Tag: Head & Neck: Oropharynx

Late Breaking Abstract – ESMO 2022: Neoadjuvant KEYTRUDA® with Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with Squamous Cell Carcinoma of the head and neck, frequently present with locoregionally advanced disease.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-412 is a randomized, double-blind, Phase III trial, conducted to evaluate the efficacy and safety of Pembrolizumab in combination with chemoradiation versus placebo in combination with chemoradiation, in treatment naïve patients with locally advanced Head and Neck Squamous Cell carcinoma. In this study, 804 patients were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV every 3 weeks plus chemoradiation (70Gy in 35 fractions along with Cisplatin 100 mg/m2 IV every 3 weeks) followed by Pembrolizumab (N=402), or placebo every 3 weeks plus chemoradiation, followed by placebo (N=402). Patients received Pembrolizumab /placebo priming dose 1 week before chemoradiation, followed by 2 doses during chemoradiation and 14 doses of maintenance therapy after chemoradiation, for a total of 17 doses. Enrolled patients had newly diagnosed, pathologically proven, treatment naive locally advanced Head and Neck Squamous Cell carcinoma (T3-T4, N0-N3 or any N2a-3, T1-T4 larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers, or T4 or N3 p16-positive oropharynx cancer). Both treatment groups were well balanced. The Primary endpoint was Event Free Survival (EFS). Secondary endpoints included Overall Survival (OS), and Safety.

At the time of data cutoff, with a median follow up of 47.7 months, there was a favorable trend toward improved Event Free Survival (EFS) with the addition of Pembrolizumab vs placebo to chemoradiation (HR 0.83, P=0.04), but the difference did not achieve statistical significance. The 2-year EFS was 63.2% in the Pembrolizumab group and 56.2% in the placebo group. In an exploratory analysis however, the 2-year EFS among patients with high expression of PD-L1 (CPS 20 or higher) was 71% in the Pembrolizumab group and 62% in the placebo group. A favorable of Overall Survival benefit was also observed among these patients, with a 3-year OS of 79% in Pembrolizumab group and 73% in the placebo group.

It was concluded that Pembrolizumab in combination with chemoradiation was associated with a favorable trend toward improved Event Free Survival, compared with placebo plus chemoradiation, in patients with locally advanced Head and Neck Squamous Cell carcinoma, but the difference did not reach statistical significance. The researchers added that perhaps patients with high CPS score on the tumor could benefit with this treatment approach.

Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Machiels J, Tao Y, Burtness B, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA5

Late Breaking Abstract – ASCO 2022: Docetaxel as Radiosensitizer Improves Overall Survival in Cisplatin-Ineligible Head and Neck cancer

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SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with squamous cell carcinoma of the head and neck, frequently present with locoregionally advanced disease. For patients in this setting, chemoradiotherapy is an effective non-surgical approach as primary treatment. Alternatively, chemoradiotherapy can be delivered as adjuvant therapy after a curative resection.

Cisplatin-based concurrent chemoradiation is generally accepted as the standard, definitive non-surgical and post-operative approach in selected patients with locoregionally advanced squamous cell carcinoma of the head and neck. This treatment can however be associated with substantial morbidity and lifelong toxicities. Cetuximab is an immunoglobulin G1 chimeric monoclonal antibody against Epidermal Growth Factor Receptor (EGFR), and the only approved targeted agent in locoregionally advanced squamous cell carcinoma of the head and neck. Cetuximab plus Radiotherapy significantly improved Overall Survival at 5 years, when compared with radiotherapy alone, in patients with locoregionally advanced squamous cell carcinoma of the head and neck (Lancet Oncol. 2010). Cetuximab plus Radiotherapy is therefore an important treatment option in this patient group. However, financial barriers make Cetuximab as a Cisplatin substitute, inaccessible to patients, in low and middle-income countries.

