Treating EGFR Exon 19 Deletions in NSCLC: Q&A With Benjamin P. Levy, MD

Benjamin P. Levy, MD

Benjamin P. Levy, MD

Activating mutations in epidermal growth factor receptor (EGFR) exon 19 are among the most commonly observed mutations in patients with non-small cell lung cancer (NSCLC). Abundant evidence points to a role for therapy with tyrosine kinase inhibitors (TKIs) in these patients, although it is not yet clear whether all TKIs will perform equally well in this setting, or whether one TKI could be recommended over another.^1-4

EGFRMutations in NSCLC: Key Findings

• Most patients with NSCLC who haveEGFRmutations have sensitizing exon 19 deletions (see Figure), or substitutions in exon 21 (eg,L858R).²
• Studies have shown that patients withEGFRexon 19 mutations have significantly longer survival and higher response rates to TKIs than those with other mutations, such as exon 21L858R.^2-4For example, in one retrospective study, patients withEGFRexon 19 mutations treated with gefitinib or erlotinib, had significantly longer survival versus those with exon 21L858Rmutation (34 months vs 8 months;P=.01).²
• Subanalysis from the LUX-Lung 3 and LUX-Lung 6 trials has shown a benefit in overall survival with afatinib over chemotherapy in the subgroup of patients with exon 19 deletions.¹
• The addition of an antiangiogenesis agent (bevacizumab) to erlotinib therapy in patients with activatingEGFRmutations improved progression-free survival (PFS) over erlotinib alone in a study from Japan; further confirmation of this combination therapy is warranted in a larger NSCLC population.⁵
• Third-generation TKIs (AZD9291; rociletinib) are becoming available for patients withT790Mmutations and may be useful for patients with exon 19 deletions whose disease progresses with first-line TKIs.^6,7

Figure. Immunohistochemical detection of EGFR exon 19 E746-A750 deletion.

Figure. Immunohistochemical detection of EGFR exon 19 E746-A750 deletion.

Benjamin P. Levy, MD, assistant professor at the Icahn School of Medicine, medical director of the Thoracic Oncology Program, Mount Sinai Health Systems, and associate director of the Cancer Clinical Trials Office at Mount Sinai Hospital in New York spoke withTargeted Oncologyabout the treating patients with exon 19 deletions.

Q:Why is it important to identify patients with NSCLC who haveEGFRexon 19 mutations?

A:We now have ample data that patients with advanced-stage NSCLC harboringEGFRmutations have dramatic responses to treatment with TKIs. Eight randomized studies have now demonstrated improvement in response rates and PFS for patients harboringEGFRmutations treated with TKI therapy versus chemotherapy, with some of these studies importantly demonstrating improvements in quality of life. In-frame deletions in exon 19 comprise approximately 50% of allEGFRmutations, and may represent a more sensitive molecular cohort than otherEGFRmutations. Thus, it is important to search and select these mutations in all patients with advanced-stage, nonsqaumous NSCLC so that TKI therapy can be delivered in a timely fashion.

Q:How might the treatment of these patients differ from that of patients with other NSCLC mutations (eg, exon 21L858R)?

A:A recent exploratory subset analysis of exon 19 patients from the LUX-Lung 3 and 6 trials demonstrated a survival advantage for those patients treated with afatinib versus chemotherapy.¹This trend was not demonstrated in the subset of patients with exon 21 mutations. Some have argued that, based on the improved outcomes demonstrated in the exon 19 population, afatinib should be the preferred TKI for this molecular cohort. However, this finding does not prove that the same trend would not be witnessed with either erlotinib or gefitinib. Several retrospective studies have suggested that exon 19 mutations may be more sensitive to TKIs than exon 21.^2,3In addition, a very nice meta-analysis recently published in theJournal of Clinical Oncologysuggests that the relative benefits of all TKIs (gefitinib, erlotinib, afatinib) compared to chemotherapy were greatest in patients whose tumors harbor exon 19 deletions.⁴The survival advantage demonstrated in the LUX-Lung studies remains intriguing. We are eagerly awaiting results for the LUX-Lung 7 study, which is comparing frontline gefitinib versus afatinib in patients who are EGFR positive who are treatment naïve and in the advanced stages of their disease. Given that EGFR exon 19 and 21 are most likely biologically distinct and behave differently, future studies will benefit from stratifying based on the subtype of EGFR mutations.

