- A recent retrospective study of an NSCLC cohort suggests that the presence of the EML4-ALK fusion oncogene defines a subset of NSCLC tumors with unique clinical features, that are less likely to respond to EGFR-targeted therapy.
- Similar to patients with EGFR mutations, patients with the EML4-ALK genotype were more likely to be never/light smokers and to have a more advanced disease stage compared to patients with a wild-type genotype of either EGFR or ALK (WT/WT).
- Factors uniquely associated with the EML4-ALK genotype, compared to the EGFR-mutated or WT/WT genotypes, include younger age and male sex.
- The presence of EML4-ALK predicted a lack of response to EGFR-targeted tyrosine kinase inhibitors, highlighting the critical importance of EGFR mutation testing before beginning EGFR TKI therapy.
PLEASE NOTE: Each article is selected by faculty on the scientific merits of the new data. It is one part of a bundled series of articles that, as a group, provide a full and balanced perspective.
Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) have proven particularly beneficial in treating a subset of patients with advanced nonâsmall-cell lung cancer (NSCLC) whose tumors harbor activating mutations in EGFR. The EML4-ALK fusion oncogene is another potential target in NSCLC. EML4-ALK arises from rearrangements of the echinoderm microtubule-associated protein-like 4 (ELK4) gene and the anaplastic lymphoma kinase (ALK) gene. It results in the expression of a chimeric tyrosine kinase with oncogenic activity that can be blocked by a TKI targeting ALK. Previous small studies in unselected populations have reported a low frequency of the EML4-ALK oncogene in patients with NSCLC (1% â 6.7%). To learn more about the subset of patients with EML4-ALK, a recent study examined clinical features and outcomes in patients with NSCLC, either with or without EML4-ALK.
Tumor samples were analyzed from 141 NSCLC patients who were selected for having two or more of the following characteristics: female sex, Asian ethnicity, never/light smoker (<100 cigarettes lifetime/â¤10 pack years), and adenocarcinoma histology. This screening method, based on characteristics associated with EGFR mutations, allowed the authors to focus on never/light smokers and to compare patients with either EML4-ALK or EGFR mutations in the same group. The majority of patients had metastatic disease (68% stage IV), were female (66%), were never/light smokers (60%), had non-Asian ethnicity (94%), and had adenocarcinoma or bronchioloalveolar carcinoma (BAC) histology (92%).
The EML4-ALK rearrangement was observed in 19 tumors (13% of patients) and EGFR mutations were observed in 31 (22%). No tumors with EML4-ALK had EGFR mutations, and no tumors with EGFR mutations had the EML4-ALK rearrangement. The remaining 91 tumors (65%) were wild-type for both ALK and EGFR (WT/WT). Patients with EML4-ALK were significantly younger (median age = 52 years) than those with EGFR mutations (66 years) (P <.001) or WT/WT genotypes (64 years) (P = .005).
Figure 1. Clinical features associated with the presence of the EML4-ALK rearrangement genotype compared to EGFR mutation or WT/WT genotypes.
EML4-ALK was also significantly associated with male sex (58%), relative to mutant EGFR (26%) (P = .036) and WT/WT (32%) (P = .039) genotypes. Like EGFR mutations, EML4-ALK was significantly more common in patients who were never/light smokers: 74% of patients with EML4-ALK were never smokers versus 26% for WT/WT (P <.001); and 100% of EML4-ALK patients were never/light smokers versus 42% for WT/WT (P <.001). There was also a trend toward more advanced disease stage associated with EML4-ALK: 89% of patients had stage IV disease, compared with 58% for WT/WT (P = .051).
In addition, there were histological differences between EML4-ALK tumors and EGFR mutant or WT/WT tumors. While there were no significant differences in the percentage of patients with adenocarcinoma or BAC among the three groups, EML4-ALK tumors were more likely than EGFR mutant tumors or WT/WT tumors to have abundant (â¥10% of cells) signet ring cells.
None of the 10 evaluable patients with EML4-ALK tumors and metastatic disease who received EGFR TKI therapy (erlotinib) had a clinical response. The response rate for patients with EGFR mutations was 70%, significantly higher than for EML4-ALK (P <.001) or for WT/WT (13%, P <.001).
Figure 2. Response rates to platinum-based chemotherapy or EGFR TKI therapy for patients with EML4-ALK-positive, EGFR mutation-positive, or WT/WT tumors.
The response rate to a platinum-based chemotherapy regimen (carboplatin or cisplatin in combination with standard chemotherapy with or without an angiogenesis inhibitor, such as bevacizumab) was also examined. In the 12 evaluable patients with EML4-ALK and metastatic disease who received platinum-based chemotherapy, 3 (25%) had a response, which was not significantly different from the response rate for WT/WT patients (35%) (P = .723) or patients with EGFR mutations (50%) (P = .356).
Time to progression (TTP) and overall survival (OS) were also analyzed. TTP for EML4-ALK-positive patients on an EGFR TKI was 5 months, which was not significantly different from WT/WT patients (6 months) (P = .337), but was significantly lower than that observed in patients with an EGFR mutation (16 months) (P = .004). All three genotypes had similar TTP on platinum-based chemotherapy (8â10 months). The OS for EML4-ALK-positive patients was 20 months, shorter than that observed in patients with an EGFR mutation (32 months) and longer than that seen in patients with WT/WT genotype (16 months), although the differences were not significant (P = .468 and .152, respectively).
This study represents the largest series of NSCLC patients with EML4-ALK to date. Among 141 patients screened using a procedure designed to enrich the cohort with patients with activating EGFR mutations, 13% had the EML4-ALK rearrangement, higher than previously reported for unselected patients. The frequency of patients with EML4-ALK was higher still (22%) among never/light smokers, and among never/light smokers without EGFR mutations (33%). Like EGFR mutations, EML4-ALK was associated with never/light smoking history and more advanced disease stage. Unique features associated more strongly with EML4-ALK tumors than EGFR mutant or WT/WT tumors were younger age, male sex, and the presence of abundant signet ring cells. In terms of response to therapy, EML4-ALK tumors were more similar to WT/WT tumors than to EGFR-mutated tumors. EML4-ALK tumors were resistant to EGFR TKIs, with significantly lower response rates and faster TTP compared to tumors with EGFR mutations. EML4-ALK tumors also did not show the higher response rates to platinum-based chemotherapy compared to WT/WT tumors that had been previously reported for tumors with EGFR mutations.
The authors of this study conclude that EML4-ALK-positive NSCLC constitutes a new subset with unique clinical and pathologic features. Because some of the clinical features associated with EML4-ALK overlap with those associated with EGFR mutations, while the outcomes on EGFR TKIs are markedly different, they stress the importance of EGFR mutation testing before initiating EGFR TKI therapy. They also suggest that ALK-targeted TKIs currently under investigation may someday benefit patients with EML4-ALK-positive NSCLC.
Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253.