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IASLC LUNG CANCER NEWS / JUNE 2020
E V O LV I N G S TA N D A R D S O F C A R E
Broad Molecular Testing in Lung Cancer: The Struggle to Translate Recommendations to Clinical Practice By Kara Nyberg, PhD
2010
Decade in Review
2020
Over the past decade, lung cancer has emerged as a shining example of how precision medicine can dramatically improve patient outcomes. Up to 85% of patients with lung cancer harbor potentially actionable driver mutations, and matching targeted therapy to druggable alterations in the first-line setting prolongs survival two to three times over compared with cytotoxic chemotherapy.1-3 To capitalize on the power of precision medicine for patients, several major medical societies have long recommended routine testing for genomic alterations in driver oncogenes to guide the selection of first-line treatment for patients with NSCLC. Initial guidance in 2013 focused solely on EGFR and ALK mutational analysis for patients with advanced-stage adenocarcinoma,4 but many additional biomarkers have since been added to the diagnostic landscape, both for adenocarcinoma and other disease histologies. Current guidelines now recommend numerous biomarkers for upfront testing at the time of NSCLC diagnosis—EGFR, ALK,
ROS1, BRAF, KRAS, NTRK, MET, RET, and HER2—underscoring the wide breadth of targets and corresponding therapies that can be leveraged for disease management.4-6 The speed at which the field is moving has made it difficult to stay abreast of current testing standards for some oncology facilities, particularly community hospitals that outsource pathology tests or where shortcomings in interdepartmental communication occur. Even when molecular testing involved just a handful of biomarkers, community-based testing lagged behind the benchmarks set in academic practice. An analysis of genomic tests ordered by community oncologists throughout New Jersey and Maryland published in 2017 showed that only 59% of patients underwent EGFR and ALK biomarker testing, and only 8% were tested for all seven mutations recommended by the National Comprehensive Cancer Network guidelines as of 2014.3 The lead author of the study, Martin E. Gutierrez, MD, co-chair of Thoracic Oncology, John Theurer Cancer Center, Hackensack Meridian Health, thinks that testing rates have increased since his study was published, “but there is still a gap that needs to be improved,” he said. Eric S. Nadler, MD, MPP, who serves as medical director of U.S. Oncology
Health Informatics and Internet Technology at Baylor University Medical Center, confirmed that the rates of genomic biomarker testing are improving but that testing of new markers consistently falls behind that of the familiar ones such as EGFR, ALK, and ROS1. “Instead of testing [becoming] more streamlined over the past few years, with clear guidelines and guidance, the exposure of testing and manners of testing have made the testing patterns more heterogenous and the practice of ordering specific tests more confusing for the clinical oncologist,” Dr. Nadler said.
“Instead of testing [becoming] more streamlined over the past few years, with clear guidelines and guidance, the exposure of testing and manners of testing have made the testing patterns more heterogenous and the practice of ordering specific tests more confusing for the clinical oncologist.” –Eric S. Nadler, MD, MPP
Testing deficiencies do not necessarily stem from a lack of awareness. “I think the recognition that testing has to happen is an understood proposition in the community. There are not a lot of patients with adenocarcinoma who
are not getting tested these days,” Dr. Nadler said. “The problem has to do with logistics more than lack of awareness,” Dr. Gutierrez said. Several retrospective analyses of biomarker testing in realworld clinical practice underscore a variety of clinical and logistical challenges for community-based oncologists. Common setbacks include insufficient tissue for testing, lack of infrastructure in obtaining and sending biopsy samples for testing, unacceptably long turnaround times for results, and uncertainty regarding reimbursement. As time ticks away in getting all the pieces to fall into place, the pressure to treat patients reaches a tipping point, so sometimes testing is just not done or oncologists resort to chemotherapy before genomic test results are available. Given the burgeoning number of recommended molecular tests for lung cancer, multigene panel testing using next-generation sequencing (NGS) offers an attractive diagnostic alternative that can keep pace with the dynamics of precision medicine. In a single push, NGS enables identification of all the point mutations, insertions, deletions, copy number alterations, fusion genes, and microsatellite instability information needed to guide the potential use of targeted therapy. NGS can also identify continued on page 12
INDUSTRY AND REGULATORY NEWS Two New Drug Approvals for Mutation-Driven Cancers Change the Therapeutic Landscape of NSCLC May 2020—During the first full week of May, The US Food and Drug Administration (FDA) approved two separate targeted therapies for RET and MET-driven lung cancers, neither of which had pre-existing marker-specific approvals.
Selpercatinib for RET-driven NSCLC Based on the phase I/II LIBRETTO-001 trial, the largest trial of patients with RETdriven cancers, selpercatinib received accelerated approval on May 9, 2020 for patients with metastatic RET fusion-positive NSCLC, agnostic to line of therapy. LIBRETTO-001 enrolled both treatment-naive (n = 39) and heavily pretreated (n = 105) patients with a RET
fusion-positive NSCLC. The ORR was 85% (95% CI: 70%, 94%) and 64% (95% CI: 54%, 73%), respectively. The median DoR was not reached for treatmentnaive patients, but the minimum DoR was reported as 12 months; median DoR for pretreated patients was 17.5 months (95% CI: 12, not reported). Prespecified secondary endpoints included central nervous system (CNS) ORR and CNS DoR. Among those patients with NSCLC and measurable brain metastases, 10 of 11 demonstrated intracranial responses. Of these, 100% demonstrated a CNS DoR of > 6 months. The most frequent serious adverse event was pneumonia. There was a 5% discontinuation rate for patients in LIBRETT0-001, across all cancer types.
Capmatinib for MET-driven NSCLC Just 3 days prior to selpercatinib’s approval, accelerated approval was granted to capmatinib for patients with MET exon 14 skipping mutation-driven NSCLC. A companion diagnostic—the FoundationOne CDx assay— was also approved. Efficacy was demonstrated in the multicenter, nonrandomized, open-label, multicohort GEOMETRY mono-1 trial, which enrolled 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping mutation. Capmatinib (400 mg, oral, twice daily) was administered until disease progression or unacceptable toxicity. ORR was evaluated by a blinded independent review committee
using Response Evaluation Criteria in Solid Tumors, version 1.1. ORR for treatment-naive patients (n = 28) was 68% (95% CI; 48%, 84%) with a median response duration of 12.6 months (95% CI: 5.5, 25.3). ORR was 41% (95% CI: 29%, 53%) for patients who had received prior therapy (n = 69) with a median response duration of 9.7 months (95% CI: 5.5, 13.0). The most common adverse reactions (in ≥ 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. Sensitivity to sunlight is possible so patients should be advised to take precautions including covering their skin and using sunscreen. ✦
