Randomized Phase II Trial of Erlotinib Beyond Progression in Advanced Erlotinib‐Responsive Non‐Small Cell Lung Cancer

Background.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy isclearly beneficial in patients with advanced EGFR-mutated non-small cell lungcancer (NSCLC). However, acquired resistance develops uniformly and the benefit ofcontinuation of EGFR TKI therapy beyond progression remains unclear.

Materials and Methods.

This was a randomized phase II study of chemotherapy (arm A: pemetrexed ordocetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients withprogressive NSCLC following clinical benefit from erlotinib. In arm B,chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days2–19 of each cycle to minimize negative pharmacodynamic interactions. Theprimary endpoint was that continuation of erlotinib in this patient populationcould extend progression-free survival (PFS) by 50%.

Results.

A total of 46 patients were randomized (arm A: 24; arm B: 22). Patientcharacteristics were well balanced except there were more female patients in arm A(p = .075). The median PFS of patients in arm A was 5.5months and for those in arm B, 4.4 months (p = .699). Theresponse rates were 13% and 16% in arms A and B, respectively (p= .79). EGFR status data were available for 39 of the 46 patients and nosignificant difference in PFS was seen for continuing ERL beyond progression inmutation-positive patients. Substantially more toxicity was seen in arm B than armA.

Conclusion.

There was added toxicity but no benefit with the continuation of ERL beyondprogression along with chemotherapy as compared with chemotherapy alone.

Implications for Practice:

The benefits of continuing erlotinib upon progression alongside conventionalchemotherapy are unclear. This randomized phase II study, initiated prior to theestablishment of routine epidermal growth factor receptor (EGFR) mutation testing,addressed this clinically relevant issue through randomizing patients with priorclinical benefit from erlotinib (thereby enriching for EGFR-mutated tumors) uponprogression in the second- or third-line setting to conventional chemotherapy(single-agent pemetrexed or docetaxel) with or without continued erlotinib. Theresults showed no benefit to continuing erlotinib beyond progression, whilesignificantly more side effects were noted in the combination arm. Along withother recently presented study findings, these results argue against the routinepractice of continuing erlotinib in this setting.