2019 ASCO: NEOSTAR: Neoadjuvant Nivolumab Plus Ipilimumab in Early-Stage, Resectable NSCLC
Neoadjuvant treatment with nivolumab plus ipilimumab resulted in an overall major pathologic response rate of 33% of treated patients with early-stage, resectable non–small cell lung cancer (NSCLC). With these results, the combination immunotherapy met the prespecified trial efficacy endpoint of the phase II NEOSTAR trial conducted by researchers at The University of Texas MD Anderson Cancer Center. These findings were presented by Cascone et al at the 2019 ASCO Annual Meeting (Abstract 8504).
The trial arm testing nivolumab alone in the treated population of patients achieved a 17% major pathologic response rate, for an overall major pathologic response rate across both trial arms of 25%.
“The NEOSTAR trial results definitely tell us this combination is clinically promising and warrants further investigation, possibly in combination with other therapies,” said principal investigator Tina Cascone, MD, PhD, Assistant Professor of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “By learning from these results and from our preclinical and translational findings, we can identify the best combination and make a major step forward in the field to limit tumor recurrence for [patients with] early-stage lung cancer.”
Trial Background
Preclinical studies in mice revealed that increased expression of programmed cell death ligand 1 (PD-L1) in lung adenocarcinoma tumors is critical for the development and survival of metastases, providing the rationale for testing immunotherapy in the neoadjuvant setting.
“Prior to this study, we knew that single-agent neoadjuvant immunotherapy has achieved a major pathologic response rate of 22% to 45%, but the combination of anti–PD-1 and anti–CTLA-4 immune checkpoint blockade before surgery in [patients with] resectable NSCLC had not yet been tested,” said Dr. Cascone. “In mouse models of resectable and spontaneously metastatic NSCLC, the combination of immunotherapy prior to surgery was superior to adjuvant combined therapy in prolonging survival and reducing the frequency of lung metastases, supporting further investigation of neoadjuvant combined immune checkpoint blockade in the clinical setting.”
Study Methods
The researchers designed the trial to test the effectiveness of combination immune checkpoint inhibitors priory to surgery. The trial enrolled 44 patients who were randomly assigned to receive either neoadjuvant nivolumab alone or nivolumab plus ipilimumab.
The trial’s primary endpoint was major pathologic response, hypothesized to be higher for single and/or combination immune checkpoint inhibitors compared to the rate induced by historical neoadjuvant chemotherapy controls. The prespecified trial efficacy endpoint for a specific treatment to be considered promising was greater than or equal to six major pathologic response in the intent-to-treat population. Major pathologic response has been adopted as a surrogate endpoint in neoadjuvant trials for patients with resectable NSCLC, as it has been shown to positively correlate with improved overall and recurrence-free survival outcomes, explained Dr. Cascone.
Results
Seven out of 21 patients treated preoperatively with the combination therapy achieved a major pathologic response, and 4 of 23 patients treated with nivolumab alone achieved a major pathologic response.
Although the trial was not powered to make a comparison between the two arms, the combination therapy appeared more effective at reducing viable tumor at surgery. Six patients (38%) that received the combination therapy and underwent surgery on trial achieved a complete pathologic response compared to two patients (10%) receiving nivolumab alone. The majority of patients with more than 50% viable tumor remaining at surgical resection received single-agent nivolumab therapy.
The treatments were generally well tolerated, said Dr. Cascone, with no unacceptable toxicity or increased perioperative morbidity and/or mortality noted. However, careful perioperative monitoring is advised with these agents.
Biospecimens
The trial also collected a variety of biospecimens from patients before, during, and after treatment, which enabled researchers to investigate why results vary from patient to patient and understand the dynamic changes induced by therapy in potential biomarkers. They discovered that elevated tumor expression of PD-L1 prior to therapy was positively correlated with radiographic responses and with pathologic tumor regression at surgery.
Preliminary immunologic characterization of resected tumors from patients treated with immunotherapy indicated that the combination therapy is associated with an increased number of tumor-infiltrating lymphocytes as compared to monotherapy, and that some of these T cells might have tumor-reactive activity. Additional results presented by Reuben et al at the 2019 ASCO Annual Meeting showed that combination therapy appeared to be associated with greater diversity and reactivity of T lymphocytes in resected tumors as compared to pretreatment tumor specimens (Abstract 8532).
“This is important because we don’t see patients with early-stage lung cancer as often as patients with metastatic disease in the clinic, and we want to take advantage of this opportunity for our patients. There are limitations to this trial, as it was overall a small cohort, but the positive results suggest we should continue to evaluate neoadjuvant combination immunotherapy as an option for our patients. Our ongoing exploratory analyses will help us to better understand this response and to identify potential biomarkers that could inform future trials,” said Dr. Cascone.
The researchers already have added and are nearing complete enrollment in a third arm of the NEOSTAR trial to evaluate neoadjuvant nivolumab plus platinum-based chemotherapy. Because of successful accrual, additional arms are being considered to evaluate further combination approaches.
Disclosure: This study was supported by Bristol-Myers Squibb-MD Anderson Lung Strategic Alliance, the Conquer Cancer Foundation ASCO Career Development Award, the MD Anderson Physician-Scientist Training Program, the NIH/NCI P30 CA016672 CCSG New Faculty Award, the Khalifa Scholar Award supported by the Khalifa Bin Zayed Al Nahyan Foundation, and the Bob Mayberry Foundation. For full disclosures of the study authors, visit coi.asco.org.
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