Neoadjuvant Nivolumab/Ipilimumab Enhances Pathologic Responses in Resectable NSCLC

The addition of neoadjuvant ipilimumab (Yervoy) to nivolumab (Opdivo) resulted in higher rates of major pathologic response (MPR) and pathologic complete response (pCR), while enhancing tumor immune cell infiltrates in patients with resectable non–small cell lung cancer (NSCLC), according to data from the phase 2 NEOSTAR trial (NCT03158129).¹

Results published in Nature Medicine showed that patients treated with the combination of achieved a MPR rate of 38% (95% CI, 18%-62%; n = 8/21) vs 22% (95% CI, 7%-44%; n = 5/23) with nivolumab alone (P = .235), meeting the prespecified primary end point threshold of at least 6 MPRs in 21 patients. Additionally, among the 37 patients who underwent surgical resection on the study, the combination induced a higher MPR rate of 50% (n = 8/16) vs 24% (n = 5/21) with nivolumab alone. The combination also elicited a higher pathological complete response (pCR) rate of 38% vs 10% with nivolumab alone.

“More than 50% of patients with localized NSCLC will relapse if treated with surgery alone. Adding chemotherapy produces only a modest improvement in overall survival, and it comes with toxicity,” Tina Cascone, MD, PhD, lead study author and assistant professor of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in a press release.² “The results from our study with neoadjuvant combination immunotherapy are particularly encouraging in that we found that this dual treatment can induce higher pathologic responses and trigger immunological memory. This may translate into a reduced risk for tumor relapse in more patients with early-stage NSCLC.”

Previous studies have shown that the doublet can augment antitumor immunity through distinct cellular mechanisms. These data have provided the rationale for adding ipilimumab to nivolumab in the treatment of those with advance disease. Although the addition of ipilimumab to nivolumab has significantly impacted the care of this patient population, the impact of the doublet on the immune microenvironment of resectable NSCLC has not been determined.

To this end, NEOSTAR set out to examine the clinical activity of neoadjuvant ipilimumab/nivolumab vs nivolumab alone in this patient population. To be eligible for enrollment, patients needed to be at least 18 years of age, with resectable, pathologically confirmed, stage I to IIIA NSCLC and an ECOG performance status of 0 or 1. Patients could not have received prior systemic therapy. Participants were stratified by disease stage.

Overall, 44 patients were enrolled to the study and they were randomized 1:1 to nivolumab alone at 3 mg/kg on days 1, 15, and 29 (arm A; n = 23) or to nivolumab at 3 mg/kg on days 1, 15, and 29 plus ipilimumab at 1 mg/kg on day 1 (arm B; n = 21).

The primary end point of the study was MPR in the intent-to-treat (ITT) population. Secondary end points included safety, perioperative morbidity and mortality, objective response rates per RECIST v.1 criteria, recurrence-free survival (RFS), overall survival, evaluation of complete resection, and pCR.³

The mean age of study participants was 65.6 years, and the majority were male (64%) and White (84%). Moreover, 59% of patients were former smokers, 23% were current smokers, and 18% were never smokers. Regarding disease stage, 18% had stage IA disease, 34% had stage IB disease, 16% had stage IIA disease, 11% had stage IIB disease, and 20% had stage IIIA disease. Most patients (59%) had adenocarcinoma and an ECOG performance status of 0 (59%).

Of the 44 patients who comprised the ITT population who received at least 1 dose of neoadjuvant immune checkpoint inhibitors on trial, 39 underwent curative-intent surgery on or off trial while 5 did not undergo surgery. Of the 39 patients who were resected, 37 underwent surgery on trial and 2 were resected following receipt of additional systemic therapies off the trial. As such, 7 patients did not undergo surgery on the trial in the ITT analysis.

