In this article, we review the new developments in neoadjuvant therapy for lung cancer.
Lung cancer is the leading cause of cancer death in the United States and worldwide. While most patients present with advanced metastatic disease for which a cure is elusive, increased use of spiral CT screening has led to identification of more early-stage patients who can be treated. At the same time, immunotherapy and new targeted therapies have improved survival in advanced disease. These new therapies are now being studied in the neoadjuvant and adjuvant settings to reduce systemic recurrences and improve cure rates. The results of early clinical trials of checkpoint inhibitor immunotherapy alone and combined with chemotherapy, as well as those of neoadjuvant studies of molecular therapies, have been promising. Ongoing large neoadjuvant trials of immunotherapies and molecular therapies alone and in combination with chemotherapy are underway and eagerly awaited. In this article, we review these new developments in neoadjuvant therapy for lung cancer.
Click here to read an expert perspective from Fred R. Hirsch, MD, PhD, and Thomas Marron, MD, PhD.
While surgical resection of early-stage lung cancer cures some patients, only a minority remain recurrence-free at 5 years. Multiple trials have shown that the majority of recurrences are in distant sites. The high incidence of distant recurrence suggests that systemic therapies are important to improve cure rates. Systemic chemotherapy with cisplatin-based doublets has been shown to improve survival in advanced metastatic disease, so it was logical to evaluate this therapy following surgical resection. Early trials delivered neoadjuvant, perioperative, and adjuvant chemotherapy with surgical resection. Encouraging results of these early studies led to randomized trials of surgery alone vs surgery plus adjuvant or neoadjuvant chemotherapy, the results of which now inform clinical decision making. More recently, new targets in advanced non–small-cell lung cancer (NSCLC) utilizing molecular therapies or immunotherapies have improved survival in these patients.[3,4] Trials of these therapies in early-stage NSCLC are now underway. In this article, we review the data in support of chemotherapy, molecular therapy, and immunotherapy in early-stage lung cancer.
Since the majority of recurrences after surgical resection are in distant sites, starting systemic therapy as early as possible maximizes the likelihood of eradicating all micrometastases. Of note, the median age at diagnosis of NSCLC is approximately 70 years, and comorbidities are often present in these patients, particularly those with a history of smoking. This population is best able to tolerate systemic therapy and handle its complications when administered prior to surgery. Neoadjuvant therapy may prevent unnecessary surgery by identifying patients with resistant micrometastatic disease who progress in distant sites despite therapy. The neoadjuvant therapy phase can also be an opportunity to uncover additional comorbid conditions, the management of which can lead to safer surgery or, if not remediable, permit efficient planning of nonoperative therapies.
Pathologic changes in primary tumors at the time of resection provide a reliable way to assess the impact of neoadjuvant treatment on the tumor, and present an opportunity to determine which pathways are involved in allowing cells to persist despite therapy. The presence or absence of residual tumor also presents an opportunity to change or continue the induction regimen after surgery. Objective pathologic responses can be quantitated, and effects on the tumor microenvironment and on the tumor can be assessed.[5-7]
Compared with other types of therapy, neoadjuvant approaches can more rapidly translate clinical research findings into early drug approvals. Compliance with subsequent therapies may also be improved. The neoadjuvant therapy interval can provide additional time to implement and maintain smoking cessation preoperatively, an intervention critical to minimizing risk and allowing for pulmonary “prehabilitation” strategies. Advantages of neoadjuvant therapy are summarized in Table 1.
