The immune “tsunami” has arrived at the shores of early-stage non-small cell lung cancer
Editorial Commentary

The immune “tsunami” has arrived at the shores of early-stage non-small cell lung cancer

Antonio Rossi1, Ettore Mari2, Domenico Galetta3

1Oncology Centre of Excellence, Therapeutic Science & Strategy Unit, IQVIA, Milan, Italy; 2Medical Science and Strategy Hematology/Oncology, IQVIA, Milan, Italy; 3Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

Correspondence to: Antonio Rossi, MD. Oncology Centre of Excellence, Therapeutic Science & Strategy Unit, IQVIA, Via F. Filzi, 29 - 20019 Milan, Italy. Email: arossi_it@yahoo.it.

Comment on: Rosner S, Reuss JE, Zahurak M, et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res 2023;29:705-10.

Keywords: Chemotherapy; immunotherapy; neoadjuvant; nivolumab; non-small cell lung cancer (NSCLC)

Received: 03 August 2023; Accepted: 30 August 2023; Published online: 06 September 2023.

doi: 10.21037/actr-23-9

According to the 2022 global cancer statistics, lung cancer remains the leading cause of cancer deaths worldwide with non-small cell lung cancer (NSCLC) accounting for approximately 85% of diagnosis (1). Around 30% of NSCLC patients are diagnosed with resectable disease for which the surgical resection with curative intent is considered to be the best treatment option. Overall, only 20–25% of these patients are suitable for potential curative resection, because they have a high risk of postoperative recurrence, ranging from 25% to 70% based on the disease stage (2). The 5-year survival rates ranged from 68% for stage IB, to 36% for IIIA disease (2). These data underline the urgent need for improvements in systemic control also considering that, over the past decades, the wider adoption of chest low-dose CT as a screening modality has gradually increased the early stages detection of NSCLC leading to an increase in high unmet medical need (3).

In the past, several attempts and efforts were performed, with many randomized trials run in neo-adjuvant setting and investigating systemic treatments. The results coming from these trials were pooled in two main meta-analyses (4,5) with the following results: platinum-based chemotherapy is the mainstay of treatment in the adjuvant context showing an approximately 5% improvement in overall survival (OS) at 5 years (4). Similar modest OS improvements have been reported also with neoadjuvant platinum-based chemotherapy (5). In view of these limited benefits, newer approaches for the treatment of early-stage NSCLC need to be investigated.

Metastatic NSCLC showed continuous survival improvements due to the availability of targeted therapies directed against oncogenes aberrations, and the use of immune checkpoint inhibitors (ICIs), able to promote host antitumor responses, which, only recently, have emerged also for the treatment of early-stages disease (6,7). Atezolizumab, an anti-programmed-cell death ligand protein-1 (PD-L1), and pembrolizumab, an anti-programmed death-1 (PD-1), based on impressive results from phase 3 trials evaluating their role as adjuvant therapy, already reached the market for the post-operative treatment of early-stage NSCLC (7). Neoadjuvant immune checkpoint inhibition is attractive, since it may have enhanced antitumor effects owing to superior suitability of host immunity and reduced tumor clonal heterogeneity. The primary tumor may be leveraged as an antigen source for the expansion and activation of tumor-specific T cells and systemic surveillance of micrometastases. In other words, the activation of a previously suppressed anti-tumor immune response to affect tumor kill depends on interactions between tumor cells and immune cells and results in the generation of a CD8+ T-cell response against tumor antigens (8).

The first phase Ib/II clinical trial investigated neoadjuvant nivolumab, an anti-PD-1 therapy, in resectable stage I–IIIA NSCLC. A total of 21 NSCLC patients were enrolled to receive two pre-operative doses of intravenous nivolumab (3 mg/kg of body weight) every 2 weeks, with surgery planned approximately 4 weeks after the first dose, with safety and feasibility as the primary endpoints of the study (9). Twenty patients were completely resected with one patient subsequently considered inoperable due to primary progression of the disease. Neoadjuvant nivolumab was well tolerated and not associated with any previously unreported toxic effects, showing any grade adverse events occurring in 23% of patients, mainly grade 1 or 2 and only one grade 3 pneumonia. A partial response was reported in 10% of patients with a stable disease in 86% of cases. The pathological complete response (pCR), defined as 0% residual viable tumor, was reported in 10% of resected patients with a major pathological response (MPR), defined as ≤10% residual viable tumor, in 45% of cases (9).

