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Original research|Articles in Press

Predictive value of radiological response, pathological response and relapse-free survival for overall survival in neoadjuvant immunotherapy trials: pooled analysis of 29 clinical trials

  • Author Footnotes
    1 These authors contributed equally to this study.
    Runcong Nie
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Foping Chen
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Radiology Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Mariano Provencio
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
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  • Author Footnotes
    1 These authors contributed equally to this study.
    Yun Wang
    Footnotes
    1 These authors contributed equally to this study.
    Affiliations
    Department of Hematologic Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Tom van den Ende
    Affiliations
    Amsterdam UMC, Department of Medical Oncology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
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  • Hanneke W.M. van Laarhoven
    Affiliations
    Amsterdam UMC, Department of Medical Oncology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
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  • Shuqiang Yuan
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Miklos Pless
    Affiliations
    Department of Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland

    Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern, Switzerland
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  • Stefanie Hayoz
    Affiliations
    Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern, Switzerland
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  • Zhiwei Zhou
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Author Footnotes
    2 These authors are co-senior authors.
    Yuanfang Li
    Correspondence
    Correspondence to: Department of Gastric Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Eastern Road, Guangzhou, Guangdong 510060, PR China.
    Footnotes
    2 These authors are co-senior authors.
    Affiliations
    Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Author Footnotes
    2 These authors are co-senior authors.
    Sacha I. Rothschild
    Correspondence
    Correspondence to: Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
    Footnotes
    2 These authors are co-senior authors.
    Affiliations
    Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Basel, Basel, Switzerland

    Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center, Bern, Switzerland
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  • Author Footnotes
    2 These authors are co-senior authors.
    Muyan Cai
    Correspondence
    Correspondence to: Department of Pathology, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Eastern Road, Guangzhou, Guangdong 510060, PR China.
    Footnotes
    2 These authors are co-senior authors.
    Affiliations
    Department of Pathology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
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  • Author Footnotes
    1 These authors contributed equally to this study.
    2 These authors are co-senior authors.
Open AccessPublished:March 17, 2023DOI:https://doi.org/10.1016/j.ejca.2023.03.010
Predictive value of radiological response, pathological response and relapse-free survival for overall survival in neoadjuvant immunotherapy trials: pooled analysis of 29 clinical trials
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      Highlights

      • •
        We investigated the predictive factor for OS in neoadjuvant immunotherapy trials.
      • •
        ORR, MPR, and pCR correlate with OS using neoadjuvant ICIs.
      • •
        The strength of association between RFS and OS was strong.
      • •
        MPR, pCR and RFS may be the optimal surrogates for OS.

      Abstract

      Background

      An increasing number of clinical trials are being conducted exploring the efficacy of neoadjuvant immune checkpoint inhibitors. Surrogate end-points for overall survival (OS) are urgently needed.

      Methods

      Phase II or III trials of neoadjuvant immunotherapy that reported data on OS and surrogate end-points were identified from January 1, 2000, to November 25, 2022. Individual patient data, and trial-level data were requested from corresponding authors or extracted from eligible trials. At the individual level, correlations between radiological and pathological response and OS were measured by the Cox model and quantified by hazard ratio (HR). C-statistic was used to quantify the predictive performance of radiological and pathological response for OS. The coefficient of determination (R2) between RFS and OS was evaluated by a bivariate survival model.

      Results

      A total of 29 trials reporting 2901 patients were included. ORR correlated with improved OS (3-year OS: 87.0% versus 70.4% for ORR versus non-ORR, respectively; HR, 0.34, 95% CI, 0.17–0.68). The HRs for OS in patients achieving MPR and pCR were 0.24 (95% CI, 0.12–0.46) and 0.13 (95% CI, 0.05–0.36). The survival benefit maintained after adjusting tumour type. C-statistics of ORR, MPR and pCR were 0.63, 0.63 and 0.65, respectively. The strength of association between RFS and OS was strong (R2 = 0.88, 95% CI, 0.79–0.94).

      Conclusions

      These findings suggest that ORR, MPR, pCR and RFS are valid predictors for OS when using neoadjuvant immune checkpoint inhibitors. Moreover, MPR, pCR and RFS may be the most optimal surrogates for OS.