Docetaxel is a semisynthetic taxane that affects polymerized tubulin to promote microtubule formation and inhibit its disassembly. Docetaxel has been shown to have significant antitumor activity as a single agent in head and neck cancer, when given in the neoadjuvant setting. Docetaxel is also a potent radiosensitizer. The researchers evaluated Docetaxel as a radiosensitizer in this clinical trial.

The authors in this open-label, randomized, Phase III study enrolled 356 Cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma, planned for treatment with radical or adjuvant chemoradiation. The patients were randomly assigned 1:1 to receive Radiation alone (N=176) or Radiation with concurrent Docetaxel 15 mg/m2 IV weekly for a maximum of 7 cycles (N=180). Both treatment groups were well balanced. The median age was 62 yrs, approximately 45% of patients had a ECOG Performance Status of 2, and reasons for Cisplatin ineligibility included low creatinine clearance (26%), and hearing loss (43%). Approximately 33% of patients had oral cavity cancer and about two-thirds of patients had Stage IVA disease. The FACT-G, and Head and Neck questionnaires were completed by patients at baseline, 6 months, 12 months and at 24 months. FACT-G (Functional Assessment of Cancer Therapy-G) is a 27-item questionnaire designed to measure four domains of Health-Related Quality of Life (HRQOL) in cancer patients, which includes physical, social, emotional, and functional well-being. The Primary endpoint was Disease Free Survival (DFS), and key Secondary endpoints included Overall Survival (OS), adverse events and Quality of Life.

It was noted that the 2-year DFS was 30.3% with Radiation alone versus 42% with Docetaxel plus Radiation Therapy (HR=0.67; P=0.002). Docetaxel plus Radiation Therapy also significantly improved Overall Survival. The median Overall Survival was 15.3 months with Radiation Therapy alone, versus 25.5 months in the Docetaxel plus Radiation Therapy group (P=0.035). The 2 -year Overall Survival was also significantly higher in the Docetaxel plus Radiation Therapy group and was 41.7% with Radiation Therapy alone, versus 50.8% in the Docetaxel plus Radiation Therapy group (HR=0.74; P=0.035). These survival outcomes were observed across all preplanned subgroups.

Grade 3 or above adverse events were seen in 58% of patients receiving Radiation Therapy alone and in 81.6% of patients receiving Docetaxel plus Radiation Therapy. The addition of Docetaxel to Radiation Therapy resulted in a higher incidence of Grade 3 and above mucositis (49.7% versus 22.2%; P<0.001), odynophagia (52.5% versus 33.5%; P<0.001) and dysphagia (49.7% versus 33%; P<0.002). The addition of Docetaxel however did not lead to a worsening of Quality of Life, including Trial Outcome Index and FACT-G scores at 6 months.

The authors concluded that the addition of Docetaxel to Radiation Therapy improved Disease Free Survival and Overall Survival, in Cisplatin-ineligible locally advanced head and neck squamous cell carcinoma, and provides an evidence based, financially more viable treatment option, for this patient group.

Results of phase 3 randomized trial for use of docetaxel as a radiosensitizer in patients with head and neck cancer unsuitable for cisplatin-based chemoradiation. Patil VM, Noronha V, Menon NS, et al. DOI: 10.1200/JCO.2022.40.17_suppl.LBA6003 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) LBA6003.

PET Response-Based Radiotherapy De-Escalation in p16 Positive Oropharyngeal Cancer

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SUMMARY: The American Cancer Society estimates that about 54,000 new cases of oral cavity or Oropharyngeal Cancer will be diagnosed in the US in 2022 and about 11,230 patients will die of the disease. According to the CDC, based on data from 2014 to 2018, about 46,143 HPV-associated cancers occur in the United States each year (25,719 among women, and 20,424 among men). Cervical cancer is the most common HPV-associated cancer among women, and Oropharyngeal cancers are the most common among men. There has been a significant increase in the incidence during the past several decades, due to changes in sexual practices.

HPV-positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) is an entirely distinct disease entity from HPV-negative Oropharyngeal Squamous Cell Carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.

HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and Radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste.Oropharynx

To address these toxicities, the authors conducted a prospective Phase II de-escalation study utilizing FDG-PET response criteria to select patients eligible for de-escalated radiotherapy. The researchers hypothesized that early swallow function and quality of life will improve with lower dose radiation. This study enrolled 59 patients (N=59) with Stage I-II (AJCC) p16-positive Oropharyngeal cancer, with FDG-avid disease and any smoking history. Patients with matted lymph nodes or history of head and neck surgery were excluded.

All enrolled patients had a pre-treatment FDG-PET/CT imaging and received weekly Carboplatin and Paclitaxel concurrently with planned radiotherapy at 70 Gy in 35 fractions. FDG-PET was repeated midway through treatment after 2 weeks at fraction 10. Patients who had tumors with lower metabolic activity before treatment and more than 50% reduction in Metabolic Tumor Volume after 2 weeks of treatment were de-escalated from the standard radiotherapy total dose of 70 Gy in 35 fractions, to a total dose of 54 Gy in 27 fractions. The median patient age was 60 years and baseline characteristics showed that both standard and de-escalated cohorts had similar patient demographics and pathology. At the planned interim analysis, early toxicity and Patient Reported Outcomes (PROs) were examined.

Fifty percent (50%) of the patients met de-escalation criteria and received the lower radiation dose, leading to 20-30% reductions in radiation exposure to sensitive structures in the head and neck prone to toxicities such as larynx, constrictors, oral cavity and salivary glands. De-escalation from the standard radiotherapy resulted in significantly less acute toxicity, and at one month after treatment, patients who received de-escalated therapy lost less weight as a percentage of baseline, compared to standard treatment group (6% versus 11%; P<0.001) and had improved videofluoroscopic swallowing function following treatment, and fewer patients required feeding tube placement during treatment.

The authors concluded that although the trial remains ongoing, mid-treatment FDG-PET response adaptation allows for approximately 50% of early stage p16 positive Oropharyngeal cancer patients to be de-escalated to a total dose of 54 Gy. This in turn can result in approximately 25% reduction in dose delivered to organs known to affect toxicity and quality of life, with significantly better objective measures of toxicity and numerically improved Patient Related Outcomes.

Early Toxicity and Patient Reported Outcomes From a Phase 2 Trial of FDG-PET Response-Based De-Escalated Definitive Radiotherapy for p16+ Oropharynx Cancer. Allen SG, Rosen BS, Aryal MP, et al. 2022 Multidisciplinary Head and Neck Symposium; February 24-26, 2022; Phoenix, AZ. Abstract 1.

Late Breaking Abstract – ASTRO 2019 Detectable HPV Circulating Tumor DNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. HPV is a non-enveloped, double-stranded, DNA virus that infects epithelial cells and majority of the HPV subtypes cause epithelial lesions such as warts or papillomas, which are of low malignant potential. However, there is a subset of high-risk HPV that can cause cancer by integrating its DNA into the host genome, with the resulting expression of two important oncogenes E6 and E7 in the host cell. The E6 oncogene binds and degrades tumor suppressor TP53 via ubiquitin-mediated processes thereby preventing the host cell from engaging in cell cycle checkpoints and enduring an apoptotic response. The E7 oncogene binds to and destabilizes tumor suppressor retinoblastoma (pRb) resulting in transcription of genes involved in proliferation and cell cycle progression. One of the main molecular pathways amplified through E7 is the CDKN2A/p16 gene pathway, which results in the overexpression of p16 protein. E7 also induces cellular proliferation by disrupting the activity of Cyclin Dependent Kinase inhibitors p21 and p27. In essence, HPV infection induces failures in cell cycle checkpoints, resulting in genetic instability and over time, progression of premalignant lesions to invasive Squamous Cell Carcinoma. Unlike tobacco induced HNSCC where TP53 and pRb pathways are nullified due to mutation and epigenetic alterations, in HPV-related HNSCC, wild-type TP53 and pRb are functionally inactivated by the viral oncogenes.

Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV infection. The HPV-positive primary Squamous Cell Carcinoma tends to be smaller in size, with early nodal metastases, and HPV status particularly in OroPharyngeal Squamous Cell Carcinoma is an independent prognostic factor for Overall Survival (OS) and Progression Free Survival (PFS). These patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Further, HPV positive patients demonstrate higher Response Rates to chemoradiation as well as an improved Overall Survival. However, approximately 20% of patients diagnosed with HPV-positive OPSCC experience cancer progression within 5 years.

The role of circulating tumor DNA (ctDNA) as a cancer biomarker in the post-operative surveillance of patients with HPV-associated OPSCC has remained unclear. The authors in this study aimed to investigate ctDNA detectability rates by post-op risk category and association with prognosis in this patient population. The researchers prospectively collected and tested serum samples from 29 patients with HPV-associated OPSCC who had not yet undergone treatment, for assay validation. As a control, 7 HPV negative OPSCC patients were included. A cohort of 46 patients with HPV-associated OPSCC who had undergone surgery for the disease had serum samples collected prior to beginning adjuvant therapy. The serum collected from this total group of 82 patients (N=29+7+46) was analyzed in a blinded fashion for E6/E7 HPV ctDNA using ddPCR multiplex assay (HPV 16, 18, 31, 33), and HPV ctDNA detectability was compared statistically across groups. Associations of patient and tumor characteristics with recurrence were assessed and estimates of Progression Free Survival (PFS) and Overall Survival (OS) were made using the Kaplan-Meier (KM) method.

The researchers found that ctDNA was detectable in 27 of 29 patients who had not yet undergone treatment, for a sensitivity rate of 93%, whereas none of the 7 HPV-negative patients had detectable ctDNA, for a specificity rate of 100%. Post-op serum was collected at a median of 25 days after surgery prior to beginning adjuvant therapy and ctDNA was detectable in 43% of patients including 47% with high-risk features (Extra Nodal Extension or R1-microscopic residual tumor). All detected ctDNA was HPV type 16.

At a median follow up of 20 months for the post-op HPV-OPSCC cohort, 24% of these patients had recurrent disease. Among those who recurred, 64% had detectable ctDNA compared with 35% whose disease did not recur (P=0.1). There was a significant association between detectable ctDNA and 24-month Progression Free Survival (45% versus 84%; P=0.04) and Overall Survival (80% versus 100%; P=0.02). Overall, detectable ctDNA, T4 tumors, and more than 4 positive lymph nodes were positively associated with disease recurrence.

It was concluded that detectable HPV circulating tumor DNA is a highly sensitive and specific means of determining HPV-status and was significantly associated with worsened Progression Free Survival and Overall Survival among post-op patients with Human Papilloma Virus (HPV)-associated OroPharyngeal Squamous Cell Carcinoma. HPV circulating tumor DNA as a cancer biomarker may also assist in risk stratification, treatment assessment, and surveillance. Detectable HPV ctDNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression. Routman DM, Chera BS, Jethwa KR, et al. International Journal of Radiation Oncology • Biology • Physics 2019;105, 682-683. LBA5

KEYTRUDA® (Pembrolizumab)

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The FDA on June 10, 2019 approved KEYTRUDA® for the first-line treatment of patients with metastatic or unresectable recurrent Head and Neck Squamous Cell Carcinoma (HNSCC). KEYTRUDA® is a product of Merck.

Radiotherapy plus ERBITUX® Inferior to Radiotherapy plus Cisplatin in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades, due to changes in sexual practices. They represent approximately 70% of all OPSCC in the United States and Canada. HPV-positive oropharyngeal squamous cell carcinoma is an entirely distinct disease entity from HPV-negative oropharyngeal squamous cell carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.
Parts-of-the-Oropharynx
HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate Cisplatin chemotherapy such as the elderly, and those with poor kidney function, receive ERBITUX® (Cetuximab), an Epidermal Growth Factor Receptor (EGFR) inhibitor with radiotherapy.

