Will Pass

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

Photo courtesy of NIH

Older patients with untreated Hodgkin lymphoma (HL) can achieve significantly improved survival by adding brentuximab vedotin to their treatment before and after standard chemotherapy, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported lead author Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey, and colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 HL patients with a median age of 69 (range, 60 – 88).

All patients underwent geriatric assessment for comorbidities and loss of activities of daily living.

Treatment consisted of two doses of brentuximab followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of brentuximab (consolidation doses).

The primary endpoint was complete remission at completion of AVD.

Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half the patients (52%) completed all cycles of therapy, and almost three quarters (73%) received at least one consolidation dose of brentuximab.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

Historical 2-year progression-free survival rates in similar older patients is poor, at 50%, so the progression-free survival rate of 84% in this study represents a significant improvement.

Of note, patients with fewer comorbidities and without loss of instrumental activities of daily living showed more robust responses.

Patients with Cumulative Illness Rating Scale for Geriatrics (CIRS-G) comorbidity scores of less than 10 had a 2-year progression-free survival rate of 100% versus 45% for those with higher scores.

Similarly, patients without loss of instrumental activities achieved a progression-free survival rate of 94% versus 25% for those who had lost some instrumental activities.

Grade 3 or 4 adverse events occurred in 42% of patients, with neutropenia being the most common (44%).

“This study represents among the best-reported outcomes to date for untreated older patients with HL,” the investigators concluded.

Seattle Genetics supported the investigator-initiated trial. 

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.

Courtesy Memorial Sloan Kettering Cancer Center

Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.

“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”

Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.

“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.

The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.

Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.

The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.

“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.

Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.

SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.

Future epigenetic drugs could activate human endogenous retroviruses (HERVs) in cancer cells to enable immunotherapy, investigators suggest.

Activated HERVs may sensitize cancer cells or serve as novel tumor-associated antigenic targets, reported Anders Steenholdt Attermann, PhD, of the department of micro- and nanotechnology at the Technical University of Denmark in Kongens Lyngby, and colleagues.

A remarkable 8% of the human genome is composed of HERVs.

“They are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny, but their viral replication is defective in the present-day human genome,” the authors wrote in Annals of Oncology.

The therapeutic potential for these remnants is complex, as is their relationship with the immune system and neoplasia. Studies dating back to 2002 have found unique associations between HERVs and various types of cancer, including renal cell carcinoma, melanoma, gastrointestinal cancer, colorectal cancer, and breast cancer.

“Early data point towards distinct features for the expression profiles of different HERVs,” the authors wrote, “but these characteristics remain to be fully elucidated. There may be substantial differences in their biological effects, potential roles in immune sensitization, and ability to form an antigen reservoir.”

HERVs may be activated by cancer or epigenetic drugs. While certain cancers may activate particular HERVs into targetable antigens, other cancer-activated HERVs actually shield tumors from the immune system. Still other HERVs require epigenetic drugs for activation, such as DNA methyltransferase inhibitors. These drugs could transform HERVs into “intrinsic adjuvants” or novel antigens; either of which may improve the efficacy of existing immunotherapies like checkpoint inhibitors.

To leverage HERVs for immunotherapy, a better understanding of immune tolerance is needed. Some research suggests that since HERVs share similarities with exogenous viruses, tolerance to HERVs must be incomplete to allow for immune responses to exogenous viruses. In contrast, incomplete tolerance would conceivably lead to autoimmune disease.

“Hence, peripheral tolerance and ignorance mechanisms may play prominent roles in the control of HERV-specific T-cell recognition in healthy individuals,” the authors wrote. “Understanding the differences in HERV expression in the thymus and peripheral tissues would be of great importance for the use of HERVs as immunotherapeutic targets.”

When more clearly understood, HERVs may feature in emerging combination therapies.

“The combination of epigenetic drugs and immunotherapy is exciting for future cancer therapy,” the authors wrote, “especially for cancer types with low mutational burden that respond poorly to immunotherapy or cancer types with poor responses to immune checkpoint inhibitor treatment.”

