Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

Wakelee, Heather A.; Liberman, Moïshe; Kato, Terufumi; Tsuboi, Masahiro; Lee, Se‐Hoon; Gao, Shugeng; Chen, Ke-Neng; Dooms, Christophe; Majem, Margarita; Eigendorff, E.; Martinengo, Gaston Lucas; Bylicki, Olivier; Rodríguez-Abreu, Delvys; Chaft, Jamie E.; Novello, Silvia; Yang, Jing; Keller, Steven M.; Samkari, Ayman; Spicer, Jonathan

doi:10.1056/nejmoa2302983

Cited by 317 publications

(239 citation statements)

References 18 publications

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“…Patients could benefit from the treatment of toripalimab regardless of PD-L1 tumor expression levels. In this study, 78% of all enrolled patients had squamous NSCLC, which is higher than expected based on previously reported data in patients with NSCLC . This difference might partly be caused by the exclusion of a higher proportion of patients with nonsquamous NSCLC and EGFR alterations in Chinese patients.…”

Section: Discussioncontrasting

confidence: 66%

“…The results from the current study (together with the KEYNOTE-671 study and the AEGEAN trial) establish the critical role of a perioperative checkpoint blocker in patients with resectable NSCLC. A perioperative checkpoint blocker in combination with chemotherapy will soon become a therapeutic option in addition to the established regimen of a checkpoint blocker with neoadjuvant or adjuvant treatment for patients with resectable NSCLC.…”

Section: Discussionmentioning

confidence: 56%

“…A perioperative checkpoint blocker in combination with chemotherapy will soon become a therapeutic option in addition to the established regimen of a checkpoint blocker with neoadjuvant or adjuvant treatment for patients with resectable NSCLC. The KEYNOTE-671 and AEGEAN studies implemented 4 cycles of a checkpoint blocker with neoadjuvant chemotherapy, followed by a single-agent adjuvant checkpoint blocker. In contrast, patients in the current study received 240 mg of toripalimab or placebo combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by single-agent toripalimab or placebo for up to 13 cycles, which ensured that patients received a total of 4 cycles of perioperative chemotherapy while allowing surgeons to determine the optimal cycles of neoadjuvant therapy and surgical timing.…”

Section: Discussionmentioning

confidence: 99%

“…The phase 2, NADIM II randomized clinical trial, revealed that the addition of perioperative nivolumab demonstrated a higher pathological complete response rate and improved survival compared with chemotherapy alone. In the KEYNOTE-671 study, the addition of pembrolizumab to neoadjuvant chemotherapy plus adjuvant pembrolizumab led to significant improvements in event-free survival (HR, 0.58 [95% CI, 0.46-0.72]) in patients with stage II to IIIB NSCLC compared with those who received chemotherapy alone. Similarly, in the AEGEAN trial, perioperative durvalumab in combination with chemotherapy significantly improved event-free survival (HR, 0.68 [95% CI, 0.53-0.88]) and the pathological complete response rate compared with chemotherapy alone.…”

Section: Introductionmentioning

confidence: 99%

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Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non–Small Cell Lung Cancer

Lu,

Zhang,

et al. 2024

JAMA

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ImportanceAdjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non–small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown.ObjectiveTo determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone.Design, Setting, and ParticipantsThis randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022.InterventionsPatients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles.Main Outcomes and MeasuresThe primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events.ResultsOf the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P &lt; .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P &lt; .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups.Conclusions and RelevanceThe addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT04158440

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non–Small Cell Lung Cancer

Lu,

Zhang,

et al. 2024

JAMA

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“…Finally, the KEYNOTE-671 trial administered neoadjuvant platinum doublet chemotherapy with either pembrolizumab or placebo for 4 cycles, followed by surgery and then an additional year of pembrolizumab or placebo, to 797 patients with stage II-IIIB NSCLC per AJCC Staging Manual eighth edition criteria. After a median follow-up of 25.2 months, there was a significant improvement in EFS with the addition of pembrolizumab (HR, 0.58; P < .001; 2-year EFS, 62.4% vs 40.6%); a more recent analysis also revealed a significant improvement in OS with chemotherapy/pembrolizumab (HR, 0.72, median OS not reached vs 52.4 months).…”

Section: Perioperative Chemoimmunotherapy and The Incremental Value O...mentioning

