Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial

Uppaluri, Ravindra; Campbell, Katie M.; Egloff, Ann Marie; Zolkind, Paul; Skidmore, Zachary L.; Nussenbaum, Brian; Paniello, Randal C.; Rich, Jason T.; Jackson, Ryan; Pipkorn, Patrik; Michel, Loren S.; Ley, Jessica; Oppelt, Peter; Dunn, Gavin P.; Barnell, Erica K.; Spies, Nicholas C.; Lin, Tianxiang; Li, Tiantian; Mulder, David T.; Hanna, Youstina; Cirlan, Iulia; Pugh, Trevor J.; Mudianto, Tenny; Riley, Rachel; Zhou, Liye; Jo, Vickie Y.; Stachler, Matthew D.; Hanna, Glenn J.; Kass, Jason; Haddad, Robert I.; Schoenfeld, Jonathan D.; Gjini, Evisa; Lako, Ana; Thorstad, Wade L.; Gay, Hiram A.; Daly, Mackenzie; Rodig, Scott J.; Hagemann, Ian S.; Kallogjeri, Dorina; Piccirillo, Jay F.; Chernock, Rebecca D.; Griffith, Malachi; Griffith, Obi L.; Adkins, Douglas R.

doi:10.1158/1078-0432.ccr-20-1695

Cited by 223 publications

(262 citation statements)

References 38 publications

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“…The CRR of neoadjuvant anti‐PD‐1/PD‐L1 therapy in lung cancer was 0.200 (95% CI 0.117, 0.282, I 2 = 37%), and the MRR was 0.471 (95% CI 0.367, 0.575, I 2 = 0%). The pooled MRR of head and neck cancer was 0.062 (95% CI 0.003, 0.122) 26–28 . Overall, PD‐1/PD‐L1 inhibitors provided an obviously reduced risk in the included cancer, and the I 2 indicated there was low heterogeneity in these studies (Table 2).…”

Section: Resultsmentioning

confidence: 96%

“…Further, 313 articles were excluded when assessing the eligibility according to the inclusion criteria. Eventually, 20 eligible articles were included in this meta‐analysis 20–39 . The procedure is demonstrated in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…PD‐1/PD‐L1 inhibitors like atezolizumab and pembrolizumab showed superior efficacy in clinical utilization 12,14–19 . Some studies try to uncover the clinical value of the utilization of PD‐1/PD‐L1 inhibitors in neoadjuvant therapy 20–39 . To evaluate the efficacy and safety of the therapy, this meta‐analysis pooled and analyzed the data of these trials.…”

Section: Introductionmentioning

confidence: 99%

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Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Zhao

et al. 2021

MedComm

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PD‐1/PD‐L1 (programmed cell death‐1 and programmed death‐ligand 1) inhibitors utilization in neoadjuvant therapy has been assessed in tumors. This study focused on the clinical benefits of neoadjuvant anti‐PD‐1/PD‐L1 therapy. A comprehensive search was conducted in electronic databases to identify eligible studies. Major response rate (MRR) and complete response rate (CRR) were pooled in this analysis to assess the efficacy of neoadjuvant anti‐PD‐1/PD‐L1 utilization, all grades and high‐grade adverse events (AEs) were pooled to evaluate its safety. Twenty studies were included in this meta‐analysis, with 828 patients suffering from different tumors. The pooled CRR of triple‐negative breast cancer was 0.569 (95% CI 0.514, 0.624, I2 = 0%) and the pooled MRR of lung cancer was 0.471 (95% CI 0.267, 0.575, I2 = 0%). The most frequent adverse event was fatigue (0.272 95% CI 0.171, 0.402, I2 = 87%), and the most common high‐grade adverse event was febrile neutropenia (0.084 95% CI 0.063, 0.112, I2 = 85%). In conclusion, neoadjuvant anti‐PD‐1/PD‐L1 therapy received satisfactory clinical results in these tumors included.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Zhao

et al. 2021

MedComm

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“…The primary specimen and all abnormal lymph nodes were sectioned in their entirety, and all slides containing tumor were included in the analysis. Pathologic treatment effect (PTE) was defined as the area of tissue exhibiting predefined histologic criteria of tumor response as a percentage of total tumor area (S2) ( 8 ). Tumors with PTE of ≥20% were defined as “moderate” responders, while those with PTE <20% were defined as “minimal” responders.…”

Section: Methodsmentioning

confidence: 99%

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

et al. 2020

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PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.Patients and MethodsForty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.ResultsSixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8+ T cells and CD163+ macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, p < 0.001) and in LN (slope = 0.62, p < 0.05). 89% (16/18) of radiographic non-responders with T1–T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.ConclusionNivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.

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“…In some of these patients PD-1 blocking leads to long lasting responses [ 2 ]. Recently, the clinical use of checkpoint inhibitors is shifting towards early stages of OSCC treatment with the first results of successful neoadjuvant PD-1 inhibition being published [ 3 , 4 ] and currently evaluated in a large prospective study (KEYNOTE-689 study; NCT03765918).…”

Section: Introductionmentioning

confidence: 99%

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

et al. 2021

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Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

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Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial

Cited by 223 publications

References 38 publications

Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Clinical benefit of neoadjuvant anti‐PD‐1/PD‐L1 utilization among different tumors

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

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