There has been dramatic progress with the introduction of targeted therapies and immune checkpoint inhibitors in the management of advanced non—small cell lung cancer (NSCLC). Biomarker-driven targeted therapy has revolutionized the management of oncogene-driven lung adenocarcinomas. Multiple generations of agents are now available for the treatment of 

-aberrant lung adenocarcinomas. Furthermore, effective agents are either available or rapidly emerging for 

, and ErbB2-positive subsets. In addition, immune biomarkers, such as PD-L1 and tumor mutational burden (TMB) analysis, inform clinicians as to the proper choices of immunotherapies, alone or in combination with chemotherapy, as treatment for the majority of patients without actionable alterations. By now there is very little justification for the use of conventional chemotherapy alone as first-line therapy. We have similarly witnessed a sea change in the management of locally advanced disease. The PACIFIC study has established a new standard with adjuvant durvalumab (Imfinzi) following concurrent chemoradiation, leading to major survival benefits.

Table 1. Key Studies of TKIs in Early-Stage NSCLC

In this context, it is extremely disappointing that for the very population of early-stage patients for whom cure is most likely, and for whom the impact of novel therapies could be the most substantial, little has changed since the acceptance of adjuvant chemotherapy for resected stage IB-IIIA patients as the standard of care about 2 decades ago. Since then, we have only witnessed failed attempts at improving on the status quo, with negative results from postoperative radiation (PORT meta-analysis Trialists Group),

 Furthermore, outside of nodal involvement and tumor size, no validated biomarkers exist in this setting to guide patient management. Adjuvant chemotherapy remains the standard of care for patients with resected NSCLC. Results from the landmark International Adjuvant Lung Cancer Trial showed that cisplatin-based postoperative chemotherapy improved survival, marking a new era in NSCLC management.

 The Lung Adjuvant Cisplatin Evaluation meta-analysis of the 5 key trials of this era echoed these results, showing an overall survival (OS) benefit of 5.4% at 5 years—although adjuvant chemotherapy was found to be harmful in stage IA NSCLC.

 Nonetheless, outcomes remain poor; the modest benefit offered by adjuvant chemotherapy indeed seems to lessen over time due to significant toxicities and other long-term complications of treatment. The time is thus ripe to reenergize research with a focus on improving our curative strategies in this setting.

The introduction of targeted therapies in the adjuvant setting highlights this general disappointment. Over the past 15 years, EGFR tyrosine kinase inhibitor (TKI) therapies have been tested in several adjuvant studies, yielding mixed results—partly due to misguided patient selection and poor trial design (

). The nonmolecularly selected NCIC CTG BR19 trial found no improvement in survival for patients receiving gefitinib (Iressa) compared with placebo in stage IB-IIIA surgically resected patients, even in a subset analysis based on 

 mutation status—although this subset was very small, leading to underpowered analyses.

 The RADIANT study randomized resected stage IB-IIIA 

-positive patients, as defined by immunohistochemistry (IHC) or fluorescence in situ hybridization, to receive erlotinib (Tarceva) or placebo following optional adjuvant chemotherapy, and similarly did not find any difference in disease-free survival (DFS) or OS—not surprisingly, in retrospect, given incorrect biomarker choice.

mutations showed a DFS advantage, the results were not significant owing to the hierarchical study design, and OS appeared identical. The subsequent multicenter phase II SELECT study of erlotinib for 2 years following resection of stage IB-IIIA 

-mutated NSCLC used more scientifically valid biomarker selection and included only patients with 

 The study had excellent overall results and reached its endpoint of improved DFS compared with historical controls, but the results are difficult to interpret in the absence of a true control group. Furthermore, a significant relapse rate soon after stopping adjuvant therapy is worrisome. This highlights the specific concern that adjuvant targeted therapy might lack actual curative effect, possibly leading only to delays in recurrence. The results, therefore, are not viewed as practice changing. The latest major trial to conclude, ADJUVANT, a randomized phase III Chinese study comparing adjuvant chemotherapy with gefitinib, reached its primary endpoint of significant DFS improvement (median DFS of 28.7 vs 18 months).

 However, available OS data argue against a substantial true benefit, and the study was criticized for not offering standard-of-care chemotherapy in the gefitinib arm. Based on these studies, adjuvant EGFR TKIs may be beneficial to delaying recurrence, but clear OS benefits—the key endpoint in such studies&mdash;remain elusive. Erlotinib has also been studied in the neoadjuvant setting (CSLC 0702, ML25444).

 Although well tolerated, it is unclear given the limited data whether neoadjuvant erlotinib holds any meaningful survival benefits.