ERBITUX® is an EGFR targeted monoclonal antibody and the goal of this present study was to find an alternative to Cisplatin, and this study was designed to see if ERBITUX® with radiation would be less toxic than Cisplatin with radiation, without compromising survival among HPV-positive OPSCC patient population. RTOG 1016 is a randomized, multicentre, non-inferiority, phase III trial which included patients with Human PapillomaVirus (HPV)-positive Oropharyngeal Squamous Cell Carcinoma. This study enrolled 987 patients (N=987) at 182 centers in the US and Canada and enrollees had histologically confirmed HPV-positive Oropharyngeal carcinoma and clinical categories included T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0 groups. Patients were randomly assigned in a 1:1 ratio to receive either radiotherapy plus ERBITUX®, or radiotherapy plus Cisplatin. Treatment groups were well balanced and were stratified by T (T1–T2 vs T3–T4), N category (N0-N2a vs N2b-N3), and smoking history (10 pack-years or less vs more than 10 pack-years). Patients were randomized to receive either ERBITUX® at a loading dose of 400 mg/m2 IV 5-7 days before radiotherapy initiation, followed by ERBITUX® 250 mg/m2 IV weekly for seven doses (N=425) or Cisplatin 100 mg/m 2 on days 1 and 22 of radiotherapy (N=424). All patients received accelerated Intensity-Modulated RadioTherapy (IMRT) delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 hours apart). The Primary endpoint was Overall Survival.

The third and final interim analysis was done after a median follow-up of 4.5 years. Radiotherapy plus ERBITUX® did not meet the non-inferiority criteria for Overall Survival and the estimated 5-year Overall Survival was 77.9% in the ERBITUX® group versus 84.6% in the Cisplatin group, suggesting that the Overall Survival on the ERBITUX® arm was significantly inferior to the Cisplatin arm. Progression Free Survival (PFS) was also significantly lower in the ERBITUX® group compared with the Cisplatin group, with a 5-year PFS of 67.3% versus 78.4%, respectively. Five year locoregional failure rates were significantly higher in the ERBITUX® group compared with the Cisplatin group (17.3% versus 9.9%, respectively. Serious (grade 3-5) adverse events were similar for patients in both treatment groups and as expected, toxicities were different, with adverse events of renal toxicity, hearing loss, and bone marrow suppression more common in patients in the Cisplatin group, where as body rash was more common in the ERBITUX® group. All patients in this study were able to complete therapy at the time of this analysis.

It was concluded that this trial is the first randomized clinical trial specifically designed for patients with HPV-positive Oropharyngeal cancer, and among this patient group, radiotherapy plus ERBITUX® showed inferior Overall Survival and Progression Free Survival compared with radiotherapy plus Cisplatin. Radiotherapy plus Cisplatin should therefore be the standard of care for eligible patients with HPV-positive Oropharyngeal carcinoma. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Gillison ML, Trotti AM, Harris J, et al. Published:November 15, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)32779-X

Late Breaking Abstract – ESMO 2018 Frontline KEYTRUDA® Improves Overall Survival in Advanced Head and Neck Cancer

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SUMMARY: The American Cancer Society estimates that 65,410 people will be diagnosed with Head and Neck cancer in 2019 and 14,620 patients will die of the disease. Patients with Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a short median Overall Survival. The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of Immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the Immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells.

KEYNOTE-048 is an open-label, three arm, randomized, phase III trial, in which KEYTRUDA® monotherapy and KEYTRUDA® plus chemotherapy was compared to ERBITUX® (Cetuximab) plus chemotherapy, as first-line systemic therapy, among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma. A total 882 patients were randomized in a 1:1:1 ratio to receive either KEYTRUDA® 200 mg IV every 3 weeks for 24 months (N=301), KEYTRUDA® 200 mg IV every 3 weeks for 24 months plus Cisplatin 100 mg/m2 IV or Carboplatin AUC 5 IV (investigator’s choice) on day 1, along with 5-FU 1,000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=281) or the control arm (EXTREME) consisting of ERBITUX® 400 mg/m2 loading dose followed by 250 mg/m2 weekly, plus Cisplatin 100 mg/m2 or Carboplatin AUC 5 IV on day 1 along with 5-FU 1000 mg/m2/day IV, days 1-4 of each 3-week cycle, for a maximum of 6 cycles (N=300).