Past trials evaluating neoadjuvant chemotherapy in early-stage NSCLC were heavily influenced by results from adjuvant chemotherapy trials. Large randomized trials and meta-analyses of these adjuvant trials showed improved survival in the adjuvant chemotherapy arms, with a hazard ratio (HR) of 0.87 and an improved 5-year survival rate of about 5%. Multiple neoadjuvant trials were ongoing at the time that meta-analyses of adjuvant trials were published. Thus, many randomized neoadjuvant trials with a surgery-alone arm were stopped early. However, meta-analyses of these neoadjuvant chemotherapy trials were conducted. A meta-analysis of 15 randomized controlled neoadjuvant trials of 2,385 patients demonstrated that overall survival (OS) was significantly improved with preoperative chemotherapy followed by surgery compared with surgery alone (HR, 0.87; 95% CI, 0.78–0.96; P = .007). Preoperative chemotherapy translated into a 5% absolute improvement in OS at 5 years. Recurrence-free survival (RFS) was also improved with neoadjuvant chemotherapy (HR, 0.85; 95% CI, 0.76–0.94; P = .002). The absolute increase in RFS at 5 years was 6%. Additionally, neoadjuvant chemotherapy decreased the risk of distant recurrence (HR, 0.69; 95% CI, 0.58–0.82; P < .0001). The absolute increase in freedom from distant recurrence at 5 years was 10%. In contrast, adjuvant chemotherapy provided only a 5% absolute improvement in freedom from distant recurrence at 5 years. This meta-analysis of neoadjuvant therapy indicated that the time to locoregional recurrence was not significantly improved with preoperative therapy, suggesting its OS benefit is mainly secondary to decreased rates of distant recurrence.
The magnitude of OS benefit of neoadjuvant chemotherapy was similar to that of adjuvant chemotherapy, although head-to-head comparisons of these two systemic therapy approaches are scarce. One randomized trial, however, did attempt to directly compare neoadjuvant and adjuvant chemotherapy. In this trial, there was no significant difference in 5-year disease-free survival (DFS) or OS.
Thus, current guidelines recommend either neoadjuvant or adjuvant cisplatin doublet chemotherapy for patients with stage IB–IIIA NSCLC. There is still some uncertainty regarding the treatment of patients without nodal involvement. While some studies found that patients with tumors larger than 4 cm without nodal involvement had improved survival with adjuvant chemotherapy, others did not show such an advantage.
Additionally, the large meta-analysis discussed previously suggested that several other variables did not influence the relative OS benefit of neoadjuvant chemotherapy, including the particular chemotherapy regimen used, the number of chemotherapy agents in the regimen, and the type of platinum (cisplatin or carboplatin). Age, sex, histology (squamous vs non-squamous), performance status (0 vs 1 vs 2+), and number of chemotherapy cycles (2 vs 3) also did not appear to significantly influence the OS benefit of neoadjuvant chemotherapy. In some of the neoadjuvant chemotherapy trials, patients also received subsequent adjuvant chemotherapy and/or adjuvant radiation. For those receiving neoadjuvant chemotherapy, the relative OS benefit when compared with the surgery-alone group did not appear to differ between the adjuvant chemotherapy and/or adjuvant radiation groups. Because chemotherapy improved survival by only a small amount and recurrence occurred in local sites in some cases, chest radiotherapy was added to chemotherapy in both the adjuvant and neoadjuvant trials. In the adjuvant setting, postoperative chest radiotherapy was associated with decreased survival in stage I disease, but possible slightly improved survival in stage IIIAN2 disease.[9,13] Given controversy in the literature, common practice in the neoadjuvant stage IIIAN2 setting has also been variable, with some patients receiving triple-modality therapy with chemotherapy and radiotherapy along with surgery and others receiving chemotherapy alone. It is important that all patients be presented at multidisciplinary conferences so that a therapeutic strategy is determined before initiating treatment.
Several concerns with neoadjuvant chemotherapy are that it could increase perioperative complications, and that patients may progress to become unresectable prior to potentially curative surgery. Across several trials and meta-analyses, the incidence of perioperative complications and post-surgical mortality did not differ significantly between patients receiving neoadjuvant chemotherapy prior to surgery and those proceeding directly to surgery.[9,14] Additionally, the percentage of patients progressing during neoadjuvant chemotherapy to become unresectable was low, at 3% to 3.5%.
One of the potential benefits of neoadjuvant chemotherapy is that it may lead to downstaging of tumors, with resultant smaller surgeries and more complete resections. A few studies have suggested lower rates of pneumonectomy and higher rates of lobectomy for patients receiving neoadjuvant chemotherapy compared with those undergoing surgery. However, several other trials, as well as a large meta-analysis, suggest that the type of operation does not differ significantly between patients receiving neoadjuvant chemotherapy vs those who proceed directly to surgery. The complete resection rate has not been shown to be higher in those receiving neoadjuvant chemotherapy followed by surgery compared with patients undergoing surgery alone.