 Meanwhile, principally through the ALCHEMIST study, there is a continued effort in the United States to demonstrate the value of TKIs for early-stage NSCLC. ALCHEMIST was originally designed to test adjuvant targeted therapy in resected stage IB-IIIA patients following receipt of adjuvant chemotherapy.

 Despite high hopes for ALCHEMIST, a group of trials studying adjuvant erlotinib and crizotinib (Xalkori), accrual has been slow, leading to concerns about whether it can be successfully completed and, of more concern, whether it is becoming obsolete as more effective EGFR- and ALK-targeted agents have shown great success in the advanced setting. The potential of another first-generation TKI, icotinib (Conmana), as adjuvant therapy for stage II-IIIA NSCLC is currently being investigated in a number of phase III studies in China, including ICWIP (NCT02125240), EVIDENCE (NCT02448797), and ICTAN (NCT01996098).

The important ADAURA study being conducted in a similar setting utilizes adjuvant osimertinib (Tagrisso), a third-generation EGFR TKI with greater central nervous system penetrance that targets the T790M resistance mutation. Osimertinib has become the standard-of-care frontline option in advanced disease, thereby making ADAURA the most relevant of ongoing targeted adjuvant trials. In general, the lack of investment in adjuvant studies has led to a series of missed opportunities over the past decade and a half, hopefully informing us about the next wave of studies ahead.

Immunotherapy represents the next frontier of oncology, with the FDA already approving checkpoint inhibitors for a growing variety of cancer types, including 2 anti—PD-1 and 2 anti–PD-L1 agents for the management of advanced and locally advanced NSCLC.

 Although checkpoint inhibitors are in widespread use for treatment-refractory advanced NSCLC, they remain investigational for early stages, which is when their efficacy would likely be the most robust and their impact could be the most significant. Clearly, great efforts urgently need to be expanded to assess these agents. To this end, a variety of studies are ongoing in both the adjuvant and neoadjuvant settings. The latter has been speculated to be particularly attractive (

Table 2. Key Studies of Immunotherapy in Early-Stage NSCLC

The administration of immunotherapy prior to surgical resection might be particularly advantageous, as larger tumors are thought to generate greater immune activity than micrometastatic disease. Furthermore, the pathologic specimen allows for an early and robust readout of therapeutic activity, which might be particularly helpful in the selection of combination regimens for further studies. Completed efforts investigating this theory include TOP1201 and the pilot study by Forde and colleagues. Results of the phase II TOP1201 study by Yi et al demonstrated significant activation of CD4/CD8 lymphocytes after chemotherapy and ipilimumab (Yervoy) in stage II-IIIA NSCLC, although it did not meet the primary endpoint of detecting a significant increase in circulating T cells with specificities against tumor-associated antigens.

 Yang et al subsequently demonstrated the safety and feasibility of surgical resection in this study population.

 Forde and colleagues treated a cohort of 22 patients with resectable stage I-IIA NSCLC with 2 cycles of nivolumab (Opdivo) prior to surgical resection.

 The neoadjuvant nivolumab was not only safe and feasible but also associated with a 45% pathologic response rate in 9 of 20 patients who underwent resection, and 3 patients had a complete response. In addition, biomarker analysis of this cohort yielded remarkable data as to neoantigen discovery and identification of activated T-cell clones, providing an excellent platform for future studies.

The single-arm nature of the above pilot studies limits further interpretation of the data. Notable ongoing neoadjuvant studies include a series of now-pivotal and potentially practice-changing phase III trials. IMpower030 is studying the role of neoadjuvant atezolizumab in resectable II, IIIA, or select IIIB NSCLC. KEYNOTE-671 (PEARLS) is investigating the combination of both neoadjuvant doublet chemotherapy and neoadjuvant/ adjuvant administration of pembrolizumab (Keytruda) in patients with resectable stage IIB or IIIA NSCLC. Finally, CheckMate-816 is studying whether either combined nivolumab and ipilimumab or nivolumab plus platinum doublet chemotherapy is superior to doublet chemotherapy alone in the neoadjuvant treatment of stage IB-IIIA NSCLC.

 Another immune checkpoint inhibitor, durvalumab, was recently approved for treatment of unresectable stage III NSCLC.

 This agent is now being investigated in a number of phase II neoadjuvant studies, including IONESCO, NCT02572843, and NCT02904954. In addition to studying durvalumab therapy, NC02904954 is examining whether there is an added benefit from the administration of stereotactic body radiation therapy (SBRT) prior to, or concurrently with, durvalumab therapy. Another ongoing trial, NCT03148327, examines this combination as adjuvant therapy in patients who are medically inoperable or who decline surgery. The investigation of SBRT in conjunction with durvalumab could further expand treatment options for early-stage patients who are undergoing immunotherapy, thanks to the abscopal effect, through which local irradiation of the primary tumor is followed by regression of disease at nonirradiated metastatic sites—a phenomenon hypothesized to occur due to generation of a systemic immune response following the release of neoantigens from the irradiated tumor.

