Introduction

More than 50% of patients with early-stage (I–III) non–small cell lung cancer (NSCLC) relapse within 5 years of surgical resection. For patients with resectable stages II–IIIA disease at time of diagnosis, standard of care after surgery is 4 cycles of platinum-doublet chemotherapy. Chemotherapy also may be considered in those patients with stage IB disease with high-risk features, such as poorly differentiated tumors, size greater than 4 cm, unknown lymph nodes status, vascular invasion, wedge resection, and visceral pleural involvement. The overall benefit from chemotherapy, however, remains modest. In 2008, the Lung Adjuvant Cisplatin Evaluation group performed a pooled analysis of individual patient data from the largest cisplatin-based adjuvant trials performed since 1995, including 5 trials, with a total of 4584 patients. The primary endpoint was overall survival. There was a statistically significant reduction in mortality of 5.4% at 5 years in patients who received chemotherapy compared with those who did not (hazard ratio [HR] = 0.89; 95% CI, 0.82–0.96; P = .005). This benefit was seen across all stages (IB, IIA, and IIB) with the exception of IA, although increased benefit was seen in those with higher stages of disease. In addition, the benefit from chemotherapy was the greatest in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and seemed to be detrimental to those patients with PS of 2. PS was not available, however, for all trials included in the analysis. A follow-up meta-analysis in 2010 confirmed the benefits of adjuvant chemotherapy after evaluating 34 trials and 8447 patients and showing an increase in overall survival by 4% at 5 years with the addition of adjuvant chemotherapy. Therefore, all patients with resected stages IB–IIIA disease should be referred to a medical oncologist for discussion of adjuvant chemotherapy.

Adjuvant Versus Neoadjuvant Chemotherapy

A meta-analysis published in 2009 compared the impact of timing of chemotherapy in patients with resectable lung cancer. They looked at 32 randomized trials, including 22 trials of adjuvant therapy and 10 trials of neoadjuvant therapy, and compared pooled HRs for death. The HR for overall survival was 0.80 (0.74–0.87; P <.001) in postoperative chemotherapy and 0.81 (0.68–0.97; P = .024) in preoperative chemotherapy. The secondary outcome, disease-free survival (DFS), was compared between 15 postoperative and 7 preoperative chemotherapy trials and similarly did not show a difference between the 2 groups. The pooled HR for recurrence or death was 0.76 (0.68–0.85; P <.001) in postoperative chemotherapy and 0.80 (0.66–0.92; P = .021) in preoperative chemotherapy. Overall, the results demonstrate that there is no difference in DFS or overall survival between patients with operable lung cancer who receive postoperative versus preoperative chemotherapy. At this time, with current chemotherapy options, adjuvant chemotherapy is preferable to neoadjuvant for patients who are surgically resectable at time of diagnosis in order to prevent delays in potentially curative surgical therapy.

Postoperative Complications

Many of the adjuvant chemotherapy trials excluded patients with severe postoperative complications and mandated chemotherapy initiation within 6 weeks to 9 weeks after surgery. ^, For patients with surgical complications who have a prolonged recovery period, however, the question of whether to give adjuvant chemotherapy outside the accepted window arises. Although this has not been evaluated in a randomized setting, real-world data from a retrospective analysis of 12,473 patients from the National Cancer Database suggest that these patients still benefit from chemotherapy. The study included patients with tumors greater than 4 cm, lymph node involvement, or local extension. The lowest mortality was observed in patients in whom chemotherapy was started within 50 days of resection. Approximately 30% of patients, however, received chemotherapy outside the accepted window (57–127 days postoperative) yet still had a survival benefit over patients who received surgery alone. Therefore, patients with a complicated postoperative course and prolonged recovery still may benefit from adjuvant chemotherapy up to 4 months after surgery.

Choice of Chemotherapy

Acceptable choices for chemotherapy include a platinum backbone (generally cisplatin) with vinorelbine, pemetrexed, gemcitabine, or docetaxel. In patients with metastatic NSCLC, comparison of cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel in a randomized study of 1207 patients with advanced NSCLC (stages IIIB–IV) failed to show a difference in survival between the 4 arms. In the adjuvant setting, ECOG E1505 study also did not show a difference in outcome between chemotherapy doublets, although patients were not randomized to chemotherapy arm and the chemotherapy doublet utilized was not the primary question. In this study, 1500 patients were randomized to chemotherapy plus bevacizumab versus chemotherapy alone. The chemotherapy regimen was investigator’s choice and included cisplatin paired with gemcitabine, pemetrexed, vinorelbine, or docetaxel. Although the study was not powered to compare the chemotherapy regimens, a subset analysis showed similar efficacy between platinum doublets in the chemotherapy arm.