Enrolled patients had Recurrent or Metatastic Squamous Cell Carcinoma of the Oral cavity, Oropharynx, Hypopharynx or Larynx, and had not received prior systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, HPV p16 status, and ECOG Performance Status. PD-L1 expression was measured using the Combined Positive Score (CPS) and Tumor Proportion Score and a CPS of 20 or more indicated high PD-L1 expression, whereas a CPS of 1 or more was the lower threshold of positivity. (CPS measures high PD-L1 expression in the tumor and surrounding immune cells, whereas TPS only captures PD-L1 expression on tumor cells). Approximately 21% of patients were positive for Human Papillomavirus Virus (HPV) p16.

In this analysis, the authors compared the outcomes with KEYTRUDA® alone versus EXTREME (ERBITUX® plus chemo combination) in patients stratified for PD-L1 expression as well as KEYTRUDA® plus chemotherapy versus ERBITUX® plus chemotherapy in all patients with any PD-L1 status. The Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) in patients with a PD-L1 CPS of 20 or more and CPS of 1 or more in all enrolled patients. The Secondary endpoints of the study were PFS at 6 months and 12 months, Objective Response Rate (ORR), and time to deterioration in Quality of Life. The minimum follow up was about 17 months.

It was noted that in patients with PD-L1 CPS of 20 or more (high expressors, N=255), single agent KEYTRUDA® was superior to ERBITUX® combination, with a median OS of 14.9 months in patients who received single agent KEYTRUDA® versus 10.7 months in patients who received ERBITUX® with combination chemotherapy (HR=0.61; P=0.0007). There was however no difference in PFS in this PD-L1 subset between the 2 treatment groups (HR=0.99; P=0.5). Similar benefit was seen for patients with a PD-L1 CPS of 1 or more subset (low expressors, N= 512), in which the median OS for KEYTRUDA® monotherapy versus ERBITUX® plus chemotherapy was 12.3 months versus 10.3 months respectively (HR=0.78; P=0.0086). The OS for KEYTRUDA® monotherapy was noninferior to ERBITUX® plus chemotherapy in the total population of patients (N=601). The ORRs were 23% and 36%, with single agent KEYTRUDA® and ERBITUX® combination respectively, in the high expressor subgroup and 19% and 35%, respectively in the low expressor subgroup. However, the median Duration of Response was almost 5 times longer with KEYTRUDA® monotherapy compared to ERBITUX® combination.

When KEYTRUDA® plus chemotherapy was compared with ERBITUX® plus chemotherapy, KEYTRUDA® combination was non-inferior and in fact was superior to ERBITUX® combination for OS in the total population (N = 559), with a median OS of 13.0 versus 10.7 months respectively (HR=0.77; P=0.0034).

It was concluded that among patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma, KEYTRUDA® monotherapy significantly improved Overall Survival compared to ERBITUX® plus chemotherapy in patients with PD-L1 Combined Positive Score of 1 or more. Additionally, KEYTRUDA® plus chemotherapy significantly improved Overall Survival in the total patient population, compared to ERBITUX® plus chemotherapy. Responses associated with single agent KEYTRUDA® and KEYTRUDA® chemotherapy combination, were durable. These data support KEYTRUDA®, as well as KEYTRUDA® plus platinum and 5-FU as the new first-line standards of care for this patient group. KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Burtness B, Harrington KJ, Greil R, et al. Proceedings from the 2018 ESMO Congress: October 19-23, 2018; Munich, Germany. Abstract LBA8_PR.

