Head & Neck/Thyroid Cancers

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma trial is an interventional study recruiting patients with human papillomavirus (HPV)–positive oropharyngeal cancer.

Patients who are recruited will undergo robotic surgery after being screened for poor prognosis. Patients with good prognosis will be followed without receiving postoperative radiation. Those in this group who experience a recurrence will receive either more surgery and postoperative radiotherapy or postoperative chemoradiotherapy alone. Patients with poor prognosis will receive reduced-dose radiotherapy or chemoradiotherapy based on pathology.

Few trials have examined deescalation using surgery alone in intermediate- and early-stage HPV-positive cancer, the investigators noted, adding that they expect more than half of participants will undergo curative treatment with surgery alone and that withholding radiation in these patients will not noticeably affect their long-term survival.

Patients are eligible for the study if they have early- or intermediate-stage, resectable, HPV-positive oropharyngeal cancer. Patients must be at aged at least 18 years; cannot be pregnant; cannot have active alcohol addiction or tobacco usage; must have adequate bone marrow, hepatic, and renal functions; have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; have a limiting serious illness; and have had previous surgery, radiation therapy, or chemotherapy for squamous cell carcinoma other than biopsy or tonsillectomy.

The primary outcome measures of the study are disease-free survival and local regional control after 3 and 5 years. Secondary outcome measures include overall survival, toxicity rates, quality of life outcomes after 3 and 5 years, and local regional control after 5 years.

Recruitment for the study ends in March 2019. About 200 people are expected to be included in the final analysis.

Find more information on the study page at Clinicaltrials.gov.

[email protected]

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma trial is an interventional study recruiting patients with human papillomavirus (HPV)–positive oropharyngeal cancer.

Patients who are recruited will undergo robotic surgery after being screened for poor prognosis. Patients with good prognosis will be followed without receiving postoperative radiation. Those in this group who experience a recurrence will receive either more surgery and postoperative radiotherapy or postoperative chemoradiotherapy alone. Patients with poor prognosis will receive reduced-dose radiotherapy or chemoradiotherapy based on pathology.

Few trials have examined deescalation using surgery alone in intermediate- and early-stage HPV-positive cancer, the investigators noted, adding that they expect more than half of participants will undergo curative treatment with surgery alone and that withholding radiation in these patients will not noticeably affect their long-term survival.

Patients are eligible for the study if they have early- or intermediate-stage, resectable, HPV-positive oropharyngeal cancer. Patients must be at aged at least 18 years; cannot be pregnant; cannot have active alcohol addiction or tobacco usage; must have adequate bone marrow, hepatic, and renal functions; have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; have a limiting serious illness; and have had previous surgery, radiation therapy, or chemotherapy for squamous cell carcinoma other than biopsy or tonsillectomy.

The primary outcome measures of the study are disease-free survival and local regional control after 3 and 5 years. Secondary outcome measures include overall survival, toxicity rates, quality of life outcomes after 3 and 5 years, and local regional control after 5 years.

Recruitment for the study ends in March 2019. About 200 people are expected to be included in the final analysis.

Find more information on the study page at Clinicaltrials.gov.

[email protected]

The Sinai Robotic Surgery Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma trial is an interventional study recruiting patients with human papillomavirus (HPV)–positive oropharyngeal cancer.

Patients who are recruited will undergo robotic surgery after being screened for poor prognosis. Patients with good prognosis will be followed without receiving postoperative radiation. Those in this group who experience a recurrence will receive either more surgery and postoperative radiotherapy or postoperative chemoradiotherapy alone. Patients with poor prognosis will receive reduced-dose radiotherapy or chemoradiotherapy based on pathology.

Few trials have examined deescalation using surgery alone in intermediate- and early-stage HPV-positive cancer, the investigators noted, adding that they expect more than half of participants will undergo curative treatment with surgery alone and that withholding radiation in these patients will not noticeably affect their long-term survival.

Patients are eligible for the study if they have early- or intermediate-stage, resectable, HPV-positive oropharyngeal cancer. Patients must be at aged at least 18 years; cannot be pregnant; cannot have active alcohol addiction or tobacco usage; must have adequate bone marrow, hepatic, and renal functions; have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; have a limiting serious illness; and have had previous surgery, radiation therapy, or chemotherapy for squamous cell carcinoma other than biopsy or tonsillectomy.

The primary outcome measures of the study are disease-free survival and local regional control after 3 and 5 years. Secondary outcome measures include overall survival, toxicity rates, quality of life outcomes after 3 and 5 years, and local regional control after 5 years.

Recruitment for the study ends in March 2019. About 200 people are expected to be included in the final analysis.

Find more information on the study page at Clinicaltrials.gov.

[email protected]

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

Infection with certain viruses has been causally linked to the development of cancer. In recent years, an improved understanding of the unique pathology and molecular underpinnings of these virally associated cancers has prompted the development of more personalized treatment strategies, with a particular focus on immunotherapy. Here, we describe some of the latest developments.