Concurrent neoadjuvant chemotherapy and radiation also benefits patients with superior sulcus tumors that are T3 to T4 and N0 to N1, which are a special clinical type of NSCLC. With this treatment approach, 2 cycles of cisplatin/etoposide are given concurrently with 45 Gy of radiation; patients with stable disease or better are given 2 more cycles of cisplatin/etoposide after surgery. Among patients receiving neoadjuvant chemoradiation, the 5-year OS rate is superior compared with historical controls receiving only neoadjuvant radiation (44% vs 30%). The OS with concurrent chemoradiation in these patients did not differ by tumor stage at baseline (T3 vs T4). In addition, a progression-free survival (PFS) benefit and fewer local recurrences were seen with neoadjuvant chemoradiation vs radiation in these patients.
Immunotherapy with checkpoint inhibitors that interrupt the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) regulatory axis have revolutionized the treatment of metastatic NSCLC and stage III disease that is not amenable to surgical resection.[4,16-19] By blocking the PD-1/PD-L1 axis, tumor-reactive T cells are better able to recognize and eliminate cancer cells, resulting in improved disease control. These therapies have rapidly become a mainstay of advanced NSCLC treatment due to their improved efficacy and favorable side effect profile compared with chemotherapy. In patients with high PD-L1 expression, the PD-1 inhibitor pembrolizumab alone produced superior survival compared with chemotherapy. On the other hand, in patients with lower levels of PD-L1 expression, the combination of chemotherapy plus an immune checkpoint inhibitor produced superior survival compared with chemotherapy alone.[17-19] With the success seen in the setting of advanced disease, checkpoint inhibitors are starting to be tested in patients with resectable lung cancer as well.
Multiple ongoing clinical trials incorporating checkpoint inhibitors into therapy for early-stage NSCLC are focused on the neoadjuvant setting (Table 2). Preclinical studies and early clinical trials appear to support this neoadjuvant approach. The optimal timing of preoperative checkpoint inhibition was studied in two orthotopic mouse models of breast cancer. Animals were treated with a variety of immune therapies before or after surgical resection. Long-term survivors were observed only in the groups that received neoadjuvant regulatory T-cell ablation or checkpoint inhibitors with a combination of PD1- and CD137-blocking antibodies. The survival advantage was dependent on cytotoxic CD8+ T cells, and, to a lesser extent, on CD4+ T cells; it was also significantly associated with the expansion of tumor-specific CD8+ T cells, which was not seen with immune intervention in the adjuvant setting. Similar results were reported in a xenograft mouse model of NSCLC utilizing combined cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and PD-1 blockade. Animals treated in a neoadjuvant fashion followed by surgery experienced improved OS and an increase in tumor-specific T-cell expansion compared with those treated in the adjuvant setting. These results highlight the possibility that the antitumor T-cell repertoire is optimally harnessed by checkpoint inhibitors when a larger amount of antigen is present vs minimal or micrometastatic disease postoperatively.
In the first published trial of neoadjuvant checkpoint therapy, 21 patients with operable stage I to III NSCLC were given nivolumab once every 2 weeks for 2 doses. At the time of surgery, approximately 4 weeks after the first nivolumab dose, 2 patients experienced radiographic disease response, 18 had stable disease, and 1 patient progressed. Remarkably, 9 of the 20 patients who underwent resection experienced a major pathologic response (MPR) with ≤ 10% viable tumor remaining. The radiographic and pathologic discordance appeared secondary to a dense immune infiltrate, areas of tumor cell death, and tissue repair with fibrosis. Exploratory analyses found an association between higher tumor mutational burden and a decreased degree of residual tumor at the time of surgery. Additionally, one patient with a complete pathologic response demonstrated expansion of tumor-specific T-cell clones in the peripheral blood. Despite these encouraging findings, one patient with MPR experienced a mediastinal lymph node recurrence and received concurrent chemoradiation, and two patients with significant residual tumor at the time of surgery developed metastatic disease. The neoadjuvant immunotherapy NEOSTAR trial at the University of Texas MD Anderson Cancer Center randomized patients to receive nivolumab or nivolumab plus ipilimumab before surgery. Preliminary results in 31 patients indicated an MPR rate of 25% in patients treated with nivolumab and 27% in patients treated with nivolumab plus ipilimumab.
