Adjuvant Epidermal Growth Factor Receptor Inhibitors in Non-Small Cell Lung Cancer

Abstract

Nonrandomized studies have suggested a potential benefit with use of an EGFR tyrosine kinase inhibitor in the adjuvant setting in patients with EGFR-mutated non-small cell lung cancer. These nonrandomized studies cannot substitute for well-conducted, adequately powered, prospectively randomized phase III trials. Such trials are under way, and their results are eagerly anticipated.

The optimal initial treatment for patients with stage I–II non-small cell lung cancer (NSCLC) is surgical resection [1]. In the appropriate setting, patients with stage IIIA NSCLC may also be offered surgical resection following neoadjuvant chemotherapy with or without radiotherapy [2]. Adjuvant chemotherapy with a cisplatin-based regimen can be recommended for selected patients with stage IB disease with high-risk features as well as for patients with stages II–IIIA [3, 4]. Adjuvant chemotherapy improves the 5-year survival rate by approximately 4% [5]. Cisplatin may be combined with vinorelbine, vinblastine, etoposide, gemcitabine, pemetrexed, or docetaxel [6–8]. The LACE collaborative group’s analysis concluded that multiple different chemotherapy regimens with cisplatin are equally effective. Unfortunately, despite the advances in the management of stage I–III NSCLC, the 5-year survival of these patients still remains inferior compared with other early stage solid malignancies.

In the past decade, targeted therapy has transformed treatment for a subset of patients with advanced NSCLC harboring mutations or translocations that mediate sensitivity to targeted treatments. The best described of these are EGFR mutations and ALK or ROS1 translocations. EGFR inhibitors such as erlotinib, gefitinib, and afatinib target the tyrosine kinase domain of the EGFR receptor. Sensitizing EGFR mutations that predict response to these tyrosine kinase inhibitors (TKIs) include in-frame deletions in exon 19 and L858R substitution in exon 21 [9–11]. EGFR inhibitors have been shown to improve progression-free survival and response rates in patients with advanced stage NSCLC with sensitizing EGFR mutations in the first-line setting compared with platinum-based chemotherapy (hazard ratio [HR] 0.48 at 12 months) [12].

In general, we use our most active drugs in the adjuvant setting. Because EGFR and ALK inhibitors are more active than chemotherapy in patients with targetable mutations, it would be rational to test EGFR TKIs or ALK inhibitors in patients with resected tumors that harbor EGFR-activating mutations or ALK gene rearrangements, respectively. The possibility of targeted agents improving cure rates in the adjuvant setting is not without precedent. The use of trastuzumab in combination with chemotherapy in the adjuvant setting for early stage HER2 receptor-positive breast cancer with moderate to high risk of recurrence has improved both disease-free survival (DFS) and overall survival (OS; HR 0.63 for OS and 0.60 for DFS) [13]. Similarly, the use of imatinib in patients with completely resected gastrointestinal stromal tumors (GIST) significantly improved recurrence-free survival at 1 year compared with observation alone (HR 0.35) [14].

Rationale for Adjuvant TKIs

There are emerging clinical data evaluating EGFR TKIs in the adjuvant setting. The group at Memorial Sloan Kettering Cancer Center (MSKCC) analyzed patients treated at that institution with completely resected NSCLC that harbored EGFR mutations (exon 19 or 21). A total of 167 patients were included for analysis, with 70% of patients having stage I disease. Of these 167 patients, 56 had received either gefitinib or erlotinib pre- and/or postoperatively in a clinical trial or at the discretion of the treating oncologist. The remaining patients were considered the control population because their tumors harbored EGFR-activating mutations but they did not receive an EGFR TKI. The median time of treatment with erlotinib or gefitinib was 20 months. Patients treated with perioperative TKI therapy had a 2-year DFS rate of 89% compared with 72% for patients who did not receive the EGFR TKI (p = .06). OS also favored the group treated with the EGFR TKI (96% vs. 90%; p = .296). Although this study was not randomized, doses of the TKI were not standardized, and the patients receiving an adjuvant TKI tended to have more advanced stages; this study suggested that adjuvant TKIs may improve outcomes in patients with early stage NSCLC with EGFR-sensitizing mutations [15].

