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Perioperative Nivolumab in Resectable Lung Cancer

Tina Cascone, M.D., Ph.D., Mark M. Awad, M.D., Ph.D., Jonathan D. Spicer, M.D., Ph.D., Jie He, M.D., Ph.D., Shun Lu, M.D., Ph.D., Boris Sepesi, M.D., Fumihiro Tanaka, M.D., Ph.D., Janis M. Taube, M.D., Robin Cornelissen, M.D., Ph.D. , Libor Havel, M.D., Nina Karaseva, M.D., Jaroslaw Kuzdzal, M.D., Ph.D., Lubos B. Petruzelka, M.D., Ph.D., Lin Wu, M.D., Jean-Louis Pujol, M.D., Ph.D., Hiroyuki Ito, M.D., Ph.D., Tudor-Eliade Ciuleanu, M.D., Ph.D., Ludmila de Oliveira Muniz Koch, M.D., Annelies Janssens, M.D., Ph.D., Aurelia Alexandru, M.D., Sabine Bohnet, M.D., Fedor V. Moiseyenko, M.D., Ph.D., Yang Gao, M.D., Ph.D., Yasutaka Watanabe, M.D., Ph.D., Cinthya Coronado Erdmann, M.D., Padma Sathyanarayana, Ph.D., Stephanie Meadows-Shropshire, Ph.D., Steven I. Blum, M.B.A., M.A., and Mariano Provencio Pulla, M.D., Ph.D., for the CheckMate 77T Investigators†

NEJM May 15, 2024

Background: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non–small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes.

背景：新辅助nivolumab联合化疗的标准治疗显著改善了可切除非小细胞肺癌(NSCLC)患者的预后。使用nivolumab进行围手术期治疗(即先进行新辅助治疗，然后进行手术和辅助治疗)可能会进一步改善临床结果。

METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety.

方法：在这项III期的随机双盲试验中，我们将可切除的IIIB期NSCLC患者分配到IIIB NSCLC，每3周接受一次新辅助nivolumab化疗或新辅助化疗加安慰剂，共4个周期，然后每4周接受手术和nivolumab或安慰剂治疗，为期一年。根据盲法独立回顾，主要结果是无事件生存。根据独立盲法回顾、总体存活率和安全性，次要结果为病理完全缓解和主要病理反应。

RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group.

结果：在这项预先指定的中期分析中(中位随访25.4月)，nivolumab组和化疗组18个月无事件生存率分别为70.2%和50.0%(疾病进展或复发、放弃手术或死亡的风险比为0.58；97.36% [CI]为0.42-0.81；P<0.001)。病理完全缓解率为25.3%，化疗组为4.7%(OR 6.64；95%CI 3.40~12.97)，有效率分别为35.4%和12.1%(OR 4.01；95%CI 2.48~6.49)。与治疗相关的3级或4级不良事件在nivolumab组中有32.5%的患者发生，在化疗组中有25.2%。

CONCLUSION: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.)

结论：在可切除的非小细胞肺癌患者中，围手术期应用nivolumab的患者的无事件生存期显著长于化疗。没有观察到新的安全信号。(由百时美施贵宝提供资金；Checkmate 77T ClinicalTrials.gov编号，NCT04025879。)

目录

1. INTRODUCTION

2. METHODS

    2.1 Patients

    2.2 TRIAL DESIGN AND TREATMENTS (Fig. S1)

    2.3 OUTCOMES AND ASSESSMENTS

    2.4 TRIAL OVERSIGHT

    2.4 Statistical Analysis

3. Results

    3.1 PATIENTS AND TREATMENT SUMMARY (Fig. S2)(Table 1 and Table S1-3)(Fig. S3)(Table S4-5)

    3.2 EFFICACY (Fig. 1)(Fig. S4-8)(Fig. 2)(Fig. S9)(Table S6)(Fig. 3A)(Fig. S10-11)

    3.3 PATIENT-REPORTED OUTCOMES (Fig. 3B)(Table S7)

    3.4 SAFETY AND SURGICAL COMPLICATIONS (Table 2)(Table S8)

4. Discussion

— 图表汇总—

2. METHODS

    2.2 TRIAL DESIGN AND TREATMENTS

Fig. S1. Study Design.*

*NCT04025879. 

†Testing for EGFR mutations was mandatory for all patients with nonsquamous disease, and testing for ALK alterations was mandatory for all patients with a history of ALK alterations. 

EGFR and ALK testing were performed using Food and Drug Administration– or local health authority–approved assays. 

‡Tumor PD-L1 expression was determined by the PD-L1 IHC 28-8 pharmDx assay (Dako). 

§Patients with squamous tumor histology received either cisplatin plus docetaxel or carboplatin plus paclitaxel. Patients with nonsquamous tumor histology received either cisplatin plus pemetrexed, carboplatin plus pemetrexed, or carboplatin plus paclitaxel. 