 Within the past decade, as the use of immunotherapy has risen, there has been a growing consensus that a combination of radiotherapy and immunotherapy is superior to either modality alone, which certainly warrants further investigation in earlier-stage NSCLC. With the expanding use of curative radiation-based strategies in lung cancer management, these studies will provide key data for large groups of patients.

Additional studies are ongoing into the use of immunotherapy in the adjuvant setting. The pivotal ANVIL trial is a component of the phase III ALCHEMIST trial, which is studying the effects of adjuvant nivolumab versus observation for 

negative patients, while the KEYNOTE-091 trial is investigating the adjuvant use of pembrolizumab versus placebo, with or without standard adjuvant chemotherapy, in resected NSCLC. Additional adjuvant studies currently recruiting participants with stage IB-IIIA NSCLC are NCT02273375 (investigating durvalumab vs placebo) and IMpower010 (comparing adjuvant atezolizumab [Tecentriq] vs best supportive care following 4 cycles of doublet chemotherapy). Another study currently in the recruitment phase, NCT03447769, aims to evaluate the role of canakinumab (Ilaris) as adjuvant therapy in patients with stage II-IIIA and completely resected stage IIIB NSCLC. Canakinumab, a monoclonal antibody against the pro-inflammatory cytokine IL-1ß, was originally approved for treatment of a spectrum of autoinflammatory conditions. Analysis of the results of the 2017 CANTOS cardiovascular study incidentally revealed a highly significant reduction in lung cancer incidence and mortality in the canakinumab group relative to placebo, prompting further interest in its potential as a lung cancer therapy and opening novel avenues into the exploration of the role of the myeloid cell compartment in the tumor microenvironment.

As the role of targeted therapies and immunotherapy in early-stage lung cancer continues to be explored, it is crucial that further investments be made in the development of better biomarkers to facilitate patient selection and risk stratification. Research continues into additional biomarkers beyond 

 that represent actionable therapeutic targets or are associated with risk of progression of earlystage NSCLC. For instance, the myPlan Lung Cancer proprietary prognostic test developed by Myriad Genetics measures cell cycle progression genes; it has been validated in a cohort of 650 patients with stage I-II NSCLC and found to be a more significant indicator of mortality than pathologic cancer stage.

 Another important biomarker being explored is TMB, a measure of the number of mutations in a given tumor, as well as a surrogate marker for a tumor’s potential to generate an immune response via neoantigens. Initial studies in NSCLC have demonstrated an association between higher TMB and better response to immunotherapy; it appears that TMB might serve as a complementary biomarker to PD-L1 IHC in patient selection.

 Further studies will be necessary in the setting of early-stage NSCLC as this biomarker is further elucidated and refined. Finally, plasma-derived circulating tumor DNA (ctDNA) holds the potential to further expand the role of personalized therapy—making it available to those patients not amenable to tissue biopsy and enabling noninvasive repeat sampling so that therapy can be modified as needed over the course of treatment, as the molecular profile of an individual’s cancer changes.

 Its most promising role in the definitive setting might be as a biomarker of residual microscopic disease, allowing patient enrichment in adjuvant studies following delivery of definitive surgery or radiation-based therapy. The recently published study by Chaudhuri et al highlights the potential tremendous utility of ctDNA testing for risk stratification in this context.

 Among the outcome measures of the ALCHEMIST Screening Trial (NCT02194738) are the identification of new mutations at time of cancer recurrence and the correlation of ctDNA level with survival measures in these patients. Another study that recently started recruitment (NCT03465241) is investigating the role of ctDNA dynamic monitoring of stage II-IIIA NSCLC to verify its prognostic predictive effect.

In summary, following a 2-decade, significant lull in this critical area of research, we are now seeing much better-designed neoadjuvant and adjuvant studies based on proper biomarker selection, as well as optimized treatment choices founded upon recent advances in the metastatic setting. There is real hope that in the coming years, we will see tremendous changes in the management of early-stage lung cancer. The only way this can be achieved is through support by all relevant thoracic disciplines to allow timely completion of important studies whose results could hold the key to improving cure rates for the large number of patients with early-stage lung cancer worldwide.

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Articles

Following a 2-decade lull in early-stage lung cancer, we are now seeing much better-designed neoadjuvant and adjuvant studies based on proper biomarker selection, as well as optimized treatment choices founded upon recent advances in the metastatic setting.

Jason E. Sandler, MD

Articles

Early-Stage NSCLC Is Ripe for Change