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The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials. [ABSTRACT FROM AUTHOR]

Background Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. Patients and methods This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. Results No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. Conclusions Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688) [ABSTRACT FROM AUTHOR]

Background: Precision medicine is rapidly evolving within the field of oncology and has brought many new concepts and terminologies that are often poorly defined when first introduced, which may subsequently lead to miscommunication within the oncology community. The European Society for Medical Oncology (ESMO) recognises these challenges and is committed to support the adoption of precision medicine in oncology. To add clarity to the language used by oncologists and basic scientists within the context of precision medicine, the ESMO Translational Research and Personalised Medicine Working Group has developed a standardised glossary of relevant terms. Materials and methods: Relevant terms for inclusion in the glossary were identified via an ESMO member survey conducted in Autumn 2016, and by the ESMO Translational Research and Personalised Medicine Working Group members. Each term was defined by experts in the field, discussed and, if necessary, modified by the Working Group before reaching consensus approval. A literature search was carried out to determine which of the terms, 'precision medicine' and 'personalised medicine', is most appropriate to describe this field. Results: A total of 43 terms are included in the glossary, grouped into five main themes--(i) mechanisms of decision, (ii) characteristics of molecular alterations, (iii) tumour characteristics, (iv) clinical trials and statistics and (v) new research tools. The glossary classes 'precision medicine' or 'personalised medicine' as technically interchangeable but the term 'precision medicine' is favoured as it more accurately reflects the highly precise nature of new technologies that permit base pair resolution dissection of cancer genomes and is less likely to be misinterpreted. Conclusions: The ESMO Precision Medicine Glossary provides a resource to facilitate consistent communication in this field by clarifying and raising awareness of the language employed in cancer research and oncology practice. The glossary will be a dynamic entity, undergoing expansion and refinement over the coming years. [ABSTRACT FROM AUTHOR]

The current standard of care for patients (pts) with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For pts who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant, a first-in-class, small-molecule inhibitor of apoptosis protein inhibitor, has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in pts with unresected LA SCCHN, xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and a 67% lower risk of death or disease progression after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant + RT in cisplatin-ineligible pts with LA SCCHN. XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo + intensity-modulated RT (IMRT) in pts with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible pts must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4–10 weeks before the start of treatment (if possible, it is recommended to start treatment within 8 weeks from surgery); high risk of relapse; no residual disease by CT scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: eGFR <60 mL/min/1.73 m2; grade ≥2 audiometric hearing loss or grade ≥2 tinnitus; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14] or ineligible for cisplatin due to age limit according to national guidelines). Other eligibility criteria include ECOG PS of 0–2 and adequate hematologic and hepatic function. Approximately 700 eligible pts will be randomized to oral xevinapant (200 mg/day; Days 1–14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy/fraction, 5 days/week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Pts will be followed up until the last pt has been assessed for 60 months post randomization or until premature treatment discontinuation. Enrollment is ongoing in 21 countries worldwide, including the US, Mexico, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Pending Pending [ABSTRACT FROM AUTHOR]

Novel patterns of response and progression to immunotherapy have been reported that are not observed with conventional cytotoxic or targeted anticancer treatments. A major breakthrough with immunotherapy is its potential to achieve durable responses in a subset of patients with advanced cancer that can be maintained several years even after stopping the treatment. No standardized definition of durable response exists in the literature, and the optimal duration of treatment in case of durable response is not clearly established. However, the majority of patients do not respond to immunotherapy. Initially reported in advanced melanoma patients, pseudoprogression occurs when tumor index lesions regress after initial progression, supporting the concept of treating some patients beyond progression. Overall, reported rates of pseudoprogression never exceeded 10%, meaning that the large majority of patients who have a disease progression will not eventually respond to treatment. The decision to pursue treatment beyond progression must therefore only be taken in carefully selected patients with clinical benefit, who did not experience severe toxicities with immunotherapy. Conversely, rapid progressions, called hyperprogressions, were reported by several teams with rates ranging from 4% to 29%. These observations need to be confirmed from randomized trials. It is essential to interrupt the treatment in patients with hyperprogression, in order to switch to another potentially active treatment. Finally, some patients experience dissociated responses, with some lesions shrinking and others growing. Local treatment with surgery or radiotherapy for growing lesions may be considered. Several immune-specific-related response criteria were developed to better capture benefits of immunotherapy. These criteria only address the pseudoprogression pattern of response, and do not capture the other patterns of response such as hyperprogression and dissociated response. The classic RECIST remains a reasonable and meaningful method to assess response to immunotherapy in the clinic. [ABSTRACT FROM AUTHOR]

Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45–100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005. [ABSTRACT FROM AUTHOR]

Background Phase 2 studies (NCT02296684 and NCT02641093) with neoadjuvant and adjuvant pembro have demonstrated pathological response (PR) and acceptable safety in pts with high-risk resectable LA HNSCC. The randomized, global, open-label, phase 3 KEYNOTE-689 trial (NCT03765918) will evaluate the efficacy and safety of neoadjuvant pembro and adjuvant pembro plus SOC in pts with previously untreated resectable LA HNSCC. Trial design Pts will be randomly assigned 1:1 to two arms. In arm A, pts will receive neoadjuvant pembro (200 mg Q3W, 2 cycles), followed by surgical resection, then SOC plus adjuvant pembro (200 mg Q3W, 15 cycles). In arm B, pts will undergo surgical resection followed by adjuvant SOC without pembro. SOC is radiotherapy (RT) alone (pts at low risk) or RT plus concurrent cisplatin (3 cycles of 100 mg/m2 Q3W) (pts at high risk). RT is standard fractionation at 2 Gy/fraction for 30, 33, or 35 fractions (60 Gy, 66 Gy, or 70 Gy) for pts at low risk or high risk or with gross residual disease, respectively. Randomization will be stratified by primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA), and HPV p16 status (oropharynx p16–positive vs oropharynx p16–negative or larynx/hypopharynx/oral cavity). Eligible pts are adults with newly diagnosed, resectable, nonmetastatic stage III/IVA HNSCC (AJCC Cancer Staging Manual, 8th edition), evaluable tumor burden, and ECOG PS 0 or 1 who are eligible for primary surgery. Treatment will continue until disease progression, unacceptable toxicity, or decision to withdraw in both arms. Co-primary end points are major PR (≤10% invasive SCC within resected primary tumor and sampled regional lymph nodes per blinded central pathology) and event-free survival. Secondary end points include overall survival, pathological complete response, quality of life, and safety. The first radiologic imaging in arm A will occur after 2 cycles of pembro and before surgery. Postoperative imaging will occur in both arms 12 weeks after SOC, then every 3 months until year 3 and every 6 months thereafter. Recruitment is ongoing; estimated enrollment is ∼700 pts. Clinical trial identification NCT03765918. Legal entity responsible for the study Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp. a subsidiary of Merck & Co. Inc. Kenilworth, NJ, USA. Disclosure E. Cohen: Advisory / Consultancy: Amgen; AstraZeneca; Bayer; Bristol-Myers Squibb; Incyte; MSD; Merck. R. Uppaluri: Advisory / Consultancy, Research grant / Funding (self): Merck. N. Lee: Advisory / Consultancy: Merck, Merck Serono, Pfizer, Sanofi; Spouse / Financial dependant, Spouse Stockholder: AstraZeneca. W. Westra: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck. R. Haddad: Advisory / Consultancy: Celgene, Merck, Eisai, Bristol-Myers Squibb, AstraZeneca, Pfizer, Loxo, Genentech, Immunomic Therapeutics; Research grant / Funding (institution): Boehringer Ingelheim, Merck, Bristol-Myers Squibb, Celgene, AstraZeneca, VentiRx, Genentech, Pfizer, Kura. C. Le Tourneau: Honoraria (self), Advisory / Consultancy: Merck Serono, Bristol-Myers Squibb, MSD, Amgen, Novartis, Nanobiotix; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Amgen, MSD, Merck Serono. R. Chernock: Advisory / Consultancy: Merck, Roche. Y. Tao: Research grant / Funding (institution): Debiopharma, MSD, Pfizer; Travel / Accommodation / Expenses: MSD, Merck Serono. I. Brana: Advisory / Consultancy: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, AstraZeneca, Merck Serono; Research grant / Funding (self): AstraZeneca, Bristol-Myers