      Keywords

      1. Introduction

      In the last decade, drugs targeting the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis have dramatically improved the clinical outcome of a variety of metastatic tumours [
      • He X.
      • Xu C.
      Immune checkpoint signaling and cancer immunotherapy.
      Cell Res. 2020; 30: 660-669
      ,
      • Kraehenbuehl L.
      • Weng C.H.
      • Eghbali S.
      • et al.
      Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways.
      Nat Rev Clin Oncol. 2021;
      ]. Drug regulatory authorities of multiple countries (e.g. FDA, EMA and NMPA) have approved the use of anti-PD1/PD-L1 immune checkpoint inhibitors in more than 20 cancer types. This success in patients with metastatic disease has accelerated the investigation in earlier disease stages such as the adjuvant [
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      N Engl J Med. 2021; 384: 1191-1203
      ] or neoadjuvant setting.
      In specific cancer types (e.g. oesophageal cancer [
      • van Hagen P.
      • Hulshof M.C.
      • van Lanschot J.J.
      • et al.
      Preoperative chemoradiotherapy for esophageal or junctional cancer.
      N Engl J Med. 2012; 366: 2074-2084
      ], breast cancer [
      • Asselain B.
      • Barlow W.
      • Bartlett J.
      • et al.
      Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.
      Lancet Oncol. 2018; 19: 27-39
      ] and rectal cancer [
      • Sauer R.
      • Becker H.
      • Hohenberger W.
      • et al.
      Preoperative versus postoperative chemoradiotherapy for rectal cancer.
      N Engl J Med. 2004; 351: 1731-1740
      ]), neoadjuvant therapy has a large number of advantages over adjuvant therapy, such as early elimination of occult micrometastases, downstaging tumours to improve surgical resectability, and assessing the sensitivity of anti-tumour drugs. Moreover, neoadjuvant therapy could potentially spare patients from surgery in cases with a clinical complete response. From a research perspective, neoadjuvant therapy can offer the chance to access pre- and post-treatment tumour tissue to identify underlying mechanisms for treatment success and failure. Pre-clinical and translational studies have suggested improved therapeutic efficacy of the use of neoadjuvant immune checkpoint inhibitors compared to their adjuvant use [
      • Liu J.
      • Blake S.J.
      • Yong M.C.
      • et al.
      Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.
      Cancer Discov. 2016; 6: 1382-1399
      ,
      • Blank C.U.
      • Rozeman E.A.
      • Fanchi L.F.
      • et al.
      Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.
      Nat Med. 2018; 24: 1655-1661
      ].
      Importantly, chemotherapy, radiotherapy, and chemoradiotherapy are able to alter the composition of the tumour immune microenvironment, and when already applied in the neoadjuvant setting may provide attractive backbones for neoadjuvant immunotherapy [
      • van den Ende T.
      • van den Boorn H.G.
      • Hoonhout N.M.
      • et al.
      Priming the tumor immune microenvironment with chemo(radio)therapy: a systematic review across tumor types.
      Biochim Biophys Acta Rev Cancer. 2020; 1874188386
      ]. Several adjuvant immunotherapy trials have also demonstrated survival benefit in oesophageal adenocarcinoma and lung cancer [
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      N Engl J Med. 2021; 384: 1191-1203
      ,
      • Felip E.
      • Altorki N.
      • Zhou C.
      • et al.
      Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
      Lancet. 2021; 398: 1344-1357
      ]. The gold standard end-point in clinical trials for cancer patients is overall survival (OS) because of its importance to the patient, its reliability, easy interpretation, and unbiased measurement. However, OS as primary end-point has its disadvantages: it requires sufficient sample size and follow-up period to detect statistically significant and clinically meaningful differences. Therefore, some neoadjuvant trials investigating immune checkpoint inhibitors included radiological response, pathological response and relapse-free survival (RFS) as the primary or co-primary end-points [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      N Engl J Med. 2020; 382: 810-821
      ,
      • Mittendorf E.A.
      • Zhang H.
      • Barrios C.H.
      • et al.
      Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
      Lancet. 2020; 396: 1090-1100
      ,
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Schoenfeld J.D.
      • Hanna G.J.
      • Jo V.Y.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial.
      JAMA Oncol. 2020; 6: 1563-1570
      ] to speed up the assessment of treatment. However, whether these end-points can reliably predict OS remain a point of debate. To address this issue, we performed a pooled analysis of eligible clinical trials at the individual and trial level to evaluate the correlation between the potential surrogate end-points and OS.

      2. Methods

      2.1 Data Sources and Selection

      This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      PLoS Med. 2009; 6e1000097
      ]. Two investigators (RCN and FPC) independently searched PubMed, Web of Science, Cochrane library, and Embase databases for eligible articles from 1st January 2000, to 25th November 2022, using the following key words: nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, durvalumab, PD-1, PD-L1, checkpoint inhibitors, neoadjuvant and clinical trial (eBox 1 in the Supplement). Phase II or III clinical trials were included if they tested the efficacy of neoadjuvant CTLA4/PD1/PDL1 inhibitors, alone or in combination with other treatments, and reported the individual patient data (IPD) and/or trial-level of OS (OS rate or hazard ratio for OS), regardless of tumour types. The other essential criterion is that the eligible trial must report the results of objective response rate (ORR), major pathological response (MPR), complete pathological response (pCR), or RFS. We excluded reviews, case reports, trials with sample size less than 20, and articles that did not report data on OS or other surrogate end-points. For articles reporting on the same patient population, the most recent one with the largest population was included. We also manually searched the abstracts of two conference proceedings [the 2022 American Society of Clinical Oncology (ASCO) annual meeting and the European Society for Medical Oncology (ESMO) 2022 congress] to retrieve additional studies. The risk of bias of the eligible trials were assessed using Newcastle-Ottawa scale [

      GA W., B S., DO C. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2011.

      ].

      2.2 Data Extraction and Synthesis

      We extracted the following data of each eligible trial if available: cancer type, tumour stage, study type, primary end-point, treatment regimen, sample size, ORR, MPR, pCR, RFS and OS. For trials that reported the survival data on OS and RFS at specific time points (e.g. 6, 12, 18, or 24 months), we used the reported results. If trials only provided the Kaplan-Meier curves with number at risk information, we used a digitizer software to extract the specific survival rate (Engauge Digitizer tool V.12.1, http://markummitchell.github.io/engauge-digitizer/). For eligible trials, we contacted all corresponding authors to request individual patient data. The authors of the NADIM [
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ], SAKK 16/14 [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ] and PERFECT [
      • van den Ende T.
      • de Clercq N.C.
      • van Berge Henegouwen M.I.
      • et al.
      Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase ii feasibility trial (PERFECT).
      Clin Cancer Res. 2021; 27: 3351-3359
      ] trials were willing to provide anonymous individual patient data. For other trials, we reviewed the full text and the supplementary material to extract individual patient data (Table S1).

      2.3 End-point Definition

      OS was defined as the time from inclusion to death, irrespective of cause. RFS was defined as the time from inclusion to recurrence or death. Of the eligible trials, three used event-free survival as primary end-point [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • André T.
      • Tougeron D.
      • Piessen G.
      • et al.
      Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study.
      J Clin Oncol. 2022; Jco2200686
      ,
      • Forde P.M.
      • Spicer J.
      • Lu S.
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      N Engl J Med. 2022; 386: 1973-1985
      ], one progression-free survival [
      • Schoenfeld J.D.
      • Hanna G.J.
      • Jo V.Y.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial.
      JAMA Oncol. 2020; 6: 1563-1570
      ], and one lung cancer-related RFS [
      • Cascone T.
      • William Jr., W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
      Nat Med. 2021; 27: 504-514
      ]. Because of the relative similarity between these end-points, they were regarded as RFS for analysis. ORR was defined as the proportion of patients with the best confirmed complete response (CR) or partial response (PR), based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Eur J Cancer. 2009; 45: 228-247
      ]. MPR was defined as 10% or less of residual viable tumour cells at the time of surgery, and pCR as no viable tumour cells at the time of surgery [
      • Hellmann M.D.
      • Chaft J.E.
      • William W.N.
      • et al.
      Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
      Lancet Oncol. 2014; 15: e42-e50
      ].

