Personalized biomarker-based treatment strategy in patients with recurrent/metastatic squamous cell carcinoma of the head and neck

Patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) have a dismal prognosis. The genomic landscape of SCCHN harbors potentially actionable alterations but targeted agents have only minor activity in unselected populations. We designed the UPSTREAM trial (EORTC-HNCG-1559), a biomarker-driven umbrella trial for recurrent/metastatic SCCHN to propose a personalized treatment strategy and potentially improve patient’s outcome. This is the first European multi-country umbrella trial, for which we demonstrated the feasibility through a successful global accrual rate, the addition of new patient cohorts and the release of the results of the first immunotherapy cohort. We have demonstrated that obtaining a tissue biopsy suitable for sequencing at recurrent/metastatic disease can be challenging. We therefore studied the relevance of mutational profiling through liquid biopsy for SCCHN using targeted next-generation sequencing (NGS) on a broad custom gene panel. The likelihood of ctDNA detection was higher for metastatic disease. Liquid biopsy alone could identify potentially actionable alterations but did not reflect the full landscape of the solid tumor. The use of Iiquid biopsy hold promise for the future but should be investigated using a more sensitive technique.(MED - Sciences médicales) -- UCL, 202

A phase II study of monalizumab and durvalumab in patients with recurrent/metastatic(RM) squamous cell carcinoma of the head and neck (SCCHN): result s of the I2 cohort of the EORTC-HNCG-1559 trial (UPSTREAM.

Background Monalizumab (mona), a IgG4 Ab targeting the NKG2A receptor, has limited activity as monotherapy in RM SCCHN. Targeting the NKG2A-HLA-E pathway with PD(L)1 blockade improved tumor control in mice. Preliminary data of mona and durvalumab (durva), have shown encouraging activity in pretreated MSS colorectal cancer. Methods The UPSTREAM trial is an umbrella trial of targeted therapies and immunotherapy for RM SCCHN (post platinum, ECOG 0-1). The immunotherapy 2 (I2) cohort was a phase II, randomized, open label substudy evaluating the efficacy of the combination of durva (iv, 1500mg Q4W) and mona (iv, 750mg Q2W or Q4W) (D+M) vs physician’s choice (control, ctrl) (2:1 ratio). Pts non-eligible for the biomarker-driven cohorts and pretreated with PD(L)1, were included in the I2 cohort. The primary endpoint was objective response rate (RECISTv1.1) during the first 16 weeks (2-stage Simon design applied to the D+M arm, H1 15%, H0 3%, 1-sided α 10%, power 90%). Secondary endpoints included response duration, toxicity, PFS, and OS. Results 66 RM SCCHN pts were included in the I2 cohort (D+M: n=45, ctrl: n=21). 61 pts were evaluable (D+M: n=43, ctrl: n=18): median age 62 yrs; oral cavity 20%, oropharynx 39%, hypopharynx 20%, larynx 21%; 87% with 2 or 3 previous lines. In D+M 1 partial response (PR) was recorded and stable disease (SD) was observed in 11 pts (26%). 1 PR was reported in the ctrl arm and SD in 8 (44%). The median PFS was 2.0 mo (95% CI: 1.8-2.4) and 3.1 mo (95% CI: 1.9-3.9) in the D+M arm and ctrl arm, respectively. The median OS was 4.4 mo (95% CI: 3.3-9.2) and 8.0 mo (95% CI: 3.1-14.9) in the D+M and ctrl arm, respectively. In the D+M arm, 4 pts (9%) reported grade 3 treatment-related adverse events. Conclusions The substudy of mona and durva did not meet its primary objective. No benefit was seen in PFS and OS. These are preliminary results, definitive results will be presented at the congress. ClinicalTrials.gov: NCT0308805

Current applications and challenges of circulating tumor DNA (ctDNA)in squamous cell carcinoma of the head and neck

