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New Precision Oncology Options Emerge at ASCO in First-Line EGFR-Mutated, ALK-Positive Lung Cancer

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CHICAGO (GenomeWeb) – Two next-generation precision oncology drugs, one an EGFR inhibitor and an ALK inhibitor, have shown to be far more effective against advanced non-small cell lung cancer than older drugs in their class.

At the American Society of Clinical Oncology's annual meeting, researchers presented data from two head-to-head NSCLC trials, one comparing the first targeted EGFR inhibitor Iressa (gefitinib) against the next-generation dacomitinib; and another comparing the first ALK-inhibitor Xalkori (crizotinib) against newer agent Alecensa (alectinib).

In the 452-patient Phase III trial comparing Pfizer's dacomitinib against Iressa in first-line advanced NSCLC with EGFR mutations, median progression-free survival was 14.7 months versus 9.2 months, respectively. The objective response rate by blinded independent review was 74.9 percent for dacomitinib versus 71.6 percent for Iressa; and duration of response was 14.8 months versus 8.3 months, respectively. The overall survival data were not mature, as there were only 36.9 percent of events at the time of data cutoff.

Lead author Tony Mok from the Chinese University of Hong Kong said at the meeting that based on the results of this meeting, dacomitinib should be considered a new first-line treatment option for advanced, EGFR-mutated NSCLC.

In an earlier, single-arm Phase II study, the drug given in the first-line NSCLC setting to a subgroup of patients with EGFR mutations, more than 75 percent of patients responded and median progression-free survival was 18.2 months. Given these earlier findings, researchers wanted to find out if dacomitinib was better than Iressa.

In the present study, patients had to be treatment naïve and had to have an EGFR mutation as determined by Qiagen's Therascreen test. Approximately 75 percent of enrolled patients were from Asia and 65 percent were never smokers. "This is quite classical of any first-line study on an EGFR tyrosine kinase inhibitor," Mok said.

Dacomitinib is different from earlier drugs in that it irreversibly binds to and blocks EGFR/HER1, HER2, and HER4 receptors. "This implies more potent inhibition of the EGFR," said Mok. He noted that though response rates were similar between the two arms, patients receiving dacomitinib had greater reductions in tumor size, reflecting the fact that the newer drug is thwarting the receptor more effectively.

At two years, 31 percent of patients getting dacomitinib were progression free, compared to under 10 percent on Iressa. ASCO expert John Heymach from MD Anderson Cancer Center agreed that dacomitinib offered a substantial efficacy advantage over Iressa in the Phase III study, but it came with a toxicity cost.

EGFR-mutated NSCLC patients currently have three options in the first-line setting: AstraZeneca's Iressa, Genentech's Tarceva (erlotinib), and Boehringer Ingelheim's Gilotrif (afatinib). Comparing these drugs across separate studies, there isn't a substantial difference in their comparative ability to stave off progression, according to Heymach.

"This is more than a five-month difference in progression-free survival," he said of the dacomitinib/Iressa comparison. "So, from the perspective of doctors who treat lung cancer daily, this is really a substantial advance … rather than just another tyrosine kinase inhibitor that would join the others. This would really put it at the front of the pack in terms of efficacy."

But because dacomitinib more potently inhibits EGFR, the drug can block not only mutated receptors, but also wild-type EGFR. This led to more patients on the dacomitinib arm having diarrhea, infection of tissues around fingernails, acne, and mouth sores, around 10 percent of which were serious grade 3 toxicities. Comparatively, grade 3 toxicities were uncommon for patients receiving Iressa.

Around two-thirds of patients on dacomitinib required dose modifications, while 8 percent of Iressa-treated patients required dosing changes.

Heymach reasoned that the toxicities with dacomitinib are manageable and not life-threatening, but would require close monitoring of patients. "These are toxicities that doctors who treat [lung cancer] for a living, become accustomed to managing," he said, adding that Phase III data suggest "a clear, potential option for patients."

Patient-reported outcomes were generally similar for both drugs, though for gastrointestinal toxicities and mucositis, patients rated dacomitinib worse. Though there are higher toxicities with dacomitinib, requiring dose modificaitons, "at the end [of the] day, we have one additional choice" for NSCLC patients with EGFR mutations, Mok said.

In another presentation at ASCO, Alice Shaw from Massachusetts General Hospital reported data from a Phase III trial in 300 newly diagnosed advanced NSCLC patients with ALK rearranged tumors, who were randomized to receive Pfizer's Xalkori (crizotinib) or Genentech's Alecensa (alectinib). Patients had their ALK status determined by Ventana ALK IHC assay.

The US Food and Drug Administration approved Alecensa a few years ago for advanced ALK-positive NSCLC patients who were progressing on or couldn't tolerate Xalkori ― the first ALK inhibitor to come to market in 2011. Xalkori is the standard of care in this setting, but Shaw noted that while the drug is very effective initially, patients often fail on therapy within the first year of treatment, and commonly the disease spreads to the brain.

"This likely reflects the drug's poor penetration to the brain," Shaw said. In the study, progression-free survival had not been reached in Alecensa-treated patients, but was 11.1 months for patients on Xalkori, translating to a 53 percent reduction in the risk of progression for those on Alecensa. Independent reviewers reported that Alecensa more than doubled median progression-free survival, compared to Xalkori — 25.7 months versus 10.4 months.

The newer agent also significantly delayed metastasis to the brain compared to Xalkori. "Patients treated on alectinib had significantly lower incidence of central nervous system progression compared to those treated with crizotinib," Shaw reported. Patients on the Alecensa arm had 84 percent lower risk of brain metastasis than those on Xalkori.

There were fewer severe side effects related to Alecensa, compared to Xalkori, and fewer patients required dose reductions or had to discontinue treatment with the newer agent. "Taken together, both the efficacy and safety results of this study establish alectinib as the new standard of care for patients with advanced, previously untreated, ALK-positive lung cancer," Shaw said.

Heymach said this study marked a "watershed moment" for the treatment of ALK-positive lung cancer. "Often, studies comparing different, similar-type agents will show incremental improvements," he said.

When Xalkori was compared to chemotherapy, the ALK inhibitor improved progression-free survival by around four months. "This one is really different because it's a dramatic difference in efficacy … but it's also accompanied by improved tolerability," Heymach said. The fact that Alectinib drastically reduced the risk of brain metastasis, a common and debilitating type of cancer progression, was a "striking" advance, he added.

In the front-line setting for ALK-positive, metastatic NSCLC, the agency recently also approved Novartis' Zykadia (ceritinib), which can be given to patients with brain metastasis. In advanced, previously treated patients, another recently approved option for patients with ALK-positive NSCLC is Takeda/Ariad's Alunbrig (brigatinib). At ASCO's annual meeting, Pfizer also presented data on its next-generation ALK inhibitor lorlatinib, which showed activity in previously treated patients with brain metastases, and has breakthrough therapy status from the FDA.