¶pCR and MPR were assessed according to pan-tumor immune-related pathological response criteria.1,2 

AJCC denotes American Joint Committee on Cancer, BICR blinded independent central review, BIPR blinded independent pathological review, ECOG Eastern Cooperative Oncology Group, EFS event-free survival, MPR major pathological response, NSCLC non–small-cell lung cancer, ORR objective response rate, OS overall survival, pCR pathological complete response, PD-L1 programmed death ligand 1, PRO patient-reported outcome; Q3W every 3 weeks, Q4W every 4 weeks, and R randomized.

3. Results

    3.1 PATIENTS AND TREATMENT SUMMARY

Fig. S2 CONSORT Flow Diagram. 

*Reasons for no longer meeting study criteria included not having stage IIA (>4 cm) to IIIB (T3N2) NSCLC, having metastases, having a tumor with a genetic mutation, or having an unresectable tumor. 

NSCLC denotes non–small-cell lung cancer.

Table 1 

Table S1 Representativeness of Study Participants. 

Table S2 Neoadjuvant Treatment Exposure. 

Table S3 Surgical Outcomes. 

Fig. S3 Treatment and Surgery Summary. 

The denominators were based on patients who were randomly assigned treatment. 

*Other reasons included adverse event unrelated to study treatment, death, patient request, withdrawn consent, no longer meeting study criteria, and being lost to follow-up.  

†Surgery status was not reported in two patients (0.9%) in the nivolumab group.  

‡Three patients (1.3%) in each group did not undergo definitive surgery but did receive adjuvant treatment. 

§In addition to these eight patients continuing adjuvant treatment, two additional patients in the nivolumab group were reported to be continuing treatment; however, the treatment status of these patients could not be confirmed prior to the closure of their study site. 

Table S4 Adjuvant Treatment Exposure. 

Table S5 Subsequent Anticancer Therapy. 

    3.2 EFFICACY

Fig. 1 Event-free Survival.

Shown is event-free survival as assessed by blinded independent central review in the intention-to-treat population (Panel A) and in patient subgroups (Panel B). Disease progression included progression that precluded surgery, resulted in abandoned surgery owing to unresectability, and progression or recurrence that occurred with or without surgery. In Panel A, the P value was calculated by means of a stratified two-sided log-rank test, with the hazard ratio and confidence intervals estimated according to a stratified Cox proportional-hazards model with the treatment group as a covariate. In Panel B, the randomization stratification was not applied to the analysis of the subgroup population, so unstratified data are reported. Confidence intervals were not adjusted for multiplicity and should not be used for hypothesis testing; all subgroup analyses were prespecified except for analyses according to node stage, which were performed post hoc. ECOG denotes Eastern Cooperative Oncology Group, NR not reached, and PD-L1 programmed death ligand 1.

Fig. S4 Event-free Survival According to Investigator Assessment. 

CIs were not adjusted for multiplicity and should not be used for hypothesis testing; 95% CIs for the landmark rates are designated in the parentheses. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and NR not reached.

Fig. S5 Event-free Survival Assessed by Blinded Independent Central Review According to Baseline Disease Stage. 

Panel A shows EFS in patients with stage IIA or IIB disease, and Panel B shows EFS in patients with stage IIIA or IIIB disease. 

CIs were not adjusted for multiplicity and should not be used for hypothesis testing; 95% CIs for the landmark rates are designated in the parentheses. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and NR not reached.

Fig.S6 Event-free Survival Assessed by Blinded Independent Central Review According to Tumor Histology. 

Panel A shows EFS in patients with squamous tumor histology, and Panel B shows EFS in patients with nonsquamous tumor histology. 

CIs were not adjusted for multiplicity and should not be used for hypothesis testing; 95% CIs for the landmark rates are designated in the parentheses. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and NR not reached.

Fig. S7 Event-free Survival Assessed by Blinded Independent Central Review According to Tumor PD-L1 Expression. 

Panel A shows EFS in patients with tumor PD-L1 <1%,

Panel B shows EFS in patients with tumor PD-L1 ≥1%,

Panel C shows EFS in patients with tumor PD-L1 1–49%,

Panel D shows EFS in patients with tumor PD-L1 ≥50%.  

CIs were not adjusted for multiplicity and should not be used for hypothesis testing; 95% CIs for the landmark rates are designated in the parentheses. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, NR not reached, and PD-L1 programmed death ligand 1.

Fig. S8 Event-free Survival Assessed by Blinded Independent Central Review According to Neoadjuvant Platinum Chemotherapy Received. 

Panel A shows EFS in patients who received cisplatin, and Panel B shows EFS in patients who received carboplatin. 

CIs were not adjusted for multiplicity and should not be used for hypothesis testing; 95% CIs for the landmark rates are designated in the parentheses. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and NR not reached.

