Introduction

Despite significant recent advances in treatment strategies, lung cancer remains the most common and lethal cancer worldwide, accounting for 11.6% of all new cancer diagnoses (greater than 2 million cases) and 18.4% of all cancer deaths per year [1]. It is anticipated that over 228,000 new cases of lung cancer will be diagnosed and 135,000 deaths will occur in the USA in 2020 [2]. Of these cases, the vast majority (85%) are classified as non-small cell lung cancer (NSCLC) [3, 4]. Though the majority of new NSCLC diagnoses are stage IV, approximately 40% of new NSCLC cases are stages I–III at presentation, representing a significant group of patients who could be treated with curative intent and benefit from early surgical resection [5]. Efforts to increase lung cancer screening may increase the proportion of patients diagnosed in earlier stages. For patients with pathologically confirmed stage IA NSCLC, 5-year survival rates are as high as 80–90% [6]. Unfortunately, many patients treated with complete surgical resection experience disease recurrence and have poor survival outcomes. In one study, 20% of patients with stages I–II surgically resected had recurrence and 7% developed new primary lung cancers using the AJCC 7th ed. staging system [7]. In this study, most recurrences occurred at distant sites and within 4 years of the surgery. Other reports indicate higher recurrence rates, particularly as stage increases [8,9,10]. As a result, 5-year survival rates range from 90% in those with localized disease to as low as 30% in those with regional disease [11]. This is substantially worse than most other solid tumors [12, 13].

In an effort to decrease rates of post-surgical relapse and improve overall survival, adjuvant chemotherapy following complete resection was investigated with the hope that treatment of microscopic residual and micro-metastatic disease would improve outcomes. This hypothesis was supported in a 1995 meta-analysis that showed a 5% absolute benefit in 5-year overall survival with adjuvant cisplatin-based chemotherapy [14]. Adjuvant chemotherapy received more widespread acceptance in the early to mid-2000s after several randomized phase III trials demonstrated survival improvements with its use. The largest effort was the International Adjuvant Lung Cancer Trial (IALT) that randomized 1867 patients with stages I–III NSCLC to several cisplatin-based chemotherapy regimens and demonstrated a 4% absolute survival benefit at 5 years [15]. Over 80% of patients on this trial received etoposide or vinorelbine as the cisplatin partner. The JBR.10 trial enrolled only stage IB or stage II patients and randomized to cisplatin and vinorelbine versus observation, and resulted in a larger benefit of 15% absolute survival improvement at 5 years that was statistically significant (HR 0.69; p = 0.03) [16]. The LACE meta-analysis of 5 trials of adjuvant cisplatin-based chemotherapy noted a 5.4% overall survival benefit at 5 years, with 66% of patients developing grade 3 or 4 toxicities due to therapy [17]. Importantly, this study demonstrated that the magnitude of benefit increases with stage; patients with stages II and IIIA derived a 10% and 13% overall survival benefit from adjuvant chemotherapy, respectively. A phase III study adding bevacizumab to adjuvant platinum-based regimens showed no improvement in this absolute survival benefit and demonstrated similar rates of adverse events [18]. An early comparison of subgroups based on chemotherapy regimen, which included pemetrexed and cisplatin for the first time in the adjuvant setting, did not seem to indicate a survival difference, although data was immature at the time of publication. Multiple current guidelines recommend adjuvant chemotherapy as the standard of care for patients with surgically resected stages II to III NSCLC and consideration of adjuvant therapy for patients with higher risk stage I NSCLC (such as those measuring 4.0 cm) [19,20,21].

Adjuvant chemotherapy has become the standard of care, but risks of recurrence are still high, and new strategies to further improve on these gains in surgically resectable NSCLC are needed. The most natural idea to further survival improvements is to apply the lessons learned from the gains in survival seen in the metastatic setting. This includes the use of oral targeted therapies for patients with oncogenic driver mutations (EGFR, ALK, ROS1, RET, NTRK, MET, etc.) and the incorporation of immunotherapy into treatments for early stage NSCLC. For patients with EGFR mutant NSCLC, adjuvant erlotinib has demonstrated improved disease-free survival in two completed studies (SELECT and ADJUVANT) [22, 23]. Several phase III trials are ongoing to assess the benefits of adjuvant targeted therapies in patients with EGFR mutations or ALK gene rearrangements (ALCHEMIST, ADAURA, ALINA) [24,25,26].