SELECT was a phase II multicenter single-arm study that evaluated 2 years of adjuvant erlotinib in patients with stage IA–IIIA NSCLC harboring an EGFR-activating mutation. Patients underwent surgery followed by chemotherapy, and some also received radiation. Overall, 100 patients were enrolled between January 2008 and May 2012, with 45% of patients with stage I, 27% with stage II, and 28% with stage IIIA. The median follow-up was 3 years, and two-thirds of patients received nearly 2 years of adjuvant erlotinib. The 2-year DFS was reported to be 90% for all patients. This compared favorably with the estimated 76% DFS control rate suggested by the data from MSKCC. Among the 24 patients that had disease recurrence, 22 recurred after discontinuation of erlotinib, with a median time to recurrence of 12 months. Repeated tumor biopsies at the time of disease recurrence were performed in 15 patients, with only 1 patient demonstrating T790M, a point mutation in the EGFR gene that is associated with resistance to the EGFR TKIs. Seventeen of the patients that recurred were retreated with erlotinib and demonstrated response to erlotinib [16].

The most robust randomized data to date come from the recent RADIANT trial, updated at the 2015 American Society of Clinical Oncology annual meeting. RADIANT was a phase III randomized placebo-controlled trial of adjuvant erlotinib versus placebo for patients with stages IB–IIIA who had EGFR-positive disease, defined as the presence of an EGFR mutation or EGFR positivity by immunohistochemistry or fluorescence in situ hybridization. In this study, 973 patients were enrolled, with 623 patients in the erlotinib arm and 350 patients in the placebo arm. Half of the patients had stage IB disease, 7% had stage IIA, 25% had stage IIB, and the remaining patients had stage IIIA. Approximately 50% of patients were treated with adjuvant chemotherapy. Patients were randomized in a 2:1 fashion to receive either erlotinib 150 mg daily or placebo for 2 years. There was no statistical difference in the DFS between the two groups after a median follow-up of 59.6 months. In the subgroup of patients with EGFR mutations, DFS with adjuvant erlotinib was 47.8 months compared with 28.5 months with placebo (HR 0.75, p = .1906). OS data are not mature. Although the study was negative when considering the entire patient population, the results in the cohort of patients with EGFR mutations suggest a DFS benefit with adjuvant erlotinib [17].

Collectively, the data from MSKCC and the SELECT and RADIANT trials suggest a possible DFS benefit of adjuvant EGFR TKIs in patients with EGFR mutation-positive NSCLC (Table 1); however, no substantial difference in OS has been reported. Furthermore, the NCI-BR19 trial, a placebo-controlled phase III randomized study evaluating adjuvant gefitinib 250 mg daily for 2 years in patients with completely resected stage IB–IIIA NSCLC also did not suggest a survival benefit with adjuvant gefitinib. This study enrolled 503 of 1,242 planned patients, although only 15 analyzed patients harbored an EGFR mutation. In this small subset of patients, the trend for OS favored placebo (HR 1.27) [18].

Table 1.

Evaluation of EGFR tyrosine kinase inhibitors in the adjuvant setting

The adjuvant studies evaluating EGFR TKIs included patients with EGFR-activating mutations, usually in exon 19 or 21. It is conceivable that an adjuvant EGFR TKI may have a differential impact depending on the specific mutation. In the advanced-stage setting, the LUX-Lung 3 and LUX-Lung 6 trials suggested a difference in outcome in patients with deletion 19 versus L858R EGFR mutations, with the former having a clinically significant improvement in OS with afatinib versus chemotherapy compared with the latter [19]. The next generation of adjuvant trials should consider these possible differences and should have adequately powered subgroup analyses looking at DFS and OS among different EGFR mutations.

Many questions regarding the possible impact of targeted agents in the adjuvant setting remain unaddressed. One such question concerns the optimal duration of follow-up of patients in these adjuvant studies, as 2-year follow-up might not be adequate to accurately estimate the impact of an adjuvant EGFR TKI on OS. A recent single-center retrospective analysis at a Chinese institution revealed that the median recurrence-free survival for patients with stage I NSCLC was 8.8 years [20]. In another cohort from MSKCC, most patients with early stage NSCLC (stages I–IIIA) recurred within the first 4 years [21]. In addition, the optimal duration of adjuvant targeted therapy is unknown.