The link between viruses and cancer

Suspicions about a possible role of viral infections in the development of cancer were first aroused in the early 1900s. The seminal discovery is traced back to Peyton Rous, who showed that a malignant tumor growing in a chicken could be transferred to a healthy bird by injecting it with tumor extracts that contained no actual tumor cells.¹

The infectious etiology of human cancer, however, remained controversial until many years later when the first cancer-causing virus, Epstein-Barr virus (EBV), was identified in cell cultures from patients with Burkitt lymphoma. Shortly afterward, the Rous sarcoma virus was unveiled as the oncogenic agent behind Rous’ observations.²Seven viruses have now been linked to the development of cancers and are thought to be responsible for around 12% of all cancer cases worldwide. The burden is likely to increase as technological advancements make it easier to establish a causal link between viruses and cancer development.³

In addition to making these links, researchers have also made significant headway in understanding how viruses cause cancer. Cancerous transformation of host cells occurs in only a minority of those who are infected with oncogenic viruses and often occurs in the setting of chronic infection.

Viruses can mediate carcinogenesis by direct and/or indirect mechanisms (Figure 1). Many of the hallmarks of cancer, the key attributes that drive the transformation from a normal cell to a malignant one, are compatible with the virus’s needs, such as needing to avoid cell death, increasing cell proliferation, and avoiding detection by the immune system.

Vaccines lead the charge in HPV-driven cancers

German virologist Harald zur Hausen received the Nobel Prize in 2008 for his discovery of the oncogenic role of human papillomaviruses (HPVs), a large family of more than 100 DNA viruses that infect the epithelial cells of the skin and mucous membranes. They are responsible for the largest number of virally associated cancer cases globally – around 5% (Table 1).

A number of different cancer types are linked to HPV infection, but it is best known as the cause of cervical cancer. The development of diagnostic blood tests and prophylactic vaccines for prevention and early intervention in HPV infection has helped to reduce the incidence of cervical cancer. Conversely, another type of HPV-associated cancer, head and neck squamous cell carcinoma (HNSCC), has seen increased incidence in recent years.

HPVs are categorized according to their oncogenic potential as high, intermediate, or low risk. The high-risk HPV16 and HPV18 strains are most commonly associated with cancer. They are thought to cause cancer predominantly through integration into the host genome. The HPV genome is composed of 8 genes encoding proteins that regulate viral replication and assembly. The E6 and E7 genes are the most highly oncogenic; as the HPV DNA is inserted into the host genome, the transcriptional regulator of E6/E7 is lost, leading to their increased expression. These genes have significant oncogenic potential because of their interaction with 2 tumor suppressor proteins, p53 and pRb.^6,7

The largest investment in therapeutic development for HPV-positive cancers has been in the realm of immunotherapy in an effort to boost the anti-tumor immune response. In particular, there has been a focus on the development of therapeutic vaccines, designed to prime the anti-tumor immune response to recognize viral antigens. A variety of different types of vaccines are being developed, including live, attenuated and inactivated vaccines that are protein, DNA, or peptide based. Most developed to date target the E6/E7 proteins from the HPV16/18 strains (Table 2).^8,9

Hepatocellular carcinoma: a tale of two viruses

The hepatitis viruses are a group of 5 unrelated viruses that causes inflammation of the liver. Hepatitis B (HBV), a DNA virus, and hepatitis C (HCV), an RNA virus, are also oncoviruses; HBV in particular is one of the main causes of hepatocellular carcinoma (HCC), the most common type of liver cancer.

The highly inflammatory environment fostered by HBV and HCV infection causes liver damage that often leads to cirrhosis. Continued infection can drive permanent damage to the hepatocytes, leading to genetic and epigenetic damage and driving oncogenesis. As an RNA virus, HCV doesn’t integrate into the genome and no confirmed viral oncoproteins have been identified to date, therefore it mostly drives cancer through these indirect mechanisms, which is also reflected in the fact that HCV-associated HCC predominantly occurs against a backdrop of liver cirrhosis.

HBV does integrate into the host genome. Genome sequencing studies revealed hundreds of integration sites, but most commonly they disrupted host genes involved in telomere stability and cell cycle regulation, providing some insight into the mechanisms by which HBV-associated HCC develops. In addition, HBV produces several oncoproteins, including HBx, which disrupts gene transcription, cell signaling pathways, cell cycle progress, apoptosis and other cellular processes.^15,16

Multitargeted tyrosine kinase inhibitors (TKIs) have been the focal point of therapeutic development in HCC. However, following the approval of sorafenib in 2008, there was a dearth of effective new treatment options despite substantial efforts and numerous phase 3 trials. More recently, immunotherapy has also come to the forefront, especially immune checkpoint inhibitors.