      3. Statistical Analysis

      The objective of this study is to evaluate the surrogacy of RFS for OS in the neoadjuvant immunotherapy trials. For individual patient data, Fisher’s exact test was used to quantify the correlation between radiological response (CR and PR) and pathological response (MPR and pCR). The Kaplan-Meier curves were used to plot the OS distribution of patients who achieved radiological/pathological response or not. The correlation between radiological/pathological response and OS was measured by the Cox regression model and quantified by the hazard ratio (HR). The HRs adjusting tumour types were measured to reduce the heterogeneity. The subgroup analysis of different tumour types and treatment regimens (single, dual immunotherapy and chemotherapy plus immunotherapy [CT/IO]) was performed. C-statistic was used to quantify the prognostic performance of radiological/pathological response for OS. The coefficient of determination (R2) between RFS and OS at individual level was evaluated by a bivariate survival model, as proposed by O'Quigley and Flandre [
      • O'Quigley J.
      • Flandre P.
      Quantification of the prentice criteria for surrogate endpoints.
      Biometrics. 2006; 62: 297-300
      ]. At the trial level, the strength of association between ORR, MPR, 6-months RFS rate and OS rate (6, 12, and 24 months) was quantified by Spearman’s rank correlation coefficient (r). All statistical tests were two sided, with P ≤ 0.05 regarded as statistically significant. All the analyses were performed using statistical software R version 4.1.0 (http://www.r-project.org).

