A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer

Abstract

SUMMARY Introduction The phosphotidylinositol-3 kinase (PI3K)/serine–threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory HNSCC. Methods Patients with locally advanced, recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 IV every 21 days) with or without PX-866 (8 mg PO daily; Arms A and B, respectively). The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (RR), overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results 85 patients were enrolled. There was a non-significant improvement in response rate in the combination arm (14% vs. 5%; P = 0.13). Median PFS was 92 days in Arm A and 82 days in Arm B (P = 0.42). There was no difference in OS between the two arms (263 vs. 195 days; P = 0.62). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (17% vs. 2%), nausea (7% vs. 0%), and febrile neutropenia (21% vs. 5%); grade 3 or higher anemia was more frequent in arm B (7% vs. 27%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion The addition of PX-866 to docetaxel did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC without molecular pre-selection.

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

“…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.…”

Identification of new candidate therapeutic target genes in head and neck squamous cell carcinomas

“…A partial response in a heavily pretreated patient harboring a PIK3CA mutation was observed with BYL719, an α-specific PI3K inhibitor [11]. On the opposite, no improvement has been observed with the addition of the panPI3K inhibitor PX-866 to docetaxel in patients with advanced HNSCC without any molecular selection [12]. …”

Targeted Therapy of Head and Neck Cancer

“…Mechanistic target of rapamycin (mTOR) represents another potential target in the PI3K pathway, and mTOR inhibitors have shown preliminary efficacy preclinically and clinically, including in the TEMHEAD phase II study [24,25,26]. Other trials were negative including another phase II trial with the pan-PI3K inhibitor PX-866 and a phase II trial with the mTOR inhibitor everolimus as monotherapy [27,28]. …”

“…Generally, PIK3CA mutations, amplifications, or PTEN loss could mechanistically be expected to predict sensitivity to PI3K pathway inhibitors. In clinical studies in HNSCC, these aberrations were infrequently or not at all identified, and the small sample size did not allow for correlative analyses [26,27,28]. In a retrospective study in 549 patients with breast cancer, mutations in PIK3CA or AKT and PTEN loss were associated with an improved response to everolimus compared to the ‘PI3K normal pathway' [58].…”