Last year marked the first new drug approvals in nearly a decade – the TKI regorafenib (Stivarga) and immune checkpoint inhibitor nivolumab (Opdivo), both in the second-line setting after failure of sorafenib. Treatment options in this setting may continue to expand, with the TKIs cabozantinib and lenvatinib and the immune checkpoint inhibitor pembrolizumab and the combination of durvalumab and tremelimumab hot on their heels.^17-20 Many of these drugs are also being evaluated in the front-line setting in comparison with sorafenib (Table 3).

Adoptive cell therapy promising in EBV-positive cancers

More than 90% of the global population is infected with EBV, making it one of the most common human viruses. It is a member of the herpesvirus family that is probably best known as the cause of infectious mononucleosis. On rare occasions, however, EBV can cause tumor development, though our understanding of its exact pathogenic role in cancer is still incomplete.

EBV is a DNA virus that doesn’t tend to integrate into the host genome, but instead remains in the nucleus in the form of episomes and produces several oncoproteins, including latent membrane protein-1. It is associated with a range of different cancer types, including Burkitt lymphoma and other B-cell malignancies. It also infects epithelial cells and can cause nasopharyngeal carcinoma and gastric cancer, however, much less is known about the molecular underpinnings of these EBV-positive cancer types.^26,27Gastric cancers actually comprise the largest group of EBV-associated tumors because of the global incidence of this cancer type. The Cancer Genome Atlas Research Network recently characterized gastric cancer on a molecular level and identified an EBV-positive subgroup as a distinct clinical entity with unique molecular characteristics.²⁹

The focus of therapeutic development has again been on immunotherapy, however in this case the idea of collecting the patients T cells, engineering them to recognize EBV, and then reinfusing them into the patient – adoptive cell therapy – has gained the most traction (Table 4).

Newest oncovirus on the block

The most recently discovered cancer-associated virus is Merkel cell polyomavirus (MCV), a DNA virus that was identified in 2008. Like EBV, virtually the whole global adult population is infected with MCV. It is linked to the development of a highly aggressive and lethal, though rare, form of skin cancer – Merkel cell carcinoma.

MCV is found in around 80% of MCC cases and in fewer than 10% of melanomas and other skin cancers. Thus far, several direct mechanisms of oncogenesis have been described, including integration of MCV into the host genome and the production of viral oncogenes, though their precise function is as yet unclear.^32-34

The American Cancer Society estimates that only 1500 cases of MCC are diagnosed each year in the United States.³⁵ Its rarity makes it difficult to conduct clinical trials with sufficient power, yet some headway has still been made.

Around half of MCCs express the programmed cell death ligand 1 (PD-L1) on their surface, making them a logical candidate for immune checkpoint inhibition. In 2017, avelumab became the first FDA-approved drug for the treatment of MCC. Approval was based on the JAVELIN Merkel 200 study in which 88 patients received avelumab. After 1 year of follow-up the ORR was 31.8%, with a CR rate of 9%.³⁶

Genome sequencing studies suggest that the mutational profile of MCV-positive tumors is quite different to those that are MCV-negative, which could have therapeutic implications. To date, these implications have not been delineated, given the challenge of small patient numbers, however an ongoing phase 1/2 trial is evaluating the combination of avelumab and radiation therapy or recombinant interferon beta, with or without MCV-specific cytotoxic T cells in patients with MCC and MCV infection.

The 2 other known cancer-causing viruses are human T-lymphotropic virus 1 (HTLV-1), a retrovirus associated with adult T-cell leukemia/lymphoma (ATL) and Kaposi sarcoma herpesvirus (KSHV). The latter is the causative agent of Kaposi sarcoma, often in combination with human immunodeficiency virus (HIV), a rare skin tumor that became renowned in the 1980s as an AIDS-defining illness.

The incidence of HTLV-1- and KSHV-positive tumors is substantially lower than the other virally associated cancers and, like MCC, this makes studying them and conducting clinical trials of novel therapeutic options a challenge. Nonetheless, several trials of targeted therapies and immunotherapies are underway.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON – Dual-antibody targeting with the novel immune checkpoint inhibitor monalizumab combined with the epidermal growth factor–receptor (EGFR) inhibitor cetuximab is safe and associated with deep and durable responses in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck, according to data from an ongoing cohort expansion study.

As of Aug. 21, 2018, the primary study endpoint of overall response rate in 40 evaluable patients enrolled in the single-arm, nonrandomized phase 1/2 study was 27.5%, Roger Cohen, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

There were 11 confirmed responses, including 1 complete response and 10 partial responses at a median follow-up of 8 months, said Dr. Cohen, a professor of medicine at the Hospital of the University of Pennsylvania and director of clinical research at the Abramson Cancer Center, Philadelphia.

Median progression-free survival and overall survival were 5.0 months and 10.3 months, respectively.

“We observed responses in patients who were naive to immunotherapy, as well as patients who had received and progressed after immunotherapy. We observed responses in patients who were platinum resistant, and we also saw responses in [human papillomavirus (HPV)]–positive and –negative patients,” he said, adding that responses occurred relatively early at a median of 1.6 months, and that there was little difference between those who had and had not received prior immunotherapy with programmed death-1 (PD-1) antibodies.