Early-phase clinical trial data on neoadjuvant atezolizumab as monotherapy or in combination with chemotherapy have been reported.[25,26] As monotherapy, 2 doses of atezolizumab induced an MPR in 10 of 45 EGFR/ALK wild-type patients with stage IB to IIIB NSCLC. Patients with EGFR and ALK alterations were excluded from this efficacy analysis. However, 4 patients in the trial had EGFR-activating mutations and 1 patient had an ALK rearrangement. Data are available on 3 of these 5 patients. After neoadjuvant therapy, 1 patient with an EGFR mutation was no longer resectable. At the time of surgery, a second patient with EGFR-positive disease had 90% viable tumor, and the patient with an ALK rearrangement had 60% viable tumor.
In a second early-phase study, 14 patients with stage IB to IIIA NSCLC were administered 4 cycles of neoadjuvant atezolizumab plus carboplatin and nab-paclitaxel. Unlike the reported discordance with neoadjuvant checkpoint inhibitor therapy alone, 8 of the 14 patients who received concurrent atezolizumab and chemotherapy had a radiographic response, and 7 of 14 patients were found to have an MPR. Extended follow-up has yet to be released for neoadjuvant atezolizumab monotherapy; however, after a median of 8.6 months, there have been 4 recurrences following neoadjuvant atezolizumab plus chemotherapy.
As was observed with the neoadjuvant atezolizumab plus chemotherapy study, a phase II trial showed a high MPR with 3 cycles of neoadjuvant nivolumab plus carboplatin and paclitaxel. Of 30 evaluable patients in this trial, a MPR was reported in 24 of them. Similar to the neoadjuvant chemoimmunotherapy trial with atezolizumab plus carboplatin and nab-paclitaxel, there was greater concordance between radiographic and pathologic findings in this trial, in contrast to data from immune checkpoint inhibitor monotherapy. At the time of presentation of these data, no patients had developed recurrence; however, the median follow-up was short, at only 4.1 months.
Three phase III trials-IMpower030, CheckMate 816, and KEYNOTE-671-and multiple phase I and II trials are underway to better define the role of checkpoint inhibitors in neoadjuvant therapy for resectable NSCLC (Table 2). It is worth noting that 2 of the 3 phase III trials (IMpower030 and KEYNOTE-671) will administer subsequent checkpoint inhibitors in the adjuvant setting for 1 year.
As we transition to this new era of immunotherapy for NSCLC, multiple questions remain regarding the effective use of checkpoint inhibitors in the neoadjuvant setting. What is the role of chemotherapy, radiation therapy, or concurrent chemoradiation when checkpoint inhibitors are used? Can PD-L1 or tumor mutational burden testing be used to better identify patients who can receive a checkpoint inhibitor alone vs concurrent chemoimmunotherapy, similar to the metastatic setting? Will new biomarkers, such as MPR and clonal T- cell expansion, predict which individuals will have a long-lasting response? Finally, do patients with oncogenic drivers benefit from incorporating checkpoint inhibitors into neoadjuvant therapy? While it may take years before we know how to most effectively incorporate checkpoint inhibitors into neoadjuvant treatment of NSCLC, the progress made thus far represents a major step toward achieving more long-term cures in the early-stage setting.
A number of targeted compounds are available for the treatment of metastatic lung cancer harboring activating mutations in oncogenes such as EGFR, ALK, ROS1, BRAF, and MET. In early-stage disease, the RADIANT study evaluated 2 years of adjuvant treatment with erlotinib among patients with stage IB to IIIA tumors and positive EGFR testing by immunohistochemistry or fluorescent in situ hybridization. No benefit in DFS was demonstrated in patients treated with erlotinib vs placebo, although erlotinib prolonged DFS among patients with EGFR mutations (median, 46.4 months vs 28.5 months). This difference was not statistically significant after correcting for multiple comparisons; nevertheless, it generates the hypothesis that EGFR-directed treatment can be useful in the treatment of early-stage NSCLC, either as neoadjuvant or adjuvant therapy in patients with EGFR mutations.