It appears that the authors’ excitement is shared – almost 50 clinical trials are currently studying epigenetic drug/immunotherapy combinations.

Study funding was provided by the Lundbeck Foundation Fellowship, the European Research Council, the stand-up-to-cancer (SU2C) epigenetic dream team, and StG 677268 NextDART.
 

SOURCE: Attermann et al. Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy413.

Future epigenetic drugs could activate human endogenous retroviruses (HERVs) in cancer cells to enable immunotherapy, investigators suggest.

Activated HERVs may sensitize cancer cells or serve as novel tumor-associated antigenic targets, reported Anders Steenholdt Attermann, PhD, of the department of micro- and nanotechnology at the Technical University of Denmark in Kongens Lyngby, and colleagues.

A remarkable 8% of the human genome is composed of HERVs.

“They are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny, but their viral replication is defective in the present-day human genome,” the authors wrote in Annals of Oncology.

The therapeutic potential for these remnants is complex, as is their relationship with the immune system and neoplasia. Studies dating back to 2002 have found unique associations between HERVs and various types of cancer, including renal cell carcinoma, melanoma, gastrointestinal cancer, colorectal cancer, and breast cancer.

“Early data point towards distinct features for the expression profiles of different HERVs,” the authors wrote, “but these characteristics remain to be fully elucidated. There may be substantial differences in their biological effects, potential roles in immune sensitization, and ability to form an antigen reservoir.”

HERVs may be activated by cancer or epigenetic drugs. While certain cancers may activate particular HERVs into targetable antigens, other cancer-activated HERVs actually shield tumors from the immune system. Still other HERVs require epigenetic drugs for activation, such as DNA methyltransferase inhibitors. These drugs could transform HERVs into “intrinsic adjuvants” or novel antigens; either of which may improve the efficacy of existing immunotherapies like checkpoint inhibitors.

To leverage HERVs for immunotherapy, a better understanding of immune tolerance is needed. Some research suggests that since HERVs share similarities with exogenous viruses, tolerance to HERVs must be incomplete to allow for immune responses to exogenous viruses. In contrast, incomplete tolerance would conceivably lead to autoimmune disease.

“Hence, peripheral tolerance and ignorance mechanisms may play prominent roles in the control of HERV-specific T-cell recognition in healthy individuals,” the authors wrote. “Understanding the differences in HERV expression in the thymus and peripheral tissues would be of great importance for the use of HERVs as immunotherapeutic targets.”

When more clearly understood, HERVs may feature in emerging combination therapies.

“The combination of epigenetic drugs and immunotherapy is exciting for future cancer therapy,” the authors wrote, “especially for cancer types with low mutational burden that respond poorly to immunotherapy or cancer types with poor responses to immune checkpoint inhibitor treatment.”

It appears that the authors’ excitement is shared – almost 50 clinical trials are currently studying epigenetic drug/immunotherapy combinations.

Study funding was provided by the Lundbeck Foundation Fellowship, the European Research Council, the stand-up-to-cancer (SU2C) epigenetic dream team, and StG 677268 NextDART.
 

SOURCE: Attermann et al. Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy413.

Future epigenetic drugs could activate human endogenous retroviruses (HERVs) in cancer cells to enable immunotherapy, investigators suggest.

Activated HERVs may sensitize cancer cells or serve as novel tumor-associated antigenic targets, reported Anders Steenholdt Attermann, PhD, of the department of micro- and nanotechnology at the Technical University of Denmark in Kongens Lyngby, and colleagues.

A remarkable 8% of the human genome is composed of HERVs.

“They are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny, but their viral replication is defective in the present-day human genome,” the authors wrote in Annals of Oncology.

The therapeutic potential for these remnants is complex, as is their relationship with the immune system and neoplasia. Studies dating back to 2002 have found unique associations between HERVs and various types of cancer, including renal cell carcinoma, melanoma, gastrointestinal cancer, colorectal cancer, and breast cancer.

“Early data point towards distinct features for the expression profiles of different HERVs,” the authors wrote, “but these characteristics remain to be fully elucidated. There may be substantial differences in their biological effects, potential roles in immune sensitization, and ability to form an antigen reservoir.”