A number of the responses, as well as the stable diseases, were durable for “a considerable period of time.” The median duration of response was 5.6 months, he said.

Study participants were mainly middle-aged men with recurrent or metastatic HPV-positive or -negative advanced disease and “decent” performance status. They received monalizumab at a dose of 10 mg/kg every 2 weeks plus cetuximab at the labeled loading dose of 400 mg/m² once weekly then 250 mg/m² once weekly. All had progressed after prior platinum-based chemotherapy and had no more than two prior lines of therapy in the recurrent/metastatic setting; 17 (43%) had prior anti–programmed death-ligand 1 (PD-L1) therapy, 5 (13%) had prior cetuximab, but none of those patients were cetuximab resistant.

They were treated until disease progression or unacceptable toxicity and were assessed every 8 weeks for response per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, he said.

This treatment combination was shown in the phase 1 portion of the study to have a favorable safety profile, and the safety profile was confirmed in this expansion cohort; adverse events related to the combination were dominated by EGFR antibody–related side effects in the skin, as well as hypomagnesemia. Most adverse events associated with monalizumab were grade 1-2.

“Serious adverse events are in the single digits,” Dr. Cohen said.

Monalizumab is a first-in-class humanized immunoglobulin-G4 monoclonal antibody against the human natural killer group 2A (NKG2A), which is the receptor for the NKG2A ligand, HLA-E.

“The HLA-E NKG2A diad shuts down NK cells and tumor-infiltrating CD8-positive T-cells,” he explained, adding that “the concept behind the antibody is that by blocking the interaction of the receptor for the ligand you can reduce this inhibitory signaling by NK cells and thereby unleash their ability to target tumor.”

Cetuximab is an established and approved EGFR inhibitor for the treatment of patients with head and neck SCC who progress after platinum-based chemotherapy. It has been associated with a 13% response rate.

“The therapeutic hypothesis is that dual targeting with these two antibodies will allow us to realize greater antitumor activity in head and neck cancer than is seen with cetuximab alone,” he said, later adding that “the combination of monalizumab and cetuximab results in early, deep, and durable responses in patients with squamous cell cancer of the head and neck ... and the activity indeed is higher than cetuximab alone, compared with historical data.”

Additionally, the safety is acceptable, and preliminary translational analyses do show some immunological proof-of-concept – mainly that infiltration of the tumor stroma with NK and CD8-positive T cells is correlated with response, he said.

“Importantly, this study is continuing to enroll patients, and taking account of the ever-changing landscape in the treatment of patients with advanced cancer, we are going to enroll another 40 patients, except this time we will require them to be platinum, as well as PD-1 antibody exposed. These patients still represent an enormous unmet medical need.

“We think these results do warrant further development of the combo of monalizumab and cetuximab in patients with advanced SCC of the head and neck,” he concluded.

Dr. Cohen reported receiving consulting fees and/or research funding from Cantargia, Celldex, Genocea, Innate, HEAT, Kyntherapeutics, Merck, Takeda Macrogenics, and Tmunity.

SOURCE: Cohen R et al. SITC 2018, Abstract 051.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

WASHINGTON – Adding pembrolizumab to weekly low-dose, cisplatin-based chemoradiotherapy shows promise for the treatment of locally advanced, human papillomavirus–associated head and neck squamous cell carcinoma, according to Steven F. Powell, MD.

Sharon Worcester/MDedge News

Of 34 patients with a mean age of 59 years and stage III-IVb disease enrolled as part of an expansion cohort following a prior study demonstrating the safety of the regimen, 85% had a complete response (CR) at a median follow-up of 21 months based on imaging or salvage surgery, and an additional 2 patients had no clinical evidence of disease, Dr. Powell reported in a late-breaking oral abstract session at the annual meeting of the Society for Immunotherapy of Cancer.

About 80% of the patients had intermediate-risk disease, which is “higher risk than your standard HPV-related cancers,” said Dr. Powell of Sanford Cancer Center, Sioux Falls, S.D.

“On posttreatment imaging ... we showed a 62% complete response rate based on [RECIST 1.1 CT criteria], with 11 patients having a partial response and 2 felt to have a partial response based on CT imaging. Looking at Hopkins criteria [for PET scans] alone – 78% of our patients had a complete response,” he said.

Of the patients with a partial response based on either criteria, 11 were negative for disease on PET and 1 that was positive based on Hopkins criteria underwent neck dissection and had only inflammatory tissue; these 12 patients were also considered to have had a CR.

Additionally, of the two patients with progressive disease, one had a positive PET scan, but all biopsies were negative for ongoing disease, thus that patient was also considered to have a CR, for the overall CR rate of 85%, Dr. Powell said.

Two of the four other patients with a partial response were found at surgery to have “nothing to biopsy or resect,” so it was felt that they had a complete response clinically, and the remaining two had partial responses locoregionally and had residual disease, including residual disease at the primary site in one patient, and nodal disease in one patient.

