The 5-year survival in patients with resected NSCLC ranges

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1 SHIRISH M. GADGEEL Role of Chemotherapy and Targeted Therapy in Early-Stage Non Small Cell Lung Cancer Shirish M. Gadgeel, MD OVERVIEW On the basis of several randomized trials and meta-analyses, adjuvant chemotherapy is the accepted standard of care for certain patients with early-stage non small cell lung cancer (NSCLC). Patients with stage II, IIIA, or large ( 4 cm) IB tumors are candidates for adjuvant chemotherapy. The survival improvement with adjuvant chemotherapy is approximately 5% at 5 years, though certain trials have suggested that it can be 8% to 10%. Neoadjuvant chemotherapy also has shown a survival advantage, though the volume of data with this approach is far less than that of adjuvant chemotherapy. The combination of cisplatin and vinorelbine is the most well-studied regimen, but current consensus is to use four cycles of any of the platinum-based chemotherapy regimens commonly used as front-line therapy for patients with advanced-stage NSCLC. Trials to define biomarkers that can predict benefit from adjuvant chemotherapy have not been successful, but results of other such trials are still awaited. On the basis of the benefit observed with targeted agents in patients with advanced-stage disease and driver genetic alterations in their tumors, ongoing trials are evaluating the utility of these targeted agents as adjuvant therapy. Similarly, clinical benefit observed with checkpoint inhibitors has prompted assessment of these drugs in patients with early-stage NSCLC. It is very likely, in the future, that factors other than the anatomy of the tumor will be used to select patients with early-stage NSCLC for systemic therapy and that the choice of systemic therapy will extend beyond platinum-based chemotherapy. The 5-year survival in patients with resected NSCLC ranges from 25% to 75%. 1 The primary reason for death in these patients is recurrence of the cancer, which suggests that a proportion of patients with early-stage NSCLC have micrometastatic disease that remains untreated with surgery alone. One of the major advances in the management of NSCLC during the last 15 years has been that adjuvant chemotherapy has become the standard of care on the basis of clinical trials data that showed survival improvement with the use of adjuvant chemotherapy. This review discusses adjuvant chemotherapy, the accepted criteria for the use of adjuvant chemotherapy, the available data about the use of neoadjuvant chemotherapy and adjuvant targeted therapy, and ongoing clinical trials. ADJUVANT CHEMOTHERAPY Clinical trials to assess the benefits of adjuvant chemotherapy in patients with resected lung cancer have been conducted since the late 1960s. None of these trials demonstrated a survival advantage. However, a metaanalysis published in 1995 suggested a benefit with use of platinum-based chemotherapy, with a 13% reduction in the risk of death that did not reach statistical significance. 2 This meta-analysis spurred an interest in conducting more trials to assess adjuvant chemotherapy, particular with newer agents approved for use in the late 1990s. A possible reason that adjuvant trials of the past did not demonstrate a survival advantage was the lack of chemotherapy drugs with sufficient efficacy. A Southwest Oncology Group (SWOG) study that evaluated the addition of vinorelbine to cisplatin was among the first studies to demonstrate that combination chemotherapy provided superior survival compared with single-agent cisplatin in patients with advanced NSCLC. 3 Subsequently, other chemotherapy agents introduced in the late 1990s, such as paclitaxel, gemcitabine, and docetaxel, also improved outcomes when combined with a platinum agent compared with single-agent cisplatin in patients with metastatic NSCLC. 4-6 These results prompted the evaluation of these newer combinations, such as cisplatin/vinorelbine, as adjuvant therapy. Two trials, one conducted in North America and the other in Europe, assessed the chemotherapy regimen of cisplatin and vinorelbine as adjuvant therapy (Table 1). The North American trial, JBR-10, conducted by National Cancer Institute of Canada, enrolled 482 patients with completely resected stage IB and II NSCLC, and these patients were From the Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI. Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook. Corresponding author: Shirish M. Gadgeel, MD, Department of Oncology, Karmanos Cancer Institute, Wayne State University, 4100 John Rd, 4HWCRC, Detroit, MI 48201; gadgeels@karmanos.org American Society of Clinical Oncology ASCO EDUCATIONAL BOOK asco.org/edbook

