Tag: Head & Neck: Hypopharynx

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

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.

OPDIVO® (Nivolumab)

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The FDA on November 10, 2016 approved OPDIVO® for the treatment of patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), with disease progression on or after a platinum-based therapy. OPDIVO® is marketed by Bristol-Myers Squibb company.

FDA Approves OPDIVO® for Head and Neck Cancer

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SUMMARY: The FDA on November 10, 2016, approved OPDIVO® (Nivolumab) for the treatment of patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), with disease progression on or after a Platinum-based therapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of immune evasion and the role of Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoints, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for the treatment of recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), was based on the results of CheckMate-141 study which is a randomized, open label, phase III trial. In this study, 361 patients with recurrent Squamous Cell Carcinoma of the Head and Neck (cancer of the oral cavity, pharynx, or larynx), whose disease had progressed within 6 months after Platinum-based chemotherapy, were randomly assigned, in a 2:1 ratio to receive OPDIVO® (N=240) or investigator’s choice of a standard, single agent therapy (N=121). OPDIVO® was administered at a dose of 3 mg/kg every 2 weeks, whereas standard therapy consisted of either weekly Methotrexate at a dose of 40-60 mg/m2 IV, weekly Docetaxel at a dose of 30-40 mg/m2 IV or Cetuximab administered at a loading dose of 400 mg/m2 followed by 250 mg/m2 IV weekly. The median age was 60 years, over 90% had received prior radiation therapy and 54.5% of the patients had received 2 or more lines of prior systemic therapies. The primary end point was Overall Survival and secondary end points included Progression Free Survival, Objective Response Rate, safety, and patient-reported quality of life measures. Prespecified analysis of Overall Survival according to tumor PD-L1 expression and p16 status was also performed.

The median Overall Survival was 7.5 months in the OPDIVO® group versus 5.1 months for the group that received standard therapy and this improvement was statistically significant (HR=0.70; P=0.01). The estimated 1-year survival rate was 36% in the OPDIVO® group and 16.6% with standard therapy. The median Progression Free Survival was 2.0 months with OPDIVO® versus 2.3 months with standard therapy and the rate of Progression Free Survival at 6 months was 19.7% with OPDIVO® versus 9.9% with standard therapy. The Objective Response Rate was 13.3% in the OPDIVO® group versus 5.8% in the standard therapy group. Even though preliminary biomarker analysis suggested that patients with a tumor PD-L1 expression level of 1% or more, or p16-positive tumors, or both, benefited more from OPDIVO® therapy than those whose PD-L1 level was less than 1% or who had p16-negative tumors, these interactions were not statistically significant. Treatment-related grade 3 or 4 adverse events were more common in the standard therapy group (35%) versus OPDIVO® group (13%) and quality of life measures were stable in the OPDIVO® group and were worse for those who received standard therapy.

The authors concluded that OPDIVO® prolonged survival, as compared with standard therapy, among patients with Platinum-refractory Squamous Cell Carcinoma of the Head and Neck and this benefit was accomplished with fewer toxicities, compared with standard therapy. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Ferris RL, Blumenschein G, Fayette J, et al. N Engl J Med 2016; 375:1856-1867

FDA Approves KEYTRUDA® for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

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SUMMARY: The FDA on August 5, 2016, granted accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of patients with recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC), with disease progression on or after Platinum containing chemotherapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

KEYTRUDA® 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. The accelerated approval of KEYTRUDA® was based on a multicenter, nonrandomized, open-label, multi-cohort phase Ib study (KEYNOTE-012), which included 192 patients with recurrent or metastatic HNSCC. Approximately 33% of the patients were HPV positive and patients have a median of two prior lines of therapy. Almost all enrolled patients (95%) had prior radiation therapy. Median patient age was 60 years. Treatment consisted of KEYTRUDA® 10 mg/kg IV every 2 weeks or 200 mg IV every 3 weeks and continued until disease progression or unacceptable toxicities. Patients without disease progression were treated for up to 24 months. The primary end point was Objective Response Rate (ORR) and Duration of Response. Secondary endpoints included response by HPV status, Progression Free Survival (PFS), and safety. Efficacy was evaluated in 174 of the enrolled patients. The ORR was 16% with a Complete Response Rate of 5%. The median response duration had not been reached at the time of analysis. Among the responding patients, 82% had responses of 6 months or longer. The ORR and Duration of Response were similar irrespective of dosage regimen or HPV status. In a pooled analyses after long term follow up, responses were ongoing in 76% of the patients with a median follow up duration in responders of 12.5 months. Median Overall Survival was 8.5 months and 6 month PFS rate was 24.9%. The most common adverse reactions ((20% or greater) were fatigue, decreased appetite, and dyspnea and these were similar to those occurring in patients with Melanoma or Non Small Cell Lung Cancer, with the exception of an increased incidence of facial edema and new or worsening hypothyroidism.

