by the FDA in February, 2021

, based on efficacy data from the phase 2 VISION trial (NCT02864992). The agent produced an overall response rate (ORR) of 46.7% in the cohort of patients with 

 exon 14 skipping alterations. Response rates were slightly higher in those who were given the first line treatment (50.7%) compared with those treated in the second line (43.4%).

the FDA granted regular approval to capmatinib for patients with metastatic NSCLC harboring

exon 14 skipping mutations in August of 2022

, Schneider continues. The agent had been previously granted accelerated approval for this indication in 2020 based on initial efficacy data from the phase 2 GEOMETRY mono-1 trial (NCT02414139). In this trial, capmatinib produced response rates approaching 70% when used in the front line, and 41% in the second or third-line setting.

Importantly, the efficacy of these drugs remains consistent regardless of if the genomic alteration was identified through tissue sampling or plasma DNA analysis, Schneider notes. Accordingly, these 2 drugs are now favored when considering front line treatment options for these patients after initial detection of a 

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Bryan Schneider, MD, discusses agents available for use in the targeting of MET exon 14 mutations in non–small cell lung cancer.
 

Dr Schneider on Targeted Treatment Options in MET Exon 14 Mutated–NSCLC

Breast cancer researcher, IU Simon Cancer Center

Co-director, IU Health Precision Genomics Program

Medicine & Medical and Molecular Genetics

Vera Bradley Investigator in Oncology, IU School of Medicine

Given that cancer at its essence is a disease of DNA, driven by mutations in tumor suppressors and oncogenes, genomics-based precision medicine is a natural fit for oncology therapeutics.

In patients with metastatic disease where options are typically limited, genomic analysis is frequently being used in standard clinical settings to identify alterations, which are potentially actionable with FDA-approved drugs or clinical trials.

With the growing body of evidence supporting positive outcomes with the use of precision medicine—based approaches, academic cancer centers are increasingly incorporating genomic technology into standard clinical care.

In 2014, the Indiana University Health Precision Genomics Program was initiated to provide cutting-edge genomic analysis for patients with metastatic, refractory, or rare solid tumors.

The program is operated as an outpatient referral service where, on the initial visit, patients are provided an introduction to precision medicine and cancer genomics; a history, physical, and informed consent are obtained; and either existing tissue is procured or a new tumor biopsy is performed. The service then utilizes a combination of whole-genome sequencing, whole-transcriptome sequencing, and proteomic analysis to provide a comprehensive molecular portrait of each patient’s tumor.

A molecular tumor board composed of oncologists, scientists, pharmacists, pathologists, genetic counselors, and bioethicists reviews each patient’s results to derive a therapeutic plan. Patients return to clinic to receive a layman’s education on their genomic results and counseling for the drugs that are recommended and/or logistical support for pertinent clinical trials. All results and recommendations are subsequently conveyed to their primary oncologist.

Our group recently published our experience from the first 101 patients enrolled in the program (Radovich et al. Oncotarget; 2016). The majority of patients had a diagnosis of soft tissue sarcoma, breast cancer, pancreatic cancer, or colorectal cancer, although multiple other tumor types were included.

Our efficacy analysis demonstrated that 43.2% of those patients who received genomic-guided therapy had improved progression-free survival when compared with their own prior therapy versus only 5.3% of those who did not receive genomic-guided therapy (

Of note, the majority of patients had seen at least 3 prior lines of therapy. These results demonstrate that a significant clinical benefit can be obtained with the use of genomically directed therapy in a heavily pretreated patient population.

In an effort to continue to advance the application of precision medicine beyond metastatic disease and into the curative setting, our group launched a first-of-its-kind clinical trial in patients with triple-negative breast cancer who have residual disease after neoadjuvant chemotherapy (NCT02101385).

It is well known that this patient population is at a high-risk of relapse but, unfortunately, a consensus standard of care does not currently exist. This trial utilizes genome sequencing of the residual disease to randomize patients to a genomically directed therapeutic after surgery. The primary endpoint is 2-year disease-free survival. The unique scientific question in this trial is whether using a genomically directed approach (not focused on any particular biomarker but on a large suite of potential options) can increase cure rate and keep these high-risk patients out of the metastatic setting. The trial is currently enrolling at more than 20 sites across the United States.

An additional important aspect to our program is the consideration of germline pharmacogenomics. By examining inherited genetic variation in key enzymes involved in drug metabolism, one can predict ahead of time the important and potentially life-threatening side effects to commonly used therapies. Common examples include germline polymorphisms in UGT1A1 that predict side effects to irinotecan and in DPYD for 5-fluorouracil.

Over the last several years, our group has made major headway in this arena through genomic analysis of multiple phase III clinical trials to identify markers that predict paclitaxel-induced peripheral neuropathy, bevacizumab-induced hypertension, and adriamycin-induced congestive heart failure. All these markers are currently integrated into Indiana University’s CLIA pharmacogenomics platform. Moving forward, we believe implementation of these markers into the broader cancer patient population will make significant progress in reducing unneeded side effects.

Looking into the future, using genomics to solely identify a drug target based on genomic alteration only scratches the surface of possibilities. Advances in plasma-based technologies will increase our abilities to do tumor genotyping without the need for biopsy. While plasmabased testing is commercially available today, it is currently limited by small gene panels and sensitivity for patients who have low burden of disease.

Progress in chemistry that will allow wholeexome and genome-sequencing for clinical use are on the horizon. Another anticipated advance is the use of genomic technology to determine optimal drug combinations to exploit multiple activated pathways at the same time. Preclinical data have demonstrated the complex nature of how cancers compensate and evolve when challenged with only a single anticancer agent.

Algorithms that can identify optimal drug combinations to more reliably predict a synergistic effect and avoid or delay the development of drug resistance are actively being developed. Lastly, the use of genomic data to tailor immunotherapy will continue to increase the precision medicine repertoire. A major recent example is the use of tumor mutation burden in relation to neoantigen burden to predict response to immune checkpoint therapy.

Moving forward, the use of N-of-1 genomic data to develop personalized vaccines and antibodies will enable patient-specific therapeutics. Taken together, the advancing science of precision medicine is making large strides in improving outcomes for patients with cancer. It is anticipated that this will continue to become the mainstay for how optimal care is delivered.

Articles

With the growing body of evidence supporting positive outcomes with the use of precision medicine–based approaches, academic cancer centers are increasingly incorporating genomic technology into standard clinical care. 

Bryan Schneider, MD

Articles

Dr Schneider on Targeted Treatment Options in MET Exon 14 Mutated–NSCLC

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