A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

Jimeno, Antonio; Shirai, Keisuke; Choi, Minsig; Laskin, Janessa; Kochenderfer, Mark D.; Spira, Alexander I.; Cline-Burkhardt, Vivian Jean M.; Winquist, Eric; Hausman, Diana F.; Walker, Luke; Cohen, Roger B.

doi:10.1093/annonc/mdu574

Cited by 86 publications

(67 citation statements)

References 33 publications

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“…The addition of the pan-PI3K isoform inhibitor PX-866 to cetuximab in patients with recurrent metastatic HNSCC did not confer any response benefit including four patients who had PIK3CA helical domain activating mutations(30). Similarly, the addition of the rapalog everolimus to erlotinib treatment did not induce a durable response in a patient with a PIK3CA H1047R mutation (40).…”

Section: Discussionmentioning

confidence: 97%

“…While newer generations of both classes with improved toxicology profiles have emerged, the goal here was to evaluate these classes of compounds in the treatment of HNSCC both as single agents and in combination with the standard of care cetuximab. While initial reports had initially indicated that mutations or other alterations along the PI3K/Akt/mTORC axis strongly predicted sensitivity to inhibitors targeting this pathway(12,28), more recent evidence suggests that this relationship is more complex(29,30), and that tumors both with and without such alterations may benefit from the addition of PI3K/mTORC to cetuximab treatment(16). In this work, we test both in vitro and in vivo HNSCC models containing both PI3K/Akt/mTORC altered and unaltered examples, to determine whether the addition of an ATP competitive kinase inhibitor can provide additional antitumor effects.…”

Section: Introductionmentioning

confidence: 99%

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Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Swick

Prabakaran

Miller

et al. 2017

Molecular Cancer Therapeutics

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Head and neck squamous cell carcinomas (HNSCCs) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials and identification of predictive biomarkers remains challenging. To investigate mTORC specific inhibition we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors +/− cetuximab in a panel of HNSCC cell lines and patient derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single agent mTORC inhibition inhibited growth of a PIK3CA mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA mutant model. In all models the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway’s role in driving proliferation. While single agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence suggesting approaches that attempt to match biomarkers to the optimal therapy in HNSCC remains complex and challenging.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Swick

Prabakaran

Miller

et al. 2017

Molecular Cancer Therapeutics

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“…Identification of a biomarker predicting benefit for cetuximab, dependent or independent of HPV, is probable based on tumor correlative data that should be forthcoming from completed or ongoing trials of cetuximab in HNSCC and HPV þ OPC, including RTOG 1016 and ECOG 1308 (Tables 1 and 3). No benefit in clinical efficacy endpoints was observed in either trial (65,66). In the trial with cetuximab, neither HPV status (13 patients each arm) nor PI3KCA mutation status (8 patients) appeared to influence efficacy.…”

Section: Molecularly Targeted Therapymentioning

confidence: 90%

New Strategies in Human Papillomavirus–Related Oropharynx Cancer: Effecting Advances in Treatment for a Growing Epidemic

Massarelli

Ferrarotto

Glisson

2015

Clinical Cancer Research

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The past two decades have been witness to a steadily increasing incidence of oropharynx cancer, specifically related to human papillomavirus (HPV), primarily affecting middle-aged Caucasian men, in North America and Europe. The ever-increasing incidence, now clearly an epidemic, of this unique clinicopathologic entity demands new perspectives in diagnosis and staging and presents unique challenges in clinical research, given the excellent prognosis afforded by chemoradiation for the majority of these patients. To reduce the morbidity of late toxicity in survivors without compromising the high rates of survival currently enjoyed, and simultaneously address the poor prognosis of those with recurrence, it is critical to capitalize on the viral etiology and translate discoveries in genomics, target/drug discovery, viral oncogenesis, and immunbiology to improved outcomes for patients. Herein, we review ongoing and planned clinical research for HPV-related oropharynx cancer, the basis for which is constituted by prior clinical observations, knowledge of the genomic alterations and altered biology associated with HPV-related oncogenesis, and hope that molecularly targeted and immunomodulatory therapies can be harnessed. Clin Cancer Res; 21(17); 3821-8. Ó2015 AACR. Disclosure of Potential Conflicts of Interest Editor's DisclosuresThe following editor(s) reported relevant financial relationships: J.L. Abbruzzese is a consultant/advisory board member for Celgene and Halozyme. Learning ObjectivesUpon completion of this activity, the participant should have increased knowledge regarding the epidemiology and clinical presentation of HPV-related oropharynx cancer, understand the rationale for deintensification and be familiar with clinical research strategies to reduce late effects in curative-intent treatment, and be aware of the biologic rationale for strategies targeting the immune system and molecular alterations in treatment of relapsed and refractory cancer.

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“…Importantly, this could decrease toxicity associated with chemo-radiation therapies and sequelae associated with these therapies (85). Trials with PI3K/AKT/mTOR inhibitors are underway in both HNSCC and cervical cancer (86, 87) (NCT02113878, NCT02051751, NCT01602315, NCT02145312). Interestingly PI3K/mTOR inhibition has previously been shown to sensitize cancer cells to radiation and chemotherapy (88–90).…”

Section: Clinical Perspectivesmentioning

confidence: 99%

Genomic Landscape of Human Papillomavirus–Associated Cancers

Rusan

Hammerman

2015

Clinical Cancer Research

109

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Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of Human Papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. Integration may confer a growth and survival advantage via enhanced expression of viral oncoproteins, alteration of critical cellular genes, and changes in global promoter methylation and transcription. Alteration of cellular genes may lead to loss of function of tumor suppressor genes, enhanced oncogene expression, loss of function of DNA repair genes, or other vital cellular functions. Recurrent integrations in RAD51B, NR4A2, and TP63, leading to aberrant forms of these proteins, are observed in both HPV-positive head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma. Additional genomic alterations, independent of integration events, include recurrent PIK3CA mutations (and aberrations in other members of the PI3K pathway), alterations in receptor tyrosine kinases (primarily FGFR2 and FGFR3 in HPV-positive HNSCC, and ERBB2 in cervical squamous cell carcinoma), and genes in pathways related to squamous cell differentiation and immune responses. A number of the alterations identified are potentially targetable, which may lead to advances in the treatment of HPV-associated cancers.

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A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

Cited by 86 publications

References 33 publications

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC

New Strategies in Human Papillomavirus–Related Oropharynx Cancer: Effecting Advances in Treatment for a Growing Epidemic

Genomic Landscape of Human Papillomavirus–Associated Cancers

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