HERVs may be activated by cancer or epigenetic drugs. While certain cancers may activate particular HERVs into targetable antigens, other cancer-activated HERVs actually shield tumors from the immune system. Still other HERVs require epigenetic drugs for activation, such as DNA methyltransferase inhibitors. These drugs could transform HERVs into “intrinsic adjuvants” or novel antigens; either of which may improve the efficacy of existing immunotherapies like checkpoint inhibitors.

To leverage HERVs for immunotherapy, a better understanding of immune tolerance is needed. Some research suggests that since HERVs share similarities with exogenous viruses, tolerance to HERVs must be incomplete to allow for immune responses to exogenous viruses. In contrast, incomplete tolerance would conceivably lead to autoimmune disease.

“Hence, peripheral tolerance and ignorance mechanisms may play prominent roles in the control of HERV-specific T-cell recognition in healthy individuals,” the authors wrote. “Understanding the differences in HERV expression in the thymus and peripheral tissues would be of great importance for the use of HERVs as immunotherapeutic targets.”

When more clearly understood, HERVs may feature in emerging combination therapies.

“The combination of epigenetic drugs and immunotherapy is exciting for future cancer therapy,” the authors wrote, “especially for cancer types with low mutational burden that respond poorly to immunotherapy or cancer types with poor responses to immune checkpoint inhibitor treatment.”

It appears that the authors’ excitement is shared – almost 50 clinical trials are currently studying epigenetic drug/immunotherapy combinations.

Study funding was provided by the Lundbeck Foundation Fellowship, the European Research Council, the stand-up-to-cancer (SU2C) epigenetic dream team, and StG 677268 NextDART.
 

SOURCE: Attermann et al. Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy413.

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

A woman with two distinct primary tumors achieved complete regression of both after pembrolizumab therapy, investigators report.

This is the first documented instance of a checkpoint inhibitor leading to this kind of simultaneous regression, reported Benjamin Musher, MD, of Baylor College of Medicine, Houston, and his coauthors.

The patient was a 55-year-old woman with a family history of gastric, uterine, and colon cancer. After presenting with weight loss, fatigue, and abdominal pain, colonoscopy showed a 5-cm mucosal lesion. A subsequent PET-CT scan revealed a 12-cm hepatic mass with multiple other liver masses, and bulky lymph nodes nearby. Site biopsies showed two primary cancer types: colonic adenocarcinoma and intrahepatic cholangiocarcinoma.

“Additional staining ... for proteins that repair mismatched DNA showed an absence of MLH1 expression. Sequencing of the patient’s DNA revealed a deleterious mutation in MLH1, which confirmed that Lynch syndrome caused both types of cancer,” the authors wrote in Annals of Internal Medicine.

Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), is an autosomal dominant condition that incurs a high risk of colorectal, pancreatic, bile duct, ovarian, gastric, and uterine cancer. Patients may present with more than one type of cancer simultaneously, as occurred in this case study.

Following diagnosis, the patient started pembrolizumab monotherapy (200 mg IV Q3W). After 16 months the tumors were undetectable by colonoscopy or PET-CT; 2 months later the patient was free of cancer symptoms.

“To our knowledge, our case report is the first to document complete regression of 2 simultaneous types of cancer after treatment with an immune checkpoint inhibitor,” the authors wrote.

But why the dramatic response?

“The types of cancer that develop because of a mismatch repair deficiency contain more mutations than most other kinds of cancer,” the authors explained. These highly mutated cells are recognized by the host immune system, but responses are limited, in part, by programmed cell death proteins. “These events make checkpoint inhibition an attractive and potentially effective treatment for mismatch repair deficient cancer.

“We believe that this case emphasizes the importance of eliciting a thorough family history in patients with cancer and considering the presence of multiple types of primary cancer in a patient with an extensive family history of cancer,” the authors concluded. “It also shows the value of identifying mismatch repair deficiency, [in which] immunotherapy can yield dramatic and durable benefit.”

Dr. Musher reported compensation from LOKON pharmaceuticals.
 