Pemetrexed, a folate analog, was developed later than the taxanes gemcitabine and vinorelbine but quickly was adopted into practice for nonsquamous NSCLC given its favorable toxicity profile. In the metastatic setting, a randomized phase III study of cisplatin/gemcitabine versus cisplatin/pemetrexed showed that overall survival was superior for pemetrexed in the nonsquamous arm (12.6 months vs 10.9 months) and that it is better tolerated than gemcitabine. Pemetrexed is not approved for patients with squamous histology, however, because overall survival was inferior to cisplatin/gemcitabine. Given the tolerability profile and early data from the phase II TREAT study, cisplatin/pemetrexed has been widely adopted in the adjuvant setting and was in fact the regimen used in the largest number of patients on E1505 despite that it was limited to patients with nonsquamous histology and was added to the trial only after enrollment had been ongoing for 2 years. More recently, the Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous Non-Small-Cell Lung Cancer (JIPANG) study gave us clear randomized phase III data to support the use of cisplatin/pemetrexed in the adjuvant setting. JIPANG was a phase III study of cisplatin/pemetrexed compared with cisplatin/vinorelbine for resected, stages II–IIIA, nonsquamous lung cancer. The study enrolled 804 patients and at a follow-up of 45 months there was no significant difference between the 2 treatment arms with a median recurrence free survival of 38.9 months in the cisplatin/pemetrexed cohort and 37.3 months in the cisplatin/vinorelbine cohort (HR 0.98; 95% CI, 0.81–1.2; P = .948). Overall survival was also similar between the 2 arms (83.5% cisplatin/pemetrexed vs 87.2% cisplatin/vinorelbine). Similar to prior studies, however, they also found that cisplatin/pemetrexed was less toxic and better tolerated than cisplatin/vinorelbine.

Although cisplatin is the preferred platinum agent in the adjuvant setting, its toxicity profile precludes use in many patients. Nephrotoxicity and ototoxicity top the list of adverse events, and it must be used cautiously in elderly patients and those with significant comorbidities. Due to these toxicities, carboplatin, which is mechanistically similar to cisplatin but generally better tolerated, often is substituted for cisplatin in frail or elderly patients. A Cochrane review examined the evidence from randomized clinical trials comparing carboplatin with cisplatin plus a partner drug in patients with advanced NSCLC. They included 10 trials with 5017 patients and found that there was no difference in overall survival between those patients who received carboplatin and those who received cisplatin (HR 1.0; 95% CI, 0.51–1.97). Few prospective trials, however, utilized carboplatin and caution must be taken in using carboplatin given a potential detriment in efficacy. Thus, although carboplatin is a reasonable substitution for patients unable to tolerate cisplatin-based chemotherapy, it should not be used routinely in those who can tolerate cisplatin.

Chemotherapy Combinations

Attempts to improve outcomes in early-stage patients treated with adjuvant chemotherapy led to trials adding targeted agents to chemotherapy. The E1505 examined the impact of bevacizumab, an anti–vascular endothelial growth factor (VEGF) agent on overall survival in patients with resected stages IB (>4 cm) to IIIA NSCLC. Patients were randomized to 4 cycles of chemotherapy alone (investigators choice—cisplatin plus vinorelbine, docetaxel, gemcitabine, or pemetrexed) or chemotherapy plus 1 year of bevacizumab. At a follow-up of 50 months, there was no difference in DFS (HR 0.98; P = .75) or overall survival (HR 0.99; P = .90). Therefore, bevacizumab is not given in the adjuvant setting.

Patient Selection

Improving patient selection remains an important goal of ongoing chemotherapy trials, because not all patients need adjuvant chemotherapy, yet the ability to select for those who will benefit remains difficult. ERCC1, a protein involved in DNA repair pathways, was examined retrospectively in a cohort of patients enrolled in the International Adjuvant Lung Cancer Trial. They found that expression of this protein was associated with shorter survival and lack of benefit to adjuvant chemotherapy compared with ERCC1-negative tumors. This was followed by a randomized phase II trial that enrolled 150 patients with resected NSCLC tumors and randomized patients to standard-of-care chemotherapy versus customized treatment based on ERCC1 levels (ie those ERCC1-negative patients received chemotherapy and positive patients went on observation). This trial had to be stopped, however, due to the unreliability of the ERCC1 stain, which also invalidated the earlier observations and stopped use of ERCC1 as a reliable biomarker. Other potential biomarkers for chemotherapy selection include BRCA1, RAP80, and ABRX. In the Study of Customized Adjuvant Chemotherapy (SCAT) trial, patients were assigned to 1 of 3 adjuvant chemotherapy arms based on expression of BRCA1; patients with low expression received cisplatin/gemcitabine, with intermediate expression received cisplatin/docetaxel, and with high expression received docetaxel alone. At a follow-up of 5 years, there were similar DFS and overall survival rates between the cohorts. To date, no biomarkers have been validated for patient selection of adjuvant chemotherapy.