2 SYSTEMIC THERAPY IN PATIENTS WITH EARLY-STAGE NSCLC TABLE 1. Adjuvant Trials Using Newer Platinum-Based Combinations Trial No. of Patients Stage Chemotherapy Median Follow-up (Years) 5-Year Survival Benefit (%) Hazard Ratio, p JBR IB to II Cisplatin/vinorelbine ,.04 ANITA I to IIIA Cisplatin/vinorelbine ,.017 CALGB IB Carboplatin/paclitaxel ,.12 LACE 10* 4,584 I to IIIA Several ,.005 *LACE was a meta-analysis that included trials to evaluate cisplatin-based adjuvant chemotherapy that were conducted after 1995 and had enrolled at least 300 patients. randomly assigned either to four cycles of cisplatin and vinorelbine chemotherapy or to observation. 7 At a median follow-up time of 9.3 years, adjuvant chemotherapy resulted in a significant improvement in survival (adjusted hazard ratio [HR], 0.79; 95% CI, ; p =.05) and a 5-year survival improvement of 11% (67% with chemotherapy vs. 56% with observation). Though the study design planned for four cycles of chemotherapy, the median number of cycles delivered was three. The major adverse events were fatigue, anorexia, nausea, and febrile neutropenia. Two patients died as a result of chemotherapy-related toxicity. In the European ANITA trial, 840 patients with resected stage IB/IIIA disease were randomly assigned to observation or cisplatin/vinorelbine chemotherapy. 8 After a median follow-up time of 76 months, the median survival was 65.7 months in the patients who received chemotherapy and was 43.7 months in the patients who did not (adjusted HR, 0.80; 95% CI, ; p =.017). Survival at 5 years was improved by 8.6%. Toxicities observed in this trial were similar to those in the JBR-10 trial, and seven patients died as a result of chemotherapy-related toxicities. To gain a better perspective, several meta-analyses have been conducted. The LACE (Lung Adjuvant Cisplatin Evaluation) meta-analysis included all adjuvant trials that evaluated cisplatin-based chemotherapy, were conducted after 1995, and enrolled more than 300 patients (Table 1). 10 This analysis showed that the HR for death was 0.89 (95% CI, KEY POINTS Adjuvant chemotherapy improves survival by at least 5% at 5 years in patients with early-stage NSCLC. The stage of the cancer determines if a patient is a candidate for adjuvant chemotherapy. Patients with stage II or IIIA disease are candidates for adjuvant chemotherapy. Certain patients with stage IB NSCLC (tumors 4 cm) may also be considered for adjuvant therapy. Four cycles of a platinum-based chemotherapy regimen is the accepted standard. Cisplatin can be substituted with carboplatin in appropriate patients. Neoadjuvant chemotherapy can result in survival improvement similar to adjuvant chemotherapy. Ongoing trials will determine the role of targeted therapy and immune therapy in patients with early-stage NSCLC ; p =.005) and that the absolute benefit in survival at 5 years with adjuvant chemotherapy was 5.4%. There was a trend toward greater benefit with cisplatin/vinorelbine chemotherapy compared with older regimens used in these trials. A cumulative dose of greater than 300 mg/m 2 of cisplatin also improved survival compared with lower doses. Fifty-nine percent of the patients received at least 240 mg/m 2 of cisplatin. Among the patients who received chemotherapy, the rate of grade 3 or 4 toxicities was 66%, and the rate of toxicity related death was 0.9%. Similar results were observed in the other meta-analyses. 11,12 One trial has evaluated a carboplatin-based treatment regimen as adjuvant therapy. In CALGB 9633, patients with resected stage IB NSCLC were randomly assigned to carboplatin and paclitaxel or to observation. 9 At a median follow-up time of 74 months, there was a trend for survival advantage, but it was not statistically significant (HR, 0.83; 95% CI, ; p =.12). Because most adjuvant trials were conducted with cisplatin-based regimens, there is a preference to use cisplatin for adjuvant therapy. However, in patients with NSCLC who cannot receive cisplatin because of comorbid illnesses or intolerance of cisplatin, carboplatin is an accepted substitute. Long-term follow-up of the IALT (International Adjuvant Lung Trial), one of the first trials to demonstrate a survival advantage with adjuvant therapy, showed that the benefit was not sustained. 13 The HR for survival advantage at 5 years was 0.86, and it declined to an HR of 0.91 at a median follow-up time of 7.5 years. This decline in benefit during longer follow-up was caused by an increase in non lung cancer-related deaths, which raised the concern of late toxicities from chemotherapy used in this trial. Patients in this study were treated with chemotherapy drugs that are not commonly used. A similar decline in efficacy was not observed with long-term follow-up of either the ANITA or the JBR-10 study, which suggests that choice of chemotherapy agents maybe relevant in terms of long-term toxicities. VARIABLES INFLUENCING THE USE OF CHEMOTHERAPY The data from adjuvant trials show that the 5-year survival in patients with resected NSCLC without adjuvant chemotherapy is 25% to 75% and that this rate is improved by 5% to 10% with adjuvant therapy. These data suggest that not everybody needs chemotherapy and that the benefits of adjuvant chemotherapy are modest. Therefore, it is important asco.org/edbook 2017 ASCO EDUCATIONAL BOOK 631

