Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis

Kao, Hsiang‐Fong; Liao, Bin-Chi; Huang, Yen‐Lin; Huang, Huai-Cheng; Chen, Chun‐Nan; Chen, Tseng‐Cheng; Hong, Yuan-Jing; Chang, Ching‐yi; Chia, Jean-San; Hong, Ruey‐Long

doi:10.1158/1078-0432.ccr-21-3025

Cited by 43 publications

(38 citation statements)

References 55 publications

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“…Patients receiving intensity modulated radiation therapy (IMRT) in the re-irradiation setting demonstrate improved locoregional control (52% vs 20% at 2 years), and patients who underwent gross total resection also trended towards improved locoregional control ( 35 ). While salvage surgery has been associated with improved progression free survival ( 36 ), the advantages of surgical resection prior to re-irradiation have not been universally reported when compared to re-irradiation with curative intent ( 85 ). Re-irradiation with proton therapy has also recently demonstrated promising locoregional control results (68% locoregional control at 1 year) with tolerable toxicity profiles ( 37 , 38 ).…”

Section: Considerations For Management Of Recurrent Diseasementioning

confidence: 99%

Current perspectives on recurrent HPV-mediated oropharyngeal cancer

2022

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In the recent years, the prevalence of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) has increased significantly. Currently, nearly 80-90% of all oropharynx tumors are HPV-positive. In addition, it is now recognized that HPV-positive tumor status is associated with good prognosis and improved response to chemoradiation. However, within this setting, there are still patients with HPV-positive OPSCC who will experience recurrence. With the increasing incidence of HPV-mediated OPSCC, recurrent HPV disease is also becoming more prevalent and there is an increasing need to understand the unique presentation and treatment of recurrent HPV-mediated disease. In this review, we will discuss epidemiology of recurrent HPV-positive OPSCC, role of surgical salvage, re-irradiation, and the role of upcoming novel treatments and immunotherapy. Historically, recurrent oropharyngeal disease has been associated with poor prognosis and high morbidity. However, recent advances have transformed the landscape for salvage treatment of HPV-mediated OPSCC. Liquid biomarkers offer potential for early detection of recurrence, robotic techniques may reduce morbidity of surgical salvage, improvements in re-irradiation approaches reduce toxicities, and novel immune based therapies on the horizon are offering promising results. These advances combined with the improved prognosis of HPV-positive disease offer to transform our approach to recurrent disease of the oropharynx.

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Section: Considerations For Management Of Recurrent Diseasementioning

confidence: 99%

Current perspectives on recurrent HPV-mediated oropharyngeal cancer

2022

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“…High-throughput screening of small molecule inhibitors also showed that EGFR inhibitors (including erlotinib, afatinib and gefitinib) could enhance T cell-mediated killing ( 28 ). Clinically, afatinib is being tested with pembrolizumab for platinum-refractory R/M HNC in a Phase 2 trial [NCT03695510 – ALPHA study] unveiling an impressive ORR of 41.4% ( 29 ), a drastic increase compared to 16% or 10-10.8% for pembrolizumab and afatinib monotherapy respectively ( 30 , 31 ). Biomarkers predictive of response were also investigated in this study, whereby MTAP loss or mutation was found to be associated with lower response rates, while EGFR amplification was associated with 100% ORR.…”

Section: Targeted Agents Tested In Combination With Icis In Hncmentioning

confidence: 99%

“…Biomarkers predictive of response were also investigated in this study, whereby MTAP loss or mutation was found to be associated with lower response rates, while EGFR amplification was associated with 100% ORR. On the other hand, high PD-L1 (CPS score ≥20) was associated with higher ORR (63% vs 35% in CPS score <20), albeit not statistically significant (Fisher’s exact p-value = 0.23) ( 29 ).…”

Section: Targeted Agents Tested In Combination With Icis In Hncmentioning

confidence: 99%

“…PD-1 blockade has been shown to upregulate another checkpoint receptor, Tim-3 via AKT/S6 pathway which could allow the escape of anti-PD-1 blockade in the TME, providing further support for concomitant targeting AKT/S6 to improve the efficacy of ICIs ( 48 ). Recently, targeting of PI3Kγ/δ in the leucocytes using TG100-115 or IPI-145 has been shown to improve ICIs efficacy in pre-clinical HNC models ( 27 – 29 ). This is likely attributed by the abrogation of myeloid-derived suppressor cells (MDSC)-mediated immune suppression ( 49 ).…”