      4. Results

      After screening 1542 reports, a total of 29 reports including 27 distinct publications [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Schoenfeld J.D.
      • Hanna G.J.
      • Jo V.Y.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial.
      JAMA Oncol. 2020; 6: 1563-1570
      ,
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • van den Ende T.
      • de Clercq N.C.
      • van Berge Henegouwen M.I.
      • et al.
      Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase ii feasibility trial (PERFECT).
      Clin Cancer Res. 2021; 27: 3351-3359
      ,
      • André T.
      • Tougeron D.
      • Piessen G.
      • et al.
      Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study.
      J Clin Oncol. 2022; Jco2200686
      ,
      • Forde P.M.
      • Spicer J.
      • Lu S.
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      N Engl J Med. 2022; 386: 1973-1985
      ,
      • Cascone T.
      • William Jr., W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
      Nat Med. 2021; 27: 504-514
      ,
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      Nat Med. 2018; 24: 1649-1654
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      • Shu C.A.
      • Gainor J.F.
      • Awad M.M.
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      Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 786-795
      ,
      • Topalian S.L.
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      • Amin A.
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      Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial.
      J Clin Oncol. 2020; 38: 2476-2487
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      Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021; 27: 4557-4565
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      • Ferris R.L.
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      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      ,
      • Zhang Z.
      • Ye J.
      • Li H.
      • et al.
      Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase 2 trial.
      Front Immunol. 2022; 13: 1031171
      ] and two abstracts from 2022 ASCO annual meeting [
      • Cathomas R.
      • Rothschild S.
      • Hayoz S.
      • et al.
      Perioperative chemoimmunotherapy with durvalumab for operable muscle-invasive urothelial carcinoma (MIUC): primary analysis of the single arm phase II trial SAKK 06/17.
      J Clin Oncol. 2022; 40 (4515–4515)
      ,
      • Kendra K.L.
      • Moon J.
      • Eroglu Z.
      • et al.
      Neoadjuvant PD-1 blockade in patients with resectable desmoplastic melanoma (SWOG 1512).
      J Clin Oncol. 2022; 40 (9502–9502)
      ] comprising 2901 patients were found eligible (Fig. 1). Of the eligible trials, 27 trials were phase II design, two trials were phage III design. Among these 29 trials, nine trials were done in patients with patients with non-small cell lung cancer (NSCLC), four trials in patients with head and neck squamous cell carcinoma, three trials in patients with melanoma, three trials in patients with gastric or gastric and gastroesophageal junction carcinoma, two trials in patients with oesophageal adenocarcinoma, two trials in patients with muscle-invasive bladder cancer, two trials in patients with triple-negative breast cancer, one trial in patients with oral cavity squamous cell carcinoma, one trial in patients with Merkel cell carcinoma, one trial in patients with hepatocellular carcinoma, and one trial in patients with muscle-invasive bladder cancer. The 29 studies covered 11 trials with nivolumab-based regimens, five trials with atezolizumab-based regimens, four trials with durvalumab-based regimens, three trials with sintilimab-based regimens, two trials with pembrolizumab based regimens, one trial with toripalimab-based regimens, one trial with camrelizumab-based regimens and one trial with tislelizumab-based regimens. The sample size of individual trials varied from 20 to 784. The median follow-up duration varied from 10.0 to 48.0 months. The qualities of included trials were generally moderate (Table S2). Table 1 and Table S3 present detailed information on individual trials.
      Fig. 1
      Fig. 1Flow diagram of the study selection process.
      Table 1Characteristics of the included trials.
      StudiesPopulationTumour stageStudy phasePrimary end-pointImmunotherapy drugNpCR (%)MPR (%)ORR (%)OS (%)RFS (%)
      6 months12 months24 months6 months12 months18 months
      Amaria et al. 
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      Nat Med. 2018; 24: 1649-1654
      		MelanomaStage III or oligometastatic stage IV2Pathologic responseNivolumab or Nivolumab + ipilimumab2334.8-47.8100.095.588.169.669.669.6
      Provencio et al. 
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      		NSCLCIII2PFSNivolumab4663.083.076.0100.0100.097.6100.097.690.2
      Schoenfeld et al. 
      • Schoenfeld J.D.
      • Hanna G.J.
      • Jo V.Y.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial.
      JAMA Oncol. 2020; 6: 1563-1570
      		SCC-OCcT2–4bNanyM0 or cTanyN+M0.2ORRNivolumab or Nivolumab + ipilimumab29-13.824.189.189.189.188.985.077.3
      Shu et al. 
      • Shu C.A.
      • Gainor J.F.
      • Awad M.M.
      • et al.
      Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 786-795
      		NSCLCIB-IIIA2MPRAtezolizumab3033.356.763.396.596.582.295.974.848.9
      Cascone et al. 
      • Cascone T.
      • William Jr., W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
      Nat Med. 2021; 27: 504-514
      		NSCLCIA-IIIA2MPRNivolumab or Nivolumab + ipilimumab4418.229.520.497.897.894.695.595.590.0
      Ferrarotto et al. 
      • Ferrarotto R.
      • Amit M.
      • Nagarajan P.
      • et al.
      Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021; 27: 4557-4565
      		CSCC-HNIII-IVA2ORRCemiplimab2055.570.030.0100.095.090.095.095.090.0
      Rothschild et al. 
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      		NSCLCIIIA212 m EFSDurvalumab6718.062.058.097.090.982.790.673.770.0
      Rawson et al. 
      • Rawson R.V.
      • Adhikari C.
      • Bierman C.
      • et al.
      Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.
      Ann Oncol. 2021; 32: 766-777
      ,
      • Rozeman E.A.
      • Hoefsmit E.P.
      • Reijers I.L.M.
      • et al.
      Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.
      Nat Med. 2021; 27: 256-263
      		MelanomaIII2ORRNivolumab or Nivolumab + ipilimumab8345.062.253.7100.097.494.493.984.984.4