SOURCE: Musher et al. Ann Intern Med. 2018 Sep 24. doi: 10.7326/L18-0360.

For elderly patients with untreated Hodgkin lymphoma (HL), adding brentuximab vedotin (Bv) before and after standard chemotherapy significantly improved survival, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey in New Brunswick and his colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 elderly patients (median age, 69 years) with Hodgkin lymphoma. All patients underwent geriatric assessment for comorbidities and loss of activities of daily living. Treatment consisted of two doses of Bv followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of Bv (consolidation doses). The primary endpoint was complete remission at completion of AVD. Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half of the patients (52%) completed all cycles of therapy, and almost three-quarters (72%) received at least one consolidation dose of Bv.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

SOURCE: Evens AM et al. J Clin Oncol. 2018 Sep 4. doi: 10.1200/JCO.2018.79.0139

For elderly patients with untreated Hodgkin lymphoma (HL), adding brentuximab vedotin (Bv) before and after standard chemotherapy significantly improved survival, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey in New Brunswick and his colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 elderly patients (median age, 69 years) with Hodgkin lymphoma. All patients underwent geriatric assessment for comorbidities and loss of activities of daily living. Treatment consisted of two doses of Bv followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of Bv (consolidation doses). The primary endpoint was complete remission at completion of AVD. Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half of the patients (52%) completed all cycles of therapy, and almost three-quarters (72%) received at least one consolidation dose of Bv.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

SOURCE: Evens AM et al. J Clin Oncol. 2018 Sep 4. doi: 10.1200/JCO.2018.79.0139

For elderly patients with untreated Hodgkin lymphoma (HL), adding brentuximab vedotin (Bv) before and after standard chemotherapy significantly improved survival, a recent study found.

In patients with low comorbidity scores, responses were even more robust, reported Andrew M. Evens, DO, of the Rutgers Cancer Institute of New Jersey in New Brunswick and his colleagues.

“Causes of poor outcomes for older patients with HL are not fully understood but have been attributed to a combination of factors, including presence of comorbidities, poorer performance status, disease and biological differences, inability to tolerate chemotherapy at the full dose, and increased treatment-related toxicities,” the authors wrote in the Journal of Clinical Oncology.

The primary goal of the study was to improve outcomes for untreated, older patients, a group that’s historically been a difficult-to-treat patient population.

The phase 2 trial included 48 elderly patients (median age, 69 years) with Hodgkin lymphoma. All patients underwent geriatric assessment for comorbidities and loss of activities of daily living. Treatment consisted of two doses of Bv followed by six cycles of doxorubicin, vinblastine, and dacarbazine (AVD), then four more doses of Bv (consolidation doses). The primary endpoint was complete remission at completion of AVD. Secondary outcomes included overall response rate, 2-year progression-free survival, 2-year overall survival, and safety.

Just over half of the patients (52%) completed all cycles of therapy, and almost three-quarters (72%) received at least one consolidation dose of Bv.

Among the first 23 evaluable patients, both the complete remission rate and overall response rate were 96%. Intention-to-treat survival rates for all 48 patients were 84% for 2-year progression-free survival and 93% for 2-year overall survival.

SOURCE: Evens AM et al. J Clin Oncol. 2018 Sep 4. doi: 10.1200/JCO.2018.79.0139

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.

Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.

After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.

About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.

“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.

Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”

The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.

Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.

SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.

Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.

After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.

About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.

“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.

Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”

The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.

Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.

SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.

Ulipristal acetate reduces breakthrough bleeding in women with etonogestrel implants, according to new findings.

After 30 days, patients treated with ulipristal were more satisfied with their bleeding profiles than were those given placebo, reported Rachel E. Zigler, MD, of the department of obstetrics and gynecology at Washington University in St. Louis and her colleagues.

About half of women experience unscheduled bleeding within the first 6 months of etonogestrel implantation, causing many to discontinue treatment. The etiology of this phenomenon is poorly understood.

“One leading theory is that sustained exposure to a progestin can lead to endometrial angiogenesis disruption, resulting in the development of a dense venous network that is fragile and prone to bleeding,” the researchers wrote in Obstetrics & Gynecology.