It is important to consider the challenges of PET imaging in this study, he noted, explaining that in one patient with progressive disease, a posttreatment PET appeared to show bone and dermal metastases, but biopsies of all the areas showed that those were granulomatous disease – most likely sarcoidosis that was not present prior to the treatment.

“This ended up resolving over a year and the PET scan became negative, so I think this highlights that as we move into the curative intent setting we need to be very careful that with PET scanning we need to confirm with biopsy [in patients treated with immuno-oncology] therapies,” Dr. Powell said.

As for survival, the early data are “very encouraging,” with only one patient progressing to date (progression-free survival, 97.1%), but he cautioned that follow-up is “still only 23 months.”

The patient who progressed developed distant metastases and died from their disease, he said.

Treatment in this study included 40 mg/m² of cisplatin weekly (six planned doses), 200 mg of pembrolizumab every 3 weeks (eight planned doses) and radiation therapy at 2 Gy once daily for 35 fractions (total of 70 Gy). The primary efficacy endpoint was complete response at 100 days after completion of chemoradiotherapy (CRT).

“Looking at safety ... we did not see any new safety signals. We had two dose discontinuations due to immune-related adverse events, which resolved on their own without therapy. Two patients stopped early due to protocol reasons,” Dr. Powell said, noting that the discontinuation rate was comparable with that seen in pembrolizumab monotherapy studies.

Standard therapy compliance was also good, with the chemotherapy goal dose reached in 88% of patients. The CRT dose was reached in all patients with no major delays in treatment.

“So adding CRT did not impact the safety of giving standard therapy,” he said.

Enrollment in this ongoing study was completed as of August, and data for the HPV-negative cohort should be available sometime in 2019. Several correlative research projects are also underway, he said.

The findings thus far show that pembrolizumab can be safely given with CRT in both HPV-positive and HPV-negative disease, with “encouraging response and progression-free survival in predominantly higher-risk patients,” Dr. Powell said.

“It is important to know that PET may pose challenges as we move into big phase 3, randomized trials, and I would strongly recommend biopsy to confirm PET findings,” he said, adding that it will be “interesting to see how this pans out in high-risk disease.

“I’m hopeful that our correlative research will help guide how we time therapy and how we move ahead in this field,” he said.

The Merck Investigator Studies Program provided grant support for this study. Dr. Powell has received research funding (to his institution) from Bristol-Myers Squibb, Genentech, Incyte, Merck, Novartis, and Pfizer.

MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.

Neil Osterweil/MDedge News

Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.

A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.

There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.

“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.

The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.

A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m² plus 5-FU 1000 mg/m2 ^per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m² followed by 250 mg/m² once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
 

Pembrolizumab monotherapy vs. EXTREME

For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).

The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).

There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.

Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.

Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
 

Pembrolizumab plus chemo vs. EXTREME

The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.

In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.

There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.

“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.

“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.

He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”

The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.

SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.

MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.

Neil Osterweil/MDedge News

Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.

A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.

There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.

“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.

The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.

A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m² plus 5-FU 1000 mg/m2 ^per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m² followed by 250 mg/m² once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
 

Pembrolizumab monotherapy vs. EXTREME

For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).

The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).

There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.

Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.

Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
 

Pembrolizumab plus chemo vs. EXTREME

The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.

In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.

There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.

“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.

“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.

He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”

The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.

SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.

MUNICH – In patients with recurrent or metastatic head and neck squamous cell carcinoma expressing programmed death ligand-1 (PDL-1), the immune checkpoint inhibitor pembrolizumab alone or in combination with chemotherapy improved overall survival, compared with the EXTREME chemotherapy regimen, reported investigators in the Keynote 048 trial.

Neil Osterweil/MDedge News

Overall survival (OS) among patients with a PD-L1 combined positive score (CPS) of 20 or greater treated with pembrolizumab (Keytruda) monotherapy was 14.9 months compared with 10.7 months for patients treated with the EXTREME regimen, a combination of cetuximab (Erbitux), carboplatin or cisplatin, and 5-fluorouracil.

A similar overall survival benefit was seen in patients with a CPS of 1 or greater, and in the total population of patients treated with pembrolizumab plus chemotherapy followed by pembrolizumab maintenance compared with EXTREME chemotherapy, Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn.

There were no differences in response rates between either pembrolizumab monotherapy or in combination compared with chemotherapy alone, but responses were more durable with the checkpoint inhibitor than with chemotherapy.

“Pembrolizumab alone and pembrolizumab given with platinum and 5-fluorouracil should represent new standards of care for the first-line treatment of metastatic head and neck carcinoma. Immune checkpoint monotherapy with pembrolizumab allows patients to live longer and has a better safety profile than the previous standard for those patients whose tumors express PD-L1,” she said at a briefing prior to her presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“This is the first time since 10 years that we show an improvement in survival for this group of patients,” said Jean-Pascal Machiels, MD, of University Clinic Saint-Luc, Brussels, the invited discussant for the briefing and the symposium.

