In this analysis of patients with acquired clinical resistance to EGFR TKI therapy, we observed a 23% flare rate during the EGFR TKI washout period, defined as hospitalization or death attributable to disease progression. After identifying the phenomenon of disease flare in a prior study(14
), we had attempted to minimize harm by abbreviating the standard washout periods of 21-28 days to 14 days in more recent trials. Despite this precaution, patients continued to experience flare after a median of only 8 days off TKI. Characteristics associated with development of flare included a shorter time to progression on initial TKI, preceding symptoms of disease progression, and presence of CNS and pleural disease. We recently reported that when acquired resistance is attributable to a T790M point mutation, disease may follow a more indolent course than clinical resistance without T790M(10
). However, in this study there was not a lower rate of disease flare in patients with T790M-mediated acquired resistance. We believe that the rate of rapid disease progression reported here is clinically significant and should alter the design of clinical trials in this patient population.
This analysis has the inherent limitations of a retrospective study, which prevented us from identifying a matched comparison group to study the prevalence of disease flare in the absence of TKI discontinuation. Attempts to model an internal comparison group by comparing the patterns of disease progression within the same patient before and after TKI discontinuation were hampered by incomplete data on some patients prior to enrollment. This cohort was relatively fit in that all patients had a KPS of ≥70%. Furthermore, the median time from acquired resistance to discontinuation of TKI was 6 months and the hospitalization rate in the 30 days before TKI washout was not significantly different between the patients who experienced a disease flare and those who did not; this supports a causal relationship between TKI discontinuation and disease flare rather than a more aggressive underlying biology in the patients who experienced a disease flare. Due to the high event rate and no discernable difference in groups during the period between development of acquired resistance and trial enrollment, we anticipate that these observations are likely to be replicated if evaluated prospectively, although we do not advocate this as it may lead to an unacceptable risk to patients.
When acquired resistance occurs in oncogene-driven cancers with kinase activation, kinase activation persists or increases despite continued treatment with a kinase inhibitor. However, not every cell is resistant, as demonstrated in gastrointestinal stromal tumors where the resistant and clones can be visualized in a “matrix” of sensitive cells(18
). If imatinib is stopped in these patients, growth is accelerated in the sensitive clone resulting in rapid and symptomatic progression that is associated with a PET flare(19
). We believe the same mechanism occurs in EGFR
-mutant lung cancers that have developed acquired resistance to erlotinib or gefitinib(20
Based on preclinical studies that show EGFR
-mutant cells made resistant to gefitinib can become sensitive once again by successive passages in the absence of the TKI(21
) and clinical observations that after a period of TKI discontinuation patients can respond again to re-institution of the same agents(14
), some have suggested withdrawal and retreatment with the same TKI after a “drug holiday” as a strategy to counter acquired resistance. Our data suggest that this approach is not suitable for all patients and that drug holidays can lead to more rapid tumor growth. A more appropriate approach would be to immediately substitute another therapeutic agent or add a new agent to the TKI.
As we believe that oncogene-addiction persists after the development of acquired resistance, clinical trials to investigate alternative treatment strategies are essential. The data presented here suggest that the usual trial-mandated EGFR TKI washout period in this patient population may be associated with an unacceptably high risk of more rapid disease progression prior to initiation of experimental agents. Mandated drug washout periods are designed to prevent interactions between drugs but are often broadly written to include all anti-neoplastic drugs. In early phase studies evaluating the safety and efficacy of erlotinib, the half-life (t1/2
) was determined to be 8 hours(22
). Therefore, in patients with normal hepatic function, a 24-48 hour washout period should be sufficient for drug clearance and will minimize the risk of significant disease flare. Only 1 of 14 patients in the flare group experienced the flare in 3 or fewer days after TKI discontinuation.
Oncogene addiction is a phenomenon recognized in many malignancies. Targeting the downstream effects (especially kinase activation) of these driver-mutations has been a successful strategy in chronic myelogenous leukemia, gastrointestinal stromal tumors, BRAF
-mutant melanoma, and ALK
-rearranged and EGFR
-mutated lung cancer with dramatic and often durable responses(23
). Gastrointestinal stromal tumors have a unique biology with rapid disease progression when the kinase inhibitor imatinib is removed after prolonged benefit(27
). This series describes a similar flare phenomenon in the setting of acquired resistance in EGFR
-mutant lung cancer when gefitinib or erlotinib are stopped because of radiographic disease progression and we anticipate that similar observations will be made in other oncogene driven malignancies treated with targeted inhibitors. As we investigate better treatments for patients with tumors that have developed acquired resistance to gefitinib and erlotinib, clinical trials should abbreviate trial mandated washout periods to minimize the risk of disease flare upon TKI discontinuation in patients with EGFR
-mutant lung cancer.