Although driver mutations have been identified for significant NSCLC subsets, patients with metastatic disease benefit from broad panel next-generation sequencing testing because of the growing clinical relevance of less common alterations and gene signatures.
Michael Berger, PhD
Although driver mutations have been identified for significant non—small lung cancer (NSCLC) subsets, patients with metastatic disease benefit from broad panel next-generation sequencing (NGS) testing because of the growing clinical relevance of less common alterations and gene signatures, according to Michael Berger, PhD.
Berger described the NGS landscape through the lens of the experience at Memorial Sloan Kettering (MSK) Cancer Center during a presentation at the 2018 New York Lung Cancers Symposium. The center developed the MSK-IMPACT comprehensive panel for sequencing 468 cancer-associated genes. The assay also evaluates tumor mutational burden (TMB) and mismatch repair deficiency (dMMR) or microsatellite instability (MSI).
“What might have been done in the context of an individual tumor type for a small core set of genes or mutations has now expanded to all different cancer-associated genes, knowing that mutations that may be more commonly observed in one cancer may also be less frequently observed in other cancers but also can provide informed treatment decisions for those patients,” said Berger, who is associate director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSK.
As an example, he cited BRAF mutations, which have been observed in approximately 50% of melanomas and have prompted the development of dual pathway-targeting agents, including the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). In NSCLC, the same combination gained FDA approval in 2017 for patients with metastatic disease that harbors BRAF V600E mutations, which are found in 1% to 2% of lung adenocaricnomas.1
MSK now seeks to offer NGS testing to patients with metastatic cancer across all solid tumor types, particularly those with NSCLC, Berger said. He said some patients with earlier stage cancers who are treated through surgical oncology also may undergo testing.
In NSCLC, such testing is growing increasingly relevant, notably because of novel therapies being developed for less prevalent gene fusions, Berger said in an interview with OncLive. He cited the example of NTRK fusions, which have been identified in less than 3% of NSCLC cases.2 Larotrectinib, a selective TRK inhibitor, and entrectinib, which targets several kinases including TRK, are among the drugs being developed in this space.
“The broad testing allows us to capture not just the common but also the rare mutations and it also gives us information about more complex mutational signatures that are increasingly important for predicting response to immunotherapy,” Berger said.
TMB is being explored as a biomarker in NSCLC. The FDA currently is considering a supplemental biologics application for the combination of nivolumab (Opdivo) plus low-dose ipilimumab (Yervoy) for the frontline treatment of patients with advanced NSCLC with TMB ≥10 mutations per megabase.
Although dMMR/MSI is “very rare in lung cancer,” patients with this signature may be candidates for pembrolizumab (Keytruda), a PD-1 inhibitor that is approved for patients with unresectable or metastatic MSI-high or dMMR solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
In describing the current landscape for NGS testing, Berger said there are 3 main test categories: hotspot panel, with amplicon capture of approximately 10 to 50 genes; cancer gene panel, with hybridization capture of about 100 to 500 genes; and whole exome sequencing, with hybridization capture of approximately 20,000 genes. At one end of the spectrum, hotspot panel testing is a lower cost option that offers a fast turnaround, while at the other end of the scale, whole exome sequencing provides the greatest potential for discovery.
“There’s a sweet spot in the middle and this has been our approach,” he said, referring to MSK-IMPACT. “It’s cheaper, more rapid, more economical than the more comprehensive approaches and in some ways more clinically suited.”
At the same time, Berger said the choice of NGS strategy would depend upon clinical and practical factors. “There’s really no one right approach. It depends on the disease, the lab, the resources available, the throughput in the laboratory, the turnaround time requirements, and cost considerations,” he said.
One advantage of the MSK-IMPACT test, he said, is that it analyzes DNA from tumor cells and a matched normal control sample for comparison; in lung cancer, blood is the source of the normal test.
“When we set up this program and developed the test, it was really with the goal of identifying individual mutations that might elicit responses to particular targeted therapies,” Berger said. “But we can move beyond that and that’s enabled largely by the fact that we’re sequencing both tumor and matched normal [samples].”
Thus far, more than 32,000 tumors have been sequenced with MSK-IMPACT, with approximately 200 tumors tested every week, Berger said. In 2017, the FDA approved the test, which is typically available only to patients treated at MSK, as an in vitro diagnostic.
Commercially available NGS tests that the FDA has approved include the FoundationOne CDx assay, which tests for 324 genes; the Praxis Extended RAS Panel, which detects 56 mutations in RAS family genes; and the Oncomine DX Target Test, which analyzes 23 genes and ROS1 fusions. The FoundationOne and Oncomine tests are approved as companion diagnostics for NSCLC drugs targeting specific mutations.