The identification of specific carcinogenic mutations is dramatically altering the prospects for many cancer patients. One of the most important genes involved in cancer is a tyrosine kinase, epidermal growth factor receptor (EGFR). This gene is mutated in some cases of lung cancer, and it is these cases that respond to treatment with the tyrosine kinase inhibitors gefitinib and erlotinib.

However, resistance often develops in patients who are given these inhibitors, and there are few options other than cytotoxic drugs to treat such patients. Furthermore, some of these patients have been observed to develop rapid disease progression, known as cancer flare, when EGFR inhibitors are withdrawn. This can be a complication of clinical trials of subsequent therapies in which the trial design includes a "wash-out" period between an EGFR inhibitor and a second drug.

Gregory Riely and his co-workers from Memorial Sloan-Kettering Cancer Center, New York, USA have evaluated the occurrence of disease flare in patients with lung cancer that had acquired resistance to gefitinib or erlotinib who were enrolled in clinical trials in which the study protocol required the tyrosine kinase inhibitor to be withdrawn before the trial drug was begun.

They identified six relevant clinical trials of therapies for EGFR inhibitor-resistant lung cancer that together enrolled 84 patients between August 2005 and January 2011. Fourteen patients were excluded from the analysis as they did not have a documented mutation in EGFR, and a further seven patients enrolled in two or more of the trials were only counted once.

This left a total of 61 patients to be evaluated, the majority of whom were female and non-smokers; in just under two-thirds of cases the EGFR inhibitor was the first line of therapy used.

The investigators defined disease flare as hospitalisation or death related to cancer progression after discontinuation of the EGFR inhibitor. This occurred in fourteen of the 61 patients evaluated, between three and 21 days after the drug was discontinued (median 8 days).

There was no significant difference in documented EGFR mutation type between patients who experienced a flare and those who did not, and in particular there was no difference between those with and without the well-studied T790M mutation. Some reports have suggested that cancer in patients with this mutation will follow a more indolent course.

Flare was, however, significantly associated with a shorter time to disease progression while taking the tyrosine kinase inhibitor (p=0.002) and with the presence of brain or lung metastases (p=0.01 and p=0.03 respectively).

Resistance development is an important complication of tyrosine kinase inhibitor-based therapy in patients with EGFR-mutant solid tumours, and clinical trials of novel treatments for this form of the disease are essential.

However, this relatively small, retrospective study has shown that a significant fraction of patients on these trials will experience a worsening of their cancer directly associated with, and attributable to, the "wash-out" period between the tyrosine kinase inhibitor and the test compound. Some researchers have already been trying to minimise the risk of flare by shortening this period.

Riely and his co-workers suggest that the changes being made are not sufficient, and recommend a gap of 24 to 48 hours between treatments to remove the first drug from the patients' bloodstreams while minimizing the risk of flare. Only one patient out of the 61 in this study experienced flare within three days of discontinuing the tyrosine kinase inhibitor.

Reference

Chaft, J.E., Oxnard, G.R., Sima, C.S., Kris, M.G., Miller, V.A. and Riely, G.J. (2011). Disease Flare after Tyrosine Kinase Inhibitor Discontinuation in Patients with EGFR-Mutant Lung Cancer and Acquired Resistance to Erlotinib or Gefitinib: Implications for Clinical Trial Design. Clin. Cancer Res. 17(19), 6298-6303. doi: 10.1158/1078-0432.CCR-11-1468