Q:What targeted therapies (eg, TKIs, antiangiogenesis agents) have been found to be effective in treating patients with EGFR exon 19 deletions?

A:Multiple efforts are under way evaluating strategies to optimize outcomes for patients who are EGFR positive, including patients with exon 19 deletions. A recent, small, Japanese study presented at the 2014 American Society of Clinical Oncology meeting, and now published, showed that the addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, to erlotinib dramatically improved PFS (16 months vs 9 months;P=.0015) when compared with erlotinib alone in patients harboringEGFR-positive tumors.⁵As with other studies, the PFS was more pronounced in the subset of patients with exon 19 mutations: 18 months in the combination arm versus 10.3 months in the erlotinib alone arm, reinforcing the concept that exon 19 mutations are exquisitely sensitive to TKI therapy, and potentially to VEGF inhibition. Because of these results, a larger US study is evaluating erlotinib with bevacizumab versus erlotinib alone, in patients who areEGFRpositive. Until the Japanese study is confirmed by the US study, I am not routinely offering my patients, who areEGFRpositive, bevacizumab outside of the clinical trial. In addition to antiangiogenic strategies, there are ongoing efforts evaluating the addition of checkpoint inhibitors (anti-programmed cell death-1 [PD-1] and its ligand, anti-PD-L1, drugs) in combination with TKI therapy, because preclinical work suggests thatEGFRsignaling upregulates PD-L1 expression. Results of these studies will hopefully be reported soon.

Q:What are some of the key adverse events to bear in mind when using these therapies in patients with NSCLC?

A:The most common adverse events to anticipate with both first-generation and second-generation TKIs are rash and diarrhea, [because] these can occur to some degree in most patients (60%-90%). Other less common side effects that have been reported and that I have seen in my clinic include paronychia, dry skin, fatigue, and ocular disorders (keratoconjunctivitis). Overall, I think these drugs are relatively safe and side effects can generally be managed with dose reductions and supportive care measures (eg, loperamide for diarrhea, clindamycin cream or doxycycline for rash).

Q:What therapies might be considered for patients withEGFRexon 19 mutations upon disease progression?

A:Despite improved outcomes with TKI therapy, all patients with advanced-stage NSCLC who harbor sensitizing mutations will inevitably develop disease progression. This is most commonly due to the development of a second-site mutation inEGFR, known asT790M, which accounts for up to 50% of acquired resistance. One of the most exciting advances for these patients has been the recent development of third-generation TKIs that target this resistant mutation. Two third-generation TKIs, AZD9291 and CO-1686 (rociletinib), were recently reported upon in theNew England Journal of Medicine, and demonstrated response rates of up to 60% and PFS of 9 to 13 months in patients harboringT790Mmutations who had progressed on a first-generation TKI.^6,7Some [people] would argue that with continual development of active agents in this molecular cohort, we will begin to treatEGFR-positive lung cancer more as a chronic disease rather than an aggressive malignancy.

References

1. Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.Lancet Oncol. 2015;16:141-151.

2. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib.Clin Cancer Res. 2006;12:839-844.

3. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib.Clin Cancer Res. 2006;12:3908-3914.

4. Lee CK, Wu YL, Ding PN, et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis [published online April 20, 2015].J Clin Oncol.pii: JCO.2014.58.1736.

5. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.Lancet Oncol.2014;15:1236-1244.

6. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer.N Engl J Med. 2015;372:1700-1709.

7. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.N Engl J Med.2015;372:1689-1699.