A pilot study of cetuximab and the hedgehog inhibitor IPI-926 in recurrent/metastatic head and neck squamous cell carcinoma

Abstract

Background: This phase 1, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), antitumor activity, and molecular correlates of IPI-926, a Hedgehog pathway (HhP) inhibitor, combined with cetuximab in patients with relapsed/metastatic squamous cell carcinoma of the head and neck.

Patients and methods: Cetuximab was given with a 400mg/m(2) loading dose followed by 250mg/m(2) weekly. IPI-926 was given daily starting two weeks after cetuximab initiation. A "3+3" study design was used. Prior therapy with cetuximab was allowed. Tumor biopsies occurred prior to cetuximab initiation, prior to IPI-926 initiation, and after treatment with both drugs.

Results: Nine patients were enrolled. The RP2D was 160mg, the same as the single-agent IPI-926 MTD. Among 9 treated, 8 evaluable patients, the best responses were 1 partial response (12.5%), 4 stable disease (50%), and 3 disease progressions (37.5%). The median progression free survival was 77days (95% confidence interval 39-156). Decreases in tumor size were seen in both cetuximab-naïve patients (one HPV-positive, one HPV-negative). The most frequent treatment-emergent adverse events were fatigue, muscle cramps, and rash. No DLTs were observed. Tumor shrinkage and progression free survival were associated with intra-tumoral ErbB and HhP gene expression down-regulation during therapy, supporting the preclinical hypothesis.

Conclusion: Treatment with IPI-926 and cetuximab yielded expected toxicities with signs of anti-tumor activity. Serial tumor biopsies were feasible and revealed proof-of-concept biomarkers.

Keywords: Cetuximab; Combination therapy; Head and neck squamous cell carcinoma; Hedgehog signaling pathway; Phase 1.

Figure 1

Clinical responses to therapy. A) Best responses for patients treated with IPI-926 and cetuximab. B) Progression free survival by HPV status and prior cetuximab exposure. Median PFS for HPV-positive is 44 days (95% CI 39–156) versus 144 days for HPV-negative cancers (95% CI 56–190, p=0.09).

Figure 2

(A) Clinical trial biopsy collection protocol. (B) mRNA-sequencing comparisons for collected biopsies. Arrows indicate direction of comparison. (C) Volcano plots depicting global gene expression (grey) as well as expression of selected ErbB genes (red dots) that are heavily influenced by EGFR and Hedgehog pathway genes (green dots) and. Poor outcomes (left of 0) are enriched for ErbB and Hedgehog genes (more dots) compared to good outcomes after cetuximab and cetuximab plus IPI-926, respectively.

Figure 3

Volcano plots depicting global gene expression (grey) as well as expression of selected ErbB genes (red dots) that are heavily influenced by EGFR and Hedgehog pathway genes (green dots). Good (left) and poor (right) outcomes are separated. Relative expression is depicted for the comparisons on the left. In good outcomes, ErbB genes (red) and HhP genes (green) are suppressed (shifted right to left) following cetuximab and IPI-926 treatment, respectively.