      Ende et al. 
      • van den Ende T.
      • de Clercq N.C.
      • van Berge Henegouwen M.I.
      • et al.
      Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase ii feasibility trial (PERFECT).
      Clin Cancer Res. 2021; 27: 3351-3359
      		EACcT2–4aNanyM02feasibilityAtezolizumab4025.035.0-89.789.764.182.479.954.5
      Topalian et al. 
      • Topalian S.L.
      • Bhatia S.
      • Amin A.
      • et al.
      Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial.
      J Clin Oncol. 2020; 38: 2476-2487
      		MCCIIA-IIIB1/2safetyNivolumab3947.252.750.0100.093.280.194.277.568.5
      Ferris et al. 
      • Ferris R.L.
      • Spanos W.C.
      • Leidner R.
      • et al.
      Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.
      J Immunother Cancer. 2021; : 9
      		HNSCCIII-IV1/2safetyNivolumab520.02.710.294.784.276.185.373.270.2
      Hanna et al. 
      • Hanna G.J.
      • Neill A.O.
      • Shin K.Y.
      • et al.
      Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021;
      		HNSCClocoregionally recurrent212 m DFSNivolumab280.014.00.089.385.769.977.155.247.0
      Zhao et al. 
      • Zhao Z.R.
      • Yang C.P.
      • Chen S.
      • et al.
      Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.
      Oncoimmunology. 2021; 10: 1996000
      		NSCLCIIIA, T3–4N2 IIIB2MPRToripalimab3345.560.687.996.996.996.996.990.990.9
      Jiang et al. 
      • Jiang H.
      • Yu X.
      • Li N.
      • et al.
      Efficacy and safety of neoadjuvant sintilimab, oxaliplatin and capecitabine in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma: early results of a phase 2 study.
      J Immunother Cancer. 2022; : 10
      		G/GEJ adenocarcinomacT3–4NanyM02pCRSintilimab3619.447.266.6100.094.690.796.689.881.3
      Kaseb et al. 
      • Kaseb A.O.
      • Hasanov E.
      • Cao H.S.T.
      • et al.
      Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.
      Lancet Gastroenterol Hepatol. 2022; 7: 208-218
      		HCCResectable hepatocellular carcinoma2SafetyNivolumab or Nivolumab + ipilimumab2718.522.211.1100.096.087.077.877.864.5
      Zhang et al. 
      • Zhang Z.
      • Ye J.
      • Li H.
      • et al.
      Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase 2 trial.
      Front Immunol. 2022; 13: 1031171
      		EACII-IVA2pCR and safetySintilimab4522.344.425.595.790.890.884.868.363.1
      Zhang et al. 
      • Zhang Z.
      • Wu B.
      • Peng G.
      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      		HNSCCIII-IVB2pCR and safetyCamrelizumab3033.366.796.710010010010095.589.1
      Zhang et al. 
      • Zhang P.
      • Dai J.
      • Sun F.
      • et al.
      Neoadjuvant sintilimab and chemotherapy for resectable stage IIIA non-small cell lung cancer.
      Ann Thorac Surg. 2022; 114: 949-958
      		NSCLCIIIA2MPR and AESintilimab5012.026.046.098.093.7NR95.987.664.0
      Yin et al. 
      • Yin Y.
      • Lin Y.
      • Yang M.
      • et al.
      Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial.
      Front Oncol. 2022; 12959295
      		G/GEJIII2MPRTislelizumab3225.053.140.693.890.6NR93.887.5NR
      Wislez et al. 
      • Wislez M.
      • Mazieres J.
      • Lavole A.
      • et al.
      Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO).
      J Immunother Cancer. 2022; : 10
      		NSCLCIB-IIIA, non-N22Complete surgical resectionDurvalumab466.517.48.789.089.083.878.378.373.6
      Szabados et al. 
      • Szabados B.
      • Kockx M.
      • Assaf Z.J.
      • et al.
      Final results of neoadjuvant atezolizumab in cisplatin-ineligible patients with muscle-invasive urothelial cancer of the bladder.
      Eur Urol. 2022; 82: 212-222
      		MIBCT2–4aN0M02pCRAtezolizumab9530.7NR22.492.184.677.484.173.469.9
      Schmid et al. 
      • Schmid P.
      • Cortes J.
      • Dent R.
      • et al.
      Event-free survival with pembrolizumab in early triple-negative breast cancer.
      N Engl J Med. 2022; 386: 556-567
      		TNBCII-III3pCRPembrolizumabPlacebo784,39063.055.6NRNRNRNR99.499.897.498.892.391.198.298.293.392.790.185.9
      Loibl et al. 
      • Loibl S.
      • Schneeweiss A.
      • Huober J.
      • et al.
      Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.
      Ann Oncol. 2022; 33: 1149-1158
      		TNBCcT2-cT4a-d2pCRDurvalumabPlacebo878654.044.2NRNRNRNR99.0100.097.799.096.991.498.9100.096.496.494.588.7
      Funt et al. 
      • Funt S.A.
      • Lattanzi M.
      • Whiting K.
      • et al.
      Neoadjuvant atezolizumab with gemcitabine and cisplatin in patients with muscle-invasive bladder cancer: a multicenter, single-arm, phase II trial.
      J Clin Oncol. 2022; 40: 1312-1322
      		MIBCcT2N0M0-cT4aN0M02Non–muscle-invasive downstagingAtezolizumab3941.0NRNR100.097.886.294.987.284.3
      Forde et al. 
      • Forde P.M.
      • Spicer J.
      • Lu S.
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      N Engl J Med. 2022; 386: 1973-1985
      		NSCLCIB-IIIA3pCR and EFSNivolumab Placebo179,17924.02.236.98.953.637.495.196.590.390.182.770.685.981.876.163.452.768.4
      Chaft et al. 
      • Chaft J.E.
      • Oezkan F.
      • Kris M.G.
      • et al.
      Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial.
      Nat Med. 2022; 28: 2155-2161
      		NSCLCIB-IIIB2MPR
      The primary end-point was MPR in resected tumours without EGFR or ALK alterations. A total of 137 patients with R0 resection were available for IPD of MPR and OS.
      		Atezolizumab1435.620.37.397.494.185.293.587.279.5
      André et al. 
      • André T.
      • Tougeron D.
      • Piessen G.
      • et al.
      Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study.
      J Clin Oncol. 2022; Jco2200686
      		G/GEJ adenocarcinomacT2–4NanyM02pCRNivolumab + ipilimumab3258.6NRNR96.996.996.996.996.9NR
      Cathomas et al. 
      • Cathomas R.
      • Rothschild S.
      • Hayoz S.
      • et al.
      Perioperative chemoimmunotherapy with durvalumab for operable muscle-invasive urothelial carcinoma (MIUC): primary analysis of the single arm phase II trial SAKK 06/17.
      J Clin Oncol. 2022; 40 (4515–4515)
      		MIUCcT2–4aN0–1M0224 m EFSDurvalumab5831.0NRNR100.093.187.396.882.878.5
      Kendra et al. 
      • Kendra K.L.
      • Moon J.
      • Eroglu Z.
      • et al.
      Neoadjuvant PD-1 blockade in patients with resectable desmoplastic melanoma (SWOG 1512).
      J Clin Oncol. 2022; 40 (9502–9502)
      		Desmoplastic melanomaResectable stage2pCRPembrolizumab2955.2NR46.2100.0100.092.9100.0100.091.8