In recent years, the emergence of immune checkpoint inhibitors (immunotherapy) targeting PD-1 and PD-L1 has revolutionized treatment of advanced-stage NSCLC. After multiple studies demonstrated improved overall survival with immunotherapy in the metastatic setting when compared with chemotherapy alone, immune checkpoint inhibitors are now routinely used either alone or in combination with chemotherapy in the first-line setting in the majority of patients with stage IV NSCLC [27,28,29,30,31]. The PACIFIC trial showed improved survival with the anti-PDL-1 agent durvalumab as a consolidative therapy following chemotherapy and radiation in those with unresectable stage III NSCLC [32]. With additional follow-up from this trial, the 3-year survival rate was 57%, setting a new bar for future stage III trials [33]. With the remarkable success of immunotherapy in advanced disease and the relative stagnation of survival outcomes in locally advanced disease amenable to resection, attention has now turned to whether checkpoint inhibitor use could improve clinical outcomes for patients with surgically resectable, earlier-stage lung cancer.

Rationale for Neoadjuvant Therapy

There are a number of potential benefits to treating with systemic therapy prior to surgical resection. First, neoadjuvant treatment may allow for downstaging and increase the likelihood of complete surgical resection, particularly for patients with larger tumors or those in anatomically difficult locations, although this has been an elusive goal. In addition to reducing tumor size and burden, systemic neoadjuvant therapy offers earlier treatment of micro-metastatic disease, thus hopefully reducing risk of recurrence following eventual resection. It also allows for earlier assessment of response to the chosen systemic therapy, which could provide valuable prognostic information for the patient and provider; for example, tumors that are refractory to systemic therapy or exhibit rapid progression may have a particularly aggressive phenotype with a poor prognosis and high metastatic potential where surgery may have been destined to fail. Furthermore, subjects who have not yet experienced surgical intervention are potentially healthier and thus more likely to tolerate and complete a course of systemic therapy. It is estimated that only about 40–50% of patients receive the full prescribed number of cycles of adjuvant chemotherapy and, by giving it up front, compliance can increase to as high as 90–96% [34,35,36,37]. Finally, neoadjuvant therapy allows for the possibility of using pathologic response in resection specimens as a surrogate endpoint for survival that, beyond the clinical benefit of providing earlier response data, also has the potential to expedite clinical trial results that would otherwise require many years to accumulate survival data [38•]. With pathologic assessment after treatment, there also is potential to study the effects of adding additional therapy and/or changing agents postoperatively.

Beyond these clinical and logistic benefits of a neoadjuvant approach, immunotherapy use in this setting may provide additional biologic advantages owing to its unique mechanism of action. Immune checkpoint inhibitors initiate T cell activation and expansion upon interaction with tumor cells, which function as the primary antigen source [39]. Beginning immunotherapy exposure in the neoadjuvant setting, prior to surgical removal of the tumor, could maximize antigen exposure to the activated T cells and allow for not only a more robust initial response but also a durable response that could continue to act on residual micro-metastatic disease well after primary tumor removal. This hypothesis is supported by preclinical data in mice with metastatic triple-negative breast cancer that showed neoadjuvant administration of a variety of immunotherapies (anti-CD25, anti-PD1 alone, or with anti-CD137) was superior when given prior to, rather than following, primary tumor resection [40]. Not only was improvement in disease burden and increased survival seen in the neoadjuvant treatment mice, greater peripheral CD8+ T cell expansion was also observed when compared with the adjuvant group.

Neoadjuvant Immunotherapy: Safety and Surgical Outcomes

Although there may be benefits with neoadjuvant immunotherapy, its mechanism of action raises potential safety concerns in the neoadjuvant setting when planning for pulmonary resection. It is unclear if the inflammatory response that occurs with immunotherapy could present technical challenges and potentially compromise a planned resection. Immune-related adverse events, including pneumonitis, adrenal insufficiency, and other endocrinopathies, could delay the timing of resection and also increase risk perioperatively. Additionally, the treatment of some side effects with immunosuppressive therapies (including corticosteroids) could adversely affect surgical outcomes and surgical candidacy, or lead to substantial delays between systemic therapy and resection.

In an initial investigation of the safety and feasibility of neoadjuvant immunotherapy use with planned pulmonary resection, Bott and colleagues performed a retrospective review of 19 patients who underwent pulmonary resection within 6 months of receiving an immune checkpoint inhibitor [41]. This cohort included patients with primary NSCLC (47%) or other primary malignancies that had metastasized, such as melanoma (37%). The surgeries were largely successful, with margin-negative resection achieved in 95% of cases. Surgical complications occurred in 32% of patients, with only one of the complications greater than a grade 1 or a grade 2. This was in line with past reports of post-induction resections, as was the mean operative time. The authors did note that post-treatment fibrotic adhesions were documented in several cases, though this was not a universal occurrence.

