Non-Small Cell Lung Cancer
Actionable Genomic Alterations: Improving Treatment Efficacy in Non–Small Cell Lung Cancer
Targeted therapy for non–small cell lung cancer (NSCLC) has evolved with the addition of newer targets with increased specificity and potency, resulting in improved patient outcomes. These positive trends are likely to continue, in view of recent US Food and Drug Administration (FDA) approvals and the multiple promising candidate therapies that are already in clinical development.
How have actionable alterations in NSCLC been changing the treatment landscape?
“We have succeeded in moving targeted therapies to the earliest phases of the disease, but we still have work to do because of the development of drug resistance.”
Precision therapy has changed clinical practice enormously from the time of the first trials of gefitinib back in 1997 in EGFR-driven tumors (eg, lung cancer, head and neck cancers, breast cancer, prostate cancer). That was before the EGFR mutations had been identified. At that point, we only knew that these tumors frequently overexpressed EGFR. And, in fact, we saw that approximately 10% of patients responded to the EGFR–tyrosine kinase inhibitor (TKI) gefitinib, with some side effects such a diarrhea and rash. In 2005, sequencing data from responders and nonresponders revealed that gefitinib responders harbored specific mutations in the EGFR gene (eg, in exons 19 and 21). As the years went by and as genetic profiling became more routine, patients with these EGFR mutations were shown to do much better with an EGFR inhibitor in the front line than with chemotherapy, and this was seen in a number of high-quality, prospective, randomized clinical trials.
Today, we have newer-generation EGFR-TKIs, such as osimertinib, which selectively inhibits EGFR-TKI–sensitizing mutations and EGFR T790M resistance mutations. Osimertinib is more active and has lower rates of side effects than agents in the previous generations. The bottom line is that, with targeted therapy, we currently have good response rates and manageable toxicity for this group of patients, but no one is cured. EGFR-TKIs have moved up from second-line therapy to frontline therapy and are even being investigated in the adjuvant setting, as in the ongoing ADAURA trial in which osimertinib is being studied in early stage NSCLC after complete surgical resection. We do not cure patients with metastatic disease with these targeted therapies because the tumors become resistant, but we do prolong life and improve quality of life. There are now numerous targets for therapy, including EGFR, ALK, ROS1, RET, ERBB2, MET, BRAF, and NTRK. If you sequence patients, most will have some targeted drug that we can offer. For those who do not, tumor mutational burden may help to determine whether immunotherapy might be used, allowing us to bring next-generation sequencing to all patients with this disease. We have succeeded in moving targeted therapies to the earliest phases of the disease, but we still have work to do because of the development of drug resistance.
Vice Chair, Clinical Research
“Subsequent to the development of EGFR as a target, we have added ALK, ROS1, and BRAF V600E. And, just recently, the FDA approved capmatinib for METex14 mutations. There are also KRAS G12C inhibitors in development that may be approved in just a few years.”
The biggest advances we are seeing now in targeted therapy relate to the increasing number of targets for which good-quality therapies have been, and continue to be, developed. EGFR is frequently mutated in NSCLC, and, as Dr Herbst described, was the first target for which drugs were developed. Subsequent to the development of EGFR as a target, we have added ALK, ROS1, and BRAF V600E. And, just recently, the FDA approved capmatinib for tumors that have a mutation that leads to MET exon 14 (METex14) skipping. METex14 mutations occur in approximately 3% to 4% of NSCLC adenocarcinomas. The FDA granted accelerated approval to capmatinib for the treatment of patients whose tumors have a mutation that leads to METex14 skipping based on the GEOMETRY mono-1 trial, which is a study of 97 patients with metastatic NSCLC with confirmed METex14 alterations. With respect to other targets, looking just a bit further ahead, there are also KRAS G12C inhibitors in development that may be approved in just a few years. So, the story in targeted therapy for NSCLC is that we are working to develop and expand the number of actionable genomic alterations that we can identify and treat with upfront therapy. While it would be nice to have a treatment that is effective in a wide swath of patients, the treatment of NSCLC is really an incremental game where you just add up little bits here and there, and, ultimately, we hope to see better outcomes for more patients.
“I think that we will continue to see improved activity as these targeted therapies become more specific and more potent against the mutant forms of NSCLC.”
Improving the efficacy of targeted drugs entails designing and making better drugs that are specific for the oncogenic drivers. For example, the initial EGFR inhibitors gefitinib and erlotinib worked relatively well, with progression-free survivals (PFS) of approximately 10 to 12 months, but these agents were directed against the wild-type receptor. However, when osimertinib was developed to have specificity for the mutant receptor, you were able to increase the median survival to 19 months, an almost doubling of the PFS in that population. I think that we will continue to see improved activity as these targeted therapies become more specific and more potent against the mutant forms of NSCLC.
Another example is crizotinib, and it is telling that it is FDA approved both for ALK- and ROS1-positive tumors; it also has activity against MET, so it has activity against multiple types of tyrosine kinases. Solomon et al reported a median PFS of 10.9 months with the first-line use of crizotinib for advanced ALK-positive NSCLC, which is, again, nearly double the median PFS of 7 months seen with chemotherapy in this group of patients. Subsequent to the introduction of crizotinib, a number of second- and third-generation agents have been developed. Currently, the agent of choice for advanced ALK-positive NSCLC is alectinib. The median PFS times were 34.1 months with alectinib and 10.2 months with crizotinib in the randomized, open-label, phase 3 J-ALEX study. So, as each of these oncogenic drivers is targeted more effectively as newer therapies are developed, we hope to see a better and better efficacy.
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