The updated outcomes of this trial, after a median follow-up of 63 months, were published by Rosner et al. (10). The 5-year recurrence-free survival (RFS) and OS rates were 60% and 80%, respectively. Both MPR and pre-treatment tumor PD-L1 positivity trended toward favorable RFS [hazard ratio (HR), 0.61 and HR, 0.36, respectively]. At 5-year follow-up, 8/9 (89%) patients with MPR were alive and cancer-free. Patients with stage I/II disease had numerically favorable RFS compared with those with stage IIIA disease (HR 0.42). Six patients received four cycles of cisplatin-based chemotherapy as standard-of-care adjuvant therapy, with neither post-operative radiotherapy or targeted therapy. A grade 3 dermatitis herpetiformis with accompanying alopecia universalis, as late-onset immune-related adverse event (irAE), and occurring 16 months after the patient’s last dose of nivolumab, was reported and treated with immunosuppression (10).

The early results of this study together with those coming from a series of phase I–II trials have prompted an increase in randomized peri-operative treatment strategies trials, including neoadjuvant ICIs. Table 1 and Table 2 the results of the main trials investigating the neoadjuvant immunotherapy (10-25).

Table 1

Main phase 2 trials investigating neoadjuvant immunotherapy in potentially resectable NSCLC

Study (reference) Stage Treatment Pts No. ORR (%) Surgery pts No. [%] pCR (%) MPR (%) Any G ≥3 AE (%) G ≥3 irAE (%)
JHU/MSKCC (10) I–IIIA Nivo → S → SOC 21 10 20 [95.2] 10 45 5 5
MK3475-223 (11) I–II Pembro → S → SOC 10 NR 9 [90] 15 46 NR NR
PRINCEPS (12) I–IIIA Atezo → S → SOC 30 0 30 [100] 0 14 0 0
IONESCO (13) IB–IIIA Durva → S → SOC 46 9 43 [93.5] 7 19 0 0
LCMC3 (14) IB–IIIB Atezo → S → SOC or Atezo 1 year 181 NR 159 [87.8] 6 20 38 10
TOP1501 (15) IB–IIIA Pembro → S → Pembro 6 cycles 30 NR 30 [100] 8 28 NR NR
ChiCTR-OIC-17013726 (16) IA–IIIB Sinti → S → SOC 40 20 37 [92.5] 16.2 40.5 NR 10
NEOpredict-Lung (17) IB–IIIA Nivo → S → SOC 30 NR 30 [100] 13.3 27 NR 3
Nivo + Rela → S → SOC 30 30 [100] 16.7 30 NR 3
EAST ENERGY (18) IB–IIIA, PD-L1+ Pembro + Ramu → S → SOC 24 NR 22 [91.7] 25 50 34.8 30.4
NADIM (19) IIIA Nivo + CT → S → Nivo 1 year 46 76 41 [89.1] 63.4 20 30 NR
NEOSTAR (20) I–IIIA Nivo + CT → S → SOC 22 41 22 [100] 18.2 32.1 NR 45
Nivo + Ipi + CT → S → SOC 22 29 20 [91] 18.2 50 NR 20
NADIM II (21) IIIA–B Nivo + CT → S → Nivo 6 months 57 75 53 [93] 37 53 19 2.3
CT → S → SOC 29 48 20 [69] 7 14 10 NR

NSCLC, non-small-cell lung cancer; pts, patients; ORR, objective response rate; pCR, pathologic complete response; MPR, major pathological response; G, grade; AE, adverse event; irAE, immune-related adverse event; Nivo, nivolumab; S, surgery; SOC, standard-of-care; Pembro, pembrolizumab; Atezo, atezolizumab; Durva, durvalumab; Sinti, sintilimab; Rela, relatlimab; PD-L1, programmed death-ligand 1; Ramu, ramucirumab; CT, platinum-based chemotherapy; Ipi, ipilimumab; NR, not reported.

Table 2

Phase 3 trials investigating neoadjuvant immunotherapy in potentially resectable NSCLC

Study (reference) Stage Treatment Pts No. ORR (%) Surgery pts No. [%] pCR (%) MPR (%) EFS (mos) OS (mos) Any G ≥3 AE (%) Any G ≥3 irAE (%)
CheckMate-816 (22) IB–IIIA Nivo + CT → S → SoC 179 53.6 149 [83.2] 24.0 46.8 31.6 NR 40.9 43.8
CT → S → SoC 179 37.4 135 [75.4] 2.2 12.7 20.8 33.5 36.9
AEGEAN (23) IA–IIIB (N2) Durva + CT → S → Durva 366† NR 295 [80.6] 17.2 33.3 NR NR 42.3 4.0
PBO + CT → S → PBO 374† 302 [80.7] 4.3 12.3 25.9 43.4 2.5
NEOTORCH (24) (II)–III‡ Tori + CT → S → Tori + CT → Tori 202 NR 166 [82.2] 24.8 48.5 NR NR 63.4 11.9
PBO + CT → S → PBO + CT → PBO 202 148 [73.3] 1.0 8.4 15.5 30.4 54 3.0
KEYNOTE-671 (25) II–IIIB (N2) Pembro + CT → S → Pembro 397 NR 325 [81.9] 18.1 30.2 NR NR 44.9 5.8
PBO + CT → S → PBO 400 317 [79.2] 4.0 11.0 17.0 45.5 37.3 1.5

