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Neoadjuvant nivolumab/ipilimumab shows promise in resectable NSCLC

Presented by
Dr Tina Cascone, University of Texas MD Anderson Cancer Centre, USA
ASCO 2019
Medical writer: Dave Levitan

Neoadjuvant nivolumab plus ipilimumab offered a promising rate of major pathologic response (MPR) in patients with untreated, resectable non–small cell lung cancer (NSCLC), according to a phase II study (Abstract 8504). Nivolumab monotherapy also yielded some MPRs, although not at the prespecified threshold for efficacy.

“More than 50% of patients with stage I to III resectable NSCLC will relapse if treated with surgery alone,” said Tina Cascone, MD, PhD, of The University of Texas MD Anderson Cancer Centre, during an Oral Abstract Session on June 1. Because tumour upregulation of PD-L1 is critical for the spread and survival of metastases in mouse models, anti–PD-1 therapy is being tested in the neoadjuvant setting to prime an anti-tumour response and eradicate micrometastases.

The phase II NEOSTAR study included 44 patients with stage I to IIIA NSCLC who were considered surgical candidates; they were randomly selected to receive either nivolumab (Arm A; 23 patients) or nivolumab plus ipilimumab (Arm B; 21 patients). Thirty-nine of those patients eventually underwent surgery with curative intent.

The median age in the full cohort was 65.6 years, and 64% of patients were male; 84% were white, and 82% were current or former smokers. Most patients had adenocarcinoma (59%), followed by squamous cell histology (39%) and adenosquamous histology (2%). Overall, 93% of patients completed the course of neoadjuvant therapy.

In the full intention-to-treat cohort, 11 patients (25%) achieved the primary endpoint of an MPR (≤ 10% viable tumour). This was achieved in 17% of patients receiving nivolumab and 33% of those receiving the combination regimen; only the combination therapy group achieved the pre-specified trial efficacy boundary of at least six MPRs. When only the 37 patients who underwent resection on trial were considered, the overall MPR rate was 30% (19% with nivolumab and 44% with the combination).

A total of 11% of patients had the appearance of radiographic progression after the treatment, but a pathologic assessment revealed granulomas but no evidence of tumour. The investigators termed this as “nodal immune flare,” and Dr. Cascone said it is critical because distinguishing it from true disease progression could allow some patients to avoid curative surgery.

With regard to radiographic responses, there was one complete response (CR) in the combination group (5%); five patients in Arm A and three in Arm B achieved a partial response (PR), for an overall response rate of 18% (22% in Arm A, 14% in Arm B). In total, 64% of the cohort had stable disease, and 14% had progressive disease (one patient was not evaluable). There was a correlation between MPR and radiographic response: 78% of those with an MPR achieved either a CR or a PR, compared with only 22% of those with no MPR (P < 0.001). Elevated levels of PD-L1 expression at baseline were associated with both radiographic and pathologic responses.

The most common grade 1 to 2 treatment-related adverse events (TRAEs) included rash in the nivolumab plus ipilimumab group (52%) and fatigue in the nivolumab monotherapy group (35%). Grade 3 to 5 TRAEs included hypermagnesemia, hypoxia, pneumonia, and pneumonitis (4% each) in the nivolumab group, and diarrhea and hyponatremia (4% each) in the combination group.

Dr. Cascone noted the combination of nivolumab and ipilimumab was associated with increased T-cell infiltration, diversity, and reactivity. She said the MPR rate in the study supports further evaluation of the combination approach in this setting.

Discussant Maximilian Diehn, MD, PhD, of the Stanford Cancer Institute, Stanford School of Medicine, noted that the use of MPR as a surrogate endpoint has promise thanks to research suggesting an association with overall survival, and because there is strong inter-observer agreement between experienced pathologists. It is not currently accepted as a validated surrogate endpoint, however, meaning it cannot yet be used for drug approvals.

Dr. Diehn said that the results of this study, along with other new research, suggest that combining immunotherapy and chemotherapy may offer the best activity, as it has in the advanced NSCLC setting. He also stressed that patient selection remains a challenge. “We have a major unmet need for developing biomarkers for personalizing treatment in this area,” he said. He noted that PD-L1, tumour mutation burden, and circulating tumour DNA may still prove useful as biomarkers for these patients.

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