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Clinical Utility of Neoadjuvant Immune Checkpoint Inhibitors in Resectable NSCLC Remains Unknown

More research is also needed to identify optimal biomarkers
25 Jun 2019
Lung and other thoracic tumours;  Cancer Immunology and Immunotherapy

Results of the NEOSTAR and LCMC3 studies that tested neoadjuvant immune checkpoint blockade in resectable non-small cell lung cancer (NSCLC) were presented at 2019 ASCO Annual Meeting. Neoadjuvant immunotherapy has substantial activity based on major pathological response (MPR) and low toxicity. It has potential for accelerated drug approval although MPR is not a validated endpoint. MPR rates suggest that immunotherapy plus chemotherapy is most active approach.

However, at present time a clinical utility of neoadjuvant immunotherapy remains unknown and more trial results are needed. Furthermore, more research is needed to identify optimal biomarkers for personalising neoadjuvant treatment approaches.

NEOSTAR results

On behalf of the NEOSTAR Study Group, Tina Cascone of The University of Texas MD Anderson Cancer Center, Houston, TX, US presented the results from a phase II study of neoadjuvant nivolumab or nivolumab plus ipilimumab in resectable NSCLC.

Dr Cascone explained a rationale for neoadjuvant immunotherapy in operable NSCLC. More than 50% of patients with stage I to III resectable NSCLC relapse; perioperative chemotherapy lead to 5-year overall survival benefit of 5% versus surgery alone. The MPR defined as ≤10% viable tumour cells in resected specimens has been adopted as surrogate endpoint in neoadjuvant trials in NSCLC. Tumour PD-L1 upregulation is critical for the spread and survival of metastases in murine models of NSCLC. Neoadjuvant immune checkpoint blockade as a monotherapy lead to MPR rates of 22-45% and to 50-83% in combination with chemotherapy.

In the NEOSTAR, patients with stage I-IIIA (single N2) resectable NSCLC, performance status 0-1, were randomised to nivolumab (3 mg/kg i.v., D1, 15, 29) or nivolumab plus ipilimumab (1 mg/kg i.v., D1) followed by surgery. Primary endpoint was MPR (≤10% viable tumour cells), hypothesized to be higher than MPR to induction chemotherapy historical controls. Tumour immune infiltrates and pre- and post-immune checkpoint blockade tumour PD-L1 percentage were assessed by flow cytometry and immunohistochemistry.

From 53 screened patients, 44 eligible patients were randomised and treated: 23 in nivolumab arm and 21 in nivolumab plus ipilimumab arm. 

The study investigators found that nivolumab and nivolumab plus ipilimumab induced 17% and 33% MPR rates in the intention-to-treat (ITT) population, respectively. Nivolumab plus ipilimumab induced a 44% MPR rate in resected patients, met the trial pre-specified boundary (≥6 MPRs in ITT) and induced pathologic complete response (pCR) in 38% of resected patients.

No unacceptable toxicity or increased peri-operative morbidity/mortality were noted.

Nodal immune flare is an apparent radiographic progression after neoadjuvant immune checkpoint inhibitors that requires pathologic evaluation prior to avoidance of potentially curative surgery.

Nivolumab plus ipilimumab was associated with increased T cell infiltration, diversity and reactivity, and with increased frequencies of tissue resident and effector memory T cells at surgery.

The study was supported by Bristol-Myers Squibb.

LCMC3 results

David J. Kwiatkowski of the Dana-Farber Cancer Institute, Boston, MA, US presented interim analysis and biomarker data from LCMC3, a large multicentre trial that assessed the benefit of neoadjuvant treatment with atezolizumab in resectable NSCLC.

LCMC3 is a phase II study of atezolizumab in stage IB, II, IIIA or selected IIIB resectable and untreated NSCLC with planned accrual of 180 patients. A previous interim safety analysis of the study with 37 included patients demonstrated preliminary efficacy and safety. At 2019 ASCO Annual Meeting, the study investigators presented the efficacy data from interim analysis that included 101 patients.

In this study patients receive 2 cycles of atezolizumab 1200 mg on D1, 22 and then undergo resection. Primary tumour +/- node biopsies and blood samples are obtained before atezolizumab and at surgery for biomarker studies. The primary endpoint is MPR, defined as ≤ 10% viable tumour cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumour mutation burden (TMB) and gene expression signatures.

The investigators found that atezolizumab monotherapy in the neoadjuvant setting was well tolerated and no new safety signals were detected.

The pCR rate of 5% and MPR rate of 19% were encouraging in this large trial in which 46% of patients were stage IIIA/B. Pathological regression moderately correlated with target lesion measurements by RECIST. The MPR was observed irrespective of PD-L1 expression. TMB is not correlated with MPR or pathological regression. No significant associations between gene alterations and MPR were observed.

Efficacy interim analysis passed its futility boundary, and study enrolment continues. A placebo-controlled phase III study (IMpower030) of atezolizumab combined with platinum-based chemotherapy is currently ongoing.

The study was supported by Genentech Inc. 



Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol 37, 2019 (suppl; abstr 8504). 

Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol 37, 2019 (suppl; abstr 8503).

Last update: 25 Jun 2019

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