The benefit of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy with erlotinib beyond disease progression for patients with EGFR-mutated NSCLC has been unclear. But new data supports previous findings that there is no clinical benefit as well as increased toxicity with such treatment for these patients, according to the study published in The Oncologist (2015:20:1298-1303).
“Based on our trial, we concluded that there is no reason to continue erlotinib when making the decision to switch to chemotherapy in patients who have previously benefitted from erlotinib (predominantly EGFR mutation-positive [non-small cell] lung cancer),” study author Nathan Pennell, MD, PhD, Director of the Lung Cancer Medical Oncology Program in the Cleveland Clinic Department of Hematology/Oncology, said in an email.
Earlier studies had produced conflicting data on this question, he explained. But this recent data confirms the findings from the larger IMPRESS trial, also published last year, that showed continuing an EGFR inhibitor after making the switch to chemotherapy makes no difference in either progression-free survival or overall survival.
“The standard of care now is to stop [EGFR-TKI therapy with erlotinib at progression], based on these two trials,” Pennell said. “This has been pretty well accepted by the oncology community.”
This study included 46 patients with pathologically confirmed stage IIIB (with pleural effusion) or stage IV non-small cell lung cancer who showed signs of RECIST-defined disease progression after at least 12 weeks of erlotinib treatment that had previously shown clinical benefit. Patients with a history of more than one prior cytotoxic chemotherapy regimen for relapsed or metastatic disease (not including erlotinib) and any prior EGFR inhibitor (not including erlotinib) were excluded. EGFR status was known for 39 of the 46 patients and 80 percent of the subjects with known EGFR status had tumors that harbored an activating EGFR mutation. The study was initiated in 2007, prior to EGFR mutation testing becoming uniformly accepted and frontline EGFR TKI therapy being standard of care.
Patients were randomly assigned to receive: pemetrexed (500mg/m2) or docetaxel (75mg/m2) on day one, and then every three weeks, plus once-daily erlotinib (100-150mg taken orally on days 2-19 of each treatment cycle); or pemetrexed or docetaxel without erlotinib. For the patients receiving erlotinib, the dose was the one the patient had been receiving prior to enrolling in the study.
Median progression-free survival (the study's primary endpoint) for patients receiving either pemetrexed or docetaxel alone was 5.5 months; and 4.4 months for patients receiving pemetrexed or docetaxel plus erlotinib—the difference between the two arms was not statistically significant. Median overall survival for patients receiving pemetrexed or docetaxel alone was 16.4 months; and 14.2 months for the patients who received pemetrexed or docetaxel plus erlotinib. For the patients for whom EGFR status was known, subset analyses showed there was also no difference in progression-free survival or overall survival when that variable was taken into account.
A significant increase in toxicities was noted among the patients who received pemetrexed or docetaxel plus erlotinib: 24 grade 3 or 4 adverse events (as assessed by the CTCAE 4.0 criteria) were reported for those patients, compared to seven grade 3 or 4 adverse events for the patients who received just pemetrexed or docetaxel alone. One grade 5 event occurred in each study arm. Seven patients (out of 24) in the pemetrexed or docetaxel-alone group (29.2%) had at least one grade 3 or higher toxicity, compared with 16 patients (out of 22) in the pemetrexed or docetaxel plus erlotinib group (72.7%). The increased toxicity primarily appeared to be caused by hematological and gastrointestinal toxicities, the paper notes.
Trial Closed Early
The study was closed early because of slow accrual as a result of significant practice changes, the paper notes—46 of the planned 78 patients were enrolled at the time of study termination. But the statistical modeling suggested that even if the study were to be completed it was highly unlikely that positive results demonstrating the benefit of continuing erlotinib treatment would have been seen—and the findings are still of “significant value to guide practical management of patients,” the authors note.