A similar study conducted in China, the ADJUVANT/CTONG1104 trial, evaluated adjuvant gefitinib vs chemotherapy with cisplatin plus vinorelbine in patients with stage II to IIIA NSCLC and EGFR-activating mutations. An improvement in median DFS was seen with gefitinib: the median DFS was 28.7 months with gefitinib vs 18.0 months with chemotherapy (HR, 0.60; 95% CI, 0.42–0.87; P = .0054). However, gefitinib was administered for only 24 months on this trial, and the 3-year DFS rates were similar for both regimens. In addition, the DFS curves for the regimens approached each other at 36 months and beyond, suggesting that while targeted therapy may help delay recurrences when given in the adjuvant setting, this benefit may be dependent on continued drug administration and suppression of micrometastases. The OS data have not yet been reported for the RADIANT or ADJUVANT/CTONG1104 studies, and further follow-up is awaited to determine whether EGFR inhibition can increase the cure rate compared with surgery alone or surgery followed by adjuvant chemotherapy. Additionally, the optimal duration of EGFR inhibition in the adjuvant setting may need to be redefined given the findings on the ADJUVANT/CTONG1104 study after gefitinib was stopped.
Limited clinical trial data are available to guide neoadjuvant targeted therapy in molecularly defined subgroups of lung cancer patients. However, the concept of using small-molecule inhibitors of known oncogenic drivers prior to surgery in patients with earlier stages of disease is intriguing for a number of reasons. First, targeted agents induce tumor shrinkage in 60% to 70% of cases and have disease control rates of about 90%; therefore, delaying surgery poses little risk for tumor progression, a major concern with neoadjuvant treatments. Second, these agents are generally better tolerated than chemotherapy. Third, the high rate of major responses and downstaging is particularly attractive, especially in borderline resectable cases or those in which a pneumonectomy would otherwise be required. Lastly, neoadjuvant clinical trials are unique because they allow access to tissue before and after a systemic therapeutic intervention. This is particularly important for targeted therapies in patients with oncogene-driven lung cancer, where early adaptive events at the protein level are responsible for incomplete molecular inhibition of the driver and residual clinical disease.[33,34] Understanding the biology of residual disease in oncogene-driven lung cancers will help with the design of rational combination treatments in this patient population.
The CTONG1103 study randomized NSCLC patients with activating mutations in exons 19 or 21 of EGFR and stage IIIAN2 disease to either erlotinib for 42 days both before and 1 year after surgery or gemcitabine plus cisplatin for 2 cycles before and 2 cycles after surgery. Data from this trial were recently presented, and patients in the erlotinib arm achieved a higher response rate (54.1% vs 34.3%; P = .092) and longer PFS (median, 21.5 vs 11.9 months; P = .003), compared with the chemotherapy arm. Nevertheless, the rates of MPR were generally low (10.7% in the erlotinib arm vs 0% in the chemotherapy arm), and all non-censored patients in both arms had disease progression within 3 years of follow-up. Thus, it is unlikely that neoadjuvant erlotinib will improve the cure rate in this study.
A neoadjuvant clinical trial of crizotinib in patients with either ALK, ROS1, or MET alterations is underway. In this study, patients with early-stage NSCLC who are candidates for curative surgical treatment are screened for MET exon 14 skipping mutations, MET fusions, ALK fusions, and ROS1 fusions. If an alteration is identified, crizotinib is given for 6 weeks followed by PET/CT scan and surgical resection. The study has a strong translational rationale, since it will use the resection specimen to evaluate gene expression and changes in the microenvironment that occur with crizotinib treatment. A number of other neoadjuvant studies focusing on the EGFR population are also enrolling patients (Table 3).
The high rates of response to targeted therapies and the biology of lung cancers with certain oncogenic drivers offer unique opportunities to explore potentially beneficial treatments in the neoadjuvant setting, as well as to answer specific scientific questions. Further study and proof-of-concept data are needed to determine whether treatment of early-stage lung cancer with effective neoadjuvant targeted therapies can eradicate microscopic disease and improve cure rates. Additionally, genetic and pathway analyses of residual persisting tumor cells should be conducted to identify which pathways to inhibit, which in combination with tyrosine kinase inhibitor therapy, could lead to improved pathologic complete response rates-and perhaps a cure.
