NEOSTAR platform trial: neoadjuvant dual immunotherapy plus chemotherapy—more is better?

Introduction

Surgical resection is the primary treatment approach for early-stage non-small cell lung cancer (NSCLC) and approximately 30% of NSCLC patients are candidates for surgery. However, even with complete resection, a substantial 30–55% experience recurrence following curative surgeries (1-3). Given the high recurrence rate observed in operable NSCLC cases, the focus of studies has been on multidisciplinary perioperative approaches to improve outcomes. Historically, neoadjuvant chemotherapy (CT) had been employed in patients eligible for adjuvant CT with modest survival advantages (4). With the advancement in adjuvant immune checkpoint inhibitors (ICIs) for operable NSCLC (5,6), growing numbers of trials have shifted focus to neoadjuvant ICIs (7-13) or perioperative ICIs (14-18) targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 pathways, either with or without CT, and these endeavors have exhibited promising benefits.

The phase 3 randomized trial, CheckMate 816, represented a significant milestone in this landscape by evaluating neoadjuvant therapy employing nivolumab (Nivo) in combination with platinum-doublet CT against CT alone for stage IB–IIIA operable NSCLC. The trial demonstrated a significant improvement in event-free survival (EFS), pathologic complete response (pCR), and major pathologic response (MPR) with a distinct favor towards the Nivo + CT combination, in contrast to CT alone (7). This led to US Food and Drug Administration (FDA) approval of neoadjuvant Nivo + CT as the new standard of care (SOC) for operable NSCLC patients (19).

Another strategy, involving the application of dual ICIs as evidenced by the NEOSTAR trial (8), showed that the combination of Nivo + ipilimumab (Ipi) yielded higher pCR rates and less viable tumors compared to Nivo alone. The trial further progressed into a platform trial design, which forms the core focus of this editorial commentary, revealing that dual immunotherapy plus CT (Ipi + Nivo + CT) can improve pathologic responses compared to Nivo + CT in operable NSCLC (9).

NEOSTAR platform trial

The NEOSTAR platform trial is a randomized, single-center, sequential phase 2 study. In the study conducted by Cascone et al, patients with operable stage IB to IIIA NSCLC were assigned to arm C (Nivo + CT, 22 patients) or arm D (Ipi + Nivo + CT, 22 patients), followed by surgical resection (9). Although not powered for direct comparison between treatment arms, the primary endpoint in each individual arm was MPR, a potential surrogate for survival outcomes (20) and defined as ≤10% of residual viable tumor in the resected tumor specimens. It was hypothesized that MPR would exceed historical controls of neoadjuvant CT (~15%) (21). Secondary endpoints included radiological response, pCR, toxicities, surgical resectability, perioperative morbidity/mortality, EFS and overall survival (OS). The neoadjuvant regimen consisted of Nivo + CT every 3 weeks for a maximum of three cycles. Ipi was given in arm D on cycle 1 day 1 only. The CT regimen included cisplatin (or carboplatin) plus pemetrexed for non-squamous NSCLC, and cisplatin (or carboplatin) plus docetaxel for squamous NSCLC. The median follow-up was 39.2 and 24 months for arm C and arm D, respectively (9).

The primary endpoint was met in both arms. In the intention to treat (ITT) population, MPR rates were 32.1% (7/22, 80% CI: 18.7–43.1%) for the Nivo + CT arm, and 50% (11/22, 80% CI: 34.6–61.1%) for the Ipi + Nivo + CT arm. Both arms achieved significant difference compared to historical control (P=0.036 and 0.00012, respectively). Moreover, pCR occurred in 18.2% (4/22, 95% CI: 5.2–40.3%) of patients in both arms. All patients (22/22) in arm C and 91% (20/22) of patients in arm D underwent surgical resection, with median percentages of viable tumor in the resected sample measuring 50.5% and 4.5%, respectively. Subgroup analysis between the treatment arms revealed that among stage IIIA patients (50% in arm C vs. 59% in arm D), the odds of achieving MPR was much higher in arm D versus arm C [odds ratio (OR) =16.0, 95% CI: 1.54–166] (9).

Higher MPR and pCR rates were observed in subgroups with no known EGFR/ALK alterations. MPR rates were 41.2% (95% CI: 18.4–67.1%) and 62.5% (95% CI: 35.4–84.8%), while pCR occurred in 23.5% (95% CI: 6.8–49.9%) versus 25% (95% CI: 7.3–52.4%) of patients in arm C and D, respectively. The addition of Ipi resulted in a numerically lower median percentage of viable tumor (51% in arm C vs. 2.8% in arm D). Furthermore, deeper pathologic regression was noted in patients with TP53 and KRAS alterations compared to wild type and between two arms (9).