†, mature intent-to-treat population; ‡, data are presented only for stage III disease patients. NSCLC, non-small-cell lung cancer; pts, patients; ORR, objective response rate; pCR, pathological complete response; MPR, major pathological response; EFS, event-free survival; OS, overall survival; mo, months; G, grade; AE, adverse event; irAE, immune-related adverse event; Nivo, nivolumab; CT, chemotherapy; S, surgery; SOC, standard-of-care; Durva, durvalumab; PBO, placebo; Tori, toripalimab; Pembro, pembrolizumab; NR, not reported.

The primary endpoints of the study were safety and feasibility. Neoadjuvant nivolumab for 2 cycles was well tolerated with grade ≥3 irAE reported in 1 patient (5%) with no unexpected toxicity and was not associated with unexpected perioperative morbidity or mortality (10). These data have been confirmed by the other trials investigating neoadjuvant ICIs, while the addition of neoadjuvant platinum-based chemotherapy led to increased toxicity as expected (11-25). Twenty out of 21 enrolled patients were radically surgically resected, these data have been mirrored also by the other trials confirming the feasibility of this neoadjuvant approach (11-25). The small number of patients who were not amenable to surgery, mainly due to progressive disease, in most cases received definitive radiotherapy instead of surgery. Preoperative and intraoperative unresectability after neoadjuvant ICIs seems comparable to that observed with neoadjuvant chemotherapy. Overall, neoadjuvant immunotherapy can be administered safely, and is feasible without surgical delay and increases the risk of complications in the post-operative period.

The key secondary endpoints were radiologic and pathological responses to treatment. The objective response rate (ORR) was 10% that is low but in line with those reported by the other trials with single agent ICIs (11-17), while the ORR was higher when the neoadjuvant immunotherapy included also the combination with platinum-based chemotherapy, as expected (19-25). Despite the low ORR, a pathological down-staging from the pretreatment clinical stage occurred in 8 patients (40%), and the percentage of pCR (10%) and MPR (45%) were very interesting. In the primary tumors of patients who reached MPR, a high number of infiltrating lymphocytes and macrophages was found with a well-matched immunologic mechanism of response. MPR and pCR, as defined above in the text, might be considered acceptable surrogates of event-free survival (EFS) and this latter for OS (26), with the difference in outcomes between patients with and without MPR. In fact, most recurrences, 6/7 (86%), occurred in patients without MPR and only one with MPR, after neoadjuvant therapy. Twelve (60%) out of 20 patients who underwent surgical resection remained recurrence-free at five years after surgery, and 16 patients (80%) were alive. Interestingly, to evaluate associations between degree of pathologic response and long-term clinical outcomes, an alternative cutoff value of 50% residual viable tumor was used, referred to as partial pathologic response, showing an RFS HR of 0.36 (10). Should these data lead to reclassifying the definition of pathological response when neoadjuvant immunotherapy in NSCLC is administered? The assessment as a continuous variable, considering the several trials already available, should help in optimizing this classification, defining new cutoff points, also in view that in this study the increasing of residual viable tumor trended toward increasing risk for recurrence (HR 2.9). Median EFS and OS have been not reached in most of neoadjuvant trials, and the long-term immaturity of these data, might confirm the role of this approach and forecast potential impressive survival outcomes. In the CheckMate-816 trial (22), the median EFS was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (HR 0.63), while it was still not reached for immunotherapy plus chemotherapy arm in the other phase 3 trials (23-25).

Exploratory end points were immunologic, genomic, and pathological correlates of response in blood and tumor. Considering the limited number of patients, the results regarding the role of PD-L1 expression, tumor mutational burden, circulating tumor DNA, and somatic mutations cannot drive any conclusion (10). These assessments performed in other neoadjuvant trials reported preliminary similar and/or contrasting results (14,16,20-25). In the CheckMate-816 trial, the exploratory analyses to evaluate EFS and pCR by a baseline four-gene (CD8A, CD274, STAT-1, LAG-3) inflammatory signature score showed improved EFS for the combination treatment. Moreover, the baseline four-gene inflammatory signature scores were numerically higher in the combination arm in patients with pCR versus patients without pCR (22). The conflicting findings may be also influenced by the variability among blood versus tissue-based assessments, sequencing platforms and established cutoff values. Standardization of the methodologies to assess these potential predictive/prognostic factors, aiming at reaching a uniform way of data interpretation, might be a strong step away in this setting.

