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Current Treatment of Advanced NSCLC Requires Testing for Driver Mutations

August 2013 Vol 6, No 6 Special Issue - Lung Cancer

Chicago, IL—Advances in the treatment of non–small-cell lung cancer (NSCLC) to date have focused on mutations in the epidermal growth factor receptor (EGFR) gene, sensitivity to various oncologic agents, the effects of chemotherapy versus single drug on quality of life, and oncologic drug development, said Paul A. Bunn, Jr, MD, James Dudley Chair in Cancer Research, University of Colorado Denver, at ASCO 2013.

Years ago, the selection of patients for treatment was based on clinical features. Today, histology must be part of the mix, Dr Bunn said. “In the molecular era, we have to consider patients of almost any performance status [for treatment]. We have to do a special test to determine whether they have oncogene changes,” he said.

A major breakthrough was the 2004 discovery of mutations in the EGFR gene. These mutations alter the aden­osine triphosphate (ATP)-binding pocket, allowing ATP to bind.

“The tyrosine kinase inhibitors [TKIs] imatinib [Gleevec], erlotinib [Tarceva], and gefitinib [Iressa] bind and outcompete ATP for the binding pocket, so ATP can’t bind, and there’s no signal,” Dr Bunn said. Clinical trials emphasize the importance of mutation testing if TKI therapy is to be selected over chemotherapy for first-line treatment of advanced NSCLC.

In the Iressa Pan-Asia Study, in the group with EGFR mutations, gefitinib showed response in 71% of patients compared with 47% with chemotherapy. In patients without the mutation, the response was 23% with chemotherapy and 1% with gefitinib.

Patients with an EGFR mutation who received gefitinib as a single oral drug had better progression-free survival (PFS) than with chemotherapy with carboplatin/paclitaxel.

“The opposite was true for patients that did not have EGFR mutation,” Dr Bunn said. In patients with no mutation, chemotherapy was better, although the quality of life was not as good as for patients with mutations who received the oral drug, he added.

At least 6 other trials have shown that in patients with an EGFR mutation, an oral TKI was associated with superior response, with a doubling of PFS compared with platinum-based doublet chemotherapy, Dr Bunn said. Crossover prevented detecting a difference between treatments in overall survival, “but the hazard ratio always favored the TKI,” as did convenience and reduced toxicity.

He added that, based on findings, the question becomes, “when do you stop these treatments?”

For patients with a driver mutation whose tumors progress after an initial response to a TKI, “would it be better to keep the patient on the TKI, because all the cells still have the sensitizing mutation…or should you immediately stop and switch to chemotherapy?”

Preliminary data suggest no difference between giving platinum-based doublet chemotherapy immediately at progression and continuing the TKI, but the “TKI would be preferred because of convenience and toxicity,” Dr Bunn said. “In our practice, if the patients are asymptomatic, they’re continued on the TKI.”

Secondary mutations in a single metastasis may develop, and some cancers may progress in a single site, while other sites are still responding to the TKI. In this case, continuing the TKI while adding local radiation produces a PFS superior to switching to chemotherapy, said Dr Bunn.

Where Is Treatment Headed?
Cancer cells may undergo a second mutation in the ATP binding pocket of the intracellular portion of the receptor, resulting in the ATP outcompeting the TKI. This type of resistance has been reported for imatinib, erlotinib, and crizotinib. Approximately 50% to 60% of patients with an EGFR mutation who are receiving a TKI have a second mutation, and other patients have other oncogenic drivers.

These include mutations in HER2BRAF, and PI3KCA; rearrangements in ROS and RET; and amplifications in MET and FGFR1. Preliminary results in patients with ROS fusions treated with crizotinib suggest that response rates and PFS may be similar to those with TKIs in patients with EGFR mutations, or with crizotinib in patients with ALK fusions, said Dr Bunn.

“These data suggest that routine testing for additional genetic alterations will become standard in the future,” he said. “Fortunately, the costs of next-generation sequencing and other biomarker tests are decreasing, while reliability and turn-around times are improving. The future is also likely to see combinations of targeted therapies, since single agents produce few complete responses and no cures.”

Second- and third-generation TKIs have been designed to outcompete ATP for binding pockets. In patients with acquired resistance to a TKI, second-generation TKIs have not been able to produce high response rates when used alone. The newly approved afatinib (Gilotrif) is a second-generation TKI that in combination with cetuximab (Erbitux) was associated with a 50% response rate in patients whose disease progressed after treatment with a first-generation TKI.

Several second-generation ALK inhibitors are in phase 1 or phase 2 trials, including LKD378, AP26113, and CH5424802. Overall response rates in these trials are 56% to 94%. “In addition, responses in patients with central nervous system metastases are reported with all 3 of these agents,” Dr Bunn said.

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Last modified: August 30, 2021