The secondary endpoints also yielded positive results. In the Nivo + CT arm, 41% achieved partial response (PR) and 59% had stable disease (SD) on radiographic assessment, with no patients experiencing disease progression (PD). In the Ipi + Nivo + CT arm, 29% achieved PR, 67% had SD, and one patient (5%) experienced PD. All patients in the Nivo + CT arm underwent surgery, with 90% achieving R0 resection. In the Ipi + Nivo + CT arm, 91% underwent surgery, and 95% achieved R0 resection. There were no deaths within 30- or 90-days post-surgery in either arm (9).

The median EFS and OS were not reached (NR) in both arms. The 12- and 24-month EFS rates were 96% (95% CI: 87–100%) and 73% (95% CI: 56–94%) for the Nivo + CT arm, and 82% (95% CI: 67–100%) and 77% (95% CI: 61–97%) for the Ipi + Nivo + CT arm. Notably, the addition of Ipi appeared to result in fewer lung cancer-related recurrences in patients who achieved MPR and pCR (42% and 25% in arm C vs. 9% and 0% in arm D for MPR and pCR, respectively), although it is important to consider that direct comparison between the arms was not made and differences in follow-up duration may contribute to this observation (9).

In both arms, 86% (19/22) of patients completed the full 3 cycles of treatment. No new safety signals were noticed in both treatment arms. Grade 3–4 treatment-related adverse events (TRAEs) were experienced by 45% (10/22) of patients in the Nivo + CT arm and 20% (4/20) in the Ipi + Nivo + CT arm (9).

Translational studies further revealed that the Ipi + Nivo + CT combination exhibited a preferential increase in immune cell infiltration and an enrichment of a favorable gut microbiome composition. Specifically, the addition of Ipi resulted in an increased fraction of CD8⁺ TERM eff/TEM cells (22), greater infiltration of antigen-activated (GZB⁺) CD8⁺ tumor-infiltrating T lymphocytes (TILs), higher densities of activated (ICOS⁺) and cytolytic (perforin⁺) CD8⁺ TILs, and a reduced infiltration of LAG3⁺ immunosuppressive CD4⁺ TILs in tissues following Ipi + Nivo + CT therapy. These findings suggest a potential augmentation of immune activation markers with the triple combination (9).

Discussion

Following the promising results of the NEOSTAR platform trial, numerous questions persist, even amid the growing number of trials in the neoadjuvant or perioperative setting. These include the need for better identification of predictive biomarkers to different treatment regimens, selection of patient populations most suited for neoadjuvant dual ICIs with CT compared to the standard Nivo + CT or alternative approaches, exploration of the correlation between MPR and pCR with survival outcomes, assessment of the impact of PD-L1 status on neoadjuvant decision-making, and the consideration of adjuvant ICIs following neoadjuvant ICIs.

In this discussion, we provide a summary of recent phase II and III trials conducted in similar settings, supplementing the findings of the NEOSTAR platform trial, all of which pertain to neoadjuvant or perioperative ICIs for operable NSCLC (Table 1).

Neoadjuvant immunochemotherapy

The CheckMate 816 trial, the first phase 3 trial with neoadjuvant immunochemotherapy, compared Nivo + CT versus CT alone in 358 patients with stage IB–IIIA NSCLC (7). In this trial, Nivo + CT led to a median EFS of 31.6 vs. 20.8 months with CT alone. The pCR rate was 24.0% and 2.2% in the Nivo + CT and CT alone arms, respectively. The MPR rate was also statistically higher in the Nivo + CT arm (36.9% vs. 8.9%; OR =5.70; 95% CI: 3.16–10.26) (7).

In the NEOSTAR platform trial, the MPR and pCR results of Nivo + CT arm were consistent with those in CheckMate 816 after excluding patients with EGFR/ALK alterations (7,9). This allows comparison of Ipi + Nivo + CT to the SOC Nivo + CT, though the trial was not designed for direct comparison. Numerically higher MPR was observed in Ipi + Nivo + CT arm (50% in ITT group, and 62.5% in subgroup with no known EGFR/ALK alterations) compared to the Nivo + CT arm (32.1% in ITT group, and 41.2% in subgroup with no known EGFR/ALK alterations). However, pCR rates were similar between the 2 arms (9).