3 SHIRISH M. GADGEEL FIGURE 1. Treatment Schema for Adjuvant Therapy Certain patients with stage IB (particularly patients with tumors 4 cm) can be considered for adjuvant therapy. Four cycles of adjuvant chemotherapy are usually administered. Chemotherapy is usually started 6 to 12 weeks after surgery. Delayed chemotherapy also may provide survival advantage. Neoadjuvant chemotherapy has shown benefit and can be considered if thought to be in the best interest of the patient. Carboplatin-based therapy can be used if there is a concern about cisplatin use. to be familiar with factors that predict a greater potential for benefit from adjuvant therapy. Clinical Variables Influencing Benefit From Adjuvant Therapy Stage. The LACE meta-analysis showed that the benefit with adjuvant therapy varied according to stage. In patients with stage IA disease (104 patients), the HR was 1.40 (95% CI, ), which suggests a detriment with adjuvant chemotherapy. These data must be viewed with a level of caution, because the numbers are relatively small. Nonetheless, adjuvant chemotherapy should not be considered in patients with stage IA disease. There was a trend for benefit in patients with stage IB disease (HR, 0.93; 95% CI, ). The benefit was notable in patients with stage II and stage III disease (HR, 0.83; 95% CI, ). The test for interaction between survival benefit from adjuvant chemotherapy and stage of NSCLC was significant (test for trend p =.04). Thus, the benefit from adjuvant chemotherapy may be proportionally greater in patients with higher-stage disease, particularly in patients with nodal metastases. The benefits of adjuvant therapy in patients with stage IB disease were assessed in retrospective analyses of two trials. In CALB9633, patients with stage IB disease were randomly assigned to adjuvant carboplatin and paclitaxel. The overall results did not show a survival benefit in these patients. However, a post hoc analysis demonstrated that adjuvant chemotherapy improved survival in patients with tumors of 4 cm greater from a median of 77 months to a median of 99 months (HR, 0.69; 90% CI, ; p =.043). 9 In patients with tumors less than 4 cm, there was a trend toward inferior survival among patients who received chemotherapy (HR, 1.01; 90% CI, ; p =.49). A similar retrospective analysis was conducted by the investigators of JBR-10. This study included patients with both stage IB and stage II disease. Although the overall results showed improved survival with adjuvant therapy, the benefit was restricted to patients with stage II disease (HR, 0.68; 95% CI, ; p =.01), and there was no benefit in patients with stage IB disease (HR, 1.03; 95% CI, ; p =.87). Furthermore, analysis restricted to patients with stage IB disease showed that patients with tumors of 4 cm or greater had improved survival with chemotherapy (HR, 0.66; 95% CI, ; p =.13), whereas patients with smaller tumors did not (HR, 1.73; 95% CI, ; p =.06). It is important to remember that these data from CALGB 9633 and JBR-10 are based on retrospective analyses. However, on the basis of these data and the LACE meta-analysis, the consensus that has emerged is to use adjuvant chemotherapy in patients with tumors that have metastasized to regional lymph nodes (hilar or mediastinal) and in patients with large ( 4 cm) tumors (Fig. 1). Age. The median age of U.S. patients with lung cancer is 71, and the median age of patients enrolled in adjuvant trials is approximately 61. Thus, the applicability of the data from these trials to the population of older adults may be limited. Population-based studies have shown that the use of adjuvant chemotherapy is lower in older adults. 14,15 In an analysis of the National Cancer Database the odds ratio of receipt of adjuvant chemotherapy in patients older than age 75 was only 0.11 and, among patients age 66 to 75, was 0.38 compared with patients age 55 or younger. Similar results were reported in a population-based study from Ontario, Canada. The JBR-10 investigators evaluated the benefits of adjuvant therapy in patients age 65 or older and found that these patients did derive survival benefit with adjuvant therapy (HR, 0.61; 95% CI, ; p =.04). 7 The LACE meta-analysis investigators also evaluated the benefits of adjuvant chemotherapy in patients age 70 or older and found a trend toward survival advantage in these patients (HR, 0.90; 95% CI, ; p =.29). 10 On the basis of these retrospective analyses, adjuvant chemotherapy should be considered in older adults. However, a level of caution should be exercised in patients age 75 or older. Only 23 patients in this age group were enrolled in the JBR- 10 trial, and this group experienced a trend toward inferior outcomes with adjuvant chemotherapy (HR, 2.35; 95% CI, ; p =.09). A proper assessment of the risk-benefit ratio is important before adjuvant chemotherapy is initiated in very old adults. Cisplatin may have a greater propensity to cause toxicities in these patients, also; therefore, carboplatin should be considered in older patients. Performance status. Stage and performance status are the most important prognostic factors in patients with NSCLC. All of the adjuvant trials excluded patients who had poor ASCO EDUCATIONAL BOOK asco.org/edbook

