Neoadjuvant nivolumab in resectable non-small cell lung cancer: Extended follow-up and molecular markers of response.

Abstract

8524 Background: Improved therapy is needed for patients (pts) with early-stage non-small cell lung cancer (NSCLC), as the majority relapse after curative resection. Our group reported the first trial of neoadjuvant PD-1 blockade in resectable NSCLC, finding therapy to be safe and feasible. Here we report extended clinical follow-up and long-term molecular response data from this trial. Methods: IV nivolumab 3 mg/kg was given every 2 weeks for 2 doses prior to surgery in 20 pts with resectable NSCLC at Johns Hopkins and MSKCC. Blood for correlative studies was taken prior to each dose of nivolumab, prior to surgery, 2-4 weeks post-surgery, and during long-term follow up. In a subgroup of pts, longitudinal molecular data was assessed in peripheral blood for circulating tumor DNA (ctDNA) and dynamics of tumor-infiltrating T-cell clonotypes. Results: At median follow up of 30 months (m), 15 of 20 pts are disease-free and alive. Two pts have died (one from relapsed disease). Median recurrence free survival (RFS) has not been reached. The 24m RFS rate is 69% (95% CI: 51-93). Thus far, presence of ctDNA at diagnosis and major pathologic response (MPR - ≤10% viable tumor in resected specimen) do not associate with RFS. One long-term immune-related adverse event has occurred (skin, G3). All pts who on pathologic review had ≥30% reduction in viable tumor in response to nivolumab demonstrated clearance of detectable ctDNA from blood prior to surgery. Pts with MPR experienced expansion of neoantigen-specific T-cells in peripheral blood. In one patient with ongoing disease free status, expansion of tumor-associated T-cells has persisted in peripheral blood beyond 15m from surgery. By contrast, in a patient who had detectable peri-operative ctDNA and 75% residual disease at surgery, minimal T-cell expansion was observed in peripheral blood, with a decreasing frequency of expanded T-cell clones over time that correlated with eventual cancer relapse. Conclusions: Long-term follow up reinforces the safety of neoadjuvant nivolumab in resectable NSCLC. Analysis of ctDNA and peripheral T-cell expansion in responders compared with non-responders suggests potential biomarkers for response and surveillance. While RFS data is encouraging, phase 3 trials are ongoing to evaluate efficacy of PD-(L)1 blockade in early-stage NSCLC. Clinical trial information: NCT02259621.

Effective Treatment of NSCLC with Surgery After Nivolumab Combined with Chemotherapy: A Case Report and Brief Review of the Literature

“…The 24m RFS rate was 69% (95% CI: 51–93). 3 In terms of safety, this study showed treatment-related adverse reactions were 23%, only 1 case exceeded grade 3.…”

Integrating immune checkpoint inhibitors and targeted therapies in the treatment of early stage non-small cell lung cancer: a narrative review

“…Correlative analyses from NADIM trial are not currently available but, in the small cohort reported with atezolizumab plus Cht, MPR occurred regardless of PD-L1 TPS. Interestingly, molecular response data on neoadjuvant nivolumab suggests that ctDNA and peripheral T-cell expansion could be used as potential biomarkers for response and surveillance (45).…”

“…Moreover, PD-1 blockade promoted systemic expansion of T-cell clones which shared similar T-cell repertoire with T-cells found in tissue, potentially eliminating microscopic metastatic disease. In the updated analysis with a follow up of 30 months, median RFS has not been reached and the 24 months RFS rate was 69% (95% CI: 51-93%) (45). The presence of circulating DNA (ctDNA) at diagnosis and MPR was not associated with RFS.…”

Neoadjuvant and Adjuvant Immunotherapy: Opening New Horizons for Patients With Early-Stage Non-small Cell Lung Cancer

“…ctDNA appears to be present in 50–95% of stage I to III patients ( 32 , 33 ), suggesting that changes in ctDNA before and after neoadjuvant immunotherapy may be another more broadly applicable biomarker. The clearance of ctDNA and the expansion of tumor-specific T cells in peripheral blood may early monitor the treatment response and recurrence ( 34 ). However, whether ctDNA and tumor-specific T cells in peripheral blood are associated with MPR or even OS or DFS is not clear.…”