Subgroup analysis in NEOSTAR platform trial suggested improved MPR benefit in stage IIIA, with deeper pathologic response in patients harboring KRAS and TP53 alterations (9). In high-risk stage IIIA patients, representing ≥50% of the whole cohort, the addition of Ipi had higher odds of MPR compared to stage IB–II. While in CheckMate 816 trial, the Nivo + CT arm achieved more pCR and MPR regardless of baseline stages, with the addition of Nivo revealing longer median EFS vs. CT alone [31.6 vs. 15.7 months; hazard ratio (HR) =0.54, 95% CI: 0.37–0.80] in stage IIIA subgroup (7). It is reasonable to propose that in high-risk stages of operable NSCLC, dual ICIs + CT might lead to deeper pathologic response and subsequently survival benefit. However, the wide CI (1.54–166) regarding the MPR benefit in arm D with stage IIIA disease implies substantial uncertainty in this conclusion, despite its statistical significance. This observation is likely attributed to the limited sample size and sample variations. Thus, more conclusive determinations necessitate a larger sample size and extended follow-up data for validation.

In patients harboring KRAS and TP53 alterations, less viable tumor was found in the Ipi + Nivo + CT arm compared to the Nivo + CT arm, consistent with the results of the CheckMate 227 trial part 1, where improved survival was observed in patients with KRAS and TP53 alterations treated with Ipi + Nivo compared to CT alone (23,24).

Notably, no obvious correlation was found between PD-L1 status and MPR, partly due to limited samples and high percentage of PD-L1 negativity. However, in PD-L1 negative patients, numerically higher MPR was observed in the Ipi + Nivo + CT arm compared to the Nivo + CT arm (40%, 4/10 vs. 22.2%, 2/9), suggesting Ipi’s activity in PD-L1 negative tumors, consistent with prior studies (23,24).

Within the NEOSTAR platform trial’s Ipi + Nivo + CT arm, two patients did not undergo surgery. One patient died due to complications related to SARS-CoV-2 infection, which were unrelated to the trial treatment. The other patient, with a tumor abutting the arteries, was considered unsuitable for surgery despite exhibiting SD following neoadjuvant therapy. It is important to note that the feasibility of surgical resection might not be compromised by TRAEs stemming from neoadjuvant Ipi + Nivo + CT, as compared to Nivo + CT.

The NEOSTAR platform trial used MPR as the primary endpoint, whereas pCR was selected as secondary endpoint due to historically low pCR rates in neoadjuvant CT. Despite higher MPR and pCR rates in the Ipi + Nivo + CT arm, the overall EFS rates at 12 and 24 months were not higher than those in the Nivo + CT arm (96% and 73% vs. 82% and 77% in arms C and D, respectively). This contrasts with the results in CheckMate 816 (7), LCMC 3 (11), NADIM II (14) and Keynote 671 (18), in which MPR and pCR correlated with EFS. The differences in associations across different trials could be attributed to limited sample sizes, relatively short follow-up durations, confounding factors from adjuvant treatments, or the reproducibility of MPR itself, which has been the subject of ongoing debate. Nevertheless, longer follow-up and future phase III studies are warranted to assess the survival benefits of the NEOSTAR platform trial.

Neoadjuvant dual ICIs or ICI + novel agent

NEOpredict-Lung was a phase 2 trial designed to evaluate surgical feasibility after neoadjuvant Nivo alone vs. Nivo + relatlimab (13). Although no definitive benefits in terms of MPR, pCR, or survival were observed in this study, it demonstrated that neoadjuvant dual ICIs did not compromise surgical resectability (13). NeoCOAST was another platform trial that involved neoadjuvant durvalumab alone and in combination with novel immunomodulatory agents, such as oleclumab (anti-CD73), monalizumab (anti-NKG2A) and danvatirsen (anti-STAT3). Both MPR and pCR were higher in durvalumab + novel agents arms vs. durvalumab alone, with the highest MPR at 31.3% in durvalumab + danvatirsen arm (12). Both trials provide strategies for combining ICI and other agents in the neoadjuvant setting, especially in patients who are not candidates for CT.

Perioperative immunochemotherapy

Encouraged by the NADIM result, the phase 2 NADIM II study enrolled 86 patients with stage IIIA–IIIB NSCLC, who received neoadjuvant CT alone (control arm) or neoadjuvant Nivo + CT, followed by 6 months of adjuvant Nivo (experimental arm). The addition of Nivo significantly increased pCR and MPR without compromising surgery feasibility. It also revealed improved median PFS (NR vs. 15.4 months, HR =0.47, 95% CI: 0.25–0.88) and median OS (NR in both arms, HR =0.43, 95% CI: 0.19–0.98) (14).

Three phase 3 perioperative immunochemotherapy trials have been recently published: AEGEAN (16), Neotorch (17) and Keynote 671 (18). The AEGEAN study evaluated neoadjuvant CT + durvalumab followed by adjuvant durvalumab vs. neoadjuvant CT alone in stage IIA–IIIB operable NSCLC patients (n=802). This trial reached the co-primary endpoints: pCR (17.2% vs. 4.3% with durvalumab + CT and CT alone; P=0.00004) and EFS (median NR vs. 25.9 months; P=0.004) (16).

