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Gilotrif Survival Data for Del19 and L858R Patients has Implications for Treatment, Research

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NEW YORK (GenomeWeb) – Overall survival analysis of EGFR mutation subpopulations in two trials involving Boehringer Ingelheim's Gilotrif (afatinib) shows that non-Asian patients with Del19 mutated non-small cell lung cancer tumors live significantly longer – a median of an additional year – on Gilotrif compared to chemotherapy.

Meanwhile, researchers led by Massachusetts General Hospital's Lecia Sequist didn't observe similar survival advantages in non-Asian patients with L858R mutations when they received Gilotrif compared to chemotherapy.

The data from studies Lux-Lung 3 and Lux-Lung 6 strongly support that for patients with Del19 EGFR mutations, Gilotrif should become the standard of care, according to Sequist. Furthermore, the data suggest that researchers should no longer clump these different EGFR-mutated subpopulations together in terms of treatment and research, she said.

"The survival advantage observed among Del19 patients treated with afatinib means that afatinib should be considered as the top option [among] EGFR tyrosine kinase inhibitors if you have a patient with the Del19 mutation," Sequist told PGx Reporter. "However, the fact that no survival advantage was seen with L858R patients is identical to the data for L858R patients with erlotinib and gefitinib."

Roche subsidiary Genentech's Tarceva (erlotinib) and AstraZeneca's Iressa (gefitinib) are older EGFR inhibitors launched in the early 2000s. Gilotrif is a newer drug in the class that irreversibly binds to EGFR, HER2, and ErbB4.

The US Food and Drug Administration approved Gilotrif in July 2013 for the first-line treatment of metastatic NSCLC patients who harbor EGFR exon 19 deletions or exon 21 L858R substitutions. The agency simultaneously approved Qiagen's Therascreen EGFR RGQ PCR Kit to help healthcare providers pick out patients who have these mutations and therefore have an increased chance of responding well to Gilotrif.

Sequist presented the overall survival data late last month from Lux-Lung 3 and Lux-Lung 6 at the Chicago Multidisciplinary Symposium in Thoracic Oncology. These studies had previously showed that Gilotrif improved progression-free survival in EGFR-mutated patients compared to standard chemotherapy.

According to the latest overall survival data, when researchers combined the analysis of 631 Asian and non-Asian patients in the two studies with common EGFR mutations, median overall survival was statistically significantly longer in those receiving Gilotrif, 27.3 months compared to 24.3 months for those receiving standard chemo.

Then researchers looked specifically at 83 non-Asian patients with these common EGFR mutations in Lux-Lung 3, and reported that median overall survival was 28.1 months on Gilotrif compared to 20.7 months on chemotherapy. Even more detailed subgroup analysis showed that non-Asian patients with Del19 mutations had "significantly improved" median overall survival – 33.6 months on Gilotrif versus 20 months on chemotherapy.

Patients in the L858R mutation category, however, experienced median overall survival of 19.8 months on Gilotrif and 21.1 months in the chemo arm. "There was no difference between chemo and afatinib for L858R patients and importantly, there was no statistical detriment to survival with afatinib," Sequist said. "This is the same as has been seen with erlotinib and gefitinib."

She pointed out that patients with L858R mutations had experienced "great" progression-free survival on Tarceva and Iressa, and they had higher response rates and quality of life compared to chemotherapy. "So, EGFR tyrosine kinase inhibitors are still the standard of care for L858R patients; there is just no clear differential between" the drugs.

In her view, the combined analysis of these two large randomized trials provides has implications for personalized cancer treatment research as well. "The next steps are to make sure all other EGFR trials are stratifying by mutation type going forward and to learn if the stark differences seen were specific to afatinib or more generalizable to all EGFR TKIs."

William Goeckeler, Boehringer's medical director, told PGx Reporter that the firm will continue to evaluate patients with these EGFR mutations. For example, the Phase IIb LUX-Lung 7 study is investigating Gilotrif versus Iressa as a first-line option in EGFR mutation-positive advanced NSCLC patients in countries where Iressa is marketed. This study will stratify patients according to EGFR mutation type, including del19 and L858R.

Boehringer wouldn't disclose if the latest survival data would have implications for Gilotrif's labeling. The current label for the drug includes interim survival data, which at the time of analysis wasn't statistically significant.

If the latest Lux-Lung 3 and Lux-Lung 6 studies suggest that patients with these two commonly occurring EGFR mutations have different responses to Gilotrif, and possibly other drugs in the class, then it will become increasingly important to use a companion test that can identify specific markers in patients, particularly if the drugmaker wishes to learn more about these subpopulations and advance better therapies.

The Therascreen EGFR RGQ PCR Kit, the FDA-approved companion diagnostic for Gilotrif, includes seven assays that gauge a total of 29 mutations. There are four singleplex assays that assess T790M, L858R, L861Q, and S768I mutations, and three multiplex assays that gauge a range of del19 mutations, insertions, and G719X mutations. The singleplex assays gauge specific EGFR mutations. Meanwhile, the multiplex assays indicate when a certain type of mutation is detected (i.e. when a del19 mutation is present), but does not distinguish the specific mutations.

"The assay is conducted in separate tubes and reports the overall EGFR mutation status, as well as the specific mutation present in the tumor sample, allowing laboratories to specifically differentiate between patients with exon 19 deletions and the L858R mutation," a spokesperson for Qiagen told PGx Reporter.

While Sequist doesn't use the Qiagen test in her practice, she noted, however, that "it is important for a practitioner to know exactly which EGFR mutation a patient has when treating them."

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