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Part 1. Gefitinib and Erlotinib for Non-Small Cell Lung Cancer (continued)
Adverse effects associated with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors and comparison treatments are described in Table 12. The most common adverse effects of EGFR-TK inhibitors are skin toxicity and diarrhea. The skin toxicity is predominantly rash and to a lesser extent acne, pruritus, and other dermatologic reactions. For gefitinib, toxicity was more common at the higher 500 mg daily dose. Approximately half to two-thirds of patients experienced rash, and about half had diarrhea with gefitinib 250 mg. Erlotinib toxicity was somewhat more common than gefitinib toxicity; however, estimates of erlotinib toxicity are based on the results of the single published phase II trial.31
For both drugs, less than 5 percent of toxicity was grade 3 or higher. Other consistently reported toxicity included hypertransaminasemia (2 percent to 12 percent) and an uncommon interstitial lung toxicity (< 1% percent). These toxicities compare favorably to those of traditional cytotoxic agents.
Predictors of Response
All reports on predictors of response or survival from EGFR-TK inhibitor clinical studies are shown in Table 13 and Table 14. Predictors of response to EGFR-TK inhibitors were distinguished from prognostic factors, which are associated with survival. The latter were not of primary interest for this report, as the prognostic factors reported in the examined studies have generally been known for decades and are not specific to EGFR-TK inhibitors. Response predictors considered were predictors of a higher likelihood of objective tumor response (in phase II and phase III studies) or identifiers of a subgroup with differential treatment effect (for phase III studies).
Clinical factors reported as being tested for association with either response or survival are shown in Table 13. Those characteristics that were initially identified as associated with a higher response rate in more than two studies included female sex and never smoking status. Studies examining the association between these factors and response are detailed in Table 15. For sex, there is a consistent association between female sex and a doubled likelihood of response. For smoking, the effect is less consistent between studies but is, on average, stronger than that observed for sex.
Two factors had more than one study reporting an association with response: age over 70 years and East Asian ethnicity. The associations with age were not consistent in direction with some studies finding older patients more likely to respond and some studies reporting younger patients having the higher response rate. East Asian ethnicity was associated with higher responses in 2 of 3 studies reporting on this factor; this finding is consistent with data showing a higher incidence of EGFR mutation in East Asian non-small cell lung cancer (NSCLC) patients.
Two other factors have received some attention in the literature: rash and performance status. However, for rash, the associations are weak and not statistically significant in the few studies reporting on the association. Performance status is an extremely important general prognostic factor, but did not have any consistent association with likelihood of tumor response among the seven studies reporting this association.
Tumor characteristics potentially predictive of response or survival are shown in Table 14. Adenocarcinoma histology and its subtypes of BAC and papillary type were associated with better response in about half of studies. Contrary to initial expectations of many of the investigators, the majority of studies examining EGFR expression did not associate EGFR expression with response. Also, no reproducible association was found between response and the related receptor TK; Her2/neu (erbB2), which forms heterodimers with EGFR; the activated form of EGFR (p-EGFR); or the activated downstream signaling molecules (p-Akt, p-Erk/p-MAPK, and p-STAT3).
In contrast, nineteen studies have found a strong positive association between presence of somatically acquired mutation of the active site of EGFR and response to gefitinib or erlotinib (Table 16). The biological plausibility of this association is strengthened by the finding of secondary mutations of EGFR in tumors from patients with secondary resistance to EGFR-TK inhibitors. Furthermore, the EGFR mutations occur preferentially in the demographic groups with highest response rates to EGFR-TK inhibitors, most notably non-smokers but also women and East Asians, as well as patients with adenocarcinoma histology. However, findings from the BR21 study of erlotinib (the only randomized trial to show an overall survival benefit from EFGR-TK inhibitors), showed no association of EGFR mutation and survival benefit.
Additional molecular predictors of response and survival benefit are being investigated including EGFR gene copy number. While KRAS mutations were associated with non-response in preliminary reports,36,37 few data are yet available to confirm this negative association with response.
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