There is a strong rationale for incorporating immunotherapy into the treatment of early-stage non–small cell lung cancer (NSCLC), given the breakthrough results with PD-1 checkpoint inhibitors as monotherapy, combined with immunotherapy, or combined with chemotherapy in advanced-stage NSCLC. As reviewed in this issue of The ASCO Post, Catherine A. Shu, MD, of Columbia University Irving Medical Center, and colleagues recently reported the results of a phase II clinical trial studying neoadjuvant nab-paclitaxel and carboplatin plus the anti–PD-L1 antibody atezolizumab in predominantly stage IIIA NSCLC in The Lancet Oncology.1
Neal Ready, MD, PhD
The experimental neoadjuvant therapy regimen followed by standard surgery was safe and feasible with no treatment-related delays for surgery, 27 of 30 enrolled patients receiving R0 resection, and no apparent increase in serious postoperative complications. Efficacy was promising, with downstaging from N2 to N0 in 11 of 19 patients (58%), a major pathologic response rate of 57%, and a complete pathologic response in 33%.1
Pathologic response after neoadjuvant chemotherapy has been proposed as a surrogate endpoint for efficacy in the treatment of early-stage NSCLC.2 However, it remains unproven whether pathologic response after neoadjuvant immunotherapy can be used as a surrogate endpoint for improved survival after lung cancer surgery.
Immunotherapy for Early-Stage Lung Cancer Under Study
Numerous phase I to III clinical trials are studying neoadjuvant and/or maintenance immunotherapy in early-stage NSCLC.3 Immune-based neoadjuvant therapy compared with adjuvant therapy has several theoretical advantages for more effective immune system priming to eradicate occult metastatic disease: a rich source of neoantigens in the primary tumor, the presence of tumor-infiltrating lymphocytes during initiation of PD-1 checkpoint inhibition, and an intact locoregional immune environment including the primary tumor and lymph node drainage system. A preclinical model demonstrated improved efficacy for neoadjuvant compared with adjuvant immunotherapy.4
Single-agent PD-1 neoadjuvant checkpoint therapy in early-stage NSCLC with nivolumab, pembrolizumab, or atezolizumab has shown that neoadjuvant immunotherapy is safe and feasible, producing a significant number of major pathologic responses after as few as two cycles of therapy.5-8 Combination neoadjuvant nivolumab and ipilimumab has been studied in the NEOSTAR study.9 Interestingly, although the Shu et al study showed an association between radiographic Response Evaluation Criteria in Solid Tumors responses and major pathologic responses, neoadjuvant immunotherapy studies without chemotherapy often show few radiographic tumor responses after neoadjuvant treatment, even in tumors that have had a major pathologic response to immune therapy.
Understanding the Tumor Microenvironment
PD-1 checkpoint inhibitors have produced durable tumor responses and clinically meaningful survival rates at 5 years in advanced-stage NSCLC. Building on the recent advances in immunotherapy for NSCLC will require a comprehensive understanding of how tumor biology, T cells, B cells, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, the microbiome, and the tumor microenvironment contribute to immunotherapy responsiveness and immune system evasion.
The standard clinical care for advanced NSCLC does not usually include surgical resection of large tumor specimens. The core needle biopsies that typically can be obtained at the time of tumor progression on PD-1 checkpoint therapy are not optimal for analysis of neoantigens, tumor microenvironment, and T-cell and B-cell populations. Neoadjuvant immunotherapy strategies in early-stage NSCLC provide unique opportunities for collection of adequate tumor specimens to investigate factors associated with response and mechanisms associated with resistance to immunotherapy. This study showed no major difference in pathologic response rate for PD-L1–positive vs –negative tumors and no major pathologic responses in the three tumors with STK11 mutation, a mutation associated with resistance to PD-1 checkpoint therapy in advanced NSCLC.
Investigators should strive to collect optimal blood and especially tumor specimens from neoadjuvant immunotherapy clinical trials in early-stage NSCLC. Analysis of the tumor microenvironment after PD-1 checkpoint therapy may lead us to the next breakthroughs for both early- and advanced-stage NSCLCs.
Cause for Optimism
“There is cause for optimism that incorporating immunotherapy into the standard surgical and chemotherapy regimens for early-stage NSCLC will lead to improved survival outcomes.”— Neal Ready, MD, PhD
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Neoadjuvant studies combining chemotherapy plus PD-1 checkpoint therapy such as the Shu et al study with atezolizumab and the NADIM trial with nivolumab report impressive major pathologic response rates, as might have been predicted based on the responses reported for chemotherapy plus immunotherapy combinations in first-line therapy for advanced NSCLC.1,10 There is cause for optimism that incorporating immunotherapy into the standard surgical and chemotherapy regimens for early-stage NSCLC will lead to improved survival outcomes. The establishment of neoadjuvant single-agent immunotherapy, combination immunotherapy, or chemotherapy plus immunotherapy as standards of care in early-stage NSCLC will depend on the results of randomized clinical trials comparing investigational regimens including immunotherapy and standard regimens of surgery plus platinum-based chemotherapy doublets.
Dr. Ready is Professor of Medicine at Duke University School of Medicine and a member of the Duke Cancer Institute, Durham, North Carolina.
DISCLOSURE: Dr. Ready has served as a consultant or advisor to AstraZeneca, BMS, Celgene, Genentech, GI therapeutics, Merck, Jazz Pharma, Novartis, and Pfizer; has received research funding from Bristol Myers Squibb and Merck; has served as a speaker for BMS and Celgene; and has received honoraria from BMS and Celgene.
1. Shu CA, Gainor JF, Awad MM, et al: Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: An open-label, multicentre, single-arm, phase II trial. Lancet Oncol 21:786-795, 2020.
2. Hellmann MD, Chaft JE, William Jr WN, et al: Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: Proposal for the use of major pathologic response as a surrogate endpoint. Lancet Oncol 15:e42-e50, 2014.
3. Yeh J, Marrone KA, Forde PM: Neoadjuvant and consolidation immuno-oncology therapy in stage III non-small cell lung cancer. J Thorac Dis 10(suppl 3):S451-S459, 2018.
4. Liu J, Blake SJ, Yong MCR, et al: Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 6:1382-1399, 2016.
5. Forde PM, Chaft JE, Smith KN, et al: Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 378:1976-1986, 2018.
6. Rusch VW, Chaft JE, Johnson B, et al: Neoadjuvant atezolizumab in resectable non-small cell lung cancer: Initial results from a multicenter study (LCMC3). 2018 ASCO Annual Meeting. Abstract 8541. Presented June 3, 2018.
7. Ready N, Tong B, Clarke J, et al: Neoadjuvant pembrolizumab in early stage non-small cell lung cancer: Toxicity, efficacy, and surgical outcomes. 2019 World Conference on Lung Cancer. Abstract P2.04-89. Presented September 9, 2019.
8. Eichhorn F, Klotz LV, Bischoff H, et al: Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable nodal positive stage II/IIIa non-small-cell lung cancer: The NEOMUN trial. BMC Cancer 19:413, 2019.
9. Sepesi B, Cascone T, William W, et al: Surgical outcomes following neoadjuvant nivolumab or nivolumab plus ipilimumab in non-small cell lung cancer—NEOSTAR study. J Thoracic Oncol 14:S241-S242, 2019.
10. Provencio M, Nadal E, Insa A, et al: OA13.05 NADIM study: Updated clinical research and outcomes. J Thorac Oncol 14:S241, 2019.