There should be no more trials comparing front-line epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment with standard chemotherapy in patients with nonsmall-cell lung cancer (NSCLC), writes Corey Langer, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, in an editorial published onlineAugust 26 in the Journal of Clinical Oncology.
There have now been 8 separate clinical trials, and all have shown that drugs targeting EGFR mutations are better than standard chemotherapy in this patient population. The targeted drugs include erlotinib (Tarceva), which is the de facto standard; gefitinib (Iressa), which is not available in the United States; and afatinib (Gilotrif), which has been recently launched.
All of the trials have shown consistent results, notes Dr. Langer, and have demonstrated "a major statistically significant and clinically relevant improvement in response rates, quality of life, and progression-free survival that is unheralded in the history of thoracic oncology."
"Another study of this sort will result in needless redundancy," he writes. "Instead, we should determine which, if any, EGFR TKI is superior."
More important, research efforts should now be directed at preventing or overcoming resistance to these drugs and at extending survival in the first- and second-line settings, Dr. Langer writes.
"Despite dramatic improvements in response rates and progression-free survival, no trial to date has yielded a statistically significant survival advantage, although some have generated intriguing trends," he adds. The survival data have been muddied by crossover, because patients initially assigned to chemotherapy are generally offered an EGFR inhibitor on disease progression.
"Ultimately, enhancing cure rates is our chief objective," he emphasizes. "Testing these agents properly in the adjuvant and locally advanced setting must be a priority."
Where Does Afatinib Fit?
The question of which EGFR inhibitor is superior permeates the editorial, which was prompted by a study published online on July 1 in the journal. That study — the LUX-Lung 3 trial — was the basis for the approval of afatinib.
In that trial, the fact that afatinib was superior to chemotherapy in patients with NSCLC and EGFRmutations was "entirely expected and scarcely surprising," Dr. Langer notes.
However, he points out that the landmark LUX-Lung 3 study is the largest trial to be published to date in the first-line EGFR mutant setting, and is the only trial of this sort to include patients from the United States (although more than 75% of the participants came from East Asia). In addition, it employed a state-of-the-art chemotherapy comparator (pemetrexed and cisplatin).
Afatinib is also a little different than the 2 older drugs in this class, Dr. Longer explains. Whereas erlotinib and gefitinib are relatively pure EGFR inhibitors, afatinib is an irreversible HER1 and HER2 inhibitor with activity in T790 clones, which often arise with acquired resistance. "The implication is that this agent may potentially work better in the long run, and may actually provide therapeutic salvage for patients with EGFR mutations whose tumors have progressed during treatment with first-line EGFR TKIs," he notes, adding that there are some data from clinical studies to suggest that this is the case.
He does wonder, though, whether any of these findings that highlight activity in patients with acquired resistance to standard EGFR TKIs are sufficient to justify the replacement of erlotinib in the first-line setting?
In the United States, erlotinib was the de facto standard treatment for EGFR-positive NSCLC long before it was formally approved in May for first-line use by the US Food and Drug Administration and was incorporated into National Comprehensive Cancer Network guidelines, Dr. Langer writes.
In terms of efficacy, there is little difference between the 3 targeted agents, afatinib, erlotinib, and gefitinib, in the amount of benefit they offer over chemotherapy in both response rates and progression-free survival. Even though there are numerical differences in progression-free survival in patients with common EGFR mutations treated with afatinib (13 months in LUX-Lung 3 and 9 to 10 months in other trials), cross-trial comparisons are "inherently perilous," he notes.
The general perception is that the toxicity profile is somewhat worse for afatinib than for erlotinib or gefitinib, he reports. Stomatitis has been reported only with afatinib, not the other 2 drugs, and clinical trial data have shown a higher rate of diarrhea and paronychia with afatinib than with erlotinib.
"Oncologists are often creatures of habit," Dr. Langer explains. "In the absence of a direct phase 3 comparison that demonstrates clear-cut superiority [over] first-generation TKIs or an economic decision rendering afatinib less expensive, it is unclear if afatinib will be used in the first-line setting."
The LUX-Lung 3 trial was funded by Boehringer Ingelheim, the manufacturer of afatinib. Dr. Langer reports acting as a consultant for Boehringer Ingelheim, OSI Astellas, Bristol-Myers Squibb, and Eli Lilly.
J Clin Oncol. Published online August 26, 2013. Full text
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