Radiotherapy plus ERBITUX® Inferior to Radiotherapy plus Cisplatin in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades, due to changes in sexual practices. They represent approximately 70% of all OPSCC in the United States and Canada. HPV-positive oropharyngeal squamous cell carcinoma is an entirely distinct disease entity from HPV-negative oropharyngeal squamous cell carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.Parts-of-the-Oropharynx

HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate Cisplatin chemotherapy such as the elderly, and those with poor kidney function, receive ERBITUX® (Cetuximab), an Epidermal Growth Factor Receptor (EGFR) inhibitor with radiotherapy.

ERBITUX® is an EGFR targeted monoclonal antibody and the goal of this present study was to find an alternative to Cisplatin, and this study was designed to see if ERBITUX® with radiation would be less toxic than Cisplatin with radiation, without compromising survival among HPV-positive OPSCC patient population. RTOG 1016 is a randomized, multicentre, non-inferiority, phase III trial which included patients with Human PapillomaVirus (HPV)-positive Oropharyngeal Squamous Cell Carcinoma. This study enrolled 987 patients (N=987) at 182 centers in the US and Canada and enrollees had histologically confirmed HPV-positive Oropharyngeal carcinoma and clinical categories included T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0 groups. Patients were randomly assigned in a 1:1 ratio to receive either radiotherapy plus ERBITUX®, or radiotherapy plus Cisplatin. Treatment groups were well balanced and were stratified by T (T1–T2 vs T3–T4), N category (N0-N2a vs N2b-N3), and smoking history (10 pack-years or less vs more than 10 pack-years). Patients were randomized to receive either ERBITUX® at a loading dose of 400 mg/m2 IV 5-7 days before radiotherapy initiation, followed by ERBITUX® 250 mg/m2 IV weekly for seven doses (N=425) or Cisplatin 100 mg/m 2 on days 1 and 22 of radiotherapy (N=424). All patients received accelerated Intensity-Modulated RadioTherapy (IMRT) delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 hours apart). The Primary endpoint was Overall Survival.

The third and final interim analysis was done after a median follow-up of 4.5 years. Radiotherapy plus ERBITUX® did not meet the non-inferiority criteria for Overall Survival and the estimated 5-year Overall Survival was 77.9% in the ERBITUX® group versus 84.6% in the Cisplatin group, suggesting that the Overall Survival on the ERBITUX® arm was significantly inferior to the Cisplatin arm. Progression Free Survival (PFS) was also significantly lower in the ERBITUX® group compared with the Cisplatin group, with a 5-year PFS of 67.3% versus 78.4%, respectively. Five year locoregional failure rates were significantly higher in the ERBITUX® group compared with the Cisplatin group (17.3% versus 9.9%, respectively. Serious (grade 3-5) adverse events were similar for patients in both treatment groups and as expected, toxicities were different, with adverse events of renal toxicity, hearing loss, and bone marrow suppression more common in patients in the Cisplatin group, where as body rash was more common in the ERBITUX® group. All patients in this study were able to complete therapy at the time of this analysis.

It was concluded that this trial is the first randomized clinical trial specifically designed for patients with HPV-positive Oropharyngeal cancer, and among this patient group, radiotherapy plus ERBITUX® showed inferior Overall Survival and Progression Free Survival compared with radiotherapy plus Cisplatin. Radiotherapy plus Cisplatin should therefore be the standard of care for eligible patients with HPV-positive Oropharyngeal carcinoma. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Gillison ML, Trotti AM, Harris J, et al. Published:November 15, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)32779-X