4 SYSTEMIC THERAPY IN PATIENTS WITH EARLY-STAGE NSCLC performance statuses. Some patients do experience a decline in performance status after thoracic surgery. Utility of adjuvant therapy in these patients is unclear. However, a recent analysis of data in the National Cancer Database showed that delaying chemotherapy from the accepted standard of 6 to 9 weeks after surgery does not reduce the survival benefit from adjuvant therapy. 16 Similar data were also reported by Booth et al. 17 In their retrospective analysis of the Ontario Cancer Registry, the median time to start of adjuvant chemotherapy was 8 weeks. However, a third of the patients started adjuvant chemotherapy after 10 weeks, and their survival was not inferior to patients who received chemotherapy within 10 weeks of surgery. Thus, even if patients require a longer time to recover from lung cancer surgery, adjuvant therapy could be considered after the patient has recovered. Pathologic Variables Histology. Histology has emerged as an important determinant of choice of chemotherapy in patients with NSCLC, particularly with the use of pemetrexed. The combination of cisplatin and pemetrexed was evaluated in a randomized phase II trial; its primary objective was to assess the clinical feasibility of delivering this combination as adjuvant therapy compared with cisplatin/vinorelbine. 18 Clinical feasibility was defined as no grade 4 neutropenia/thrombocytopenia; grade 3 or 4 febrile neutropenia or thrombocytopenia with bleeding; and no grade 3 or 4 nonhematologic toxicity. The study showed that feasibility rates were 95.5% with the pemetrexed combination versus 75.4% with the vinorelbine combination. Dose delivery was 90% of planned dose with pemetrexed combination and was 66% with the vinorelbine combination. Overall toxicity also was less with the cisplatin/ pemetrexed combination. ECOG1505 evaluated the benefits of added bevacizumab to a variety of cisplatin-based chemotherapy regimens. 19 The study failed to show any benefit with the addition of bevacizumab. In a retrospective analysis of the trial, no difference in outcomes was observed with any of the chemotherapy regimens used. However, among patients with nonsquamous disease (patients whose tumors had any non small cell histology other than squamous), the cisplatin/pemetrexed combination had significantly less grades 3 to 5 toxicities compared with other regimens (p <.001). No notable differences in toxicities were observed in regimens used in patients with squamous cell disease. Thus, results of two separate studies, TREAT and E1505, suggest that the combination of cisplatin/pemetrexed is better tolerated as adjuvant therapy. The data from E1505 also suggest that platinum-based chemotherapy combinations used in patients with advanced-stage disease can be considered in the adjuvant setting. Histology also may have relevance for the choice of the platinum analog. CISCA (cisplatin vs. carboplatin) was a meta-analysis of randomized trials to compare cisplatin- with carboplatin-based treatments in patients with advanced NSCLC. 20 This meta-analysis showed that patients who received carboplatin-based therapy had a nonsignificant increase in the hazard of mortality compared with patients who received cisplatin-based chemotherapy (HR, 1.07; 95% CI, ; p =.100). However, in patients with nonsquamous disease, carboplatin-based regimens were associated with statistically significant inferior survival (HR, 1.12; 95% CI, ; p =.098); there was no difference in outcome among patients with squamous histology. Though these data are in patients with advanced cancer, the CISCA metaanalysis suggests that cisplatin should be the preferred platinum for adjuvant therapy, particularly in patients with nonsquamous histology. It is important to note that this meta-analysis included trials conducted before the availability of pemetrexed, an effective chemotherapeutic agent in patients with nonsquamous NSCLC. Other pathologic features. Certain tumor pathologic features are associated with worse prognosis. These include visceral pleural invasion and angiolymphatic invasion Though it is accepted that presence of these features is associated with worse outcomes, it is not known whether adjuvant therapy in patients with tumors that have these features, but do not meet any other criteria for adjuvant therapy, provides any survival benefit. If these features are present, the prognostic implications of these features with the patient should be discussed; adjuvant therapy occasionally may be considered in patients with tumors of 4 cm or smaller without lymph node metastases that have these pathologic features. The National Comprehensive Cancer Network guidelines state that pathologic features of poorly differentiated tumor, vascular invasion, visceral pleural invasion, and lung neuroendocrine tumors should be considered high-risk features and that the presence of these high-risk features should be included in the decision-making process about adjuvant therapy. 25 NEOADJUVANT CHEMOTHERAPY Systemic chemotherapy in patients with NSCLC has the capacity to treat not only the micrometastatic disease but also clinically evident cancer in the chest. Thus, neoadjuvant chemotherapy has the potential to address all sites of disease simultaneously. In addition, preoperative chemotherapy may be better tolerated than postoperative chemotherapy. For these reasons, neoadjuvant chemotherapy in patients with early-stage NSCLC has generated interest. In the early 1990s, two small randomized trials demonstrated that neoadjuvant chemotherapy can improve survival. Rosell et al 26 evaluated neoadjuvant cisplatin, mitomycin C, and ifosfamide in patients with stage IIIA disease. Similarly, Roth et al 27 evaluated neoadjuvant cisplatin, etoposide, and cyclophosphamide in the same group of patients. Both trials showed a survival advantage and sparked additional assessment in the neoadjuvant approach. One of the largest studies conducted in the United States to evaluate neoadjuvant chemotherapy was S Patients with stage IB/IIIA disease were randomly assigned to surgery alone or to three cycles of carboplatin/paclitaxel followed by surgery. The plan was to enroll 300 patients per asco.org/edbook 2017 ASCO EDUCATIONAL BOOK 633