The CPS is a ratio of PD-L1-positive tumor cells, lymphocytes, and macrophages to the total numbers of cells counted multiplied by 100. The investigators looked at progression-free survival (PFS) and OS in three cohorts of patients with squamous cell carcinomas of the oropharynx, oral cavity, hypopharynx, or larynx that were recurrent or metastatic and were incurable by local therapies. They compared pembrolizumab monotherapy with the EXTREME regimen, and pembrolizumab plus chemotherapy (as described in the following paragraph) with EXTREME.

A total of 882 patients were enrolled and stratified by PD-L1 expression (on 50% or greater of tumor cells, or less than 50%), p16 positive or negative status in the oropharynx, and Eastern Cooperative Oncology Group performance status of 0 or 1. The patients were then randomly assigned on a 1:1:1 basis to either pembrolizumab monotherapy at 200 mg every 3 weeks for up to 35 cycles, pembrolizumab plus a standard chemotherapy regimen (carboplatin to an area-under-the curve [AUC] of 5 or cisplatin 100 mg/m² plus 5-FU 1000 mg/m2 ^per day for 4 days for six cycles, followed by pembrolizumab maintenance for up to 35 cycles or EXTREME (cetuximab at a loading dose of 400 mg/m² followed by 250 mg/m² once weekly plus the chemotherapy regimen described above, followed by maintenance cetuximab).
 

Pembrolizumab monotherapy vs. EXTREME

For the coprimary endpoint of OS in the CPS 20 or greater population, pembrolizumab was associated with significantly better survival than EXTREME at both the 12- and 24-month time points (56.9% vs. 44.9%, and 38.3% vs. 22,1%, respectively). After a minimum follow-up of 17 months, the median OS was 14.9 months with pembrolizumab, vs. 10.7 months for EXTREME. The hazard ratio (HR) for death with pembrolizumab was 0.61 (P = .0007).

The median OS in the CPS 1 or greater population was 12.3 months and 10.3 months, respectively (HR 0.78, P = .0086).

There were no differences between the arms in PFS, however, either in the CPS 20 or greater or CPS 1 or greater populations.

Although, as noted, response rates did not differ between the groups, the median duration of response was 20.9 months with pembrolizumab in both the CPS 20 and CPS 1 populations, compared with 4.2 and 4.5 months, respectively, for EXTREME.

Treatment-related adverse events of any grade occurred in 58% of patients in the monotherapy arm, vs. 96.9% in the EXTREME arm. Fatal adverse events occurred in 1% vs. 2.8%, and events leading to drug discontinuation occurred in 4.7% vs. 19.9%, respectively. There were more immune-mediated events in the pembrolizumab arm, including one death (from pneumonitis) vs. no deaths from immune-related causes in the EXTREME arm.
 

Pembrolizumab plus chemo vs. EXTREME

The combination of pembrolizumab was also superior to EXTREME in the total population, with 12- and 24-month OS rates of 53% vs. 43.9%, and 29% vs. 18.7%, respectively. The median OS was 13 months with the pembrolizumab/chemo combination, vs. 10.7 months for EXTREME, translating into an HR of 0.77 (P = .0034). In this analysis as well as in the pembrolizumab monotherapy combination, there was no difference in PFS or response rates, but responses in the pembrolizumab arm were more durable.

In this comparison, treatment-related adverse events were generally similar between the groups, although there were 10 treatment-related deaths with pembrolizumab, compared with eight in the EXTREME arm.

There was one immune-related death, from pneumonitis, in the pembrolizumab arm, vs. none in the EXTREME arm. Hypothyroidism, pneumonitis, hyperthyroidism and colitis were more frequent with pembrolizumab, whereas infusion reactions and severe skin reactions were more frequent with EXTREME.

“There are further analyses of biomarker and clinical predictors that will be forthcoming from this study, and these may eventually optimally guide the choice of whether to administer pembrolizumab alone or in the novel combination, Dr. Burtness said at the briefing.

“What’s extremely important also is that for a subgroup of patients with high expression of PD-L1, we can probably remove the cisplatin and have a good outcome with immunotherapy alone,” Dr. Machiels said.

He said that more work needs to be done to determine which patients are most likely to benefit from immunotherapy in the recurrent/metastatic setting, and “we have to see how we can now bring this active drug to the curative treatment of the patient, in combination with chemoradiation.”

The study was funded by Merck Sharp & Dohme. Dr. Burtness disclosed being and advisory board member and receiving travel expenses from MSD and others. Dr. Machiels disclosed speaker honoraria, travel expenses, and an uncompensated advisory role with MSD.

SOURCE: Burtness B et al. ESMO 2018. Abstract LBA8_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

MUNICH – The term “practice-changing trial” usually implies change for the better, but results of a study comparing two regimens for patients with low-risk human papillomavirus–positive oropharyngeal cancer showed that cetuximab plus radiation was associated with worse local control and worse overall survival than the older standard of cisplatin plus radiation, investigators in the De-Escalate HPV trial reported.