The median duration of follow-up following randomization was 22.2 months for all 44 patients enrolled to the trial. Additional data showed that the median OS and lung cancer–related RFS had not yet been reached. One patient who received nivolumab died within 90 days of surgery and 4.1 moths following randomization. Moreover, 1 patient received the doublet and experienced disease progression at 2.6 months following randomization and died from the disease at 17.1 months post randomization. A total of 6 patients had lung cancer–related recurrence.

Additional data indicated that 6 patients (29%) treated with the combination achieved a pCR (95% CI, 11%-52%; P = .126), compared vs 2 patients (9%) in the monotherapy arm (95% CI, 1-28), while the radiographic objective response rate (ORR) was 19% (95% CI, 5%-42%) with nivolumab plus ipilimumab and 22% (95% CI, 7%-44%) with nivolumab monotherapy. Additionally, among patients who underwent surgical resection, the ORR was 19% (95% CI, 4%-46%) with the combination and 19% (95% CI, 5%-42%) with the monotherapy (P = 1.00).

Additionally, study authors performed an exploratory analysis of resected tumor tissues and found that PD-L1 expression was higher in tumor samples collected from patients who had achieved radiographic responses and MPR; however, patients without PD-L1 expression in these cells also experienced responses. Moreover, fewer viable tumor cells were found in resected tumor samples with tumor PD-L1 expression of 1% or greater vs tumors samples with PD-L1 expression of less than 1%. Overall, PD-L1 expression was not associated with responses, and no significant differences were reported in terms of the percentage of malignant PD-L1–expressing cells in tumors among the 2 treatment arms.

Immune profiling of resected tumor tissue via flow cytometry uncovered higher frequencies of CD45+CD3+ tumor-infiltrating lymphocytes (P = .021), CD3+CD4+CD103+ tissue-resident memory T cells (P = .041), CD3+CD8+CD103+ effector tissue-resident memory cells (P = .057), CD3+CD4+CD27−CD28+ effector memory T cells (P = .034) in tumors resected after the combination therapy vs those resected after the monotherapy.

An exploratory analysis was also performed to analyze the impact that immune checkpoint inhibitors had on the composition of the gut microbiome. These data showed no significant impact in terms of the diversity or composition of the gut microbiome but did demonstrate that a variety of bacteria is correlative to pathologic responses.

“Our exploratory results suggest the gut microbiome may play a role in responses to neoadjuvant immune checkpoint inhibitors in lung cancer,” Cascone explained. “The immune microenvironment findings also give us an opportunity to look at immune cell populations and potential biomarkers that can be evaluated in the future to identify those patients who are most likely to benefit from these agents in new prospective trials.”

No new safety signals were reported and toxicities were determined to be manageable, overall. Treatment-emergent adverse effects (TEAEs) that were grades 3 to 5 were experienced by 10% of patients in the combination arm (n = 2/21) and 13% of those in the monotherapy arm (n = 3/23). Additionally, 1 patient treated in the nivolumab monotherapy arm developed pneumonia and pneumonitis, which ultimately resulted in respiratory failure and death.

“The NEOSTAR trial results set the stage for evaluating the role of dual immunotherapy added to neoadjuvant chemotherapy, which we are currently exploring, and expediting the investigation of novel agents in the perioperative setting,” Cascone concluded. “This is a population with potentially curable disease. We should do whatever it takes to minimize the risk of relapse and increase the cure rates for these patients.”

References

1. Cascone T, William W, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med. 2021;27(3): 504–514. doi:10.1038/s41591-020-01224-2
2. Neoadjuvant combination immunotherapy improves outcomes for early stage non-small cell lung cancer. News release. The University of Texas MD Anderson Cancer Center. February 18, 2021. Accessed May 25, 2021. https://bit.ly/2Pgorgw
3. Nivolumab with or without ipilimumab or chemotherapy in treating patients with previously untreated stage I-IIIA non-small cell lung cancer. ClinicalTrials.gov. Updated January 13, 2021. Accessed May 25, 2021. https://clinicaltrials.gov/ct2/show/NCT03158129