Ulipristal acetate is a selective progesterone receptor modulator approved for emergency contraception in the United States. Outside the United States, it is used to treat abnormal uterine bleeding in cases of uterine leiomyoma. Ulipristal acts directly upon myometrial and endometrial tissue and “may also displace local progestin within the uterus to counteract bleeding secondary to … a dense, fragile venous network.”

The double-blind, placebo-controlled study included 65 women aged 18-45 years with etonogestrel implants. Eligibility required that implants be in place for more than 90 days and less than 3 years and that participants experienced more than one bleeding episode over a 24-day time frame.

Patients received either 15 mg ulipristal (n = 32) or placebo (n = 33) daily for 7 days. From the first day of treatment until 30 days, patients self-reported bleeding events. Weekly phone questionnaires also were conducted to determine satisfaction with medication and side effects.

SOURCE: Zigler RE et al. Obstet Gynecol. 2018;132:888-94.

The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.

Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.

Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.

The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.

It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.

“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest^®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”

The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).

Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.

Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO₂, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.

“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”

However, not all of the prognostic measures were reliable, particularly CI.

Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”

Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.

Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050

The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.

Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.

Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.

The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.

It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.

“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest^®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”

The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).

Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.

Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO₂, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.

“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”

However, not all of the prognostic measures were reliable, particularly CI.

Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”

Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.

Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050

The results of guideline-recommended prognostic tests that measure mortality risk in patients with pulmonary arterial hypertension (PAH) are strongly associated with survival in those who are receiving a parenteral prostanoid, according to a recent study.

Patients with no lower-risk findings or at least two higher-risk findings had the worst outcomes, reported lead author Sonja Bartolome, MD, of the University of Texas Southwestern Medical Center in Dallas, and her colleagues.

Prostanoids are the most effective therapy for advanced PAH. However, patients may respond inadequately, so guidelines recommend lung transplant evaluation 3 months after starting a prostanoid.

The current study relied upon the 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) consensus guidelines. The guidelines recommend several tests to determine adequate response to therapy, including invasive hemodynamic measures, brain natriuretic peptide (BNP) level, N-terminal BNP (NT-proBNP) level, 6-minute walk distance (6MWD), and functional class (FC). Results of these tests are sorted into three hazard ratios for mortality: lower, intermediate, or higher risk.

It is commonly accepted that these risk categories can predict survival. For example, a patient with several higher-risk results and no lower-risk results would have a poor prognosis. However, the reliability of this method is poorly studied.

“In practicality the definition of an ‘inadequate response’ remains nebulous given that data on prognostic markers in patients on advanced therapy is limited,” the authors wrote. Their report was published in Chest^®. “We therefore sought to evaluate whether consensus guidelines recommended prognostic measures associate with survival free from transplant in PAH patients initiating parenteral prostanoids.”

The retrospective study involved 195 patients with group 1 PAH at multiple treatment centers who received a parenteral prostanoid between 2007 and 2016. Diagnosis relied upon CT angiography, ventilation-perfusion scan, pulmonary function testing, cardiac catheterization, or echocardiogram. Eligible diagnoses were idiopathic PAH (n = 111), heritable PAH (n = 9), and PAH associated with connective tissue disease (n = 61), congenital heart disease (n = 12), and HIV (n = 2).

Patients received either IV epoprostenol (n = 132), SC treprostinil (n = 38), or IV treprostinil (n = 25). Routine prognostic testing was done prior to prostanoid therapy, and again at least 90 days later (with right heart catheterization). The investigators then analyzed the data for associations between test outcomes and survival.

Results showed that survival rates at 1, 2, and 3 years were 84%, 77%, and 67%, respectively. All major prognostic measures improved after patients started a prostanoid. Better SVO₂, BNP, NT-proBNP, 6MWD, and FC were associated with survival, but cardiac index (CI) was not. Survival was least likely in patients who had at least two higher-risk measures or no lower-risk measures; of these patients, less than 50% were alive after 2 years.