Although rates of severe toxicity, the primary endpoint, were similar between cisplatin and radiation and cetuximab (Erbitux) plus radiation, 2-year overall survival was significantly worse with cetuximab, a finding that caught the investigators off guard, admitted Hisham Mehanna, PhD, a surgeon at the Institute of Head and Neck Studies and Education at the University of Birmingham (England).

Neil Osterweil/MDedge News

“This difference in overall survival was underpinned by a significantly higher recurrence rate with cetuximab,” he said at the European Society of Medical Oncology Congress. “And that recurrence rate was both in locoregional control as well as in distant control.”

The results of the study reaffirm that cisplatin remains the standard of care in patients with low-risk human papillomavirus (HPV)–positive oropharyngeal cancer, and highlight the vital importance of carefully controlled clinical trials.

“I think there’s a salutary lesson: Changes in standard of care really should only be done of the basis of high-level, phase 3 comparative evidence, even, as was in our case, when treatments have been approved by regulatory bodies,” he said.

The trial raises the question of whether deintensification strategies should continue to be used in locally advanced HPV-positive oropharyngeal cancer, and suggests that clinicians should rethink the use of targeted agents in these patients in the absence of predictive biomarkers, commented Amanda Psyrri, MD, PhD, from the University of Athens and Attikon University Hospital.

The standard of care for patients with head and neck cancers is radiotherapy with concomitant cisplatin, which has been shown to improve absolute overall survival at the cost of increases in both acute and late severe toxicities.

The De-Escalate HPV trial was designed to see whether replacing cisplatin with cetuximab, a tyrosine kinase inhibitor targeted against the epidermal growth factor receptor, could be associated with less toxicity, better quality of life, and better swallowing in patients with low-risk HPV-positive oropharyngeal cancer.

The investigators enrolled 334 patients from 32 centers in the United Kingdom, Ireland, and the Netherlands, and randomly assigned them to therapy with 70 Gy radiotherapy given in 35 fractions over 7 weeks, plus either intravenous cisplatin 100 mg/m² per day on days 1, 22, and 43, or IV cetuximab at a 400 mg pretreatment loading dose, then 250 mg weekly.

There were no significant differences between treatment arms in the primary endpoint of toxicity, either severe (grade 3-5) or all grades of toxicity (1-5). In addition, there were no significant differences between the treatment arms in global health status assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) or in swallowing as evaluated by the MD Anderson Dysphagia Inventory-Global.

There were, however, significantly more serious adverse events in the cisplatin arm, at 162 versus 95 in the cetuximab arm.

But as noted before, the investigators were surprised to see that 2-year overall survival was worse with cetuximab at 89.4%, compared with 97.5% for cisplatin (P = .001). The hazard ratio for death with cetuximab was 4.99 and the adjusted HR was 5.94 (P = .001). Dr. Mehanna did not report factors considered in the adjusted HR.

The number needed to treat for harm was 12.

“Our study was not powered to identify a difference in survival, and hence our surprise to find a significantly worse overall survival with cetuximab,” he said.

The 2-year recurrence rates were 6.0% in the cisplatin arm versus 16.1% in the cetuximab arm (HR, 3.39; P = .0007).

Locoregional recurrence rates were 3% in the cisplatin arm versus 12% in the cetuximab arm and rates of distant recurrence were 3% versus 9%, respectively.

The results suggest that clinicians should be cautious when considering deescalation treatments that reduce the use of systemic chemotherapy, either with radiotherapy alone or with surgery, Dr. Mehanna said.

Neil Osterweil/MDedge News

In a briefing prior to the presentation of the data in a presidential symposium, discussant Jean-Pascal Machiels, MD, from the University Clinic Saint-Luc in Brussels, said that, prior to this study, “the common belief was that [cetuximab and radiation] could be used, maybe, instead of chemoradiation in these patients, because also we believed that this may decrease toxicity.

“But clearly we have a signal that the chemoradiation has more activity in this setting, and it should remain the standard of care,” he continued.

Dr. Machiels cautioned that the findings cannot be extrapolated to patients with HPV-negative disease.

The study was sponsored by the University of Warwick (England), University of Birmingham, University of Oxford (England), and Cancer Research UK. Dr. Mehanna reported honoraria from AstraZeneca, MSD, Sanofi Pasteur, and Merck, and is a director and stockholder of the Warwickshire Head and Neck Clinic. Dr. Psyrri reported honoraria from Merck Serono, Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Bayer, Pfizer, Medscape, and Prime Oncology. Dr. Machiels reported a consulting or advisory role with Boehringer Ingelheim, Debiopharm Group, Innate Pharma, Merck, Nanobiotix, and Pfizer, and research funding from Bayer, Janssen Pharmaceuticals, Novartis, and Sanofi.