5 SHIRISH M. GADGEEL arm, but the study closed after 354 patients were enrolled in the study because data about benefits of adjuvant therapy became available during the conduct of the study; it became challenging to continue to randomly assigned patients to surgery alone. Among the patients enrolled, there was an improvement in survival (median, 62 vs. 41 months; HR, 0.79; p =.11) and progression-free survival (median, 33 vs. 20 months; HR, 0.80; p =.10) with neoadjuvant chemotherapy, but this improvement was not statistically significant, possibly because of lower-than-planned enrollment. The surgical resection rate among randomly assigned patients was similar at 87% among patients who had surgery alone and 84% among patients who had neoadjuvant chemotherapy. Postoperative adverse events were similar among patients who did and did not undergo neoadjuvant chemotherapy. However, the postoperative mortality was higher among patients in the neoadjuvant chemotherapy arm who underwent pneumonectomy (4 of 24 vs. 0 of 26 in the surgery-alone arm). Another trial, CHEST (chemotherapy in early-stage NSCLC trial) evaluated neoadjuvant cisplatin and gemcitabine followed by surgery versus surgery alone. 29 This study enrolled only 270 of the planned 700 patients. Both progression-free survival (HR, 0.70; p =.003) and overall survival (HR, 0.63; p =.02) were significantly improved with neoadjuvant chemotherapy. The study found that the survival benefit with neoadjuvant chemotherapy was restricted to patients with stage IIB/IIIA disease (HR, 0.42; p <.001). In patients with stage IB/IIA disease, the majority of whom were stage IB, there was no improvement in survival with neoadjuvant chemotherapy (HR, 1.02; p =.94). Several meta-analyses of studies to evaluate neoadjuvant chemotherapy have been performed These meta-analyses suggest that neoadjuvant chemotherapy does improve survival, with an absolute benefit of 5% to 6% at 5 years; this rate is similar to the benefit observed with adjuvant chemotherapy. Few trials have compared neoadjuvant and adjuvant chemotherapy. A prominent study was the NATCH trial that randomly assigned patients with stage I or stage II, T3N1 NSCLC to surgery alone, to neoadjuvant chemotherapy with carboplatin and paclitaxel followed by surgery, or to surgery followed by adjuvant chemotherapy with the same regimen. 33 The study failed to demonstrate improvement in survival either with neoadjuvant or adjuvant chemotherapy. It is possible that the reason for lack of survival advantage with chemotherapy was that greater than 70% of the patients in each arm had stage I disease a group that the LACE meta-analysis showed may not derive benefit from chemotherapy. However, outcomes with neoadjuvant chemotherapy were similar to adjuvant chemotherapy, which suggested that there is neither an advantage nor a disadvantage with neoadjuvant chemotherapy compared with adjuvant therapy. However, 97% of the patients in the neoadjuvant group started chemotherapy, compared with 66% in the adjuvant group (p <.0001), which suggests that neoadjuvant chemotherapy may be better tolerated than adjuvant chemotherapy. An indirect meta-analysis to compare preoperative and postoperative chemotherapy was conducted by Lim et al. 34 It is important to note that the majority of the trials included in this analysis did not directly compare the two approaches. More than 10,000 patients were included in this analysis, though the number of adjuvant trials far exceeded trials that assessed neoadjuvant chemotherapy. This analysis showed that both overall survival and disease-free survival were similar with adjuvant or neoadjuvant chemotherapy. 34 In summary, chemotherapy improves survival in patients with stage IB/IIIA NSCLC who have undergone surgical resection, irrespective of administration before or after surgery. The data for adjuvant chemotherapy are far more robust than the data for neoadjuvant chemotherapy; therefore, adjuvant chemotherapy should be the preferred approach. However, if there are concerns about surgical resection, then in the author's opinion neoadjuvant chemotherapy could be considered and the feasibility of surgical resection could be re-evaluated after chemotherapy. PREDICTORS OF CHEMOTHERAPY SENSITIVITY Only a proportion of patients with advanced-stage and earlystage NSCLC benefit from currently available chemotherapy drugs. Therefore, there has been an interest in identifying markers that can predict for benefit of, or lack thereof from, chemotherapy drugs. Several molecular markers, such as ERCC1, RRM1, BRCA1, and thymidylate synthase (TS), have been assessed independently and collectively to identify patients most likely to benefit from specific chemotherapy drugs. The expectation was that assessment of such molecules may spare patients who are unlikely to