The Neotorch trial enrolled patients with stage II–III operable NSCLC, without EGFR/ALK alterations for non-squamous (n=404), and randomly assigned to toripalimab (anti-PD-1 mAb) + CT or placebo + CT for three cycles before surgery and one cycle after surgery, followed by toripalimab or placebo monotherapy for 13 cycles. EFS was significantly improved in the toripalimab arm (HR =0.40, 95% CI: 0.28–0.57; P<0.0001). MPR and pCR were also higher in the toripalimab arm (48.5% vs. 8.4%; P=0.0001; and 24.8% vs. 1.0%; P<0.001 for MPR and pCR, respectively). OS outcome was also favoring toripalimab arm (HR =0.62, 95% CI: 0.38–0.99; P=0.050) (17).

The Keynote 671 trial assessed 797 operable stage II–IIIB NSCLC patients who were assigned to neoadjuvant pembrolizumab (Pembro) + CT vs. placebo + CT, followed by adjuvant Pembro or placebo. The dual primary endpoints EFS (HR =0.58, 95% CI: 0.46–0.72; P<0.001) and MPR/pCR were both reached (MPR: 30.2% vs. 11.0%, difference, 19.2%; 95% CI: 13.9–24.7%; P<0.0001; pCR: 18.1% vs. 4.0%, difference, 14.2%; 95% CI: 10.1–18.7%; P<0.0001) (18).

Although cross-trial comparison is not an ideal approach, it is intriguing to note that the 24-month EFS rate in the NEOSTAR Ipi + Nivo + CT arm was 77% (95% CI 61–97%), while in the Keynote 671 Pembro + CT arm, it was 62.4% (95% CI: 56.8–67.5%) (18), and in AEGEAN durvalumab + CT arm 63.3% (95% CI: 56.1–69.6%) (16). This difference raises the question of whether the addition of adjuvant ICIs after neoadjuvant ICIs (either single or dual) in combination with CT could provide further survival benefits. On the other hand, an updated result from the LCMC3 trial suggested an improved 3-year disease-free survival (DFS) rate (83% vs. 64%, P=0.025) and a trend towards improved OS in patients who received adjuvant atezolizumab, particularly in the MPR negative subgroup. These findings suggest a potential contribution of adjuvant ICIs to post-neoadjuvant ICI survival (25). As a result, future trials are warranted to directly evaluate the benefits of adding adjuvant immunotherapy after neoadjuvant chemoimmunotherapy and surgery, including subgroup analyses and strategies based on pathologic response.

Furthermore, the proportion of patients who received at least one cycle of adjuvant therapy in AEGEAN and Keynote 671 was 60.0% and 73.1%, respectively. On the other hand, only 24.0% of the durvalumab + CT cohort completed adjuvant therapy in the AEGEAN trial (16,18). For patients susceptible to poor compliance with adjuvant therapy due to factors such as post-op performance status or comorbidities, a potential future approach involves adding neoadjuvant Ipi + Nivo + CT to improve MPR.

Conclusions

In summary, the NEOSTAR trial represents a promising advancement in the neoadjuvant landscape, demonstrating that neoadjuvant Ipi + Nivo + CT yields higher MPR rates compared to Nivo + CT. Subgroup analysis further suggests potential advantages, particularly in stage IIIA disease, KRAS/TP53-altered tumors, and PD-L1 negative cases. Moreover, the addition of Ipi does not compromise surgical resectability or increase toxicity. Nevertheless, the study underscores the complexity of predicting treatment responses in NSCLC patients and emphasizes the need for personalized approaches that consider various factors. Recognizing that not all patients respond to neoadjuvant chemoimmunotherapy, and some may encounter treatment-related adverse events, ongoing efforts to discover predictive biomarkers and enhance treatment strategies remain crucial. Beyond conventional biomarkers like PD-L1 status, gaining insights into the immune cell composition in tumors and blood, as well as the role of the microbiome, may further refine patient selection for specific chemoimmunotherapy regimens. While challenges persist, continued research and future phase 3 trials will further fine-tune treatment strategies and determine the role of CTLA-4 blockade in the management of NSCLC patients in the perioperative setting.

Acknowledgments

Funding: This study was supported by AstraZeneca and Genentech (to H.C.).

Footnote

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

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-26/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-26/coif). H.C. receives funding support from AstraZeneca and Genentech; consulting fees from Janssen and G1 therapeutics. The other author has no 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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