Section: Targeted Agents Tested In Combination With Icis In Hncmentioning

confidence: 99%

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Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

2022

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Immunotherapy, especially the immune checkpoint inhibitors (ICIs) such as the pembrolizumab and nivolumab have contributed to significant improvements in treatment outcomes and survival of head and neck cancer (HNC) patients. Still, only a subset of patients benefits from ICIs and hence the race is on to identify combination therapies that could improve response rates. Increasingly, genetic alterations that occur within cancer cells have been shown to modulate the tumor microenvironment resulting in immune evasion, and these have led to the emergence of trials that rationalize a combination of targeted therapy with immunotherapy. In this review, we aim to provide an overview of the biological rationale and current strategies of combining targeted therapy with the approved ICIs in HNC. We summarize the ongoing combinatorial clinical trials and discuss emerging immunomodulatory targets. We also discuss the challenges and gaps that have yet to be addressed, as well as future perspectives in combining these different drug classes.

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“…A previous study by 21-gene recurrence score (OncotypeDX) showed that F/B from the tumor–stroma interface can be an independent prognostic indicator of metastasis-free survival in TME ( Desa et al, 2020 ). Based on the 29 eligible patients and 523 patients/samples of TCGA database with metastatic head and neck squamous cell carcinoma, the phase II ALPHA study by FoundationOne CDx panel demonstrated that patients with MTAP mutation or loss led to a low fraction of CD8 + T cells and was associated with suppressed immune reaction factors in the TME ( Kao et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in ER (+) and/or PR (+) and HER2 (−) Breast Cancer

Zheng

Han

et al. 2022

Front. Pharmacol.

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Background: Although intrinsic molecular subtype has been widely used, there remains great clinical heterogeneity of prognosis in the estrogen receptor (ER)- and/or progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC).Methods: The transcriptome expression data of messenger RNA (mRNA) were downloaded from The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and the Gene Expression Omnibus (GEO) databases. Immune-related genes were acquired from the ImmPort database and additional literature search. Univariate Cox, LASSO regression, and multivariate Cox regression were used to screen prognostic immune-related genes and establish the risk signature. The correlation between the risk signature and clinical characteristics, the abundances of immune cells within the tumor microenvironment, and cancer phenotypes were further assessed.Results: Of note, 102 immune-related prognostic genes were identified in the METABRIC dataset by univariate Cox analysis. Consecutively, 7 immune-related genes (SHMT2, AGA, COL17A1, FLT3, SLC7A2, ATP6AP1, and CCL19) were selected to establish the risk signature by LASSO regression and multivariate Cox analysis. Its performance was further verified in TCGA and GSE21653 datasets. Multivariate Cox analysis showed that the risk signature was an independent prognostic factor. The 7-gene signature showed a significant correlation with intrinsic molecular subtypes and 70-gene signature. Furthermore, the CD4+ memory T cells were significantly higher in the low-risk group while a significantly higher proportion of M0-type macrophages was found in the high-risk group in both METABRIC and TCGA cohorts, which may have an influence on the prognosis. Furthermore, we found that the low-risk group may be associated with the immune-related pathway and the high-risk group was with the cell cycle-related pathway, which also showed an impact on the prognosis.Conclusion: These seven immune-related gene risk signatures provided an effective method for prognostic stratification in ER (+) and/or PR (+) and HER2 (−) BC.

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Afatinib and Pembrolizumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (ALPHA Study): A Phase II Study with Biomarker Analysis

Abstract: Boehringer Ingelheim Taiwan: drug supply (afatinib) and partial research funding.Merck Sharp & Dohme Corp (I.A.) LCC, Taiwan Branch: drug supply (pembrolizumab).

Cited by 43 publications

References 55 publications

Current perspectives on recurrent HPV-mediated oropharyngeal cancer

Current perspectives on recurrent HPV-mediated oropharyngeal cancer

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in ER (+) and/or PR (+) and HER2 (−) Breast Cancer

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