The present neoadjuvant nivolumab single-agent trial in NSCLC is the first showing the longest follow-up data in this setting (10). Favorable long-term clinical outcomes, with a low rate of toxicity, and together with the results from other trials, give hope to change the strategic therapeutic approach and the natural history of early-stage NSCLC. To reach these goals, we should have the answers to some questions of paramount importance. Neoadjuvant, adjuvant, or peri-operative trials? Defining a complete strategic approach including pre-definite neoadjuvant, surgery and adjuvant therapy, with appropriate criteria for patients’ selection, might produce more homogeneous results with an appropriate interpretation of the data. How to manage NSCLC patients harboring gene aberrations, such as EGFR or ALK alterations? Some neoadjuvant immunotherapy trials (20,25) were open to the enrollment also of NSCLC patients with these alterations. The results of a phase II study (20), showed that MPR rate is higher, if patients whose tumors have driver alterations in EGFR and ALK are excluded, considering that these sub-groups are usually non-responsive to immune checkpoint blockade. However, the very limited number of patients enrolled will not lead to driving any conclusions. It might be more appropriate to consider them for the eligibility within the ongoing early-stage NSCLC trials specifically designed for these subgroups of patients with the appropriate targeted therapies (27). This means that the biomarker testing might be mandatory also for patients with early-stage disease at the time of diagnosis and should be included in the routine clinical practice with the potential risk for delays to plan preoperative treatment. The lesson learned from the metastatic disease will help in applying this future procedure taking timing into account. What is the most appropriate neoadjuvant treatment, immunotherapy alone or combined with platinum-based chemotherapy, and how many cycles should it include? The role of pCR and MPR as potential predictive/prognostic factors for survival outcomes together with the availability of tumor tissue and blood samples, that should be mandatory to obtain biomarker results, are crucial to plan preoperative therapy. Identifying patients who may derive equivalent benefit from immunotherapy single-agent versus chemoimmunotherapy, by incorporating predictive biomarkers, for instance, PD-L1 expression like happen in metastatic setting, or the lower risk stage I/II disease, is an important goal in pursuing personalized treatment in early-stage NSCLC. In this regard, the role of NSCLC histology, squamous versus nonsquamous, should also be evaluated, as should the right number of neoadjuvant cycles. Further long-term data and subgroup analyses from the other neoadjuvant trials are pending and might help in improving the knowledge in this setting. Are the results of these trials generalizable in the clinical practice? The management of early-stage NSCLC, especially stage III, requires a team of experts in different disciplines, including thoracic surgeon, medical oncologist, pneumologist, radiotherapist, pathologist, etc., challenging the implementation of this multidisciplinary approach in some sites. For instance, the role of thoracic radiotherapy, alone or combined with chemotherapy, is not still defined in this setting, considering that the neoadjuvant chemoradiotherapy was not associated with an OS or progression-free survival (PFS) benefit compared with induction chemotherapy alone, and the negative results reported in the postoperative setting (28). The role of radiotherapy in resectable NSCLC should be re-investigated in this new era of (neo)-adjuvant immunotherapy. To prevent potential survival gaps, establish a network involving all the experts needed, even if in different locations, to discuss, also through organized virtual meetings, each clinical case and providing the appropriate strategic approach, might be helpful in applying the appropriate treatment, broadly reducing the disparities for potentially life-saving therapies.

These are only some questions that arise from the favorable long-term clinical outcomes reported by Rosner et al. (10), the answers of which are expected soon, from the analysis of larger-scale neoadjuvant trials. In the meanwhile, based on the results of the CheckMate-816 trial (22), Food and Drug Administration (FDA) approved neoadjuvant nivolumab with platinum-doublet chemotherapy for patients with resectable (tumors ≥4 cm or node positive) NSCLC, and European Medicines Agency (EMA), in the same neoadjuvant setting, for NSCLC patients at high risk of recurrence whose tumours have PD-L1 expression ≥1%.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-9/coif). AR declares stock options by IQVIA Holdings Inc. The other authors have no conflicts of interest to declare.

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doi: 10.21037/actr-23-9
Cite this article as: Rossi A, Mari E, Galetta D. The immune “tsunami” has arrived at the shores of early-stage non-small cell lung cancer. AME Clin Trials Rev 2023;1:4.

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