It was concluded that KEYTRUDA® has significant antitumor activity in recurrent/metastatic Head and Neck Squamous Cell Carcinoma and PD-L1 testing is not needed prior to use of KEYTRUDA® for this indication. As a condition of the accelerated approval, a multicenter, randomized trial is to be conducted for continued approval, establishing the superiority of KEYTRUDA® over standard therapy. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-012. Mehra R, Seiwert TY, Mahipal A, et al. J Clin Oncol 34, 2016 (suppl; abstr 6012)

KEYTRUDA® (Pembrolizumab)

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The FDA on August 5, 2016 granted accelerated approval to KEYTRUDA® injection for the treatment of patients with recurrent or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

OPDIVO® Granted Breakthrough Designation by FDA for Head and Neck cancer

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SUMMARY: The FDA granted breakthrough therapy designation to Nivolumab (OPDIVO®), as a treatment for patients with recurrent or metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN), following a platinum based therapy. This designation was based on the findings from CheckMate-141 study, which demonstrated an improvement in Overall Survival (OS) with OPDIVO®, compared to investigator’s choice of therapy. The American Cancer Society estimates that 61,760 people will be diagnosed with Head and Neck cancer in 2016 and 13,190 patients will die of the disease. Patients with recurrent/metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN) have a poor prognosis with a median Overall Survival (OS) of about 13 months with first line therapy and about 6 months or less with later lines of therapy. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response. CheckMate-141 is an open-label, phase III trial, in which 361 patients with recurrent or metastatic Squamous Cell Carcinoma of the oral cavity, pharynx, or larynx, were randomly assigned in a 2:1 ratio to receive either OPDIVO® (N= 240) or investigator’s choice of ERBITUX® (Cetuximab), TAXOTERE® (Docetaxel) or Methotrexate (N=121). OPDIVO® was administered intravenously at 3 mg/kg every 2 weeks. ERBITUX® dosing was 400 mg/m2 for the first dose followed by 250 mg/m2 weekly, TAXOTERE® dosing was 30 mg/m2 weekly and Methotrexate dosing was 40 mg/m2 weekly. The median age was 60 years, majority of patients were male, had received 2 or more prior systemic therapies and prior radiation therapy. Patients were stratified based on prior therapy with monoclonal antibody, ERBITUX® and HPV status was known for 50% of the participants. The primary endpoint was Overall Survival and secondary endpoints included Response Rates and Progression Free Survival (PFS).

This study was stopped earlier than scheduled after an independent monitoring panel determined that the primary endpoint for this study was met, with significant superiority of OPDIVO® over the investigator’s choice of therapy. The median Overall Survival with OPDIVO® was 7.5 months, compared to 5.1 months with investigator’s choice of therapy (HR=0.70; P=0.010). The 1-year Overall Survival with OPDIVO® was 36%, which was more than double, compared with investigator’s choice of therapy, which was 16.6%. Patients with PD-L1 expression of 1% or more benefited the most from treatment with OPDIVO®, with a median OS of 8.7 months, compared to 4.6 months in the control group (HR=0.55). For patients with PD-L1 expression less than 1%, median OS was 5.7 with OPDIVO® versus 5.8 months, for the control group (HR=0.89). HPV status also had an impact on outcomes. HPV-positive patients had a median OS of 9.1 months with OPDIVO® compared with 4.4 months with investigator’s choice of therapy (HR=0.56), whereas those who were HPV-negative and receiving OPDIVO®, had a median OS of 7.5 months compared to 5.8 months with investigator’s choice of therapy (HR=0.73). Grade 3 or 4 adverse events were significantly lower with OPDIVO®, compared with investigator’s choice of therapy(13.1% vs 35.1%).

