Multicenter Phase 2 Trial of C is/Carboplatin, nAb -Paclitaxel, and C e TUX imab ( CACTUX ) as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Abstract

To quantify HPV16 copies in plasma circulating tumor DNA (ctDNA) from patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) during the receipt of deintensified chemoradiotherapy (CRT) on a prospective phase II clinical trial (NCT02281955). Materials/Methods: The major inclusion criteria were: 1) T0-T3, N0-N2c, M0, 2) HPV or p16 positive (tumor sample), and 3) minimal/moderate smoking history. De-intensified CRT consisted of 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/ m 2). Blood specimens were collected at baseline and weekly during CRT for plasma circulating nucleic acid extraction (Qiagen). A Taqman assay targeting the HPV16 E6 gene was developed and implemented on the Bio-Rad QX100 droplet digital PCR (ddPCR) platform. Tumor genomic analyses were performed using a hybrid capture next generation sequencing assay that included probes targeting high-risk HPV strains. A bioinformatics pipeline was developed to quantify normalized HPV counts and to determine the high-risk HPV strain that was most abundantly represented in each sample. Results: Plasma HPV16 ctDNA was analyzed for 47 patients who completed 6 weeks of de-intensified CRT. Pre-treatment plasma ctDNA quantification by ddPCR stratified patients into three groups: undetectable HPV16 ctDNA (10/47 patients, 21%), low HPV16 ctDNA (12/47 patients, 26%, mean 69 copies/mL, range 29-118 copies/mL), and high HPV16 ctDNA (25/47 patients, 53%, mean 3924 copies/mL, range 257-22,684 copies/mL). Baseline HPV16 ctDNA levels did not correlate with T stage, N stage, or smoking status. Analysis of matched tumor genome sequencing for a subset of 25 patients revealed a strong correlation between tumor HPV copy number and plasma HPV16 ctDNA levels (p Z 0.0037). Non-HPV16 strains were detected in 27% (3/11) of tumor biopsies with undetectable or low plasma HPV16 ctDNA, compared to 0% (0/14) among patients with high plasma HPV16 DNA (p Z 0.07). The 1-year actuarial rate of freedom from persistent or recurrent disease after de-intensified CRT was significantly higher in patients with high versus undetectable/low baseline HPV16 ctDNA levels (100% vs. 83%, p Z 0.046). The majority of patients with high baseline HPV16 ctDNA converted to undetectable by week 6 of CRT (81%), with a subset of "early responders" who cleared HPV16 ctDNA by week 4 (42%). Conclusion: Plasma HPV16 ctDNA is detectable in the majority of favorable risk HPV-associated OPSCC, and may be a clinically useful biomarker of disease control in the setting of de-intensified CRT. Specifically, undetectable or low HPV16 ctDNA may reflect adverse tumor genomics, including an increased prevalence of non-HPV16 high-risk strains.

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

“…On the other hand, only 22% of patients in the CACTUX trial received PD-1 inhibitor immunotherapy after progression and demonstrated a: median PFS of 2.2 months. 33 Comparatively, in our study, 19 of 33 patients who progressed (57.5%) received immunotherapy (nivolumab) and showed good response with an ORR of 26.3% and median PFS and OS of 6.5 months and 20.6 months, respectively.…”

Consistent administration of cetuximab is associated with favorable outcomes in recurrent/metastatic head and neck squamous cell carcinoma in an endemic carcinogen exposure area: a retrospective observational study

“…The effects of carcinogen were also not mentioned in the Chinese and Korean population. The results of these studies are summarized in Table 6 ( Adkins et al, 2018 ; Bossi et al, 2017 ; De Mello et al., 2014 ; Friesland et al., 2018 ; Guigay et al, 2016 ; Guigay et al, 2012 ; Guigay et al, 2019 ; Guo et al., 2015 ; Tahara et al, 2016 ; Vermorken et al, 2008 ).…”

“…The addition of cetuximab to platinum-based chemotherapy with fluorouracil (platinum-fluorouracil) improved the overall response rates, median progression-free survival (PFS), and overall survival (OS) compared with chemotherapy alone. Another combination of cetuximab with chemotherapy agents such as taxane also demonstrated substantial benefits ( Adkins et al, 2018 ; Friesland et al., 2018 ; Guigay et al, 2019 ). However, most of these clinical trials were conducted in Western countries with fewer patients with primary oral cavity cancer; data regarding the effect of carcinogens such as betel nuts on outcome are very limited.…”

First-line cisplatin, docetaxel, and cetuximab for patients with recurrent or metastatic head and neck cancer: A multicenter cohort study

“…The addition of fluorouracil to a taxane seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel[ 12 , 13 ]. Cetuximab-, platinum-, and taxane-based schedules have been associated with promising survival results and cytoreductive properties in clinical studies[ 14 - 18 ]. TPExtreme was the first large, phase 3, randomized trial comparing the TPEx regimen (cetuximab, taxane, and platinum) with the EXTREME scheme in a first-line setting[ 19 ].…”