Liquid biopsies (LB) are emerging in the oncology field, with promising data as new diagnostic, prognostic and treatment-monitoring tools. Squamous cell carcinoma of the head and neck (SCCHN) is a heterogenous disease and many challenges remain to improve patient outcomes. Liquid biopsy could be of interest at different stages of SCCHN disease, including better screening to diagnose more patients at an early stage, early detection of relapse after curative treatment, and the implementation of precision medicine. As LB is very attractive by the ease of sampling, this field is moving fast. Therefore, it is important to be aware of the potential applications but also the limitations of these new tools in regards to technical aspects and interpretation of the data. In this review, we will first give an overview of potential clinical applications and technical challenges of circulating tumor DNA (ctDNA) and then focus on current available data of ctDNA in SCCHN. Although the literature on ctDNA analysis for SCCHN is scarce compared to other tumors, preliminary results seem to hold promise for the future, including the detection of minimal residual disease or the detection of potentially targetable events through liquid biopsy. Prospective liquid-biopsy driven clinical trials are needed to validate its clinical relevanc

Safety of drug treatments for head and neck cancer

The treatment of squamous cell carcinoma of the head and the neck depends on the disease's stage. In locally-advanced stage disease, multimodal treatment strategies, including surgery, radiotherapy and chemotherapy, give the best outcome in terms of overall survival. Those treatments are not without negligeable adverse events, which can lead to late debilitating toxicities. In recurrent/metastatic disease, not amenable to surgery or radiation therapy, palliative chemotherapy is the most appropriate treatment. Areas covered: This review aims to provide an overview of the safety of standard drug regimens used to treat SCCHN in daily practice, including platinum-based chemoradiation, induction chemotherapy, cetuximab and immunotherapy. The toxicities induced by single modality radiotherapy, or those resulting from surgery, are not part of the discussion. Expert opinion: Toxicities observed with multimodal treatment of SCCHN are the highest we can tolerate in terms of treatment-related mortality, morbidity and late consequences. Patients at high risk of developing such complications should be identified upfront for optimal prevention and management. There is a medical need to identify less toxic regimens without compromising the treatment efficacy, especially for patients with Human Papilloma Virus-induced oropharyngeal cancers. Finally, it is crucial in future trials to better standardize the scales used to report treatment related adverse events

Afatinib in patients with recurrent/metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN) harboring alterations in the HER pathway: results of the B1 cohort of the EORTC-HNCG-1559 trial (UPSTREAM).

Background Afatinib (A) is an irreversible pan-HER inhibitor that improved PFS in second line RM SCCHN after platinum (LUX-H&N1 trial). In a retrospective biomarker analysis, subgroups of pts with p16 negative, PTEN high or EGFR amplification SCCHN seem to benefit the most. Other studies suggest that A has activity in tumors with HER2 gene activation. Methods The UPSTREAM trial is a biomarker-driven umbrella trial of targeted therapies and immunotherapy for RM SCCHN (post-platinum, ECOG 0-1, measurable disease). The B1 cohort was a phase II, randomized, open-label substudy evaluating the efficacy of afatinib (orally, 40mg/day) vs physician’s choice (ctrl) (2:1 ratio) in pts with p16 negative RM SCCHN harboring one of the following biomarkers (fresh biopsy): EGFR mutation(mut)/amplification(amp) or HER2 mut/amp or PTEN high by immunohistochemistry (IHC, H-score > 150). Only KRAS/HRAS/NRAS wild type tumors were included. The primary endpoint was progression-free survival rate (PFSR) at 16 weeks after randomization. A 2-stage Simon optimal design was applied to arm A (H1 40%, H0 20%, 1-sided α 10%, power 90%) with 17 and 20 pts enrolled in the first and second stage respectively. Secondary endpoints included ORR, toxicity, PFS, and OS. Results 59 RM SCCHN pts were included in the B1 cohort (A: n=40, ctrl: n=19). Out of the 59 patients, EGFR amp, HER2 amp and HER2 mut were found in 6 pts (10%), 1 pt (2%) and 1 pt (2%), respectively. PTEN (IHC) was high in 97%. 55 pts were evaluable (A: n=38, ctrl: n=17) (median age: 62, oral cavity: 29%, oropharynx: 36%, hypopharynx: 24%, larynx: 11%). 69% of pts had received 2 lines of systemic treatment for RM disease. 80% were pretreated with cetuximab. In arm A, 13/38 patients were alive and free of objective progression at 16 weeks (34.2%, 1-sided 90%CI, 23.9-+inf), meeting the predefined criteria of success. The PFSR at 16W in ctrl arm was 29.4% (5/17). 4 objective responses were observed in arm A (3 PR and 1 CR) (ORR 11%, 95%CI 2.9-24.8%) and 1 PR in ctrl arm (6%). The median duration of response under A was 5.7 mo (range: 3.7-25.9 mo). All responding patients had previously been treated with cetuximab, were PTEN high but none had EGFR or HER2 alterations. The median PFS and OS were 2.2/2.4 mo and 7.2/5.0 mo in the A/ctrl arms, respectively. Grade 3 drug-related AEs were reported in 31% in arm A and 12% in ctrl arm. The most frequent drug-related AE with A were diarrhea (67%, G3:8%), rash (41%, G3: 3%), fatigue (31%, no G3) and mucositis (23%, G3: 3%). Conclusion The B1 substudy met its primary endpoint of PFSR at 16 weeks. Responses were seen in cetuximab pre-treated pts. However, the clinical activity of A in this biomarker-selected population remains limited. Translational research is ongoing to better define potential biomarkers. ClinicalTrials.gov: NCT0308805