confidence: 99%

Rapid Advances in Resectable Non–Small Cell Lung Cancer

West,

Kim

2024

JAMA Oncol

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ImportanceA series of high-profile clinical trials for patients with resectable early-stage non–small cell lung cancer (NSCLC) have recently changed the standard of care in this setting. Specifically, studies have demonstrated statistically and clinically significant improvements in efficacy with the targeted therapy for adjuvant osimertinib in patients with resected NSCLC harboring an epidermal growth factor receptor (EGFR) genomic abnormality (GA), whereas trials with chemotherapy combined with nivolumab in the neoadjuvant setting and others testing atezolizumab or pembrolizumab as adjuvant therapy have all demonstrated improvements in event-free survival (EFS) (for neoadjuvant therapy) or disease-free survival (DFS) (for adjuvant therapy). These trials introduce many open questions about how to apply these findings in clinical practice.ObservationsTreatment with adjuvant osimertinib for 3 years was associated with significant improvement in both DFS and overall survival (OS), but the erosion of the DFS benefit after the duration of treatment ends suggests a potential value for more longitudinal treatment. The potential value of highly effective targeted therapies as adjuvant therapy for other GAs has a compelling rationale but no data at this time. Adjuvant atezolizumab or pembrolizumab, generally administered for 1 year after postoperative chemotherapy, are appropriate considerations, but only atezolizumab for patients with tumor programmed death-ligand 1 (PD-L1) levels of 50% has demonstrated a benefit in OS. Neoadjuvant chemotherapy with nivolumab offers a strong EFS benefit, a shorter interval of treatment, and radiographic and pathologic feedback for patients with resectable stage IB to IIIA NSCLC, although very recent randomized clinical trials of perioperative immunotherapy both combined with chemotherapy preoperatively and administered postoperatively highlight the debatable value of adjuvant immunotherapy after prior chemoimmunotherapy. Improved tumor shrinkage rates with neoadjuvant chemoimmunotherapy suggest the possibility that criteria for resectability may potentially be redefined in anticipation of a good response to neoadjuvant chemoimmunotherapy.Conclusions and RelevanceDevelopments in resectable NSCLC have arrived so rapidly that they have also created practical challenges of identifying optimal patients and prioritizing options among these new competing standards. In some cases, practical management requires clinical judgment and discussion with the patient to cover the gaps in prospective data. Caution should be exerted when extrapolating beyond the available data.

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Neoadjuvant-Adjuvant vs Neoadjuvant-Only PD-1 and PD-L1 Inhibitors for Patients With Resectable NSCLC

Zhou,

Li,

et al. 2024

JAMA Netw Open

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ImportanceNeoadjuvant therapy combining programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors with platinum-based chemotherapy has demonstrated significant improvement in pathologic response and survival rates among patients with resectable non–small cell lung cancer (NSCLC). However, it remains controversial whether PD-1 blockade therapy given before and after surgery (neoadjuvant-adjuvant treatment) is associated with better outcomes than when given only before surgery (neoadjuvant-only treatment).ObjectiveTo compare the efficacy and safety associated with neoadjuvant-adjuvant anti–PD-1 and anti–PD-L1 therapy with neoadjuvant-only anti–PD-1 and anti–PD-L1 therapy for patients with resectable NSCLC.Data SourcesA systematic search was conducted across databases including PubMed, Embase, and the Cochrane Library, as well as major oncology conferences, through July 31, 2023.Study SelectionRandomized clinical trials comparing neoadjuvant-adjuvant or neoadjuvant-only PD-1 and PD-L1 inhibitor therapy vs chemotherapy alone for patients with resectable NSCLC were selected.Data Extraction and SynthesisFollowing the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 authors independently extracted data. Hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) were extracted and then pooled through the generic inverse-variance methods. Relative risks (RRs) for treatment-related adverse events (TRAEs) were derived via the Mantel-Haenszel method. Using chemotherapy as a common comparator, indirect comparisons between neoadjuvant-adjuvant immunotherapy and neoadjuvant-only immunotherapy were conducted using frequentist methods. A random or fixed model was used based on intertrial heterogeneity identified through the Cochran Q test.Main Outcomes and MeasuresThe primary outcome was EFS, with secondary outcomes including OS and TRAEs.ResultsThe study encompassed 4 trials of neoadjuvant-adjuvant immunotherapy and 1 trial of neoadjuvant-only immunotherapy, involving 2385 patients. Direct meta-analysis revealed significant improvements in EFS for both neoadjuvant-adjuvant and neoadjuvant-only immunotherapy compared with chemotherapy alone. In indirect meta-analysis, the addition of adjuvant immunotherapy to neoadjuvant immunotherapy was not associated with improved EFS (HR, 0.90; 95% CI, 0.63-1.30; P = .59) or OS (HR, 1.18; 95% CI, 0.73-1.90; P = .51) compared with neoadjuvant-only immunotherapy. Moreover, the incidence of any grade of TRAEs significantly increased with the addition of adjuvant immunotherapy (RR, 1.08; 95% CI, 1.00-1.17; P = .04).Conclusions and RelevanceThis meta-analysis suggests that adding PD-1 or PD-L1 inhibitors in the adjuvant phase to neoadjuvant treatment with PD-1 or PD-L1 inhibitors and chemotherapy may not improve survival outcomes for patients with resectable NSCLC and may be associated with increased adverse events. Future validation of these findings is warranted through head-to-head randomized clinical trials.

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Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer

Cited by 317 publications

References 18 publications

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non–Small Cell Lung Cancer

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non–Small Cell Lung Cancer

Rapid Advances in Resectable Non–Small Cell Lung Cancer

Neoadjuvant-Adjuvant vs Neoadjuvant-Only PD-1 and PD-L1 Inhibitors for Patients With Resectable NSCLC

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