      NSCLC, non-small-cell lung cancer, CSCC-HN, cutaneous squamous cell carcinoma of the head and neck; SCC-OC, oral cavity squamous cell carcinoma; MCC, Merkel cell carcinoma; HNSCC, head and neck squamous cell carcinoma; EAC, Esophageal adenocarcinoma; G/GEJ, gastric or gastric and gastroesophageal junction; HCC, hepatocellular carcinoma; MIBC, muscle-invasive bladder cancer; TNBC, triple-negative breast cancer; MIUC, muscle-invasive urothelial carcinoma; pCR, pathological complete response; MPR, major pathological response; ORR, objective response rate; AE, adverse event; OS, overall survival; RFS, relapse-free survival; EFS, even-free survival; NR, not reported/reached.
      * The primary end-point was MPR in resected tumours without EGFR or ALK alterations. A total of 137 patients with R0 resection were available for IPD of MPR and OS.
      The correlation between radiological response and pathological response is shown in Fig. 2. Of the 29 eligible trials, 15 reported a total of 500 individual patients for the assessment of ORR and MPR [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • van den Ende T.
      • de Clercq N.C.
      • van Berge Henegouwen M.I.
      • et al.
      Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase ii feasibility trial (PERFECT).
      Clin Cancer Res. 2021; 27: 3351-3359
      ,
      • Cascone T.
      • William Jr., W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
      Nat Med. 2021; 27: 504-514
      ,
      • Shu C.A.
      • Gainor J.F.
      • Awad M.M.
      • et al.
      Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 786-795
      ,
      • Topalian S.L.
      • Bhatia S.
      • Amin A.
      • et al.
      Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial.
      J Clin Oncol. 2020; 38: 2476-2487
      ,
      • Ferrarotto R.
      • Amit M.
      • Nagarajan P.
      • et al.
      Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021; 27: 4557-4565
      ,
      • Ferris R.L.
      • Spanos W.C.
      • Leidner R.
      • et al.
      Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.
      J Immunother Cancer. 2021; : 9
      ,
      • Hanna G.J.
      • Neill A.O.
      • Shin K.Y.
      • et al.
      Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021;
      ,
      • Rawson R.V.
      • Adhikari C.
      • Bierman C.
      • et al.
      Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.
      Ann Oncol. 2021; 32: 766-777
      ,
      • Zhao Z.R.
      • Yang C.P.
      • Chen S.
      • et al.
      Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.
      Oncoimmunology. 2021; 10: 1996000
      ,
      • Kaseb A.O.
      • Hasanov E.
      • Cao H.S.T.
      • et al.
      Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.
      Lancet Gastroenterol Hepatol. 2022; 7: 208-218
      ,
      • Zhang P.
      • Dai J.
      • Sun F.
      • et al.
      Neoadjuvant sintilimab and chemotherapy for resectable stage IIIA non-small cell lung cancer.
      Ann Thorac Surg. 2022; 114: 949-958
      ,
      • Zhang Z.
      • Wu B.
      • Peng G.
      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      ,
      • Zhang Z.
      • Ye J.
      • Li H.
      • et al.
      Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase 2 trial.
      Front Immunol. 2022; 13: 1031171
      ]. For patients who achieved radiological response (CR and PR), the MPR rate was 69.1% (170/246), compared with 26.0% (66/254) of whom did not (P < 0.001; Fig. 2A). The MPR rate for patients who achieved CR, PR, SD and PD were 92.9%, 67.3%, 27.1% and 8.0%, respectively (P < 0.001; Fig. S1A). Individual data of ORR and pCR were available for 531 patients [
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • Cascone T.
      • William Jr., W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.
      Nat Med. 2021; 27: 504-514
      ,
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      Nat Med. 2018; 24: 1649-1654
      ,
      • Shu C.A.
      • Gainor J.F.
      • Awad M.M.
      • et al.
      Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 786-795
      ,
      • Topalian S.L.
      • Bhatia S.
      • Amin A.
      • et al.
      Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial.
      J Clin Oncol. 2020; 38: 2476-2487
      ,
      • Ferrarotto R.
      • Amit M.
      • Nagarajan P.
      • et al.
      Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021; 27: 4557-4565
      ,
      • Kaseb A.O.
      • Hasanov E.
      • Cao H.S.T.
      • et al.
      Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.
      Lancet Gastroenterol Hepatol. 2022; 7: 208-218
      ,
      • Zhang P.
      • Dai J.
      • Sun F.
      • et al.
      Neoadjuvant sintilimab and chemotherapy for resectable stage IIIA non-small cell lung cancer.
      Ann Thorac Surg. 2022; 114: 949-958
      ,
      • Zhang Z.
      • Wu B.
      • Peng G.
      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      ,
      • Zhang Z.
      • Ye J.
      • Li H.
      • et al.
      Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase 2 trial.
      Front Immunol. 2022; 13: 1031171
      ]. ORR strongly correlated with pCR based on the Fisher’s exact test (51.3% and 13.4% for ORR and non-ORR, respectively, P < 0.001; Fig. 2B). The pCR rate decreased in cases with a radiological poor response (85.7%, 48.6%, 13.1% and 4.0% for CR, PR, SD and PD, respectively, P < 0.001; Fig. S1B).
      Fig. 2
      Fig. 2Correlation between radiological response and pathological response. The bar plot estimates of the correlation of objective response rate (ORR) and major pathological response (MPR) (A) and pathological complete response (pCR) (B).
      The correlation between surrogate end-points and OS at individual-level is shown in Fig. 3. A total of 248 individual patients had data available on ORR and OS [
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      Nat Med. 2018; 24: 1649-1654
      ,
      • Ferris R.L.
      • Spanos W.C.
      • Leidner R.
      • et al.
      Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.
      J Immunother Cancer. 2021; : 9
      ,
      • Hanna G.J.
      • Neill A.O.
      • Shin K.Y.
      • et al.
      Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021;
      ,
      • Zhang P.
      • Dai J.
      • Sun F.
      • et al.
      Neoadjuvant sintilimab and chemotherapy for resectable stage IIIA non-small cell lung cancer.
      Ann Thorac Surg. 2022; 114: 949-958
