Afatinib Plus Cetuximab in Resistant NSCLC

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The FDA approved afatinib as a treatment for patients with metastatic non-small cell lung cancer (NSCLC) who harbor an EGFR exon 19 or 21 mutation in July 2013. In patients who develop resistance, this drug has also demonstrated promise in combination with cetuximab in early phase clinical trials, notes Corey J. Langer, MD.

Results from a phase Ib expansion study demonstrated similar response rates in patients with resistant NSCLC, regardless of T790M mutation status, notes Alice T. Shaw, MD, PhD. However, nearly all patients enrolled in the study experienced a treatment-related adverse event, including rash (90%), diarrhea (71%), and stomatitis (56%).

When considering the efficacy and low toxicity profile seen with third-generation targeted agents, such as AZD9291 and rociletinib (CO-1686), the afatinib-cetuximab combination seems unlikely to be utilized for patients with the T790M mutation, believes Shaw.

Clinical trial data for long-term outcomes with targeted therapies remains elusive, given the high-level of crossover in many of the studies. In general, only a small portion of patients in the trials looking at EGFR and ALK inhibitors did not crossover from the chemotherapy arm to receive the targeted agent, notes Mark A. Socinski, MD. Moreover, subanalyses are difficult, since patients generally did not crossover as a result of progressive disease.

To further explore overall survival (OS) in this population, the ALCHEMIST trial will screen patients with stage IB-IIIA NSCLC following surgery. If EGFR-positive, the patient will be offered the phase III ALCHEMIST-EGFR study, which will compare erlotinib with placebo in the adjuvant setting. If ALK-positive, the patient will be offered the phase III ALCHEMIST-ALK study, which will compare crizotinib with placebo. OS is the primary endpoint of both studies.

Regardless of the stage, setting, or type of treatment, downstaging in the nodes or primary tumor is a good predictor of OS, Socinski notes. However, when these therapies are utilized in the adjuvant setting, the duration of treatment could become a concern, since targeted therapies have known side effects. As a result, the long-term side effects will need to be monitored closely, Shaw adds.