Squibb, Celgene, Gliknik, GlaxoSmithKline, Janssen Oncology, Kura, Merck Sharp & Dohme, Novartis, Orion Pharma GmbH, Pfizer; Travel / Accommodation / Expenses: AstraZeneca Spain, Merck Serono. J.Y. Ge: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. R. Swaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. Inc. B. Bidadi: Full / Part-time employment: Merck. D. Adkins: Advisory / Consultancy: Pfizer, Eli Lilly, Merck, Celgene; Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background α-selective PI3K inhibitors improve PFS in patients with HR+/Her2- metastatic breast cancer (mBC) and PIK3CA mutation. Recent studies have reported that a subset of patients with PIK3CA-mutated HR+/Her2- mBC are chemoresistant. Therefore, there is a need to identify these patients in order to propose them alternative therapies, including PI3K inhibitors. Methods 44 patients from SAFIR02 trial (NCT02299999), with mBC and PIK3CA mutation, detected by NGS on metastatic samples, were analyzed. We studied the prognostic value of the level of cell-free circulating PIK3CA mutations, determined by NGS and digital PCR, in plasma samples during chemotherapy. They were obtained after one cycle of chemotherapy in 66% of patients, two cycles in 20% of patients, and three cycles in 14% of patients. Results PIK3CA mutations were detectable on circulating DNA in 26 of the 44 patients (59%) analyzed. 38 (88%) tumors were HR+/Her2- and there were only 5 (12%) TNBC. The most frequent metastatic sites were liver (79%), bone (75%), and lung (23%). 89% of patients received first-line of chemotherapy at the time of screening. The level of PIK3CA mutations detected in plasma during chemotherapy was associated with a poor outcome (continuous variable, Hazard Ratio for Overall Survival (OS): 1.03, 95% CI [1.01-1.05], p = 0.007). The median OS for patients with a minor allele frequency (MAF) ≥ median was 14 months vs 26 for patients with a MAF < median (p < 0.0001), and 6 months vs 25.6 for patients with a MAF ≥ or < 5 respectively (p < 0.0001). Conclusions Patients with persistent levels of cell-free circulating PIK3CA mutations during chemotherapy present a poor outcome. Pending a validation study, these patients could be eligible to innovative therapy as soon as 1stline chemotherapy. Legal entity responsible for the study The authors. Funding Fondation ARC Pour La Recherche Sur Le Cancer, Breast Cancer Research Foundation, Operation Parrain Chercheurs and Transcan. Disclosure C. Le Tourneau: Advisory / Consultancy: Amgen; Advisory / Consultancy: GSK; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche. M.P. Sablin: Speaker Bureau / Expert testimony: Servier. J-C. Soria: Honoraria (institution), full time employer since September 2017: AstraZeneca; Advisory / Consultancy: Astex; Advisory / Consultancy: Clovis; Advisory / Consultancy: GSK; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Mission Therapeutics; Advisory / Consultancy: Merus; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Takeda; Advisory / Consultancy: Symphogen; Honoraria (self), Shareholder: AstraZeneca/Genentech. M. Campone: Honoraria (institution): Novartis. T. Bachelot: Honoraria (self), Research grant / Funding (self), Non-financial support: Novartis; Honoraria (self), Research grant / Funding (self), Non-financial support: AstraZeneca; Honoraria (self), Research grant / Funding (self), Non-financial support: Pfizer; Honoraria (self): Seattle Genetics. F. André: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Research grant / Funding (self), Outside the work: Pfizer, Lilly, Sanofi, Roche, AstraZeneca, Daiichi. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]