derive benefit from toxicities of chemotherapy drugs. However, despite promising results in pilot studies, randomized studies have failed to demonstrate the predictive utility of these markers The ITACA (International Tailored Chemotherapy Adjuvant Therapy) phase III trial is evaluating the predictive utility of the mrna expression levels of molecular markers ERCC1 and TS. 38 Patients will undergo assessment of both markers by quantitative reverse transcriptase polymerase chain reaction. Patients were randomly assigned to investigator s choice of platinum-based chemotherapy or chemotherapy defined by the molecular markers. Patients with tumors that had high ERCC1 and high TS received single-agent docetaxel; patients with high ERCC1 and low TS received single-agent pemetrexed; patients with low ERCC1 and high TS received cisplatin and gemcitabine; finally, patients with low ERCC1 and low TS received cisplatin and pemetrexed. The study has completed enrollment, and the results are awaited. Currently, no factor other than histology is predictive of benefit of, or lack thereof from, specific chemotherapy in patients with NSCLC. Despite this, several laboratories continue to perform assessments of these markers in tumors of patients with NSCLC. For now, therapy should not be based on the results of these markers ASCO EDUCATIONAL BOOK asco.org/edbook

6 SYSTEMIC THERAPY IN PATIENTS WITH EARLY-STAGE NSCLC Genomic Markers Lung cancer, like most cancers, is a result of genetic alterations that initiate an oncogenic phenotype in the affected tissue. There is a notable interest in identification of specific gene signatures that can provide prognostic and predictive guidance. Genomic assessment is conducted routinely to determine adjuvant therapy for breast cancer. 39 Various investigators have proposed different genomic signatures as prognostic markers and/or predictive markers in resected NSCLC by using different testing platforms. Chen et al 40 analyzed 125 patients with resected stage I to III NSCLC with different histologic subtypes by microarray gene expression analysis and identified a prognostic score that was based on the expression of five genes. All of the tissues analyzed were fresh-frozen. The patients with high gene scores had a lower median survival than patients with low gene scores (20 vs. 40 months; p <.001). In a multivariable analysis, the five-gene score was significantly (p =.03) associated with death, as were patient age and tumor stage. Kratz et al 41 defined a 14-gene signature on paraffin-embedded tumor specimens of patients with nonsquamous NSCLC. The investigators were able to categorize patients into three distinct prognostic categories. The 5-year survival rates in the three different categories were 74% in low-risk group, 58% in the intermediate-risk group, and 45% in the high-risk group. Among 330 total patients with stage I NS- CLC, the median survival times were 113 months in the 78 low-risk patients, 88 months in the 104 intermediate-risk patients, and 70 months in the 151 high-risk patients. The investigators confirmed the results in an independent cohort of resected NSCLC obtained from a database in China. The ability to use formalin-fixed and paraffin-embedded tissue to generate such a gene expression based score has greater clinical utility than signatures derived from studies that used fresh-frozen tissues. Apart from assessment of genetic signatures, investigators also have assessed prognosis on the basis of levels of certain micrornas (mirna), which are small noncoding RNAs that function in regulation of gene expression by targeting either the 3-prime or 5-prime region of specific mrnas. Expression levels of various mirnas are altered in cancers, including lung cancer. 42 Several investigators have identified that expression of certain mirnas may have prognostic relevance. This is a new and exciting area of research and could complement the prognostic utility of gene expression signatures. Although assessment of gene expression to predict prognosis and benefit from adjuvant chemotherapy is a rational approach, none of the studies to date have proven the clinical value of gene signatures in prospective trials. In addition, the technologies, the tissue sources, and gene sets have varied among reports, and this variance severely limits the clinical applicability of gene signatures in current practice. ADJUVANT TARGETED THERAPY EGFR Inhibitors as Adjuvant Therapy One of the major advances in the management of NSCLC is the identification of driver genetic alterations that can be targeted for therapeutic benefit. The first driver genetic alteration that was successfully targeted for therapeutic benefit was EGFR mutation. Approximately 10% to 15% of patients with NSCLC, particularly those with adenocarcinomas of the lung, have mutations in the tyrosine kinase domain of the EGFR gene. Exon 19 deletions and the point mutation L858R in exon 21 constitute 90% of all EGFR mutations identified in NSCLC. Randomized trials have shown that patients with advanced NSCLC who are positive for these EGFR mutations derive greater clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) than standard front-line chemotherapy. 