Guideline for Human Papilloma Virus Testing in Head and Neck Carcinomas

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management.Molecular-Characteristics-of-HPV-Positive-Head-and-Neck-Carcinomas
There is currently no consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16, and which tests to choose. The College of American Pathologists convened a panel of experts and following review of evidence from over 400 peer reviewed articles, came up with the following Guideline. This guideline is recommended for all new Oropharyngeal Squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
Summary of Guideline Statements
1) High-Risk (HR) HPV testing should be performed on all patients with newly diagnosed OPSCC, including all histologic subtypes and may be performed on the primary tumor or a regional lymph node metastasis when the clinical findings are consistent with an oropharyngeal primary. This test should not be routinely performed on nonsquamous carcinomas of the oropharynx, or nonoropharyngeal primary carcinomas of the head and neck.
2) For oropharyngeal tissue specimens (ie, noncytology), HR-HPV testing should be performed by surrogate marker p16 ImmunoHistoChemistry (IHC). Additional HPV-specific testing may be done at the discretion of the pathologist and/or treating clinician, or in the context of a clinical trial.
3) HR-HPV testing by surrogate marker p16 IHC should be routinely performed on patients with metastatic Squamous Cell Carcinoma of unknown primary in a cervical upper or mid jugular chain lymph node. An explanatory note on the significance of a positive HPV result is recommended.
4) HR-HPV testing should be performed on head and neck FNA (Fine Needle Aspiration) Squamous Cell Carcinoma samples from all patients with known OPSCC not previously tested for HR-HPV, with suspected OPSCC, or with metastatic SCC of unknown primary.
5) Pathologists should report p16 IHC positivity as a surrogate for HR-HPV in tissue specimens (ie, noncytology) when there is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity.
6) Pathologists should not routinely perform low-risk HPV testing on patients with head and neck carcinomas.
7) For HPV-positive/p16 cases, tumor grade (or differentiation status) is not recommended.
8) HR-HPV testing strategy should not be altered based on patient smoking history.
9) Pathologists should report primary OPSCCs that test positive for HR-HPV or its surrogate marker p16 as HPV positive and/or p16 positive
Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. Lewis JS, Beadle B, Bishop JA, et al. https://doi.org/10.5858/arpa.2017-0286-CP

Guideline for Human Papilloma Virus Testing in Head and Neck Carcinomas

RR

SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a signifiant increase in incidence during the past several decades. They represent approximately 70% of all OPSCC in the United States and Canada. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management.Molecular-Characteristics-of-HPV-Positive-Head-and-Neck-Carcinomas

There is currently no consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16, and which tests to choose. The College of American Pathologists convened a panel of experts and following review of evidence from over 400 peer reviewed articles, came up with the following Guideline. This guideline is recommended for all new Oropharyngeal Squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.

Summary of Guideline Statements

1) High-Risk (HR) HPV testing should be performed on all patients with newly diagnosed OPSCC, including all histologic subtypes and may be performed on the primary tumor or a regional lymph node metastasis when the clinical findings are consistent with an oropharyngeal primary. This test should not be routinely performed on nonsquamous carcinomas of the oropharynx, or nonoropharyngeal primary carcinomas of the head and neck.

2) For oropharyngeal tissue specimens (ie, noncytology), HR-HPV testing should be performed by surrogate marker p16 ImmunoHistoChemistry (IHC). Additional HPV-specific testing may be done at the discretion of the pathologist and/or treating clinician, or in the context of a clinical trial.

3) HR-HPV testing by surrogate marker p16 IHC should be routinely performed on patients with metastatic Squamous Cell Carcinoma of unknown primary in a cervical upper or mid jugular chain lymph node. An explanatory note on the significance of a positive HPV result is recommended.

4) HR-HPV testing should be performed on head and neck FNA (Fine Needle Aspiration) Squamous Cell Carcinoma samples from all patients with known OPSCC not previously tested for HR-HPV, with suspected OPSCC, or with metastatic SCC of unknown primary.

5) Pathologists should report p16 IHC positivity as a surrogate for HR-HPV in tissue specimens (ie, noncytology) when there is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity.

6) Pathologists should not routinely perform low-risk HPV testing on patients with head and neck carcinomas.

7) For HPV-positive/p16 cases, tumor grade (or differentiation status) is not recommended.

8) HR-HPV testing strategy should not be altered based on patient smoking history.

9) Pathologists should report primary OPSCCs that test positive for HR-HPV or its surrogate marker p16 as HPV positive and/or p16 positive

Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. Lewis JS, Beadle B, Bishop JA, et al. https://doi.org/10.5858/arpa.2017-0286-CP