Neoadjuvant immunotherapy for non-small cell lung cancer: right drugs, right patient, right time?

Abstract

Standard curative treatment of early-stage non-small cell lung cancer (NSCLC) involves surgery in combination with postoperative (adjuvant) platinum-based chemotherapy where indicated. Preoperative (neoadjuvant) therapies offer certain theoretical benefits compared with adjuvant approaches, including the ability to assess on-treatment response, reduce the tumor bulk prior to surgery, and enhance tolerability in the preoperative setting. Indeed, the use of neoadjuvant therapies are well established in other cancers such as breast and rectal cancers to debulk the tumor and guide ongoing therapy, and neoadjuvant chemotherapy has similar efficacy but less toxicity in NSCLC. More recently, immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD1)/PD1-ligand 1 (PD-L1) have transformed the treatment of advanced NSCLC; the unique mechanisms of action of ICI offer additional rationale for assessment in the neoadjuvant setting. Preclinical studies in mouse cancer models support the proof of concept of neoadjuvant ICI (NAICI) through improvement of T-cell effector function and long-term memory induction. Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach. However, outstanding issues include defining optimal treatment combinations which balance high efficacy with acceptable toxicity, validating biomarkers to aid in patient selection, and avoiding potential pitfalls such as missing a window for successful surgery, that is, choosing the right drugs, for the right patient, at the right time. Predictive biomarkers to direct selection of therapy are required, and the validation of major pathological response (MPR) as a surrogate for survival will be important in the uptake of the neoadjuvant approach.

EGFR Status Assessment for Better Care of Early Stage Non-Small Cell Lung Carcinoma: What Is Changing in the Daily Practice of Pathologists?

“…Pre-operative and/or post-operative treatments of NSCLC by targeted therapies or by immunotherapy (in association or not with chemotherapy) have recently revolutionized the care of early stage lung cancers and thus may prevent recurrence and progression of these tumors after surgery. Apart from the targeted therapy which has been described above, early stage NSCLC wild type for EGFR and ALK can benefit from neoadjuvant and/or adjuvant immunotherapy or immunochemotherapy in the context of ongoing large phase 3 clinical trials [3,6,12,13,17]. Therefore, these treatments provide great hope for a cure for all these cancers.…”

“…In fact, these associated treatments provided a moderate benefit in terms of progression-free survival and overall survival [3,4]. The recent results of adjuvant therapy targeting activating mutations in EGFR (exon 19 deletion and L858R mutation) and of preoperative immunotherapies of early stage (I-IIIA) NSCLC open up great perspectives for the prevention of relapse and/or post-operative tumor progression [6][7][8][9][10][11][12][13][14]. In this context, laboratories of pathology have been required to meet new challenges in developing a number of analyses to assure optimal care of patients in a routine clinical practice.…”

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC)

“…PD-L1 expression and bTMB levels were reported to correlate with response rate and PFS of anti-PD-L1 ICIs in the treatment of advanced NSCLC [ 128 , 129 ]. Pretreatment PD-L1 expression and TMB levels were also tested in neoadjuvant ICIs trials of early-stage NSCLC including NEOSTAR, LCMC3, NADIM and Forde et al trials [ 78 , 79 , 83 , 87 , 89 , 130 ]. The MPR was positively and significantly associated with the PD-L1 expression level in the NEOSTAR trial but was not significantly associated with the PD-L1 expression level in LCMC3, NADIM, and Forde et al studies [ 78 , 79 , 83 , 87 , 89 , 130 ].…”

“…Pretreatment PD-L1 expression and TMB levels were also tested in neoadjuvant ICIs trials of early-stage NSCLC including NEOSTAR, LCMC3, NADIM and Forde et al trials [ 78 , 79 , 83 , 87 , 89 , 130 ]. The MPR was positively and significantly associated with the PD-L1 expression level in the NEOSTAR trial but was not significantly associated with the PD-L1 expression level in LCMC3, NADIM, and Forde et al studies [ 78 , 79 , 83 , 87 , 89 , 130 ]. TMB was associated with MPR in the study of Forde et al but was not observed in the LCMC3 trial [ 78 , 79 , 89 ].…”

“…TMB was associated with MPR in the study of Forde et al but was not observed in the LCMC3 trial [ 78 , 79 , 89 ]. Heterogenous associations between PD-L1 expression, TMB levels and MPR were observed in these clinical trials [ 78 , 79 , 83 , 87 , 89 , 130 ]. The PD-L1 expression and TMB levels should be carefully and interpreted before and during neoadjuvant therapy.…”