| General information |
| Database: | DB00393 |
| Objective: | The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to antiEGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of antiEGFR therapy. |
| Authors: | Bauman JE, et al |
| Title: | a phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinumrefractory head and neck squamous cell carcinoma. |
| Journal: | Oral Oncol. |
| Year: | 2013 |
| PMID: | 23384718 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | erlotinib
|
| Target: | Epidermal growth factor receptor
|
| Cancer Type: | head and neck cancer |
| Cancer Subtype: | advanced head and neck squamous cell carcinoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | temsirolimus and erlotinib |
| Study Type: | singlestage, phase II design study |
| Key Patients Feature: | age more than and equal to 18 years;histologic/cytologic diagnosis of HNSCC from any primary site, including unknownprimary; distant metastases or locoregional recurrence unsuitable for surgical salvage;platinumrefractory disease defined as progressing during/after first line platinumbasedchemotherapy for R/M disease or progression within 6 months of platinumbasedchemoradiotherapy for localized disease; measurable disease by RECIST criteria version1.126; Eastern Cooperative Oncology Group Performance Status (ECOGPS) 0-2; adequatehematologic reserve and end organ function. |
| Biomarker: | PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre and posttreatment plasma levels of 20 immunomodulatory cytokines |
| Biomark Analysis: | Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferongamma levels marginally associated with tumor progression. |
| Control Group Info: | single arm |
| Treatment Info: | Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinumrefractory R/M HNSCC and ECOG performance status 02. |
| Primary End Point: | PFS. |
| Secondary End Point: | RR and OS. |
| Patients Number: | 12 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 1.9 months |
| Median OS A vs. C: | 4.0 months |
| Adverse Event(agent arm): | Overall, seven patients (58%) experienced Grade more than and equal to 3 toxicity. Two patients withdrew due to severe diarrhea (nonresponsive to loperamide), gastrostomy tube infection, and peritonitis; one of these patients presented with simultaneous aspiration pneumonia. In both cases, peritonitis resolved with antibiotics and nonoperative management. An additional two patients withdrew for profound asthenia. The fifth patient developed grade 4 laryngeal edema requiring emergent tracheostomy, the day following first temsirolimus administration. The event was initially attributed to preexisting, nearobstructing tumor recurrence for which elective tracheostomy had been declined. however, as the study accrued a unique edema pattern emerged. Six (50%) patients experienced treatment emergent Grade more than and equal to 1 edema of the face, neck or larynx within 1-35 days of starting protocol therapy. In five cases, facial and/ or neck edema was manageable with manual lymphatic drainage; temsirolimus dose reduction was also necessary in one patient. One treatmentunrelated death occurred, from hypoxic arrest afterfailure of portable oxygen equipment. |
| Conclusions: | The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in RM disease. Investigation of more tolerable combinations of EGFR and PI3KAktmTOR pathway inhibitors in selected HNSCC patients is warranted. |