Circulating tumor DNA (ctDNA) identification of minimal residual disease (MRD) has emerged as a potential tool to improve patient selection. A retrospective study of 40 patients with localized lung cancer found that those patients with detectable ctDNA MRD after curative therapy were highly likely to recur (freedom from progression at 36 months: 93% in patients with undetectable ctDNA MRD and 0% in patients with detectable ctDNA). ctDNA is still under investigation, and there are several ongoing trials using MRD to either select patients for adjuvant chemotherapy or provide escalated treatment to those patients with MRD after completion of standard adjuvant therapy.

Vaccine Trials

The MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell Lung Cancer Immunotherapy) trial was a randomized, double-blind, placebo-controlled, phase II study of MAGE-A3 (melanoma associated antigen 3) vaccine in patients with resected stages IB, II or IIIA NSCLC whose tumors expressed MAGE-A3; 2312 patients were enrolled in the study and randomized 2:1 to 13 injections of the MAGE-A3 vaccine versus placebo. Patients were allowed to have received adjuvant chemotherapy but it was not mandated. There were 3 coprimary endpoints: DFS in all-comers, DFS in the no-chemotherapy group, and DFS in patients stratified by potentially predictive gene signature. In all patients, the DFS was 60.5 months in the MAGE-A3 arm and 57.9 in the placebo group (HR 1.02; 95% CI, 0.89–1.18; P = .74). Similarly, in the no-chemotherapy arm, DFS was 58 months in the MAGE-A3 group compared with 56.9 in the placebo group (HR 0.97; 95% CI, 0.80–1.18; P = .76). Given the negative study, no other trials have been conducted with this compound. Other therapeutic vaccine trials in NSCLC have largely been conducted in patients with unresectable stages IIIB–IV disease.

Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor in Unselected Patients

Early studies looking at adjuvant epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) were performed in an unselected patient population. Gefinitib was examined in the cooperative group BR19 study in stage IB, II, or IIIA patients after surgical resection and adjuvant chemotherapy; 503 patients were enrolled and randomized to gefitinib versus placebo for 2 years. The study closed early, however, after a median of 4.7 years of follow-up after an interim analysis failed to show a difference in DFS or overall survival. Exploratory analysis of the patients with EGFR mutation–positive tumors (N = 15 [4%]) also did not show a benefit in DFS (HR 1.84; 95% CI, 0.44–7.73; P = .395) or overall survival (HR 3.16; 95% CI, 0.61–16.45; P = .15) although this was a small subset (15 patients) of the overall cohort.

Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors in Selected Patients

After trials of EGFR-TKIs in unselected patients failed to show a benefit, additional studies selecting patients for EGFR mutation or overexpression were developed as the understanding of EGFR biology improved. The RADIANT trial was a randomized, double-blind phase III trial of erlotinib versus placebo for 2 years after resection of stages IB–IIIA NSCLC. Patients were included if their tumor expressed EGFR protein by immunohistochemistry or amplification by fluorescence in situ hybridization. A total of 973 patients were enrolled. Similar to the trials in an unselected cohort of patients, this trial failed to show a difference in DFS (median 50.5 months for erlotinib and 48.2 months for placebo; P = .324) or overall survival (HR 1.13; 95% CI, 0.881–1.448; P = .3350). There was a subgroup of patients, however, with L858R and exon 19 deletion EGFR-mutant tumors (n = 161); 102 were assigned to erlotinib and 59 to placebo. In this subgroup, there was a trend toward improvement in DFS but due to hierarchical testing this difference was not statistically significant (DFS 28.5 months in placebo vs 48.2 months in erlotinib arm; HR 0.61; 95% CI, 0.384–0.981).

A nonrandomized phase II trial of adjuvant erlotinib (SELECT trial) in patients with resected stages IA to IIIA EGFR-mutant NSCLC also was conducted and reported. A total of 100 patients were enrolled and treated with erlotinib daily for 2 years after standard adjuvant chemotherapy. The data are still immature but the 5-year DFS was recently reported out at 56% (95% CI, 45%–66%) and 5-year overall survival was 86% (95% CI, 77%–92%).

