Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma

Doki, Yuichiro; Ajani, Jaffer A.; Kato, Ken; Xu, Jianming; Wyrwicz, Lucjan; Motoyama, Satoru; Ogata, Takashi; Kawakami, Hisato; Hsu, Chih‐Hung; Adenis, Antoine; Hajbi, Farid El; Bartolomeo, Maria Di; Braghiroli, Maria Ignez; Holtved, Eva; Ostoich, Sandra A; Kim, Hye R; Ueno, Masaki; Mansoor, Wasat; Yang, Wen-Chi; Liu, Tianshu; Bridgewater, John; Makino, Tomoki; Xynos, Ioannis; Li, Xuan; Lei, Ming; Kondo, Kaoru; Patel, Apurva; Gricar, J.; Chau, Ian; Kitagawa, Yuko

doi:10.1056/nejmoa2111380

Cited by 669 publications

(538 citation statements)

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“…The observed response rates with nivolumab plus ipilimumab were lower versus chemotherapy, and there was no enrichment with increasing PD-L1 CPS cut-offs. However, the median duration of response almost doubled with nivolumab plus ipilimumab versus chemotherapy, which is consistent with results in other solid tumours with this combination 19 – 22 .…”

Section: Discussionsupporting

confidence: 87%

“…Tumours in gastric, GEJ or oesophageal adenocarcinoma are composed of distinct molecular subtypes 25 , 26 . Although dual checkpoint inhibition has been proven to be effective in multiple solid tumours 19 – 22 , 27 , further research is needed to evaluate how tumour biology, molecular heterogeneity, dynamics in tumour microenvironment and other patient factors may affect the efficacy of combined PD-L1 and CTLA-4 blockade. Notably, in the small but relevant subgroup of patients with microsatellite instability, which is characterized by high tumour mutational burden and CD8-positive T-cell infiltrates and is susceptible to immune-checkpoint inhibition 25 , 28 – 30 , longer overall survival and higher ORR were observed with nivolumab plus ipilimumab versus chemotherapy in CheckMate 649.…”

Section: Discussionmentioning

confidence: 99%

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Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Shitara

Ajani

Moehler

et al. 2022

Nature

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266

173

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Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma1–4. Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial5 (programmed death ligand-1 (PD-L1) combined positive score ≥5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries6. Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively7–11. Treatment combining 1 mg kg−1 nivolumab with 3 mg kg−1 ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer12. Here we report both long-term follow-up results comparing nivolumab plus chemotherapy versus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive score ≥5 (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score ≥ 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer

Shitara

Ajani

Moehler

et al. 2022

Nature

Self Cite

266

173

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“…In patients with tumor cell PD-L1 expression of 1% or higher, the OS of nivolumab combined with ipilimumab was significantly longer than that of chemotherapy, with mPFS of 13.7 months and 9.1 months, respectively. Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy in the overall population [ 139 ].The data from CheckMate 204 showed that combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM). The 36-month intracranial PFS was 54 1%, and OS was 71 9%, supporting first-line use of nivolumab plus ipilimumab.…”

Section: Advances In Pd-1/pd-l1 Blockade-based Combination Treatment ...mentioning

confidence: 99%

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

et al. 2022

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Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

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“… 14 Beyond these preclinical observations, several phase III clinical trials have evaluated the added benefit of combining immunotherapy and chemotherapy in the first-line setting for ESCC patients. According to recently released results, 22 , 23 , 24 , 25 , 26 chemoimmunotherapy combinations using TP regimen appear to confer better survival than using 5-FU and cisplatin regimen, indicating that TP regimen could generate a more favorable tumor microenvironment to maximize the immunotherapy or targeted therapy efficacy and might be more suitable for combination. Notably, evidence from clinical studies of head and neck squamous cell carcinoma also supported the combination of cetuximab and the TP regimen, reporting a slightly longer time to treatment failure (TTF) and improved safety profile with a taxane versus 5-FU in combination with anti-EGFR antibody and platinum.…”

Section: Discussionmentioning

confidence: 99%