This article is more than 5 years old. Information may no longer be current.
Erlotinib beyond progression may delay salvage therapy in EGFR-mutated NSCLC
Erlotinib appeared effective as first-line treatment for Asian patients with EGFR mutation-positive non–small cell lung cancer, according to phase 2 study results.
Treatment beyond progression appeared feasible and may delay salvage therapy in certain patients, results showed.
“Almost all patients receiving first-line EGFR tyrosine kinase inhibitors will eventually experience disease progression according to the criteria of Jackman and colleagues that endorse both [RECIST] and WHO definitions of progression,” Keunchil Park, MD, PhD, professor at Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, South Korea, and colleagues wrote. “However, the question remains whether these are the most appropriate criteria for stopping EGFR TKI treatment.”
Park and colleagues assessed the efficacy of first-line therapy with the TKI erlotinib (Tarceva; Genentech, Astellas) in patients with NSCLC with activating EGFR mutations. They also evaluated the efficacy of erlotinib therapy following progression.
The single-arm, open-label phase 2 ASPIRATION study included adult patients with stage IV, EGFR mutation–positive NSCLC treated at 23 centers in Hong Kong, Korea, Taiwan and Thailand.
The researchers assigned patients to oral erlotinib 150 mg daily until disease progression. The decision to continue treatment after progression was made at the discretion of the patient or investigator.
PFS served as the primary endpoint. Key secondary endpoints included PFS2 — defined as time to off-erlotinib progression in patients whose therapy extended beyond progression — as well as objective response rate, disease control rate, OS and safety.
Median follow-up was 11.3 months (range, 10.9-13).
The study included data from 208 patients (median age, 60.8 years; range, 28-89; 62.3% women), 72.9% of whom were never-smokers.
The intent-to-treat population included 207 patients; of this group, 176 (87.5%) had a PFS event (disease progression, n = 171; death, n = 5). Of the 171 patients who progressed, 93 continued treatment and 78 discontinued treatment.
Overall, median PFS was 10.8 months (95% CI, 9.2-11.1). Among patients who continued erlotinib treatment beyond progression, median PFS was 11 months (95% CI, 9.2-11.1) and median PFS2 was 14.1 months (95% CI, 12.2-15.9).
Among patients with exon 19 deletions or L585R mutations, median PFS was 11 months (95% CI, 9.3-12) and median PFS2 was 14.9 months (95% CI, 12.2-17.2).
In the overall intent-to-treat population, researchers reported a 66.2% objective response rate and an 82.6% disease control rate (complete response, n = 2; partial response, n = 135; stable disease, n = 34). Median OS was 31 months (95% CI, 27.3-not reached).
Nearly all patients (99.5%) reported an adverse event, and 7.2% discontinued treatment due to adverse events. The most common adverse events included diarrhea (59.4%) and rash (52.7%).
Approximately half (50.2%) of study participants experienced grade 3 or higher adverse events, and 27.1% experienced serious adverse events.
Park and colleagues acknowledged study limitations, including the fact that treatment continuation was at patient or provider discretion rather than being mandated.
Further, because repeated biopsy at time of progression was not mandatory, investigators could not assess changes to mutation status that may have affected treatment decisions.
“The prospective ASPIRATION study supports the efficacy of first-line erlotinib therapy in Asian patients with EGFR mutation–positive NSCLC and that continuing erlotinib therapy beyond progressive disease is feasible and may be of benefit in delaying salvage anticancer therapy with no undue toxic events in selected patients,” Park and colleagues wrote. “However, validation in a randomized trial would be beneficial.”
However, results of the ASPIRATION study are hampered by flaws in the study design, David R. Gandara, MD, professor and director of the thoracic oncology program at UC Davis Health System in Davis, California, Mary Redman, PhD, associate member of the clinical research division at Fred Hutchinson Cancer Research Center in Seattle, and Fred R. Hirsch, MD, PhD, professor of medicine at University of Colorado School of Medicine in Denver, wrote in an accompanying editorial.
“The decision to continue TKI or switch to other therapy at the time of progressive disease was at physician discretion,” Gandara, Redman and Hirsch wrote. “The fact that physicians could make this determination on an individual patient basis creates the potential for tremendous bias in the analysis of subsequent patient outcomes. … The ASPIRATION trial adds to the global database on the topic of postprogression prolongation of survival, but it is handicapped by its study design so that it is unable to fully address the most important question facing practicing oncologists: ‘What do I do with the next patient in my waiting room with progressive disease after initial TKI therapy of EGFR-mutated lung cancer.” – by Cameron Kelsall
Disclosure: Park reports advisory fees and writing assistance from F. Hoffmann-La Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures. Gandara reports grants from Genentech and consultant roles with AstraZeneca, Boehringer Ingelheim and Genentech. Hirsch reports research funding from and/or advisory board memberships with Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Lilly, Merck, Pfizer and Roche. Redman reports no relevant financial disclosures.