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Intercalated chemotherapy plus erlotinib effective for EGFR-positive NSCLC
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The combination of intercalated chemotherapy and erlotinib appears to be a viable option for first-line treatment of patients with EGFR mutation-positive non–small cell lung cancer or in selected patients with unknown EGFR mutation status, according to results of a phase 3 study.
“To the best of our knowledge, this is the first randomized phase 3 trial to show an improvement in efficacy outcomes with an intercalated regimen of chemotherapy and an EGFR inhibitor for patients with advanced NSCLC,” the researchers wrote.
The phase 2 FASTACT trial showed intercalated chemotherapy and erlotinib (Tarceva; Genentech, Astellas Pharma) significantly prolonged PFS in patients with advanced NSCLC.
The follow-up phase 3 study included 451 patients with untreated stage IIIB/IV NSCLC.
All patients received six cycles of chemotherapy with gemcitabine plus platinum. The researchers randomly assigned patients to receive intercalated erlotinib (150/mg day orally, n=226) or placebo (n=225) on days 15-28 of each 4-week cycle.
All patients assigned placebo were able to switch to second-line erlotinib at time of disease progression.
PFS served as the primary outcome measure in the intent-to-treat cohort.
Researchers reported significantly longer PFS (7.6 months vs. 6 months; HR=0.57; 95% CI, 0.47-0.69) and longer OS (18.3 months vs. 15.2 months; HR=0.79; 95% CI, 0.64-0.99) among patients assigned to chemotherapy plus erlotinib.
Researchers only observed treatment benefit in patients with an activating EGFR mutation.
Median PFS was 16.8 months among patients with an EGFR mutation vs. 6.9 months for those without (HR=0.25; P<.0001), and median OS was 31.4 months for those with the mutation vs. 20.6 months for those without (HR=0.48; P=.0092).
The overall rate of serious adverse events was higher in the placebo group (34% vs. 31%).
Common grade ≥3 adverse events included neutropenia (29% of placebo group vs. 25% of erlotinib group), thrombocytopenia (14% in both arms) and anemia (12% vs. 9%).
“Benefit is higher in patients with the mutations, but there is no detrimental effect for patients without mutations,” the researchers wrote. “By use of this intercalated combination, treatment outcomes are potentially better than the standard chemotherapy regimen that the patient would otherwise receive. We would suggest that the regimen be considered for patients with an unknown mutation status in whom clinical parameters are suggestive of a high incidence of EGFR mutations.”
The study results are encouraging, but “deciphering the interactions between EGFR tyrosine kinase inhibitor and chemotherapy in patients with advanced NSCLC remains complex,” Fred R. Hirsch, MD, PhD, of the University of Colorado Denver, and David R. Gandara, MD, of UC Davis Health System, wrote in an accompanying editorial.
“Whether an intercalated strategy will ultimately delay or prevent the onset of acquired resistance remains to be proven, both in the EGFR-mutated and EGFR wild-type setting,” they wrote.
For more information:
Hirsch FR. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70281-X.
Wu YL. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70254-7.
Disclosure: The researchers report research support and honoraria from, employment and consulting relationships with, speaking fees from and stock ownership in AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Pfizer and other pharmaceutical companies. Hirsch reports consulting roles with Boehringer Ingelheim, Celgene, Genetech, Lilly Oncology, Pfizer and Roche; as well as research funding through the University of Colorado from Celgene, Genentech, Imclone, Lilly and Ventana. Gandara reports consulting roles with Lilly Oncology, Pfizer and Roche Genentech.
Perspective
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Kenneth R. Hande, MD
The investigation by Wu and colleagues studied the benefit of adding erlotinib to standard chemotherapy for the treatment of advanced non–small cell lung cancer. The strong points of this study are the phase 3 design with a large enrollment (451 patients); intention to treat analysis; careful collection of data, including a blinded assessment of PFS by both investigators and an independent radiology review; and measurement of EGFR status in roughly half of the patients. The study concludes that combined treatment with chemotherapy plus the EGFR inhibitor improves both PFS and OS with only a modest increase in toxicity.
An issue with this study is how it may impact treatment in a different study population. The benefit of adding erlotinib to chemotherapy was seen primarily in those patients with EGFR mutations, a group already recognized to have excellent response to EGFR inhibitors such as erlotinib. This was a study conducted in Asia where half the patients entered were nonsmokers and three-quarters of patients had adenocarcinoma. This is a much higher percentage of non-smokers, Asians and adenocarcinoma histology patients than would be found in a typical US population of lung cancer patients. The population studied (Asian, nonsmokers with adenocarcinoma) would be expected to be highly enriched with patients with EGFR mutations and, indeed, in the 67% of patients whose tumor was available for EGFR analysis, 40% had EGFR mutations.
I would guess that the benefit of combined erlotinib plus chemotherapy would be less in a typical US population of patients with advanced NSCLC.
Many oncologists in the United States determine EGFR mutational status prior to therapy. Those with mutated EGFR are treated with an EGFR inhibitor such as erlotinib, while those with wild-type EGFR are treated with chemotherapy.
What this study does not address is if combined chemotherapy with erlotinib benefits patients with known EGFR tumor mutations or patients known to have EGFR wild-type tumors. Patients with EGFR-mutated lung cancers should clearly receive erlotinib, but does adding chemotherapy from the beginning add much benefit or only add cost and some increased toxicity?
My bias would be there is not much benefit to adding front-line chemotherapy to this group of patients and chemotherapy should be used at progression rather than as a front-line therapy. Does erlotinib add significant survival benefit to patients with EGFR wild-type cancers? My impression is that erlotinib probably adds a modest benefit to survival to EGFR wild-type patients (based on this study’s results) but not enough benefit to warrant the increase in expense and toxicity.
The one area where this study will benefit is for those instances in which a patient’s EGFR mutational status is not available. Here, a reasonable argument can be made that optimal care would be use of intercalated chemotherapy and erlotinib as described in this paper.
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