From our experience in the metastatic setting, the therapeutic effects of TKIs are short lived because most patients progress within 12 months [22]. This suggests that 2-year duration of adjuvant TKIs may be adequate; however, because early stage NSCLC may recur up to 10 years after initial treatment [20], perhaps a prolonged duration of therapy may be justified, similar to hormonal therapy in ER-positive breast cancer. As has been shown in GIST tumors—another disease with well-defined activity of a targeted agent in the adjuvant setting—1 year of adjuvant imatinib is not enough, and 3 years of therapy may be better for both recurrence-free survival and OS [23]. Nonetheless, because most NSCLC patients are diagnosed in the seventh and eighth decades of life, the question is, how much more will adjuvant TKIs add to life expectancy while balancing long-term side effects and toxicity? Compliance with prolonged targeted therapy in the adjuvant setting may have its limits for some patients.

In the SELECT trial, most patients recurred after discontinuation of erlotinib. This result suggests that a longer duration of adjuvant therapy may prevent an earlier recurrence. It is known that tumors evolve over time and become more complex as constant genomic instability acquires more mutations over time [24]. In the curative setting, a delay in effective targeted therapy could potentially miss a window of opportunity because these tumors may no longer respond to TKIs at the time of progression; therefore, TKIs may be more effective for the patient in the adjuvant setting than the metastatic setting. A prolonged duration of adjuvant TKI may function to suppress tumor progression for as long as the patient remains on the drug, leading to improved DFS. It is unknown whether this improvement in DFS will necessarily translate into an improved OS. It is even possible that the use of TKIs in the adjuvant setting may lead to resistant tumors that are more aggressive at the time of relapse, leading to unchanged OS. In SELECT, most patients who recurred after discontinuation of a TKI maintained response with rechallenge [25]. Newer EGFR TKIs have been developed and are effective in T790M mutations; they are an option for patients with more resistant tumors, for example, those in the AURA3 trial with AZD9291 that is currently accruing [25].

Ongoing Studies

Ongoing studies are shown in Table 2. The National Cancer Institute is currently leading the ALCHEMIST trial, which aims to evaluate the role of erlotinib or crizotinib in the adjuvant setting for early stage nonsquamous NSCLC patients whose tumors harbor an EGFR mutation or ALK rearrangement, respectively [26]. In this three-step trial (Fig. 1), all patients with completely resected NSCLC will undergo testing for EML4-ALK translocations and EGFR TKI-sensitizing mutations. Patients whose disease is wild type for these driver mutations will be followed for 5 years as controls. Patients with activating EGFR mutations will be enrolled in the erlotinib treatment trial comparing erlotinib 150 mg twice daily for 2 years versus placebo following standard of care adjuvant chemotherapy and/or radiotherapy. Patients with ALK translocations will be randomized to receive crizotinib 250 mg twice daily for 2 years versus placebo in a similar fashion. Rebiopsies will be performed at recurrence if considered appropriate by the treating oncologist to confirm recurrence and to identify mechanisms of resistance. The primary endpoint of the study is OS, with accrual plans for 6,000–8,000 patients with a target of 430 patients in the EGFR treatment trial. All patients will be followed up long term after adjuvant treatment with targeted agents is completed. The ALCHEMIST trial, if successful, will hopefully answer the question of whether 2 years of adjuvant molecular targeted therapies is associated with an improvement in DFS and OS compared with observation.

Table 2.

Ongoing studies

Figure 1.

The ALCHEMIST study design (National Cancer Institute National Clinical Trials Network) [26].

Abbreviations: ALCHEMIST, Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials; NSCLC, non-small cell lung cancer.

Additional studies are ongoing in Asia to answer different questions regarding adjuvant EGFR TKI therapy. Such trials are evaluating the role of gefitinib versus chemotherapy (cisplatin plus vinorelbine) in patients with activating mutations. Another trial from the People’s Republic of China is evaluating icotinib versus observation after four cycles of adjuvant platinum-based chemotherapy or icotinib versus observation in a cohort of patients not receiving adjuvant chemotherapy.

In conclusion, nonrandomized studies have suggested a potential benefit with use of an EGFR TKI in the adjuvant setting in patients with EGFR-mutated NSCLC. These nonrandomized studies cannot substitute for well-conducted, adequately powered, prospectively randomized phase III trials. Such trials are under way, and their results are eagerly anticipated.

Author Contributions

Conception/Design: Shadia I. Jalal, Nasser Hanna

Collection and/or assembly of data: Laura S. Lourdes, Nasser Hanna

Data analysis and interpretation: Laura S. Lourdes, Shadia I. Jalal, Nasser Hanna

Manuscript writing: Laura S. Lourdes, Shadia I. Jalal, Nasser Hanna

Final approval of manuscript: Laura S. Lourdes, Shadia I. Jalal, Nasser Hanna

Disclosures

Nasser Hanna: Merck (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board