Perioperative toripalimab and chemotherapy in resectable non-small cell lung cancer: another weapon in the armamentarium

Neotorch—shedding a light on neoadjuvant chemo-immunotherapy in non-small cell lung cancer (NSCLC)?

Background

Historically, only 30% of patients diagnosed with NSCLC have resectable disease and for those patients with stage II or III disease, the 5-year disease-free survival (DFS) rate is approximately 40% (1-3). The use of adjuvant cisplatin-based chemotherapy is proven to reduce the relative risk of recurrence or death in patients with stage II or III NSCLC by approximately 17%, translating to a 10–15% absolute improvement in overall survival (OS) at 5 years (3). Further reductions in the risk of recurrence have been demonstrated through the use of adjuvant immune checkpoint inhibitors, although these findings have not yet translated into improved OS benefit. The IMPOWER 010 and PEARLS/KEYNOTE 091 trials demonstrated significantly improved DFS among patients receiving one year of adjuvant atezolizumab [hazard ratio (HR) 0.66, 95% confidence interval (CI): 0.50–0.88, P=0.0039], or pembrolizumab (HR 0.76, 95% CI: 0.63–0.91, P=0.0014) respectively, compared with placebo (4,5). The importance of programmed death-ligand 1 (PD-L1) expression on the benefit from immune checkpoint inhibitor therapy varies between these trials. Interestingly, the recently presented CCTG BR.31 trial of adjuvant durvalumab in this setting, failed to demonstrate any improvements in DFS (6).

Previous trials have demonstrated a similar benefit in DFS and OS from neoadjuvant chemotherapy compared with adjuvant chemotherapy, though more patients received neoadjuvant compared with adjuvant chemotherapy (7,8). Immunotherapy in the neoadjuvant setting, when the tumor is still in situ and tumor neoantigens are present, is hypothesized to enhance the immune response and more effectively treat micrometastatic disease. Therefore, more recently, multiple trials have evaluated the addition of an immune checkpoint inhibitor to chemotherapy in the neoadjuvant or perioperative (neoadjuvant plus adjuvant) setting (Table 1) (9-15). Small differences exist in the design of these trials and they have mostly evaluated a perioperative approach to therapy. However, there is consistent evidence (summarized in Table 1) that the addition of an immune checkpoint inhibitor to platinum-based chemotherapy, whether in the neoadjuvant, or perioperative setting, has demonstrated improvements in multiple outcomes, including pathologic complete response (pCR) rates and event-free survival (EFS). To date, the Keynote 671 trial evaluating the addition of perioperative pembrolizumab, and the NADIM II trial evaluating the addition of perioperative nivolumab, to neoadjuvant platinum-based chemotherapy have both demonstrated significant improvements in OS (13,14). Trends in improved OS have also been observed in the Checkmate 816 and AEGEAN trials (10,11). These improvements in patient outcomes are associated with a small increase in grade 3–5 toxicities and a small increase in the rate of treatment discontinuation. Not surprisingly, they are associated with an increase in the rate of immune related adverse events (irAEs). Nevertheless, the significant improvements in disease related outcomes have resulted in the implementation of neoadjuvant and perioperative use of immune checkpoint inhibitor therapy.

The Neotorch trial

The Neotorch randomized phase III clinical trial was designed to evaluate whether the addition of perioperative toripalimab [programmed cell death 1 (PD-1) inhibitor] to platinum-based chemotherapy would improve EFS and major pathologic response (MPR) in patients with resectable stage II, IIIA or IIIB [according to the 8^th edition American Joint Commission on Cancer (AJCC) tumor-node-metastasis (TNM) staging system] NSCLC vs. chemotherapy alone (15). The trial was conducted in 50 hospitals in China and included patients aged 18–70 years of age. Patients with EGFR or ALK molecular alterations were excluded. Randomization was stratified by disease stage (II vs. IIIA vs. IIIB), PD-L1 expression (<1% vs. >1% vs. not evaluable), planned surgery (lobectomy vs. pneumonectomy) and histology (squamous vs. non-squamous). Patients were randomized to three cycles of neoadjuvant platinum-based chemotherapy plus either toripalimab or placebo. Post surgical resection, patients received one additional cycle of platinum-based chemotherapy plus either toripalimab or placebo for up to 13 four-weekly cycles. The primary outcomes were EFS (assessed by investigators) and the MPR rate (assessed by blinded independent pathology review). The secondary outcomes included OS, EFS by blinded independent review, pCR rate, DFS following surgery and adverse events (AEs). PD-L1 expression was assessed by immunohistochemistry using a JS311 assay. This has been previously validated with 22C3, 28-8 and SP263 assays.

