CAPRA: Safety, efficacy, and translational biomarkers of weekly everolimus, carboplatin, and paclitaxel as induction therapy for locally advanced head and neck squamous cell carcinoma (HNSCC).

Abstract

6036 Background: ThePI3K/mTOR pathway is activated in >50% of HNSCC with preclinical synergism between everolimus and carboplatin/paclitaxel. Methods: Patients (pts) with untreated locally advanced HNSCC with ECOG PS<2 received 9 consecutive weekly (w) cycles (cy) of CAPRA combining everolimus (30 mg/w at dose-level 1 then 50 mg/w at dose-level 2) with carboplatin (AUC2) and paclitaxel (60 mg/m2) followed by chemoradiotherapy. Endpoints were safety (CTCv3.0), antitumor activity (RECIST1.1), pharmacodynamic biomarkers on tumor biopsy. Results: A total of 50 pts with stage IV HNSCC (41 males, 9 females, median age 61) were enrolled. Among 7 patients included in the phase I, no dose-limiting toxicity was reported and the recommended dose (RD) of everolimus was 50 mg/w. Safety evaluation in 46 pts treated at RD for 325 cy and a mean number cy/pt of 7.1 (95%CI: 6.3-7.8) showed grade (Gr) 1-2 adverse events consisting of asthenia (50%), nausea/vomiting (28%), alopecia (26%), mucositis (24%), and constipation (20%). Hematological toxicities (Gr1-2/3-4) were neutropenia (35%/39%), anemia (61%/17%), and thrombocytopenia (54%/13%). Everolimus-related Gr3 toxicities were rashes (1pt), pruritus (1pt), dyspnea (1pt), hyperglycemia (2pts), and Gr1-2 hypercholesterolemia (23pts). There was no toxic death. Among 38 pts evaluable for antitumor activity, one pt experienced a complete response (2.6%), 29 pts a partial response (76.3%), and 8 pts a stable disease (21%) for an overall response rate of 79% (no progression reported). Interestingly, 20 major responses (>50% reduction tumor volume) were observed in large necrotic primary tumors/N3 involvement. Efficacy was not correlated to KRAS/BRAF/PI3KCA/EGFR mutations. Significant decreases of Ki67/p-S6K activities were observed in post CAPRA biopsies compared to baseline. Conclusions: Weekly everolimus with carboplatin/paclitaxel as induction regimen was well tolerated with 11% grade 3 and no grade 4/5 toxicity. Translational data showed direct effects of everolimus in tumors. CAPRA yields high rate of objective responses in patients with locally advanced HNSCC. Clinical trial information: NCT01333085.

The PI3K/Akt/mTOR axis in head and neck cancer: functions, aberrations, cross‐talk, and therapies

“…The most impressive response, however, has come from the ongoing phase I‐II trials of everolimus in combination with carboplatin and paclitaxel as induction therapy in patients with unresectable locally advanced HNSCC. Recently presented results showed a 2.6% complete response, 76.3% partial response, as well as 21% stable disease in the 38 evaluable patients (Raymond et al , ). Everolimus continues to be investigated alone and in combinations in patients with HNSCC in five additional phase I‐II trials (Table ).…”

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

“…The number of clinical trials determined to evaluate the efficacy of the inhibitors of AKT, mTOR, or the AKT/mTOR pathway in OC patients is very few. However, several clinical trials have been reported with details of such investigation in HNSCC patients (Table 3) [191][192][193][194][195][196][197][198][199][200][201][202][203][204][205]. Some of these trials have been completed or terminated, while some are still ongoing.…”

“…Therefore, several clinical trials were conducted in HNC patients where everolimus was administered in combination with other drugs such as cetuximab, erlotinib, carboplatin and cetuximab, carboplatin and paclitaxel, cisplatin and docetaxel, cisplatin or carboplatin and cetuximab and cisplatin and radiotherapy. Most of these studies have been completed [193][194][195][196] (NCT01637194, NCT00942734, NCT01283334, NCT01333085, NCT00935961) while a few combinations have been discontinued due to severe side effects (NCT01009346, NCT01057277). However, the regime (everolimus, cisplatin and radiotherapy) was well tolerated in HNC patients with promising efficacy (NCT00858663) [197].…”

Text mining‑based drug discovery in cutaneous squamous cell carcinoma

“…Everolimus, an mTORC1 inhibitor, is undergoing a trial as part of a Phase I/II study investigating induction chemotherapy with weekly everolimus plus carboplatin and paclitaxel in locally unresectable advanced HNSCC. The treatment is well tolerated with an overall response rate of 79% (52). Another Phase I and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent or metastatic HNSCC showed an encouraging response rate, with 61.5% and 8.15 months progression-free survival, which suggested possible clinical efficacy in a select group of patients with cSCC (49).…”