      ]. ORR was related to an improvement in OS (ORR 3-year 87.0% versus non-ORR 70.4%, HR, 0.34, 95% CI, 0.17–0.68, P < 0.001; Fig. 3A). The HR adjusting tumour types was 0.31 (95% CI, 0.15–0.66). The correlations between ORR and OS per tumour types and treatment regimens are shown in Fig. S2 and Fig. S3. ORR was related to an improvement in OS mainly in patients with NSCLC, and was independent of the treatment regimens. Individual patient data of MPR and OS were available for 545 patients [
      • Rothschild S.I.
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      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
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      Neoadjuvant sintilimab and chemotherapy in patients with resectable esophageal squamous cell carcinoma: a prospective, single-arm, phase 2 trial.
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      ]. Patients who had an MPR had superior OS than those who did not achieve an MPR, with OS 92.2% versus 73.5% at 3 years (HR, 0.24, 95% CI, 0.12–0.46, P < 0.001; Fig. 3B). The HR adjusting tumour types was 0.22 (95% CI, 0.11–0.43). The prognostic value of MPR was significant or have a trend to reach significance across six tumour types (Fig. S4) and was independent of the treatment regimens (Fig. S5). Individual patient data of pCR and OS were available for 448 patients [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • van den Ende T.
      • de Clercq N.C.
      • van Berge Henegouwen M.I.
      • et al.
      Neoadjuvant chemoradiotherapy combined with atezolizumab for resectable esophageal adenocarcinoma: a single-arm phase ii feasibility trial (PERFECT).
      Clin Cancer Res. 2021; 27: 3351-3359
      ,
      • André T.
      • Tougeron D.
      • Piessen G.
      • et al.
      Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study.
      J Clin Oncol. 2022; Jco2200686
      ,
      • Amaria R.N.
      • Reddy S.M.
      • Tawbi H.A.
      • et al.
      Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma.
      Nat Med. 2018; 24: 1649-1654
      ,
      • Topalian S.L.
      • Bhatia S.
      • Amin A.
      • et al.
      Neoadjuvant nivolumab for patients with resectable merkel cell carcinoma in the CheckMate 358 trial.
      J Clin Oncol. 2020; 38: 2476-2487
      ,
      • Ferris R.L.
      • Spanos W.C.
      • Leidner R.
      • et al.
      Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.
      J Immunother Cancer. 2021; : 9
      ,
      • Hanna G.J.
      • Neill A.O.
      • Shin K.Y.
      • et al.
      Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021;
      ,
      • Kaseb A.O.
      • Hasanov E.
      • Cao H.S.T.
      • et al.
      Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.
      Lancet Gastroenterol Hepatol. 2022; 7: 208-218
      ,
      • Loibl S.
      • Schneeweiss A.
      • Huober J.
      • et al.
      Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.
      Ann Oncol. 2022; 33: 1149-1158
      ,
      • Zhang P.
      • Dai J.
      • Sun F.
      • et al.
      Neoadjuvant sintilimab and chemotherapy for resectable stage IIIA non-small cell lung cancer.
      Ann Thorac Surg. 2022; 114: 949-958
      ,
      • Zhang Z.
      • Wu B.
      • Peng G.
      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      ]. In patients with a pCR, relatively few deaths were observed (3-year 95.8%), compared with the non-pCR group (3-year 76.8%) (HR, 0.13, 95% CI, 0.05–0.36, P < 0.001; Fig. 3C). The HR adjusting tumour types was 0.17 (95% CI, 0.06–0.47). The prognostic value of pCR was significant or have a trend to reach significance across eight tumour types (Fig. S6), and was independent of the treatment regimens (Fig. S7). C-statistics of ORR, MPR and pCR were 0.63, 0.63 and 0.65, respectively. Eight eligible trials reported data on 279 individual patients for RFS and OS [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • Ferrarotto R.
      • Amit M.
      • Nagarajan P.
      • et al.
      Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021; 27: 4557-4565
      ,
      • Ferris R.L.
      • Spanos W.C.
      • Leidner R.
      • et al.
      Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.
      J Immunother Cancer. 2021; : 9
      ,
      • Hanna G.J.
      • Neill A.O.
      • Shin K.Y.
      • et al.
      Neoadjuvant and adjuvant nivolumab and lirilumab in patients with recurrent, resectable squamous cell carcinoma of the head and neck.
      Clin Cancer Res. 2021;
      ,
      • Kaseb A.O.
      • Hasanov E.
      • Cao H.S.T.
      • et al.
      Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.
      Lancet Gastroenterol Hepatol. 2022; 7: 208-218
      ,
      • Zhang Z.
      • Wu B.
      • Peng G.
      • et al.
      Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial.
      Clin Cancer Res. 2022; 28: 3268-3276
      ]. A strong correlation was observed between RFS and OS (R2 = 0.88, 95% CI, 0.79–0.94; Fig. 3D).
      Fig. 3
      Fig. 3Estimated overall survival, stratified by radiological and pathological end-point. Kaplan-Meier curves of overall survival (OS), stratified by objective response rate (ORR) (A), major pathological response (MPR) (B) and pathological complete response (pCR) (C). Kaplan-Meier curves of relapse-free survival (RFS) and OS (D).
      At trial level, the correlation between RFS and OS was first investigated. For RFS at 6 or 12 months, correlations were observed with OS at 24 months (6 months: r = 0.75, 95% CI, 0.61–1.01, P < 0.001; 12 months: r = 0.83, 95% CI, 0.73–1.02, P < 0.001; Fig. 4A). The strength of association between RFS and OS became stronger with longer OS landmarks (r = 0.49 [0.15–0.85], 0.71 [0.53–0.97] and 0.75 [0.61–1.00], and P = 0.007,<0.001 and<0.001 for RFS6-months-OS6-months, RFS6-months-OS12-months and RFS6-months-OS24-months, respectively; Fig. 4B). However, the correlations between ORR, MPR and pCR and OS became weaker with longer OS landmarks (Fig. 4B).
      Fig. 4
      Fig. 4Correlation between radiological and pathological end-point at trial level. A, Scatter plot shows the correlation between 6- and 12-months relapse-free survival (RFS) and 24 months overall survival (OS). Each trial is represented by a point. B, Scatter plot shows the correlation between objective response rate (ORR), major pathological response (MPR), pathological complete response (pCR) and 6-months RFS with OS at 6, 12, 24 months. Each point indicates a Spearman correlation coefficient.