The largest phase III trial of adjuvant EGFR-TKI to date in a selected patient population was the ADJUVANT/CTONG1104 study. As opposed to the other trials that randomized or treated patients with EGFR-TKI after completion of adjuvant chemotherapy, this multi-institutional, randomized, phase III study in China randomized patients to adjuvant gefitinib or chemotherapy. In this study, 222 patients with exon 19 deletion or exon 21 L858R EGFR mutated stages II–IIIA lung adenocarcinoma were enrolled and randomized 1:1 to gefitinib for 2 years or 4 cycles of vinorelbine/cisplatin after surgical resection. Median DFS was 28.7 months in the gefitinib arm compared with 18 months in the chemotherapy arm (HR 0.60; 95% CI, 0.42–0.87; P = .0054). Survival data are not yet available and, therefore, it is not clear whether adjuvant gefitinib given for 2 years simply delays disease recurrence without improving the overall cure rate.

Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor in the Neoadjuvant and Adjuvant Setting

A multicenter, randomized, open-label, phase II study of erlotinib versus chemotherapy as both neoadjuvant and adjuvant treatment in China was recently reported; 72 patients with EGFR mutations in either exon 19 or exon 21 were randomized 1:1 to receive erlotinib for 42 days prior to surgery and up to 12 months postoperatively or cisplatin/gemcitabine for 2 cycles prior to surgery and 2 cycles postoperatively. The primary endpoint was objective response rate. The study did not meet its primary endpoint (overall response rate 54.1 vs 34.3%; odds ratio 2.26; 95% CI, 0.87–5.84; P = .092). The secondary endpoint of progression-free survival was noted to be better for the erlotinib arm compared with the chemotherapy arm (21.5 months vs 11.4 months; HR 0.39; 95% CI, 0.23–0.67; P <.001); however, there was no difference in overall survival (45.8 vs 39.2 months; HR 0.77; 95% CI, 0.41–1.45; P = .417). Although this study was small and did not meet its primary endpoint, there are several, larger ongoing randomized trials examining EGFR therapies in the adjuvant setting (discussed later).

Ongoing Targeted Adjuvant Studies

With the promising data from the targeted adjuvant studies in NSCLC, several large randomized trials have opened in selected patient populations. Icotinib, an EGFR-targeted agent, is being examined in several adjuvant studies. The EVIDENCE trial ( NCT02448797 ) is a randomized, phase III study in China in patients with resected stages II–IIIA NSCLC with EGFR mutations. In this study, approximately 320 patients are randomized 1:1 to receive adjuvant icotinib for up to 2 years or 4 cycles of platinum-doublet chemotherapy. Crossover is allowed because patients in the chemotherapy arm will be provided free icotinib after completion of chemotherapy. The ICTAN ( NCT01996098 ) is a phase III study that randomizes patients with EGFR-mutant, stages II-IIIA NSCLC to icotinib versus observation following completion of adjuvant chemotherapy. Patients can be randomized to one of two icotinib arms to receive treatment for 6 or 12 months. Primary endpoint is DFS. Finally, the ICWIP study ( NCT02125240 ) is a randomized phase III study of icotinib versus placebo for patients with EGFR-mutant, resected stages II–IIIA NSCLC. Primary outcome is DFS. As of the last update, all 3 studies currently are recruiting.

In Japan, the IMPACT WJOG6410L study is under way examining gefitinib versus chemotherapy as adjuvant therapy in patients with resected stages II–III NSCLC with activating EGFR mutations. Patients are randomized 1:1 to gefitinib for up to 2 years or 4 cycles of vinorelbine/cisplatin. The primary endpoint is DFS.

The ALCHEMIST trial ( NCT02194738 ) currently is recruiting patients with stages IB–IIIA NSCLC in the United States. Up to 8000 patients may be enrolled in the screening portion of the study. After surgical resection and standard-of-care adjuvant chemotherapy, patients are placed in 1 of 3 treatment arms based off of their tumor’s driver mutation status. Patients with EGFR-mutant tumors are randomized to receive adjuvant erlotinib for up to 2 years versus placebo. Those with anaplastic lymphoma kinase (ALK)positive tumors are randomized to up to 2 years of crizotinib versus placebo. Finally, those patients without EGFR or ALK mutations will be randomized to up to 1 year of adjuvant nivolumab versus placebo. Coprimary endpoints are DFS and overall survival.

The ADAURA study ( NCT02511106 ) is a multicenter, double-blind, randomized, placebo-controlled trial of osimertinib, a third-generation EGFR-TKI, versus placebo. This study has finished recruiting with results anticipated in the next couple years. Patients with stages IB–IIIA NSCLC with exon 19 deletion or L858R mutation were enrolled after surgical resection; patients were allowed to receive postoperative chemotherapy but it was not mandated. They were randomized 1:1 to up to 3 years of osimertinib versus placebo. Primary endpoint is DFS; although, with any adjuvant trial, the overall survival is truly the critical outcome that would be practice-changing. The data from RADIANT have shown that a DFS benefit may not translate into overall survival benefit if the EGFR-TKI therapy is only postponing but not preventing development of metastatic disease in this setting.