“These findings are likely broadly applicable to PAH patients being treated with parenteral prostanoids,” the authors wrote, citing the fact that all patients in the study were newly started on either of the two parenteral prostanoids currently available in the United States (including patients who were treatment naive as well as those transitioning to parenteral therapy) and the study involved patients with multiple PAH subtypes. They also noted that 97% of patients were receiving combination therapy at first follow-up, “reflecting the more frequent use of combinations of medications in the modern era.”

However, not all of the prognostic measures were reliable, particularly CI.

Although CI is used as a major determinant for lung transplant, the authors noted that the lack of association between CI and survival suggests that “the strength and usefulness of some individual prognostic measures may differ for prostanoid-treated PAH patients.”

Some of the authors disclosed financial ties to United Therapeutics, which markets treprostinil for infusion (Remodulin), and Actelion, which markets epoprostenol for injection (Veletri), as well as other pharmaceutical companies.

Source: Bartolome S et al. Chest. 2018 Sep 1. doi: 10.1016/j.chest.2018.03.050

A new ICU clinical practice guideline provides updated strategies for managing adult patients with pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS).

copyright Andrei Malov/Thinkstock

The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.

A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.

“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.

Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”

The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.

“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.

One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.

“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.

Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.

“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”

The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.

SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.

A new ICU clinical practice guideline provides updated strategies for managing adult patients with pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS).

copyright Andrei Malov/Thinkstock

The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.

A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.

“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.

Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”

The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.

“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.

One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.

“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.

Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.

“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”

The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.

SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.

A new ICU clinical practice guideline provides updated strategies for managing adult patients with pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS).

copyright Andrei Malov/Thinkstock

The guideline builds upon the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium (PAD) in Adult Patients in the ICU. Given the comprehensive nature of the PADIS guideline, an accompanying commentary was published simultaneously to help with implementation and interpretation. Both papers are the result of a large-scale, multicenter collaboration and were published in Critical Care Medicine.

A panel of 32 international experts, four methodologists, and four survivors of critical illness used the Grading of Recommendations Assessment, Development and Evaluation approach to develop the PADIS guideline.

“Thousands of hours were invested by these guidelines’ authors, who were in turn were supported by formal and informal collaborators, over the 3.5 years it took to produce this effort,” reported lead author John W. Devlin, PharmD, of the department of pharmacy and health systems sciences, Bouvé College of Health Sciences at Northeastern University, Boston, and his colleagues.

Compared with the 2013 PAD guideline, the PADIS guideline includes new sections regarding rehabilitation/mobility and sleep. “We sought to clarify conceptual definitions within these relatively new critical care research domains,” the panel wrote. “The recommendation rationales, fueled by debate and discussion, circled back to the bedside experience – and the perspective of what was best for patients – held by all panelists and methodology experts.”

The result is extensive and comprehensive, consisting of both broad and specific descriptions of current ICU practices and associated evidence; the guideline includes 37 recommendations, 32 ungraded, nonactionable statements, and two good practice statements. Of note, conditional recommendations far outnumber strong recommendations (34 vs. 3). Reasons for conditional rather than strong recommendations are discussed in rationale sections within the guideline and in the accompanying paper.

“Although our goal was to provide specific recommendations for each question, we suspect some guideline readers may be discouraged by the conditional nature of many recommendations and daunted by the breadth of topics discussed,” wrote Michele C. Balas, PhD, of the Ohio State University College of Nursing in Columbus, and her colleagues. Dr. Balas was on the guideline panel and is the lead author of the accompanying article intended to facilitate implementation and interpretation.

One of the more challenging recommendations surrounds the use of antipsychotics for delirious patients. Although this intervention has become relatively common, the guideline stands against it.

“It should be emphasized that there are few supportive data on ICU antipsychotic use and that the initiation of psychoactive medications during critical illness often results in their inappropriate continuation after ICU discharge,” wrote Dr. Balas and her coauthors.

Along with a hard look at existing practices, the panel actively sought to expand upon the 2013 guideline with new interventions. Discussions ranged from the less conventional, such as aromatherapy, to the more established, such as polypharmacy. Questions, recommendations, and rationale are clearly described for each topic, with clear supporting evidence. Where evidence is missing, the panel recommends future research possibilities.