Fig. 2 Pathological Response as Assessed by Central Review.

Shown is the pathological complete response in the intention-to-treat population (Panel A), the major pathological response in the intention-to-treat population (Panel B), and the pathological complete response in prespecified patient subgroups (Panel C).

The pathological response was measured as the number of residual viable tumor cells after surgery in the primary tumor and sampled lymph nodes; the response was defined as complete if there were no residual viable tumor cells and as major if there were no more than 10% residual viable tumor cells. The confidence intervals have not been adjusted for multiplicity and should not be used for hypothesis testing. In Panel C, the unweighted difference between the treatment groups for subgroup analyses is shown according to the statistical analysis plan. Two patients in the chemotherapy group with stage IV disease at baseline were included in the stage III subgroup.

Fig. S9 Major Pathological Response Rates Assessed by Blinded Independent Pathological Review in Predefined Patient Subgroups. 

CIs were not adjusted for multiplicity and should not be used for hypothesis testing. Two patients in the chemotherapy group with stage IV disease at baseline were included in the stage III subgroup. CI denotes confidence interval, ECOG Eastern Cooperative Oncology Group, MPR major pathological response, and PD-L1 programmed death ligand 1.

Table S6 Objective Response Rate and Best Overall Response According to Blinded Independent Central Review. 

Fig. 3A Exploratory Landmark Analysis of Event-free Survival According to Pathological Complete Response and Analysis of Time to Definitive Deterioration (TTDD) in Disease-Related Symptoms.

Panel A shows the landmark analysis of event-free survival from definitive surgery according to the pathological complete response (pCR). 

In Panel A, the landmark time point was the date of definitive surgery; an unstratified Cox proportional-hazards model with the treatment group as a covariate was used to estimate hazard ratios and confidence intervals. The hazard ratio for the comparison between patients with a pathological complete response and those without such a response was 0.20 (95% CI, 0.08 to 0.50) in the nivolumab group and 0.41 (95% CI, 0.13 to 1.30) in the chemotherapy group.

Fig. S10 Landmark Analysis of Event-free Survival From Definitive Surgery Assessed by Blinded Independent Central Review According to Major Pathological Response Status and Adjuvant Treatment Status. 

Panel A shows EFS according to MPR status,

Panel B shows EFS in patients who received adjuvant treatment (post hoc analysis),

Panel C shows EFS in patients who could not receive adjuvant treatment (post hoc analysis). 

Landmark time point was the date of definitive surgery. Included only patients with EFS time at least up to the surgery. CIs were not adjusted for multiplicity and should not be used for hypothesis testing. HRs between patients with MPR and those without were 0.25 (95% CI, 0.12 to 0.50) for the nivolumab group and 0.52 (95% CI, 0.26 to 1.05) for the chemotherapy group. HRs between patients with adjuvant treatment and those without were 0.28 (95% CI, 0.15 to 0.52) for the nivolumab group and 0.21 (95% CI, 0.12 to 0.36) for the chemotherapy group. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and MPR major pathological response.

Fig. S11 Landmark Analysis of Event-free Survival From Definitive Surgery Assessed by Blinded Independent Central Review According to Pathological Complete Response Status in Patients Who Received Adjuvant Treatment. 

Post hoc analysis; landmark time point was the date of definitive surgery. Included only patients with EFS time at least up to the surgery. CIs were not adjusted for multiplicity and should not be used for hypothesis testing. HRs between patients with pCR and those without were 0.16 (95% CI, 0.05 to 0.54) for the nivolumab group and 0.47 (95% CI, 0.15 to 1.52) for the chemotherapy group. CI denotes confidence interval, EFS event-free survival, HR hazard ratio, and pCR pathological complete response.

    3.3 PATIENT-REPORTED OUTCOMES

Fig. 3B Exploratory Landmark Analysis of Event-free Survival According to Pathological Complete Response and Analysis of Time to Definitive Deterioration (TTDD) in Disease-Related Symptoms.

Panel B shows the percentage of patients without definitive deterioration in disease-related symptoms on the basis of total scores on the Non–Small-Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) in the intention-to-treat population. 

In Panel B, a stratified Cox proportional-hazards model with the treatment group and baseline NSCLC-SAQ total score as covariates was used to estimate hazard ratios and confidence intervals; the threshold for definitive deterioration in the NSCLC-SAQ total score was 3 points.

Table S7 Mixed Model for Repeated Measures Analysis of NSCLC-SAQ During the On-treatment Period.* 

    3.4 SAFETY AND SURGICAL COMPLICATIONS

Table 2

Table S8 Most Frequent Treatment-related Adverse Events. 

Table S9 Immune-mediated Adverse Events. 

Table S10 Adverse Events Leading to Surgical Delay or Cancellation and Most Frequent Surgery-related Adverse Events. 

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