Novel Agents in the
Treatment of Lung Cancer
New Approaches to First-Line Therapies
Using EGFR Mutations to Select Patients for First-line EGFR TKI Therapy (Erlotinib, Gefitinib)
Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have had a major influence on the treatment of NSCLC over the last decade. The 2 agents most widely used around the world, commonly known as "first-generation" EGFR TKIs, are gefitinib and erlotinib. Both of these compounds were initially shown to have modest single-agent activity in unselected NSCLC patients, and from early in their development it was clear that certain patient clinical characteristics (adenocarcinoma, non-smoking history, Asian ethnicity, female gender) predicted for good response to therapy.38-40 Large, randomized studies have since shown EGFR TKIs to be either superior to placebo in the second- and third-line setting (erlotinib), or noninferior to docetaxel chemotherapy in the second-line setting (gefitinib).29,41 Hence, the standard use of these drugs in the general NSCLC population is currently as a salvage therapy (second-line or higher). A more recent paradigm, and a potentially more elegant way to use these agents, is in the front-line setting for a genetically selected group of patients who are identified by biomarker analysis to have a higher likelihood of benefitting from EGFR inhibition.
EGFR Mutations
The most robust biomarker for EGFR TKI therapy selection is somatic mutation in the EGFR gene. A collection of activating mutations in the TK domain of EGFR were initially discovered in 2004 by studying tumor samples from the small but consistent minority of patients treated with these agents who displayed dramatic and sustained responses to therapy.42-44 Activating EGFR mutations primarily consist of overlapping deletions in the LREA region of exon 19 or the point substitution mutation L858R in exon 21, although there are several other rare activating mutations described in the literature.45 EGFR mutations, as might be predicted, are identified most frequently in patients with known clinical markers of TKI response, typically never-smoking patients with adenocarcinoma, and more commonly in Asian patients than North American patients. These mutations confer a state of "oncogene addiction" to the molecular biology of the tumor, such that the critical downstream signaling pathways are solely controlled by EGFR and are therefore highly susceptible to cell death by EGFR blockade.46,47 In a series of phase II studies, several groups, including my own, have examined the utility of first-line EGFR TKIs in patients known to have EGFR mutations.48,51 These trials have consistently demonstrated that EGFR TKIs yield a very high response rate (typically 75%) and a prolonged progression-free survival (PFS; usually 9 months) in a biomarker-selected cohort with EGFR mutations. The strategy of identifying patients with EGFR mutations and steering them to first-line targeted therapy has become a standard of care in 2009 with the report of 2 randomized trials.
IPASS Trial
The larger randomized trial examining this question is the IPASS study, which included 1217 patients with newly diagnosed advanced-stage adenocarcinoma.10 All patients were non-smokers or former light smokers (quit at least 15 years prior and ≤ 10 pack-years history), and all were Asian. Patients were randomly assigned to first-line gefitinib or chemotherapy with carboplatin and paclitaxel. The study utilized a noninferiority design powered to demonstrate that the 95% confidence interval (CI) for the hazard ratio (HR) for PFS of gefitinib compared to chemotherapy lay entirely below the target of 1.2. The overall PFS HR was 0.74 (95% CI, 0.65-0.85), showing that gefitinib was not only noninferior, but was actually superior to chemotherapy. Even more illustrative was the molecular subgroup analysis. EGFR mutation status was available for 36% of patients, and the mutation-positive rate was 60% in this clinically enriched study. For mutation-positive patients the results favored gefitinib even more strongly, with a PFS HR of 0.48 (95% CI, 0.36-0.64). Conversely, for mutation-negative patients chemotherapy was a better treatment, with a PFS HR of 2.95 (95% CI, 2.05-3.98). In other words, for patients known to harbor an EGFR mutation, front-line gefitinib was more effective than carboplatin and paclitaxel with regards to PFS. For patients who fit the "clinical phenotype" of a TKI-responder, however, the genotype trumped the phenotype and first-line TKI therapy did not produce a good outcome. This landmark study argues that patients with a moderate chance of harboring an EGFR mutation should undergo molecular testing at the time of diagnosis, and if an EGFR mutation is identified, front-line therapy with an EGFR TKI should be strongly considered.