Safety of drug treatments for head and neck cancer

<p><b>Introduction</b>: The treatment of squamous cell carcinoma of the head and the neck depends on the disease’s stage. In locally-advanced stage disease, multimodal treatment strategies, including surgery, radiotherapy and chemotherapy, give the best outcome in terms of overall survival. Those treatments are not without negligeable adverse events, which can lead to late debilitating toxicities. In recurrent/metastatic disease, not amenable to surgery or radiation therapy, palliative chemotherapy is the most appropriate treatment.</p> <p><b>Areas covered</b>: This review aims to provide an overview of the safety of standard drug regimens used to treat SCCHN in daily practice, including platinum-based chemoradiation, induction chemotherapy, cetuximab and immunotherapy. The toxicities induced by single modality radiotherapy, or those resulting from surgery, are not part of the discussion.</p> <p><b>Expert o</b><b>pinion</b>: Toxicities observed with multimodal treatment of SCCHN are the highest we can tolerate in terms of treatment-related mortality, morbidity and late consequences. Patients at high risk of developing such complications should be identified upfront for optimal prevention and management. There is a medical need to identify less toxic regimens without compromising the treatment efficacy, especially for patients with Human Papilloma Virus-induced oropharyngeal cancers. Finally, it is crucial in future trials to better standardize the scales used to report treatment related adverse events.</p

Unusual presentation of bladder cancer resurgence and efficacy of radiotherapy.

A 68-year-old man with a history of bladder cancer presented with perineal pain and penile priapism. The work up showed multiple lesions strictly located in the penis; biopsy confirmed metastases of bladder cancer. Surgery was judged unfeasible and chemotherapy failed to improve symptoms. Radiotherapy was therefore delivered on the whole penis and resulted in a rapid clinical benefit and persistent control of the disease. Penile metastases are very rare and no consensus exists concerning their management; radiotherapy appears as a promising therapeutic option not only to palliate pain but also to control the disease

Unusual presentation of bladder cancer resurgence and efficacy of radiotherapy

A 68-year-old man with a history of bladder cancer presented with perineal pain and penile priapism. The work up showed multiple lesions strictly located in the penis; biopsy confirmed metastases of bladder cancer. Surgery was judged unfeasible and chemotherapy failed to improve symptoms. Radiotherapy was therefore delivered on the whole penis and resulted in a rapid clinical benefit and persistent control of the disease. Penile metastases are very rare and no consensus exists concerning their management; radiotherapy appears as a promising therapeutic option not only to palliate pain but also to control the disease