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.

Keywords: Immune checkpoint inhibitor (ICI); NSCLC; Neoadjuvant; Precision oncology; Resectable; Systemic therapy; Targeted therapy.

Fig. 1

The chronological milestones for the management of NSCLC. Major advances in systemic therapy with chemotherapy, targeted therapy and immunotherapy for NSCLC are illustrated. Beginning in 1990, chemotherapy was shown to be effective for prolonging survival in patients with NSCLC and platinum-based therapy became the cornerstone of treatment. Neoadjuvant or adjuvant chemotherapy modestly increased the overall survival by ~ 5% in patients with stage II-IIIA operable NSCLC. In 2004, targeted therapy erlotinib was approved for EGFR-sensitive NSCLC. During this time, researchers began utilizing modern gene sequencing programs to identify genetic markers for targeted therapeutics. The ALK gene rearrangement was identified and crizotinib was approved for ALK-positive tumors in 2011. In 2015, ICIs were found to improve survival and three immunotherapy agents were approved, including nivolumab, atezolizumab, and pembrolizumab. In 2018, a third-generation EGFR inhibitor osimertinib was approved as first line treatment for patients with metastatic NSCLC. By the end of 2020, adjuvant targeted therapy with osimertinib was approved for EGFR-sensitive NSCLC. In 2021, adjuvant immunotherapy with atezolizumab was approved for PD-L1 positive NSCLC. Neoadjuvant nivolumab and platinum-based chemotherapy becomes a standard of care for patients with stage IB-IIIA NSCLC without known EGFR or ALK genomic alterations in March 2022

Fig. 2

Summary of stage-guided treatment selection for NSCLC. The frequency indicates the stage distribution (%) at diagnosis based on AJCC stage. Survival data is reported for adjuvant chemotherapy (stage IB-IIIA), osimertinib (stage IIA-IIIA), pembrolizumab (stage IB-IIIA), and atezolizumab (stage IIA-IIIA). Increased survival for adjuvant therapy is reported as a percentage increase in comparison to surgery or chemotherapy alone

Fig. 3

Surgical and pathological outcomes of neoadjuvant ICI alone or with chemotherapy studies. Data is stratified by complete response (pCR) rate (%), major pathologic response (MPR) rate (%), and the resection rate (%)

Fig. 4

Schema for Biomarker-Driven Precision Neoadjuvant Therapy for stage IA2-III NSCLC. The LCMC4 (LEADER) screening trial is an umbrella trial that is designed to detect actionable oncogenic drivers by NGS in patients with resectable, early-stage NSCLC. Patients whose tumors harbor one of these oncogenic drivers are matched to one of the available, effective targeted therapies for patients with metastatic NSCLC. Those patients whose tumors do not harbor actionable driver oncogenes will receive standard of care or investigational neoadjuvant nivolumab and platinum-based chemotherapy

Fig. 5

Schema for Biomarker-Driven Neoadjuvant Treatment for Early-Stage NSCLC. A multidisciplinary infrastructure is essential to implement biomarker-driven neoadjuvant treatment based on the histopathological and immunological evaluation and NGS-based molecular screening at the diagnosis of resectable NSCLC

Fig. 6

Pathological and radiographic outcomes of nivolumab alone or in combination with ipilumumab or chemotherapy in early-stage and metastatic NSCLC. The pathologic complete response (pCR, solid bar in orange) and major pathologic response (MPR, solid bar in blue) rate (%) by histopathological evaluation were shown in resectable, early-stage NSCLC. No pathological stage is available for patients with unresectable NSCLC. The overall response rate (ORR) is the radiographic evaluation of tumor response by RECIST, which is higher in early-stage NSCLC compared to mNSCLC. Per RECIST V1.1, CR (dashed bar in orange) is defined as disappearance of all targeted lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial response (PR, dashed bar in blue) is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. This PR criteria correlate with at least a 50% decrease in tumor volume

Fig. 7

Biomarkers for neoadjuvant therapy in NSCLC. Schema illustrates the emerging biomarkers of tumor tissue, blood, host, and radiology for neoadjuvant therapy in NSCLC