Prospective data supporting the safety and feasibility of neoadjuvant immunotherapy in NSCLC has also begun to emerge. As a follow-up to their phase II trial TOP 1201, Yang and colleagues gathered postoperative data on 13 patients with stages II–IIIA NSCLC who underwent resection following neoadjuvant chemotherapy plus ipilimumab and compared these outcomes with historical controls who received standard neoadjuvant chemotherapy [42]. Resection occurred within 12 weeks of completion of neoadjuvant therapy, and the authors found no difference in perioperative morbidity and mortality when compared with historical control data, including comparable rates of pneumonia, respiratory failure, re-intubation, chest tube air leak, and atrial fibrillation. Though analyses were descriptive secondary to small sample size, this study provided further support that neoadjuvant immunotherapy use for NSCLC with planned resection could be both safe and feasible.

In a prospective, single-arm phase II trial of neoadjuvant nivolumab for two cycles for patients with stage IB-IIIA disease, neoadjuvant nivolumab was found to be both safe and feasible, with all eligible patients proceeding to surgery as planned and no surgical delays noted [43••]. Though 23% of patients experienced nivolumab-related adverse events, only one experienced a toxicity of grade 3 or greater (a case of grade 3 post-obstructive pneumonia after one dose of nivolumab). Bott et al. reported surgical outcomes for the 20 patients who underwent surgery on this trial [44••]. Of note, the two centers involved in the study are known to handle high volume lung cancer surgery and are worldwide referral centers for complex cases. Over half the cases attempted by video-assisted thorascopic surgery (VATS) required conversion to thoracotomy, which is higher than expected conversion rates of 10–20% [45]. This higher rate of open procedures was attributed to hilar inflammation and fibrosis. There were no perioperative mortalities, and overall risks were felt to be within a similar and acceptable range compared with other neoadjuvant strategies.

Surgical experience with post-neoadjuvant immunotherapy remains in its infancy and is limited in most cases to clinical trial settings at academic medical centers. Anecdotally, these are cases best suited to experienced surgeons who are comfortable operating on a difficult pulmonary hilum, and minimally invasive approaches may be more challenging [42, 46].

Neoadjuvant Immunotherapy: Efficacy Outcomes

Several phase II trials evaluating neoadjuvant immunotherapy or immunotherapy in combination with chemotherapy have completed or are ongoing (Table 1). Forde and colleagues completed a phase II pilot study examining 2 cycles of neoadjuvant nivolumab in patients with untreated, surgically resectable stage IB-IIIA NSCLC [43••]. Although the primary endpoint was safety and feasibility, which was discussed above, one of the most striking findings of this study was a higher than anticipated major pathologic response rate (MPR) of 45% (9 of 20) compared with an objective radiographic response of 10%. MPR is defined as tumors with no more than 10% of viable cells remaining [38•]. The MPR seen in this study was quite impressive after only two doses of nivolumab in a PD-L1 unselected population, although the results should be interpreted with caution given the small sample size. The discrepancy between radiographic and pathologic response may indicate that radiographic assessments may significantly underestimate benefits derived from immunotherapy. Deep sequencing of the T cell receptor gene (TCR) was performed in 9 patients (3 with MPR, 6 without), and those with MPR showed increased T cell clonality overall, as well as more frequent T cell clones in not only the tumor but also the peripheral blood, supporting the hypothesis that tumor-specific T cell expansion induced by PD-1 inhibitors can spread to sites beyond the primary tumor and address micro-metastatic disease. Though the study was not powered to evaluate survival, it was noted that 80% of patients (16 of 20) were alive and recurrence free at a median of 12 months following resection. In an abstract report of extended follow-up data, 75% of patients (15 of 20) remained alive at 30 months, with recurrence-free survival of 69% at 24 months [47]. Though the significance of survival data in this study is limited by its small size and relatively short follow-up period, the clinical outcomes are promising.

Table 1 Select completed and ongoing phase II neoadjuvant immunotherapy trials for NSCLC
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The LCMC3 is a similarly designed phase II neoadjuvant trial evaluating 2 cycles of atezolizumab followed by surgery, adjuvant chemotherapy, and 12 months of atezolizumab. Interim results were reported after 101 patients enrolled, of which 77 in the primary efficacy population underwent surgery. Although the reported MPR of 18% was not as high as that seen in the Forde et al. nivolumab study, this interim analysis passed its futility boundary and accrual is ongoing [48].