Financial Disclosure: The authors received financial support in part from the Colorado Lung Cancer SPORE Grant (P50 CA058187) and the Cancer Center Support Grant (National Cancer Institute P30 CA46934). Dr. Bunn receives consulting fees/honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Pfizer, Regeneron, and Takeda. Dr. Schenk receives honoraria for an educational presentation from Takeda and serves as a consultant for Rova-T/SCLC for AbbVie. Dr. Pacheco receives an honorarium from Takeda; consulting fees from AstraZeneca and Novartis; and research funding from Pfizer. Dr. Dimou has no significant interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Fred R. Hirsch, MD, PhD, and Thomas Marron, MD, PhD
Dr. Bunn et al describe the advantages of neoadjuvant therapy in non–small-cell lung cancer: an improved disease-free interval vs adjuvant therapy, potential tumor downstaging, and more time for smoking cessation and patient optimization before surgery. Starting immunotherapy while the tumor is present may enable a more robust immune response in the adjuvant setting.
Learning more about acquired/adaptive resistance and sensitizing and resistance mechanisms is key. The neoadjuvant “window” allows us to delineate the immunologic landscape for sensitivity and resistance to immunotherapy, and to understand differences between histologies. This will aid in developing biomarkers and identifying targets for combinatorial trial design.
Questions remain, however. While major pathologic response (MPR) was validated as a surrogate of survival in those treated with neoadjuvant chemotherapy, a recent study found significant histology-specific (adenocarcinoma vs squamous cell) differences in the MPR needed to correlate with survival. Since immunotherapy’s benefit in the neoadjuvant setting may be in the degree of immune priming, MPR’s usefulness is unclear. The recent International Association for the Study of Lung Cancer workshop may help guide clinical practice.
Since neoadjuvant therapy is for resectable disease, screening is critical. The National Lung Screening Trial and the NELSON study found screening significantly reduces mortality, but only 3% to 4% of the eligible US population has been screened. We expect that the NELSON trial will confirm improved screening rates. The ability to detect more early-stage lung cancers furthers our need to develop optimal treatments.
Financial Disclosure: Dr. Hirsch participated in scientific advisory boards (compensated) for AbbVie, AstraZeneca, Biocept, Bristol-Myers Squibb, Genentech/Roche, Helsinn, HTG Molecular Diagnostics, Loxo Oncology/Bayer, Merck, Novartis, Pfizer, and VENTANA; he also receives research funding from AbbVie (pending), Amgen, Bayer, Biodesix, Inc, Bristol-Myers Squibb, Clovis Oncology, HTG, Genentech, Mensana, Merck, and Rain Therapeutics, and has patents for EGFR immunohistochemistry and gene copy number as predictive biomarkers for therapies. Dr. Marron has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Hellmann MD, Chaft JE, William WN Jr, et al; University of Texas MD Anderson Lung Cancer Collaborative Group. Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol. 2014;15:e42-50.
2. Qu Y, Emoto K, Eguchi T, et al. Pathologic assessment after neoadjuvant chemotherapy for NSCLC: importance and implications of distinguishing adenocarcinoma from squamous cell carcinoma. J Thorac Oncol. 2019;14:482-93.
3. Blumenthal GM, Bunn PA Jr, Chaft JE, et al. Current status and future perspectives on neoadjuvant therapy in lung cancer. J Thorac Oncol. 2018;13:1818-31.
4. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409.
5. de Koning HJ, van der Aalst CM, Ten Haaf K, Oudkerk M. Effects of volume CT lung cancer screening: mortality results of the NELSON randomised-controlled population based trial. J Thorac Oncol. 2018;13:S185.
Dr. Hirsch is a Professor at the Icahn School of Medicine at Mount Sinai, New York, New York.
Dr. Marron is an Assistant Professor at the Icahn School of Medicine at Mount Sinai, New York, New York.
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