43 On the basis of these data, there is a clear interest in evaluation of these drugs as adjuvant therapy in patients with EGFR mutation positive NSCLC. Retrospective analysis has suggested that adjuvant EGFR TKIs can provide clinical benefit in patients with EGFR mutation positive NS- CLC. 44 However, as yet, there are no conclusive prospective data to support the use of these drugs as adjuvant therapy. The largest trial to evaluate EGFR TKIs as adjuvant therapy was the RADIANT trial. 45 In this trial, patients were eligible if their tumors were positive for EGFR expression as assessed by immunohistochemistry or fluorescent in situ hybridization. Patients were randomly assigned in a 2:1 fashion to receive 150 mg daily of erlotinib for 2 years or to placebo. Patients who were candidates for adjuvant chemotherapy received this treatment before start of the study therapy. The primary endpoint of the study was improvement in disease-free survival. The study failed to demonstrate a disease-free survival or survival advantage with the use of adjuvant erlotinib. Of the 973 patients enrolled in the study, 161 patients had exon 19 deletion or L858R EGFR mutations. In this population of patients, the disease-free survival was superior with erlotinib (HR, 0.61; 95% CI, ; p =.0391). However, the difference could not be considered statistically significant because of hierarchical testing that allowed assessment of statistical significance of secondary endpoints only if the primary endpoint was statistically significant. At the time of data analysis, the follow-up was too limited to assess survival differences. In another randomized trial, BR19, gefitinib was evaluated as adjuvant therapy in all patients and was not restricted to EGFR mutation positive NSCLC. The study closed early after gefitinib failed to show survival advantage in patients with advanced NSCLC in the ISEL trial. The study enrolled 503 patients with resected stage IB/IIIA NSCLC, and patients were randomly assigned in a 1:1 manner to gefitinib or placebo. Patients received gefitinib for a median of 4.8 months. Gefitinib did not improve survival in these patients. Only 15 patients had EGFR mutations seven of whom received gefitinib, and eight of whom received placebo. There was a suggestion of worse survival among the seven patients with EGFR mutation positive tumors who received gefitinib (HR, 3.16; 95% CI, ; p =.15). These results have to be viewed with some level of caution because of the small number of patients with EGFR mutations, early closure of the study, and the short duration of gefitinib administered to these patients. asco.org/edbook 2017 ASCO EDUCATIONAL BOOK 635

7 SHIRISH M. GADGEEL FIGURE 2. ALCHEMIST (NCT ) Trial Design The SELECT trial was a single-arm, multicenter, phase II study to assess erlotinib as adjuvant therapy in patients with stage IA to IIIA EGFR mutation positive NSCLC. 46 Patients received erlotinib for 2 years. The study was designed to assess the ability of adjuvant erlotinib to improve 2-year disease-free survival from 76% (on the basis of historical data) to 86%. The 2-year disease-free survival in the 100 patients enrolled in the study was 89%. Of the 29 patients who experienced recurrence, 25 developed disease recurrence after erlotinib treatment was stopped. The median time to recurrence after treatment stopped was 8.5 months. In addition, the duration of treatment was significantly shorter in patients who had recurrence compared with those who were recurrence free at the time of data analysis (p =.027). These data suggest that duration of therapy with an EGFR TKI may have relevance in the adjuvant setting. Data from studies in gastrointestinal stromal tumors (GIST), which also have driver genetic alteration, have shown that 3 years of adjuvant therapy with imatinib provides greater benefit than 1 year of therapy. 47 In that trial, only 69% of the patients completed at least 22 months of therapy, whereas only half of the patients in the RADIANT trial completed all 24 months of therapy. Thus, it is possible that prolonged delivery of adjuvant EGFR TKIs is essential for improved outcomes in EGFR mutation positive NSCLC. Several ongoing or recently completed trials are addressing the use of adjuvant EGFR TKIs. The largest such effort is the ALCHEMIST trial (NCT ), conducted by all of the cooperative oncology groups in the United States under the leadership of the National Cancer Institute (Fig. 2). Patients with stage IB to IIIA disease will undergo molecular analysis. If their tumor has an EGFR mutation, then they could enter the EGFR mutation substudy that plans to enroll 410 patients and will randomly assign patients to erlotinib for 2 years or to placebo. The primary endpoint of the study is overall survival. The ALCHEMIST trial also has a substudy to evaluated the role of adjuvant crizotinib in patients with resected ALK-positive NSCLC. Other trials (C-TONG 1104, NCT ; WJOG6401L) are comparing adjuvant EGFR TKIs to adjuvant platinum-based chemotherapy by using disease-free survival as the primary endpoint. Finally, a trial in the United States (NCT ) is randomly assigning patients to receive adjuvant afatinib for either 3 months or 2 years to assess the relevance of duration of therapy. The available data do not conclusively demonstrate that adjuvant EGFR TKIs provide a survival advantage in patients with early-stage lung cancer. Therefore, adjuvant EGFR TKIs currently are not considered the standard of care. Bevacizumab Bevacizumab is a monoclonal antibody that targets VEGF. Angiogenesis is an important component of carcinogenic phenotype; therefore, targeting oncogenic angiogenesis for therapeutic benefit has been of interest for a long time. E4599 demonstrated that the addition of bevacizumab to the chemotherapy of carboplatin and paclitaxel improved survival in patients with advanced nonsquamous NSCLC. 