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Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives.

ABSTRACT: Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. Several phase II/III trials are evaluating the clinical efficacy of various neoadjuvant immune checkpoint inhibitor combinations for non-oncogene-driven NSCLC and neoadjuvant molecular targeted therapies for oncogene-driven NSCLC, respectively. However, clinical application of precision neoadjuvant treatment requires a paradigm shift in the biomarker testing and multidisciplinary collaboration at the diagnosis of early-stage NSCLC. In this comprehensive review, we summarize the current diagnosis and treatment landscape, recent advances, new challenges in biomarker testing and endpoint selections, practical considerations for a timely multidisciplinary collaboration at diagnosis, and perspectives in emerging neoadjuvant precision systemic therapy for patients with resectable, early-stage NSCLC. These biomarker-guided neoadjuvant therapies hold the promise to improve surgical and pathological outcomes, reduce systemic recurrences, guide postoperative therapy, and improve cure rates in patients with resectable NSCLC.

SUBMITTER: Godoy LA

PROVIDER: S-EPMC9847175 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives.

Godoy Luis A LA Chen Joy J Ma Weijie W Lally Jag J Toomey Kyra A KA Rajappa Prabhu P Sheridan Roya R Mahajan Shirish S Stollenwerk Nicholas N Phan Chinh T CT Cheng Danny D Knebel Robert J RJ Li Tianhong T

Biomarker research 20230118 1

Over the past decade, targeted therapy for oncogene-driven NSCLC and immune checkpoint inhibitors for non-oncogene-driven NSCLC, respectively, have greatly improved the survival and quality of life for patients with unresectable NSCLC. Increasingly, these biomarker-guided systemic therapies given before or after surgery have been used in patients with early-stage NSCLC. In March 2022, the US FDA granted the approval of neoadjuvant nivolumab and chemotherapy for patients with stage IB-IIIA NSCLC. ...[more]

PMID: 36650586

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Project description:We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Dataset Information

Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives.

Publications

Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives.

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