SOURCE: Mehanna H et al. ESMO 2018, Abstract LBA9_PR.

Results of the phase 3 KEYNOTE-048 trial investigating pembrolizumab (Keytruda) for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) will be presented during a presidential symposium at the European Society for Medical Oncology Congress.

The drug is currently approved for second-line treatment of HNSCC. Merck, the maker of the anti–programmed cell death protein therapy, announced in July that the primary endpoint of overall survival as monotherapy in the first-line setting of advanced HNSCC had been met in patients whose tumors expressed programmed death–ligand 1.

More than 800 patients in KEYNOTE-048 were randomized to receive pembrolizumab as monotherapy or in combination with cisplatin or carboplatin and 5-FU, or cetuximab plus cisplatin or carboplatin and 5-FU.

The dual primary endpoints were overall survival and progression-free survival. The secondary endpoints of the study were PFS (at 6 months and 12 months), objective response rate, and time to deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, according to the company.

Further details from the interim analysis of KEYNOTE-048 will be presented by Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn., during Presidential Symposium 3 at ESMO 2018 on Oct. 22 in Munich.

Results of the phase 3 KEYNOTE-048 trial investigating pembrolizumab (Keytruda) for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) will be presented during a presidential symposium at the European Society for Medical Oncology Congress.

The drug is currently approved for second-line treatment of HNSCC. Merck, the maker of the anti–programmed cell death protein therapy, announced in July that the primary endpoint of overall survival as monotherapy in the first-line setting of advanced HNSCC had been met in patients whose tumors expressed programmed death–ligand 1.

More than 800 patients in KEYNOTE-048 were randomized to receive pembrolizumab as monotherapy or in combination with cisplatin or carboplatin and 5-FU, or cetuximab plus cisplatin or carboplatin and 5-FU.

The dual primary endpoints were overall survival and progression-free survival. The secondary endpoints of the study were PFS (at 6 months and 12 months), objective response rate, and time to deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, according to the company.

Further details from the interim analysis of KEYNOTE-048 will be presented by Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn., during Presidential Symposium 3 at ESMO 2018 on Oct. 22 in Munich.

Results of the phase 3 KEYNOTE-048 trial investigating pembrolizumab (Keytruda) for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) will be presented during a presidential symposium at the European Society for Medical Oncology Congress.

The drug is currently approved for second-line treatment of HNSCC. Merck, the maker of the anti–programmed cell death protein therapy, announced in July that the primary endpoint of overall survival as monotherapy in the first-line setting of advanced HNSCC had been met in patients whose tumors expressed programmed death–ligand 1.

More than 800 patients in KEYNOTE-048 were randomized to receive pembrolizumab as monotherapy or in combination with cisplatin or carboplatin and 5-FU, or cetuximab plus cisplatin or carboplatin and 5-FU.

The dual primary endpoints were overall survival and progression-free survival. The secondary endpoints of the study were PFS (at 6 months and 12 months), objective response rate, and time to deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, according to the company.

Further details from the interim analysis of KEYNOTE-048 will be presented by Barbara Burtness, MD, of Yale Cancer Center, New Haven, Conn., during Presidential Symposium 3 at ESMO 2018 on Oct. 22 in Munich.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.

A combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the BRAF inhibitor vemurafenib appears safe for patients with advanced, BRAF-mutated, solid tumors that had progressed on BRAF and/or MEK therapy, investigators reported.

The combination provided partial responses in a variety of tumor types, and half of the patients achieved stable disease, reported Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center in Houston and his coauthors.

“Activation of alternative parallel signaling pathways such as the PI3K–mTOR pathway have been hypothesized to contribute to primary and acquired resistance to BRAF-targeted therapy,” the authors wrote in JCO Precision Oncology. Preclinical studies have supported this hypothesis, which led to the present study; it is the first to evaluate a combination of a BRAF inhibitor and an mTOR inhibitor.

The open-label, phase 1 trial included 20 patients with BRAF-mutated, advanced cancer that had progressed on BRAF and/or MEK therapy. Solid tumor types included melanoma (n = 7), glioma (n = 5), thyroid cancer (n = 4), appendiceal carcinoma (n = 1), colorectal cancer (n = 1), non–small cell lung cancer (NSCLC; n =1), and cancer of unknown primary (n = 1). More than half of the patients had already been treated with surgery, clinical trial therapy, radiation therapy, or chemotherapy. The median adult age was 64 years; two pediatric patients were aged 10 and 13 years.

Dose-escalation revealed a maximum-tolerated dose of everolimus 5 mg orally once a day and vemurafenib 720 mg orally twice a day. Across doses, the most common grade 3 adverse events were fatigue (20%) and rash (15%), followed distantly by anemia, thrombocytopenia, hyperglycemia, or hypertriglyceridemia, which occurred in one patient each.

SOURCE: Subbiah V et al. JCO Prec Oncol. 2018 Sep 13. doi: 10.1200/PO.18.00189.