Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer

Forde, Patrick M.; Spicer, Jonathan; Lu, Shun; Provencio, Mariano; Mitsudomi, Tetsuya; Awad, Mark M.; Felip, Enriqueta; Broderick, Stephen; Brahmer, Julie R.; Swanson, Scott J.; Kerr, Keith M.; Wang, Changli; Ciuleanu, Tudor-Eliade; Saylors, Gene B; Tanaka, Fumihiro; Ito, Hiroyuki; Chen, Ke-Neng; Liberman, Moïshe; Vokes, Everett E.; Taube, Janis M.; Dorange, Cécile; Cai, Junliang; Fiore, Joseph; Jarkowski, Anthony; Balli, David; Sausen, Mark; Pandya, Dimple; Calvet, C.; Girard, Nicolas

doi:10.1056/nejmoa2202170

Cited by 982 publications

(622 citation statements)

References 37 publications

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“…In the past decades, neoadjuvant therapy has provided extra treatment opportunities for lung cancer patients and prolonged their survival [ 1 ]. For example, in CheckMate-816 [ 2 ] trail assessing efficacy of neoadjuvant nivolumab plus chemotherapy on surgically resectable early-stage NSCLC, the combination led to a MPR rate of 36.9% and pathological complete response (pCR) rate of 24%, significantly outperforms the chemotherapy alone arm. However, very few studies reported effective surrogates indicating the outcomes of neoadjuvant immunotherapy in NSCLC.…”

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Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

et al. 2022

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Background Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. Conclusions We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

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Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

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Section: Biomarkers For Potential Use As Predictors Of Neoadjuvant Im...mentioning

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“…In the neoadjuvant settings, PD-L1 expression has been investigated as a predictive biomarker in several clinical trials with disparate results [ 12 , 21 , 38 , 57 , 58 , 59 ]. In the phase 3 Checkmate186 trial, a considerably higher benefit was observed in patients treated with nivolumab and chemotherapy in tumors with ≥1% PD-L1 expression in tumor cells compared with tumors with <1% expression of PD-L1 [ 12 ]. Similarly, in the NEOSTAR trial, an analysis of PD-L1 assessed in tumor cells by IHC showed that, in pretreatment biopsies, PD-L1 was higher in patients with MPR and patients with radiographic responses compared to patients with no MPR and no radiographic response, respectively.…”

Section: Biomarkers For Potential Use As Predictors Of Neoadjuvant Im...mentioning

confidence: 99%

“…Recently, the U.S. Food and Drug Administration (FDA) approved neoadjuvant nivolumab in combination with platinum-doublet chemotherapy for resectable NSCLC based on the results of the phase 3 Checkmate 816 clinical trial that showed an improved event-free survival and a higher cPR in patients treated with the combination, as compared to chemotherapy alone, in stage IB-IIIA NSCLC patients [ 12 ]. This phase 3 clinical trial was preceded by several clinical trials that have shown the feasibility and efficacy of several immunotherapeutic approaches for neoadjuvant therapy alone or in combination in patients with resectable NSCLC Stage IB, II, and III.…”

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“…This phase 3 clinical trial was preceded by several clinical trials that have shown the feasibility and efficacy of several immunotherapeutic approaches for neoadjuvant therapy alone or in combination in patients with resectable NSCLC Stage IB, II, and III. These studies have shown a low toxicity and a high percentage of patients achieving a major pathological response (MPR) and cPR [ 12 , 13 , 14 , 15 , 16 , 17 ].…”

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confidence: 99%

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Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors

Rojas

Parra

Wistuba

et al. 2022

Cancers

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Lung cancer is the leading cause of cancer incidence and mortality worldwide. Adjuvant and neoadjuvant chemotherapy have been used in the perioperative setting of non-small-cell carcinoma (NSCLC); however, the five-year survival rate only improves by about 5%. Neoadjuvant treatment with immune checkpoint inhibitors (ICIs) has become significant due to improved survival in advanced NSCLC patients treated with immunotherapy agents. The assessment of pathology response has been proposed as a surrogate indicator of the benefits of neaodjuvant therapy. An outline of recommendations has been published by the International Association for the Study of Lung Cancer (IASLC) for the evaluation of pathologic response (PR). However, recent studies indicate that evaluations of immune-related changes are distinct in surgical resected samples from patients treated with immunotherapy. Several clinical trials of neoadjuvant immunotherapy in resectable NSCLC have included the study of biomarkers that can predict the response of therapy and monitor the response to treatment. In this review, we provide relevant information on the current recommendations of the assessment of pathological responses in surgical resected NSCLC tumors treated with neoadjuvant immunotherapy, and we describe current and potential biomarkers to predict the benefits of neoadjuvant immunotherapy in patients with resectable NSCLC.

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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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Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer

Cited by 982 publications

References 37 publications

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors

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

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