Abstract
Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)
Main
Immune checkpoint therapy has changed the treatment paradigm for patients with non-small cell lung cancer (NSCLC); however, until recently, much of the progress had been confined to the locally advanced and metastatic setting. Now, considerable effort is focused on how to best leverage immune checkpoint therapy for patients with resectable early-stage NSCLC and prevent post-operative tumor recurrence1, using adjuvant2 or neoadjuvant3 approaches targeting the PD-(L)1 axis. Neoadjuvant immunotherapy trials are based on the premise that an intact tumor immune microenvironment elicits the most robust responses to immune checkpoint inhibitors1. These trials have benefited by using major pathologic response (MPR) or complete pathologic response (pCR) as surrogate endpoints of long-term outcomes.
Studies of neoadjuvant single-agent anti-PD-(L)1 therapy have yielded MPR rates between 6.7% and 45%4,5,6,7,8. The addition of platinum-based chemotherapy to immunotherapy has proved promising9, with initial phase 2 studies producing MPR and pCR rates of 57–83% and 33–63%, respectively10,11. CheckMate-816 was the first large-scale phase 3 randomized trial to evaluate neoadjuvant nivolumab plus chemotherapy (Nivo+CT) versus chemotherapy (CT) alone in patients with resectable stage IB–IIIA NSCLC and demonstrated a pCR rate of 24.0% with Nivo+CT compared to 2.2% with CT alone, as well as improved event-free survival (EFS)3, which led to FDA approval of neoadjuvant Nivo+CT as the new standard of care for patients with resectable NSCLC.
Another strategy to enhance the efficacy of neoadjuvant anti-PD-(L)1 therapy is to combine it with the cytotoxic T-lymphocyte-associated protein (CTLA-4) immune checkpoint inhibitor ipilimumab (Ipi), given that the two inhibitors impact the immune system through two independent, and possibly complementary, mechanisms of action12,13. In the phase 2 randomized NEOSTAR study, we evaluated neoadjuvant Nivo or Nivo+Ipi followed by surgery in 44 patients with operable NSCLC8. We found that Nivo and Nivo+Ipi produced MPR rates of 22% and 38%, respectively. Addition of Ipi to Nivo also resulted in higher pCR rates, less viable tumor and enhanced tumor immune infiltration8.
The randomized phase 2 NEOSTAR trial evolved into a platform trial of sequential, single-center, single-arm, phase 2 studies with a modular design using MPR in each individual arm as the primary endpoint, which was hypothesized to be greater than historical controls of neoadjuvant CT14. Here we report the primary efficacy results of NEOSTAR arm C evaluating neoadjuvant Nivo+CT and arm D testing neoadjuvant Ipi+Nivo+CT followed by surgical resection in patients with stage IB–IIIA NSCLC. Select secondary endpoints included radiological responses (RECIST version 1.1 (ref. 15)), pCR, toxicity, surgical resectability and perioperative morbidity/mortality, overall survival (OS) and EFS, in alignment with time-to-event analyses performed in other neoadjuvant studies3,16, and tissue immune infiltrate analysis. Exploratory endpoints included tumor molecular, immunological and fecal microbiome biomarkers (Extended Data Fig. 1).
Results
Patient baseline characteristics and treatment disposition
Between 14 December 2018 and 22 July 2019, 23 patients were screened and 22 enrolled on the Nivo+CT treatment arm (Fig. 1). A full list of inclusion and exclusion criteria can be found in Methods. The baseline clinicopathological patient characteristics are shown in Table 1. All patients underwent baseline invasive mediastinal staging. Eleven (50%) patients had clinical stage IIIA (five with N2 disease, single station). Eighty-six percent (19/22) of patients completed the three planned cycles of neoadjuvant therapy, and 14% (3/22) received two cycles owing to treatment-related adverse events (TRAEs). Eight patients experienced CT dose reduction due to TRAEs. Between 30 December 2019 and 1 December 2020, 25 patients were screened and 22 enrolled on the Ipi+Nivo+CT treatment arm (Fig. 1). The baseline clinicopathological patient characteristics are shown in Table 1. All patients underwent invasive mediastinal staging. Thirteen (59%) patients presented with stage IIIA (nine with N2 disease, single station). Nineteen (86%) patients completed the planned three cycles of neoadjuvant therapies. Two patients discontinued nivolumab—one due to colitis possibly attributed to Ipi and Nivo (grade 3) after cycle one and one due to concern for increased risk of pneumonitis after cycle two and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Neoadjuvant treatment was discontinued in one patient after cycle one due to death from SARS-CoV-2 infection-related complications (non-treatment related). Seven patients had CT dose reduction due to TRAEs. At the time of data analysis cutoff, 17 (77%) patients in the Nivo+CT arm and 15 (68%) patients in the Ipi+Nivo+CT arm had undergone ad hoc tumor molecular profiling (Supplementary Table 1). In the Nivo+CT arm, 53% had TP53 mutations; 29% had EGFR mutations; 24% had KRAS mutations; and 6% had a STK11 alteration. In the Ipi+Nivo+CT arm, 47% had TP53 mutations; 33% had EGFR mutations; 33% had KRAS mutations; 7% had an ALK rearrangement; and 7% had a STK11 alteration.