The NEOSTAR trial randomized 44 patients with stages I–IIIA NSCLC to either neoadjuvant nivolumab plus ipilimumab or neoadjuvant nivolumab monotherapy. Of the 37 patients who proceeded to resection, 30% had MPR (44% in the nivolumab plus ipilimumab arm versus 19% in the nivolumab monotherapy arm), and pre-treatment tumor PD-L1 was higher in those who achieved MPR (80%) than those who did not (1%) [49]. Results from a third arm evaluating neoadjuvant nivolumab plus platinum doublet chemotherapy have yet to be reported.

Due to significant survival improvements seen in the metastatic setting with combination chemotherapy and anti-PD-1 or anti-PD-L1 immunotherapy, several neoadjuvant trials have incorporated this approach as well. A multicenter study in Spain, the NADIM trial, evaluated three cycles of neoadjuvant nivolumab with carboplatin and paclitaxel every 3 weeks in patients with resectable stage IIIA disease, followed by 1 year of adjuvant nivolumab [50••]. Enrollment has been completed with 46 patients, with 41 undergoing surgery with a 100% R0 resection rate. Researchers reported 85% of patients achieved MPR on resection, of which 71% had pathologic complete response (pCR, the absence of any viable tumor cells at time of resection). Downstaging occurred in 90% of cases. Though these rates of pathologic and complete response are remarkably higher than previously seen in early-stage NSCLC, it is unclear if this will result in a survival benefit, as this data is still maturing. In the USA, an NCI-sponsored phase II trial, the Alliance Foundation Trial 46 (NCT04062708 or “CHIO 3”), is enrolling patients with stage IIIA/B N2 positive patients and will examine N2 nodal clearance following 4 cycles of platinum doublet chemotherapy with durvalumab. Unlike NADIM, this trial incorporates postoperative radiation therapy (PORT) in addition to the 1 year of postoperative immunotherapy.

A single-arm trial investigating neoadjuvant atezolizumab in combination with carboplatin and nab-paclitaxel is the only trial to date to report results with immunotherapy combined with chemotherapy for patients with earlier stage disease. Early data available on 14 patients showed an MPR of 50% (7 of 14), and 21% with pCR (3 of 14) [51]. Several other trials of single agent checkpoint inhibitors alone or in combination with chemotherapy are ongoing in the USA and worldwide (Table 1).

Given the early success seen in multiple phase II trials, several large phase III efforts are ongoing comparing various neoadjuvant immunotherapy approaches to neoadjuvant chemotherapy alone (or with placebo) (Table 2). Each of these has slightly different designs and endpoints. These studies will be vital in elucidating the potential clinical benefit gained from shifting immunotherapy to use earlier in the disease course and will shed light on the correlation between radiographic response, pathologic response, and survival.

Table 2 Ongoing phase III neoadjuvant immunotherapy trials for NSCLC
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Unanswered Questions, Future Directions

Many unanswered questions remain regarding the use of immunotherapy in the neoadjuvant setting. At this time, unanswered questions about immunotherapy for metastatic NSCLC are applicable to neoadjuvant treatment as well, particularly (1) which biomarkers (PD-L1, tumor mutational burden, or others), if any, should be used to identify patients appropriate for immunotherapy; (2) which therapy (immunotherapy alone, combination immunotherapy, or immunotherapy combined with chemotherapy) is safe and most effective; and (3) what is the optimal duration of immunotherapy, particularly postoperatively?

One of the most important ongoing questions is how to best evaluate response to immunotherapy in the neoadjuvant setting. Classically, radiologic response of a solid malignancy to a chosen therapy is assessed using RECIST criteria for response [52]. However, Forde and colleagues noted that a number of patients with NSCLC who showed no radiographic response to neoadjuvant nivolumab actually had MPR at time of resection, and that 2 patients with MPR were actually classified as having increased tumor size on imaging [43••]. Similarly, the NADIM trial noted an underreporting of response by RECIST criteria when compared with MPR [50••]. This suggests that current radiographic criteria may not appropriately capture response to neoadjuvant immunotherapy, and raises the concern that progression noted on imaging may in fact just be “pseudoprogression” representing an appropriate tumor infiltration of immune cells. Management of pseudoprogression in the metastatic setting typically requires repeat imaging to confirm true progression.

