Surgical resection is the preferred treatment for patients with operable early-stage non-small cell lung cancer (NSCLC). Unfortunately, however, more than 50% of patients who are treated with surgery alone will relapse, which reduces overall survival (OS). Perioperative (neoadjuvant or adjuvant) chemotherapy to prevent disease recurrence after surgery provides only a modest (~5%) improvement in five-year OS and is also a source of toxicity. Efforts to test new therapeutic strategies for patients with operable NSCLC have proved challenging because using OS as a measure of clinical benefit requires large patient numbers and increased time of follow-up. Recently, we and others demonstrated that a major pathologic response (MPR), defined as ≤ 10% viable tumor in resected specimens, provides an objective criterion of response of early-stage NSCLC to neoadjuvant chemotherapy and correlates with long-term survival outcomes. We also generated preclinical models of spontaneously metastatic and resectable NSCLC that provide a readout of tumor antigen-specific immune responses in mice treated with neoadjuvant therapy. Preclinical studies using these models revealed that a neoadjuvant strategy that inhibited both PD-1 and CTLA-4 immune checkpoint proteins was superior to either monotherapy or adjuvant combined therapy at reducing the frequency of lung metastases, improving survival and enhancing the tumor-specific and total CD8+ T cell infiltrate. Clinical studies in patients with advanced NSCLC demonstrated that combined nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) also produced greater response rates compared with nivolumab monotherapy, and first-line nivolumab plus ipilimumab treatment induced longer OS than chemotherapy in some patients. The abovementioned studies prompted us to launch the NEOSTAR study, the first reported phase 2 randomized trial evaluating neoadjuvant nivolumab and nivolumab plus ipilimumab in 44 patients with resectable NSCLC (NCT03158129) with MPR as primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy (conservative rate 15%) in localized NSCLC. The addition of ipilimumab to nivolumab crossed the prespecified efficacy trial boundary by producing an MPR rate of 38% in 21 treated patients. Nivolumab monotherapy produced an MPR rate of 22% in 23 treated patients. The combination also induced twice as many MPRs in resected patients compared with nivolumab alone (50% vs. 24%) and a greater rate of pathologic complete responses (pCRs) compared with nivolumab (38% vs. 10%). To put this into context, several clinical trials of neoadjuvant platinum doublet chemotherapy reported a median pCR rate of only 4%. Exploratory biomarker studies revealed that overall elevated tumor PD-L1 expression at baseline was associated with responses to neoadjuvant ICIs. However, we also observed responses in patients lacking pretreatment tumor PD-L1, suggesting the need for additional PD-L1 validation studies in larger clinical cohorts. Nivolumab and ipilimumab exert their effects through distinct non-redundant mechanisms and we noted differences in the immune composition of tumors in patients treated with nivolumab plus ipilimumab compared with those treated with only nivolumab. We found that tumors treated with combination therapy possessed higher frequencies of CD3+ T cells, CD4+ (non-Treg) CD103+ and CD8+CD103+ tissue-resident memory and effector memory T cells by flow cytometry. Furthermore, multiplex immunofluorescent staining of tumor samples revealed increased densities of CD3+, CD3+CD8+ and effector memory T cells in tumors treated with combination therapy as compared to baseline. We also noted that distinct gut microbiome signatures were associated with pathologic responses. The relative abundance of certain bacteria, including Ruminococcus and Akkermansia spp., was associated with pathologic responses to neoadjuvant combination ICIs and with T cell clonality in resected tumors. Further studies are needed to determine the mechanisms between microbial signatures and antitumor immune responses in these tumors. We noted that some patients enrolled in the NEOSTAR trial developed a phenomenon we referred to as nodal immune flare (NIF). NIF is characterized by the radiographic appearance of disease progression in lymph nodes that were histologically negative at baseline and became enlarged and/or FDG avid after neoadjuvant ICIs. Invasive pathologic examination of the flaring nodes after treatment demonstrated de novo non-caseating granulomas that are devoid of malignant cells. The overall incidence of NIF on imaging following neoadjuvant ICIs in our study was 16% (7/44). I will discuss new results from an independent clinical cohort of patients with resected NSCLC that suggest NIF does not occur following neoadjuvant chemotherapy, and thus may strictly be an ICI-related phenomenon. There was no significant association between NIF and response to therapy, perhaps indicating that the cellular and molecular mechanisms of systemic immunity driving NIF and the antitumor immune response may be distinct from one another. Recent studies suggest chemotherapy may be synergistic with ICIs and further enhance antitumor responses. We demonstrated that neoadjuvant chemotherapy induces higher densities of CD3+ lymphocytes and enhanced PD-L1 expression in resected NSCLC. Front-line nivolumab plus ipilimumab combined with chemotherapy improved survival compared with chemotherapy alone in patients with advanced NSCLC. Results from recent phase 2 chemo-immunotherapy studies have demonstrated robust MPR rates ranging from 57% after neoadjuvant atezolizumab plus chemotherapy (NCT02716038) to 83% following neoadjuvant nivolumab plus chemotherapy in the NADIM study (NCT03081689). Based on these results, we expanded our NEOSTAR trial to a modular, platform design of modular single-arm studies to expedite testing of promising neoadjuvant therapies using MPR as primary endpoint. We have tested neoadjuvant platinum-based chemotherapy plus nivolumab in 22 patients with resectable NSCLC (Arm C) and we are currently evaluating neoadjuvant chemotherapy combined with nivolumab plus ipilimumab. Randomized phase 3 studies are testing neoadjuvant chemotherapy compared to chemotherapy plus ICI (+/- adjuvant ICI) using event-free survival plus OS or MPR/pCR as primary endpoints and will prospectively validate the use of surrogate endpoints to predict improvements in outcomes. I will present unpublished results from the NEOSTAR study, including the clinical outcomes in patients treated with neoadjuvant platinum-based chemotherapy plus nivolumab, as well as in patients whose tumors harbor oncogenic drivers. I will compare the pathological tumor regression, and the MPR and pCR rates from neoadjuvant nivolumab plus chemotherapy arm with those from nivolumab monotherapy and nivolumab combined with ipilimumab. I will also discuss some of the challenges that we face as we strive to further improve clinical outcomes for patients with early-stage NSCLC and maximize the clinical effectiveness of ICIs, including intertrial variability in assessing tumor pathological regression and biomarkers of therapeutic response. Potential future directions for the field will also be considered.

Citation Format: Tina Cascone. Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY13-03.