Results from a prespecified interim analysis for EFS in patients with stage III NSCLC from Neotorch, were published recently in the Journal of the American Medical Association (JAMA) (15). A total of 501 patients were randomized, of which 404 patients with stage III NSCLC are included in the current analysis. Approximately 90% of patients received three cycles of neoadjuvant therapy and 82.2% of patients in the toripalimab arm and 73.3% of patients in the placebo arm proceeded to surgical resection. The majority of patients in both arms had complete (R0) resections (95.8% and 92.6%). The study demonstrated significant improvements in both primary outcomes. The median EFS was not yet reached in patients randomized to platinum-based chemotherapy plus toripalimab vs. 15.1 months for platinum-based chemotherapy (HR 0.40, 95% CI: 0.28–0.57, P<0.001). Two-year EFS was 64.7% vs. 38.7%, which is similar to other trials. The benefit in EFS was observed across all subgroups, including PD-L1 expression and histology. MPR was prognostic for EFS. Patients achieving an MPR had improved EFS compared to those who did not. Patients randomized to toripalimab still improved EFS regardless of whether they achieved (HR 0.22, 95% CI: 0.13–0.45), or did not achieve (HR 0.22, 95% CI: 0.07–0.71) an MPR. This finding differs from other trials of neoadjuvant therapy, where patients achieving a pCR had similar EFS regardless of whether they received an immune checkpoint inhibitor (ICI) or not.

Similarly, there was a significant improvement in MPR (defined as 10% or less viable tumor remaining) in favour of the intervention group [48.5% vs. 8.4%; between group difference 40.2% (95% CI: 32.2–48.1%), P<0.001]. Key secondary outcomes also favored the addition of toripalimab to platinum-based chemotherapy. The pCR rate was 24.8% vs. 1.0% in favour of the intervention group, with a between group difference of 23.7% (95% CI: 17.6–29.8%, P<0.001). Analysis of OS was immature but favored the addition of toripalimab to platinum-based chemotherapy (median not estimable vs. 30.4 months, HR 0.62, 95% CI: 0.38–1.00). Not surprisingly, the incidence of irAEs occurred more frequently among patients randomized to toripalimab (42.1% vs. 22.8%). These patients also experienced minor increases in the incidences of grade ≥3 AEs (63.4% vs. 54%), fatal AEs (3% vs. 2%) and treatment emergent AEs leading to discontinuation of treatment (9.4% vs. 7.4%). The treatment emergent AEs occurring more commonly in patients randomized to toripalimab included cough, elevated alanine transaminase (ALT), decreased appetite, rash and hypothyroidism.

What are the implications of the Neotorch trial?

To date, there have been five randomized clinical trials, including Neotorch, evaluating the addition of a perioperative immune checkpoint inhibitor to neoadjuvant chemotherapy (Table 1) (9,12-15). One additional trial (Checkmate 816) was limited to neoadjuvant therapy alone (10,11). Some differences exist in the study design of Neotorch, notably the administration of one cycle of adjuvant chemotherapy in addition to the toripalimab or placebo. The remaining trials have administered all cycles of chemotherapy prior to surgery. There does not appear to be a strong rationale to give an additional single cycle of chemotherapy post-surgery and in practice we would recommend all planned chemotherapy be administered prior to surgery. The results of the Neotorch trial are consistent with the other published data evaluating neoadjuvant or perioperative chemotherapy plus an immune checkpoint inhibitor (Table 1). Disease-based and pathologic outcomes are improved with only a small increase in treatment-related AEs. The results of the Neotorch trial may not shift practice in many jurisdictions, which already includes neoadjuvant or perioperative chemoimmunotherapy, however they will be important from a regulatory perspective in China, to allow implementation of neoadjuvant/perioperative immune checkpoint inhibitor therapy for resectable NSCLC.

Important clinical questions that still need to be answered and merit future investigation include (I) understanding whether pathologic endpoints can be surrogates of EFS or OS in this NSCLC patient population as opposed to survival-based outcomes remaining the most important endpoint in trials; (II) whether MPR is as prognostically important as pCR for patients; and (III) whether neoadjuvant chemotherapy + immunotherapy alone vs. a perioperative approach to treatment results in better outcomes for NSCLC patients.

The majority of trials evaluating neoadjuvant or perioperative chemoimmunotherapy have included co-primary outcomes that are both disease-based (EFS or OS) and pathologic (pCR or MPR) where pCR or MPR represent intermediate, or surrogate outcomes. While these provide earlier trial results, questions remain as to whether pCR or MPR are appropriate surrogates for EFS and OS. In breast cancer, outcomes such as pCR to neoadjuvant therapy are routinely used in triple negative and Her2 positive breast cancers, to inform clinical decisions about adjuvant treatment (16,17). The presence of residual disease is felt to represent tumor resistance and trials have demonstrated that switching to alternate, or additional adjuvant therapy can result in improvements in OS (16,17). In breast cancer, studies have shown patient-level associations for EFS and OS in patients who had pCR with neoadjuvant treatment, but weak trial-level associations, suggesting that while pCR could be used for individual patient management, it should not be considered a surrogate endpoint for EFS or OS (18). No data yet exists for patients with NSCLC to suggest that pCR or MPR rates can inform decisions regarding adjuvant therapy. Future phase III randomized trials of neoadjuvant therapy in early-stage NSCLC should focus on disease-based outcomes (EFS or OS) as primary trial outcomes, while pathologic outcomes (pCR or MPR) should move to secondary outcomes. However, pathologic endpoints remain valuable in earlier phase trials focusing on drug discovery and drug development, to select regimens that warrant further study in phase III trials. This approach is supported by the NeoCoast and NeoCoast II phase II multi-arm perioperative platform study of various new agents (oleclumab, monalizumab and volrustomig) in addition to durvalumab demonstrating numerically higher pCR and MPR rates (vs. historical benchmarks), to select regimens warranting further study in phase III settings (19).