Benefits in PFS, Toxicity Profile, and QoL
Of note, the overall survival HR for the EGFR mutation-positive patients in IPASS was 0.78 (95% CI, 0.50-1.20), although this analysis is premature with few overall deaths at the time of analysis. While the final survival analysis is anxiously awaited, we know mutation-positive patients treated with second-line EGFR TKIs also can achieve a good response and prolonged PFS. Consequently, an overall survival benefit may not ultimately be found since a large number of patients randomized to chemotherapy on IPASS received second-line gefitinib or erlotinib. Why is it necessary to determine the EGFR mutation status prior to front-line therapy if no survival benefit is ultimately found? The answer may be found in the adverse event profile and the quality-of-life (QoL) analysis from IPASS. The grade 3 or 4 toxicity rate on chemotherapy was 61% compared to 29% on gefitinib, and a greater proportion of patients on gefitinib had an improvement in QoL than on chemotherapy (odds ratio 1.34; 95% CI, 1.06-1.69). Thus, patients with a known EGFR mutation gain benefit in terms of PFS, toxicity profile, and QoL from first-line EGFR TKIs. In patients for whom mutation status is unknown, chemotherapy should be the preferred front-line option, given the poor performance of first-line TKIs in EGFR wild-type patients and the availability of these agents in the second-line setting.
Second Study – Asian Patients
The other recent randomized trial regarding a genotype-directed treatment strategy was published in abstract form only thus far and is a smaller study. However, all patients enrolled were positive for an EGFR mutation, so the molecular results are not a subgroup analysis but represent the entire study cohort.52 This trial consisted of Japanese patients with newly diagnosed advanced adenocarcinoma having EGFR mutations who were randomized to first-line gefitinib or chemotherapy with carboplatin and paclitaxel. The primary end point was also PFS, and the study was powered for 320 patients with an anticipated HR of 0.69, favoring gefitinib. An interim analysis after 200 patients were treated demonstrated a benefit for gefitinib, with an HR of 0.36 (95% CI, 0.25-0.51).
Conclusion
Patients known to have EGFR mutations at the time of diagnosis with advanced NSCLC gain a significant PFS benefit from first-line therapy with gefitinib compared to carboplatin and paclitaxel chemotherapy. Other ongoing randomized trials are confirming that this strategy translates to non-Asian patients as well as other TKIs and chemotherapeutics. As the treatment paradigm for NSCLC is changing, biomarkers are helping us to make personalized therapy for patients a reality.
Discussion
Dr. Hanna: For never-smokers, we know we should be checking EGFR mutation status and ALK. But for the more typical patient who has an adenocarcinoma and a substantial smoking history, is it valuable to check EGFR mutation status routinely, especially if there isn't adequate tissue and therefore may necessitate a second biopsy?
Dr. Sequist: I make more effort to test patients who have a history of less than 30-pack-years. The rate of EGFR mutations drops off significantly after 30-pack-years.
Dr. Goss: Do the Harvard investigators believe there is a group of wild-type patients that benefit from EGFR TKI therapy?
Dr. Sequist: I would not withhold TKI therapy from a patient's sequence of treatments if they are EGFR wild-type. But I wouldn't use EGFR TKIs in first-line, or even second-line, knowing they were wild-type; I would give it third-line or beyond.
Dr. Fidias: If you know someone is EGFR wild-type, you just don't use single-agent erlotinib up front.
Dr. Lynch: In a recent conversation with investigators at Memorial Sloan-Kettering, their perspective is that the rate of EGFR mutation is the same whether the patient is a smoker or non-smoker. The difference is that if they're a smoker, other types of cancer dilute out the effect of the mutations. That's why they screen all their adenocarcinomas for EGFR mutations, recognizing that less than 1% of smokers with lung cancers will have a mutation. In Japan, the overall numbers are higher, so perhaps 5% of the smokers they see will have a mutation.
Dr. Goss: It's unlikely that smoking will cause you to lose a mutation. So, smokers may have mutations, but they have other drivers of their cancers as well.