      5. Discussion

      This is the first pooled analysis of individual patient data and trial-level data to evaluate the predictive value of RECIST-based radiological response, pathological response (namely, MPR and pCR) and RFS for OS in trials investigating neoadjuvant immune checkpoint inhibitors. We found that ORR, MPR or pCR were tightly linked with OS, and that achievement of these surrogates was associated with a decreased risk of death of 66%, 76%, and 87% respectively (all P < 0.001). As expected, there was also a strong correlation between RFS and OS on the individual-level and trial-level data.
      A large number of neoadjuvant trials investigating immune checkpoint inhibitors are being conducted to explore safety and efficacy for resectable solid tumours. So far, three phase III trials have shown a significant improvement in pCR with neoadjuvant immunotherapy: patients with resectable triple-negative breast cancer [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      N Engl J Med. 2020; 382: 810-821
      ,
      • Mittendorf E.A.
      • Zhang H.
      • Barrios C.H.
      • et al.
      Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
      Lancet. 2020; 396: 1090-1100
      ] and non-small cell lung cancer [

      Forde P.M., Spicer J., Lu S. et al. Abstract CT003: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. 2021; 81: CT003-CT003.

      ]. Very promising results concerning ORR, MPR and RFS were also observed in several phase II trials [
      • Rothschild S.I.
      • Zippelius A.
      • Eboulet E.I.
      • et al.
      SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer-a multicenter single-arm phase II Trial.
      J Clin Oncol. 2021; 39: 2872-2880
      ,
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.
      Lancet Oncol. 2020; 21: 1413-1422
      ,
      • Chalabi M.
      • Fanchi L.F.
      • Dijkstra K.K.
      • et al.
      Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.
      Nat Med. 2020; 26: 566-576
      ]. Among the different standardised methods to measure tumour size and therapeutic efficacy, RECIST 1.1 is one of the most commonly used [
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Eur J Cancer. 2009; 45: 228-247
      ]. Nonetheless, novel agents that target the PD-1/PD-L1 axis have specific response patterns compared to conventional chemotherapy, such as a delay in clinical benefit [
      • Chen D.S.
      • Mellman I.
      Elements of cancer immunity and the cancer-immune set point.
      Nature. 2017; 541: 321-330
      ], pseudo-progression [
      • Beaver J.A.
      • Hazarika M.
      • Mulkey F.
      • et al.
      Patients with melanoma treated with an anti-PD-1 antibody beyond RECIST progression: a US Food and Drug Administration pooled analysis.
      Lancet Oncol. 2018; 19: 229-239
      ,
      • Chiou V.L.
      • Burotto M.
      Pseudoprogression and immune-related response in solid tumors.
      J Clin Oncol. 2015; 33: 3541-3543
      ] and hyper-progression [
      • Ferrara R.
      • Mezquita L.
      • Texier M.
      • et al.
      Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.
      JAMA Oncol. 2018; 4: 1543-1552
      ]. Therefore, the use of RECIST-based radiological response instead of OS as primary end-point remains debatable. In this study, we observed that the clinical benefit of patients achieving ORR was substantial, corresponding to a 66% reduction of death, indicating that RECIST-based end-point could be a valid predictor for OS when using neoadjuvant immune checkpoint inhibitors.
      In addition to radiological response, pathological response reflects the local effect of neoadjuvant therapy and could potentially predict OS, among which pCR is the most promising. In 2013, the FDA granted the accelerated approval of pertuzumab for early HER2-positive breast cancer, based on an improved pCR rate in the NeoSphere trial [
      • Gianni L.
      • Pienkowski T.
      • Im Y.H.
      • et al.
      Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.
      Lancet Oncol. 2012; 13: 25-32
      ]. In 2014, Hellmann and colleagues proposed the use of MPR as a surrogate end-point for neoadjuvant chemotherapy trials [
      • Hellmann M.D.
      • Chaft J.E.
      • William W.N.
      • et al.
      Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
      Lancet Oncol. 2014; 15: e42-e50
      ]. Recently, Rawson et al. reported the pathological response and its prognostic value in stage III melanoma after neoadjuvant immunotherapy [
      • Rawson R.V.
      • Adhikari C.
      • Bierman C.
      • et al.
      Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.
      Ann Oncol. 2021; 32: 766-777
      ]. They found that pathological response is an excellent predictor for RFS. However, data on OS was not reported because of small sample size (n = 83). In the present study, we found that patients achieving a pCR or MPR had 87% and 76% less chance of dying, respectively. Therefore, pathological response measured by pCR and MPR are strong predictors of OS in the neoadjuvant immunotherapy setting.
      RFS could also serve as a surrogate end-point for OS. This has previously been validated in adjuvant trials of gastric cancer [
      • Oba K.
      • Paoletti X.
      • Alberts S.
      • et al.
      Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis.
      J Natl Cancer Inst. 2013; 105: 1600-1607
      ] and melanoma [
      • Suciu S.
      • Eggermont A.M.M.
      • Lorigan P.
      • et al.
      Relapse-free survival as a surrogate for overall survival in the evaluation of stage II-III melanoma adjuvant therapy.
      J Natl Cancer Inst. 2018; : 110
      ]. In the present study, a high coefficient of determination (0.88) between RFS and OS was found at the individual patient-data level. Furthermore, the strength of association between RFS and OS was robust as OS increased at the trial-level analysis.
      In our analysis, we found that all the surrogate markers, RECIST-based ORR, MPR, pCR and RFS were valid predictors for OS in the neoadjuvant immunotherapy setting, so which one to choose? It is important that the surrogate outcome should have an unequivocal definition with strong reproducibility, correlate with OS, and can reflect the biological effect of treatment. The definition of RECIST 1.1 may limit its surrogacy for OS since measurable disease is required, which is difficult to determine in some disease entities, especially in digestive tract cancer, but also for mesothelioma and ovarian cancer. Therefore, the assessment of pathological response could be more reproducible with small interobserver variability [
      • Rawson R.V.
      • Adhikari C.
      • Bierman C.
      • et al.
      Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.
      Ann Oncol. 2021; 32: 766-777
      ]. However, surrogate end-points should occur at a clinically relevant frequency to identify a large group of patients who may benefit from treatment. Therefore, in tumour types (e.g. breast cancer) highly sensitive to neoadjuvant therapy, pCR could serve as the surrogate end-point for OS. Otherwise, MPR may be better. In addition, our study showed that pCR had a slightly higher C-statistics than MPR and pCR. However, regarding long-term OS, pCR showed a similar correlation coefficient compared to MPR based on the trial-level data. Surely, the choice of surrogate end-point for OS should be dialectical. Therefore, to increase the potential benefactors of neoadjuvant immunotherapy, prospective trials are needed to validate MPR, pCR, ORR and RFS as primary end-points. At this time, there is strong evidence to support these surrogate end-points, especially pCR.

      6. Limitations

      This study included individual patient and trial data to evaluate surrogate end-points for OS which will be inherently heterogeneous. First, the trial-level analysis showed that the strength of association between ORR, MPR and pCR and OS became weaker with longer OS landmarks, which to some extent is due to the heterogeneity of cancer types and variety in tumour stage among the eligible trials. Thus, interpretation of this result is challenging. Additionally, the data of disease-specific survival are not available. Next, since the majority of eligible trials were phase II, the sample size was relatively small and the correlations between the treatment effects on surrogate end-points and OS were not always available (only 3 trials reported the HR on OS [
      • Forde P.M.
      • Spicer J.
      • Lu S.
      • et al.
      Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.
      N Engl J Med. 2022; 386: 1973-1985
      ,
      • Loibl S.
      • Schneeweiss A.
      • Huober J.
      • et al.
      Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.
      Ann Oncol. 2022; 33: 1149-1158
      ,
      • Schmid P.
      • Cortes J.
      • Dent R.
      • et al.
      Event-free survival with pembrolizumab in early triple-negative breast cancer.
      N Engl J Med. 2022; 386: 556-567
      ]), results should be interpreted with caution. Last, the median follow-up of the eligible trials in this study was still short; therefore, whether "early surrogate" markers (ORR, pCR, MPR, and 6-months RFS) could perform well over time when predicting OS is still under investigation.

      7. Conclusions

      In this pooled analysis of 29 clinical trials, achievement of ORR, MPR or pCR was significantly associated with superior OS in patients treated with neoadjuvant immunotherapy. Given the robustness of the correlations, MPR, pCR and RFS are acceptable surrogate end-points for OS.

      Ethics approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Funding

      This work was supported by the grants of the National Key R&D Program of China (2017YFC1309001), Guangzhou Science and Technology Plan Projects (Health Medical Collaborative Innovation Program of Guangzhou; 201803040019 and 202201010885), National Natural Science Foundation of China (82103586, 81730072, 81672407, 81872001, 81902411 and 81772589), and Beijing Xisike Clinical Oncology Research Foundation (Y-tongshu2021/qn-0227).

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We thank Mariano Provencio (NADIM), Tom van den Ende (PERFECT), and the Swiss Group for Clinical Cancer Research (SAKK 16/14) for their generous sharing of individual patient data.

      Authors’ contributions

      RCN and FPC searched and analysed the data and contributed to draft the typescript. RCN guided the statistical analyses. NRC, YW, FPC and SQY contributed to collect the data. RCN and YW prepared the figures and tables. RCN prepared the initial typescript. MP (Mariano Provencio), Tom van den Ende, Hanneke W.M. van Laarhoven, MP (Miklos Pless), SH, ZWZ, YFL and SR edited and revised the typescript. MYC designed the study and takes responsibility for the integrity of the work.

      Appendix A. Supplementary material

      .
      .

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      Article info

      Publication history

      Published online: March 17, 2023
      Accepted: March 7, 2023
      Received in revised form: February 3, 2023
      Received: December 3, 2022

      Publication stage

      In Press Uncorrected Proof

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      DOI: https://doi.org/10.1016/j.ejca.2023.03.010

      Copyright

      © 2023 The Authors. Published by Elsevier Ltd.

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