“One example is the consideration of multiple pharmacologic and nonpharmacologic coanalgesic approaches to the ICU patient,” wrote Dr. Devlin and his coauthors. “When the published evidence was insufficient, limited to a narrow population or specific intervention (e.g., for procedural analgesia), or outright absent to answer the questions we posed, we structured evidence gap descriptors to inform clinicians where the uncertainty lay, and intended to provide sufficient information to apprise and invite researchers to address these gaps.”

The authors disclosed funding from AstraZeneca, Baxter, Covidien, and others.

SOURCE: Devlin JW et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003299; Balas MC et al. Crit Care Med. 2018 Sep 1. doi: 10.1097/CCM.0000000000003307.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.

A combination of trabectedin and the PARP inhibitor olaparib may be a safe and effective therapy for patients with sarcoma, the recent TOMAS trial found.

High PARP1 expression was associated with treatment response, reported Giovanni Grignani, MD, of the Medical Oncology_Sarcoma Unit at Istituto di Ricovero e Cura a Carattere Scientifico in Candiolo, Italy, and his colleagues.

PARP inhibitors prevent repair of DNA damage, suggesting potential synergisms with DNA-damaging anticancer agents. Preclinical models support this strategy; however, clinical trials have found that toxicities restrict doses below antitumor activity levels.

“In view of these findings, trabectedin could be an ideal drug to use in combination with PARP1/2 inhibitors for two reasons: its favourable haemopoietic toxicity profile and its unique mechanisms of action,” the authors wrote in The Lancet Oncology. Trabectedin bends the minor groove of DNA toward the major groove, which activates PARP1 in an attempt to repair the damage. Preclinical trials showed that a PARP inhibitor such as olaparib would block this PARP1 activation, ultimately resulting in a more robust response than with either drug alone.

The phase 1b, open-label TOMAS trial involved 50 patients with sarcoma who had experienced disease progression after standard therapy. The study was divided into two cohorts: dose-escalation and dose-expansion. Patients received a median of four cycles of therapy with a median follow-up of 10 months (some patients are still undergoing treatment). The primary endpoint was maximum tolerated dose. The investigators also evaluated pharmacokinetics, pharmacodynamics, and various response measures.

Although adverse events occurred, these were manageable, and the authors concluded that the combination is safe for further investigation. The most common grade 3 or higher adverse events were lymphopenia (64%), neutropenia (62%), thrombocytopenia (28%), anemia (26%), hypophosphatemia (40%), and alanine aminotransferase elevation (18%). The maximum tolerated dose (recommended phase 2 dose) was olaparib 150 mg twice daily and trabectedin 1.1 mg/m² every 3 weeks.

“These doses allowed us to minimize the need for dose reductions and continue treatment for as long as tumour control was maintained,” the authors wrote. Previous treatments impacted tolerability. The researchers noted that “patients who had received more than two lines of therapy had a higher risk of developing dose-limiting toxicities than those patients who had been treated with only one line of therapy.”

Overall, 14% of patients responded to therapy. Six-month progression-free survival was more common in patients with soft tissue sarcoma (38%) than other tumor types. More patients with high PARP1 expression achieved 6-month PFS compared with patients who had low PARP1 expression (59% vs. 8%; P = .01).

“The combination of olaparib and trabectedin exploits the potential of two different first-in-class drugs and shows tolerability and activity in homologous repair-proficient tumors,” the authors concluded.

They are planning two phase 2 studies in the future; one “comparing trabectedin alone versus the combination of trabectedin and olaparib, stratifying patients according to PARP1 expression,” and an “after-platinum-failure study of patients with ovarian cancer regardless of patients’ BRCA1/2 and BRCAness status.”

The TOMAS trial was funded by the Italian Association for Cancer Research, the Foundation for Research on Musculoskeletal and Rare Tumors, the Italian Ministry of Health, and PharmaMar. The authors reported compensation from Lilly, Novartis, Bayer, Eisai, Amgen, and others.

SOURCE: Grignani et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30438-8.