48 Other studies conducted did not document an overall survival benefit in patients who received bevacizumab with chemotherapy. The survival advantage observed with the addition of bevacizumab to chemotherapy in E4599 was the basis of E1505, a study that evaluated the efficacy of bevacizumab added to adjuvant chemotherapy. 19 The study randomly ASCO EDUCATIONAL BOOK asco.org/edbook

8 SYSTEMIC THERAPY IN PATIENTS WITH EARLY-STAGE NSCLC assigned 1,501 patients with stage IB to IIIA disease who had undergone surgical resection with appropriate lymph node sampling to receive four cycles of platinum-based adjuvant chemotherapy with or without 1 year of bevacizumab. Among the patients randomly assigned to receive bevacizumab, only 37% of the patients completed an entire year of treatment. Neutropenia, hypertension, and overall grade 3 to 5 toxicities were more frequent in patients who received bevacizumab. There was no difference in survival among patients who were randomly assigned to receive bevacizumab and patients who were not (HR, 0.99). IMMUNOTHERAPY The ability to evade immune surveillance is an important aspect of the oncogenic phenotype. Thus, activation or restoration of immune surveillance could treat and eradicate cancers. Vaccines Therapeutic vaccines have been evaluated as adjuvant therapy in patients with resected lung cancer. Both tumor-based vaccines and peptide-based vaccines have been evaluated in lung cancer. The largest study to test this strategy in the adjuvant setting was the MAGRIT trial, a study that evaluated the melanoma-associated antigen (MAGE) A3 vaccine. 49 MAGE-A3 is expressed on the surface of several cancers, including NSCLC, and is not expressed on normal tissues other than the placenta and testis. A randomized phase II study suggested that an adjuvant MAGE-A3 vaccine could enhance both disease-free survival and overall survival. 50 MAGRIT was a randomized phase III study that evaluated more than 13,000 patients; 2,312 of these patients were randomly assigned in a 2:1 manner to receive the vaccine or placebo during 27 months. Of the patients randomly assigned, approximately 50% had received adjuvant chemotherapy. The schedule of the vaccine and placebo was similar to the phase II trial of 13 doses administered over 27 months. The study failed to show an improvement in disease-free survival in the overall population (HR, 1.02; p =.74) or in patients who had received adjuvant chemotherapy (HR, 1.10; p =.36). Other vaccines have been evaluated for the management of patients with NSCLC, both in early and advanced stages Though some of the trials have shown very promising results, none have conclusively demonstrated survival improvement in a randomized phase III study. Whether this approach will prove to provide meaningful benefit as adjuvant therapy remains to be seen. Checkpoint Inhibitors Tumors can evade immune surveillance by activating inhibitory checkpoints on T cells. Two of the most well-studied checkpoints are PD-1 and its ligand, PD-L1. Inhibition of the PD-1 signaling pathway by antibodies directed against either PD-1 or PD-L1 has led to dramatic clinical benefits in a minority of patients with advanced NSCLC. Three drugs that target the PD-1 signaling pathway have been approved for the treatment of advanced NSCLC. Pembrolizumab is a fully humanized IgG4 antibody against PD-1. On the basis of randomized phase III studies, the drug has been approved for front-line therapy in patients with advanced NSCLC whose tumors have high PD-L1 expression. 55 It is also approved for patients with NSCLC who have PD-L1 positive cancers and who were previously treated with a platinum-based chemotherapy. 56 Nivolumab is also a fully humanized IgG4 antibody against PD-1. Currently, it is approved for patients with advanced NSCLC who were previously treated with platinum-based chemotherapy irrespective of the tumor PD-L1 expression. 57,58 Recently, atezolizumab, a fully humanized antibody that targets PD-L1, was approved for use in patients with advanced NSCLC who were previously treated with platinum-based chemotherapy. 59 There is a great deal of interest in the evaluation of these agents in early-stage NSCLC. Several randomized trials are evaluating these agents in the adjuvant setting. The AL- CHEMIST trial was modified recently to randomly assign patients whose tumors are not EGFR mutation positive or ALK mutation positive to nivolumab or placebo. Results of these trials are eagerly awaited. Whether the benefit will be restricted to patients with tumors that express a high level of PD-L1 or those that have other biomarkers remains to be seen. References 1. Goldstraw P, Crowley K, Chansky K, et al. 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