The authors concluded that OPDIVO® is the first agent to demonstrate a significant improvement in Overall Survival, in patients with advanced head and neck cancer following progression on platinum-based chemotherapy, and fulfills an unmet need for this patient group. Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab Versus Investigator’s Choice (IC) for Recurrent or Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (SCCHN): CheckMate-141. Presented at: AACR 2016 Annual Meeting, New Orleans; April 16-20, 2016. Abstract CT099.

p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Non-Oropharyngeal Head and Neck Squamous Cell Carcinoma

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SUMMARY: Squamous Cell Carcinoma of the Head and Neck (HNSCC) accounts for about 3-5% of all cancers in the United States. It is estimated that 55,070 people were diagnosed with Head and Neck cancer in 2014 and 12,000 patients died of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma involving the head and neck region (HNSCC) is therefore a heterogeneous disease and the five year survival rate of patients with head and neck cancer depends on several factors and can be variable. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Recent studies have shown that over 70% of the OroPharyngeal Squamous Cell Carcinomas (OPSCC) are caused by HPV with the HPV-16 being the predominant type present in the tumor cells. The malignant behavior of these tumors is dependent on the expression of viral E6 and E7 oncoproteins that inactivate the tumor suppressor proteins p53 and the retinoblastoma protein (pRB), respectively. HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is more common among never smokers or light smokers and patients tend to be younger with better performance status. The pathobiology of HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is different from the HPV negative OroPharyngeal Squamous Cell Carcinoma in that p53 is degraded/inactivated by viral E6 oncoprotein instead of by genetic mutation, pRB pathway is inactivated by viral E7 oncoprotein instead of Cyclin D1 amplification and p16 is overexpressed or upregulated instead of inactivation resulting from reduced negative feedback from pRB. Testing for HPV is based on several methodologies which include detection of HPV DNA by in situ hybridization (ISH) or Polymerase Chain Reaction (PCR), detection of HPV E6/E7 RNA expression by quantitative Reverse Transcriptase–PCR (qRT-PCR) and p16 protein overexpression, a surrogate marker of oncogenic HPV infection, by ImmunoHistoChemistry (IHC) staining. Both p16 overexpression testing by IHC and HPV by ISH can be easily performed on Formalin-Fixed Paraffin Embedded (FFPE) specimen whereas detection of HPV E6/E7 RNA expression, which is indicative of active viral oncogene transcription in tumor cells and is considered to be a gold standard, requires a larger tumor specimen compared with other methodologies. The concordance rate between HPV by ISH and p16 by IHC is approximately 90% in OPSCC, whereas the prevalence and significance p16 by IHC has remained unclear for HPV infection in non-OPSCC (oral cavity, hypopharynx and larynx). It is well established however that patients with HPV-positive/p16-positive OPSCC have better outcomes compared with those with HPV-negative/p16-negative OPSCC. However, the prognostic significance of p16 overexpression in non-OPSCC patients with or without evidence of HPV infection has not been clear. The authors in this study evaluated p16 protein overexpression by IHC and HPV status by HPV ISH as potential prognostic biomarkers in non-OPSCC tumors of patients enrolled in three prospective Radiation Therapy Oncology Group (RTOG) clinical trials. Of the 1921 patient enrolled in these three trials, 683 patients with non-OPSCC tumors were eligible and 52% (N=356) of these patients were tested for p16 overexpression and overall, 19.3% were p16 positive. When OPSCC and non-OPSCC patients were compared, OPSCC patients whose tumors were p16 positive had better Progression Free Survival and Overall Survival than non-OPSCC patients with p16 positive tumors. However, patients with p16 negative OPSCC and non-OPSCC have similar inferior outcomes. The authors concluded that patients with p16 negative non-OPSCC have worse outcomes than patients with p16 positive non-OPSCC, similar to that seen in patients with OPSCC and therefore HPV infection may influence outcomes in a subset of patients with non-OPSCC as well. Better methodologies for HPV detection and correlation with p16 expression will help identify “true” HPV infection related non-OPSCC and thereby enable tailored and less intense treatment, for this favorable group of patients. Chung CH, Zhang Q, Kong CS, et al. J Clin Oncol 2014; 32:3930-3938