This raises an important word of caution—in this new era of immunotherapy, we must look at all factors, not just radiographic criteria, to determine response to therapy. There are new guidelines for redefining response criteria for patients receiving immunotherapy [53,54,55]. Stable disease after 2–4 cycles of neoadjuvant immunotherapy may greatly underestimate the effects of this treatment when there may actually be an MPR with tumor infiltrating lymphocytes. Due to limited number of cycles of treatment prior to planned surgery, confirmatory imaging in cases of pseudoprogression may not typically occur. In these cases, we must be cautious that these patients who may in fact have a favorable response are not excluded from curative surgery. However, it is equally imperative that we decipher true progression from pseudoprogression. A patient with enlarging lesions coupled with worsening symptoms, declining performance status, or new distant metastases, for example, likely has true disease progression rather than an immune phenomenon. Finally, when immunotherapy is combined with chemotherapy, it remains to be seen whether immune response criteria outperform traditional RECIST.

An unintended consequence of improved therapies available for those with lung cancer, particularly in early stage disease, is that using measures such as overall survival or disease-free survival as primary endpoints now require years before data maturation. The increased time and resources required to complete such studies run the risk of delaying progress in the field. In response to this challenge, surrogate measures for survival have been explored. In breast cancer, pCR has been investigated as a surrogate endpoint for survival, and the FDA now provides guidance on using this as a surrogate endpoint for accelerated approval [56]. For NSCLC, Hellmann and colleagues proposed MPR as a surrogate measure for survival with neoadjuvant chemotherapy [38•]. This proposal is based on MPR’s association with overall survival in both retrospective and prospective studies, its ability to reflect magnitude of treatment effect, and its applicability to NSCLC regardless of stage. They opted for MPR over pCR due to the relative infrequency of pCR in past NSCLC trials, noting a median rate of 4% when reviewing 15 trials of neoadjuvant chemotherapy for NSCLC. It is unclear whether an improvement in MPR alone would be sufficient for FDA approval of an immunotherapy agent in the neoadjuvant setting. If not, event-free survival and overall survival will take much longer to read out from the ongoing phase III trials.

Recognizing that the difference in mechanism of action between immunotherapy and chemotherapy may result in different histopathologic features, Cottrell et al. proposed a novel “Immune-Related Pathologic Response Criteria” (irPRC) for neoadjuvant immunotherapy [57]. In a follow-up to their previous study of neoadjuvant nivolumab in NSCLC, they examined the resection specimens of the 20 treated patients and defined an area of immune-mediated tumor clearance, which they termed the “regression bed,” to include the following features, all of which were seen more frequently in MPR patients versus non-MPR patients: immune activation (with dense tumor-infiltrating lymphocytes); massive tumor cell death (cholesterol clefts); and tissue repair (neovascularization, proliferative fibrosis). They also noted that this regression bed accounted for the discrepancy that had previously been noted between rates of MPR and rates of response on imaging by RECIST criteria.

Previous and ongoing neoadjuvant studies reviewed here focus on stages I–III surgically resectable NSCLC. However, in some cases, there may be a role for surgery in patients with stage IV limited metastatic disease, or so-called “oligometastatic” disease. As more effective therapies are developed, consideration of surgical approaches for curative intent in patients with stage IV disease is possible and more formalized “neoadjuvant” studies may be warranted in this setting as well. A recent update on a trial that treated patients with stage IV NSCLC with 3 or fewer sites of metastatic disease with local consolidative therapy, radiation, and/or surgery demonstrated a significant improvement in median overall survival (41.2 vs. 18.9 months) [58]. Although we would not necessarily define this as neoadjuvant therapy, multidisciplinary involvement and planning for surgery up front for these patients with potentially surgically resectable disease is warranted in these cases, and further studies to elucidate the role and optimal duration of immunotherapy in this setting are needed. Carefully selected patients with stage IV NSCLC may derive significant survival improvements from this approach.

Conclusion

Shifting immunotherapy agents from use almost exclusively in advanced stage NSCLC to the preoperative setting represents a promising treatment avenue with the potential to improve survival in a subset of NSCLC patients where outcomes have otherwise stagnated. Though clinical trial data is still emerging, the most recent data support that lung resection following neoadjuvant immunotherapy is both safe and feasible. With the dramatic gains seen with immunotherapy in the metastatic and non-surgical stage III settings and early promising data in neoadjuvant studies for surgically resectable NSCLC, we eagerly await data from multiple ongoing trials. Findings from these ongoing trials will be essential in determining how to best integrate this treatment model in those with locally advanced NSCLC.