Pathologic response to neoadjuvant chemoimmunotherapy represents a strong prognostic factor. Post hoc analyses of trials of neoadjuvant or perioperative chemotherapy plus an immune checkpoint inhibitor, including the Neotorch trial, all demonstrate significant improvements in EFS for patients achieving a pCR regardless of treatment group, in contrast to patients with pathologic residual disease. Data from the Keynote 671 trial suggest that patients with an MPR have an intermediate prognosis between those patients with pCR and those with more significant amounts of residual disease (20). It is enticing to speculate that patients achieving a pCR can omit adjuvant immunotherapy. However, pathologic response to neoadjuvant therapy in NSCLC is prognostic and not an established predictive variable and does not yet help to inform decisions regarding subsequent adjuvant therapy. Important questions exist as to whether patients achieving a pCR can de-escalate adjuvant therapy, or whether patients with residual disease would benefit from additional, or alternate adjuvant systemic therapy. Future clinical trials should focus on addressing these questions.

The majority of randomized trials to date, other than Checkmate 816, have focused on evaluation of the addition of perioperative immunotherapy. No trials have directly compared a neoadjuvant vs. perioperative treatment approach, so it remains uncertain whether the addition of adjuvant immunotherapy to neoadjuvant chemotherapy plus an immune checkpoint inhibitor provides improved EFS or OS outcomes for patients with resectable NSCLC. A combined analysis of CheckMate 816 (neoadjuvant nivolumab) with CheckMate 77T (perioperative nivolumab) utilized an indirect treatment comparison to examine this question. A landmark analysis was conducted in patients from Checkmate 77T who underwent surgery and received at least one dose of adjuvant nivolumab, compared with a propensity weighted analysis of patients from Checkmate 816 (21). While there are methodologic limitations, the landmark analysis demonstrated improved EFS for patients undergoing perioperative vs. neoadjuvant nivolumab (HR of 0.61, 95% CI: 0.39–0.97). Interestingly, among those patients who had a pCR, the difference in EFS appeared to be lost (HR 0.58, 95% CI: 0.14–2.40) lending support to the question above regarding de-escalation of adjuvant therapy in patients achieving a pCR. Those patients who failed to achieve a pCR, had a trend towards improved EFS among patients receiving adjuvant nivolumab (HR 0.65, 95% CI: 0.40–1.06) (21). Trials are ongoing to evaluate the addition of novel immunotherapy agents to neoadjuvant chemoimmunotherapy treatments (e.g., relatlimab, a LAG3 inhibitor) (19,22).

One further question remains the importance of PD-L1 expression in the selection of patients for neoadjuvant, or perioperative chemotherapy plus an immune checkpoint inhibitor. Subgroup analyses examining this question have been conducted in all of the key trials, including Neotorch (Table 2). Analysis of one of the early trials, Checkmate 816, suggested that patients with PD-L1 expression less than 1% may not benefit from the addition of nivolumab to neoadjuvant platinum-based chemotherapy (10). However, taken together the entirety of data demonstrate that patients with tumors with any PD-L1 level of expression (including <1%) have improved EFS from neoadjuvant or perioperative chemoimmunotherapy. The magnitude of benefit appears greater among patients with high PD-L1 expression (>50%). Other subgroup analyses from these trials fail to identify any subgroups that do not benefit from this approach.

There is a lack of published economic data concerning cost and cost effectiveness of the various neoadjuvant and perioperative ICI therapy in resectable NSCLC, including Neotorch. These are costly therapies and it will be important to understand the incremental cost effectiveness of these agents.

Conclusions

The Neotorch trial adds to the growing amount of data supporting that perioperative chemotherapy + immunotherapy improves EFS and MPR compared with NSCLC patients who receive neoadjuvant treatment with chemotherapy alone. Some differences exist in the treatment protocol compared to the other randomized trials, though similar improvements in pathologic response to therapy and EFS were observed. We await presentation of the data for stage II NSCLC patients, as well as more mature data for EFS and OS.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-91/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-91/coif). C.H.C. reports research funding from Pfizer and AstraZeneca. P.M.E. has received honoraria in the last two years for speaking or advisory boards from AstraZeneca, Eli Lilly, Jannsen, Merck, Novartis, Pfizer, Roche and Sanofi. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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