Amy Karon

Adding the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to platinum doublet chemotherapy modestly improved progression-free survival in a randomized, placebo-controlled, phase 2 trial of 128 patients with extensive-stage non–small cell lung cancer.

Improved progression-free survival (PFS) “did not translate into reduction in overall mortality for patients treated with veliparib. However, the improvement in the point estimate of PFS was quite modest at 6.1 months, compared with 5.5 months [in the placebo control arm],” wrote Taofeek K. Owonikoko, MD, PhD, of Emory University, Atlanta, together with his coinvestigators in the Journal of Clinical Oncology.

Preclinical studies suggest that veliparib helps potentiate standard chemotherapy of non–small cell lung cancer (NSCLC), but clinical trials have yielded mixed results for PARP inhibition in this cancer. Patients in this study had untreated, extensive-stage NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. They received four 3-week cycles of cisplatin-etoposide (75 mg/m² intravenously on day 1 and 100 mg/m² on days 1-3) plus either veliparib (100 mg orally twice per day on days 1-7) or placebo.

Grade 3 or higher lymphopenia and neutropenia were more common in the veliparib arm but did not reduce treatment delivery. After a median follow-up time of 18.5 months, overall response rate was 72% in the veliparib arm versus 66% in the control arm (P =.57). Median overall survival times were 10.3 months and 8.9 months, respectively (hazard ratio, 0.83; P = .17).

The unstratified HR for PFS favored the veliparib-doublet arm but did not reach statistical significance (0.75; P = .06). After stratifying patients by sex and serum lactate dehydrogenase levels, the HR for PFS favored veliparib-doublet chemotherapy (0.63; P = .01). However, veliparib showed a much stronger effect in the subgroup of men with abnormal lactate dehydrogenase levels (adjusted HR, 0.34; P less than .001), which violated the “proportional hazards within strata assumption” on which this model was based, rendering the overall stratified HR uninterpretable, the researchers wrote.

They added that, before pursuing a larger definitive clinical trial, they await results from the ongoing phase 2 M14-361 study, in which patients with extensive-stage NSCLC are receiving platinum doublet therapy with carboplatin-etoposide plus either veliparib or placebo.

Funders included the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and the National Cancer Institute. Dr. Owonikoko reported ties to Novartis, Astellas Pharma, Celgene, and several other pharmaceutical companies.

SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.

Adding the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to platinum doublet chemotherapy modestly improved progression-free survival in a randomized, placebo-controlled, phase 2 trial of 128 patients with extensive-stage non–small cell lung cancer.

Improved progression-free survival (PFS) “did not translate into reduction in overall mortality for patients treated with veliparib. However, the improvement in the point estimate of PFS was quite modest at 6.1 months, compared with 5.5 months [in the placebo control arm],” wrote Taofeek K. Owonikoko, MD, PhD, of Emory University, Atlanta, together with his coinvestigators in the Journal of Clinical Oncology.

Preclinical studies suggest that veliparib helps potentiate standard chemotherapy of non–small cell lung cancer (NSCLC), but clinical trials have yielded mixed results for PARP inhibition in this cancer. Patients in this study had untreated, extensive-stage NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. They received four 3-week cycles of cisplatin-etoposide (75 mg/m² intravenously on day 1 and 100 mg/m² on days 1-3) plus either veliparib (100 mg orally twice per day on days 1-7) or placebo.

Grade 3 or higher lymphopenia and neutropenia were more common in the veliparib arm but did not reduce treatment delivery. After a median follow-up time of 18.5 months, overall response rate was 72% in the veliparib arm versus 66% in the control arm (P =.57). Median overall survival times were 10.3 months and 8.9 months, respectively (hazard ratio, 0.83; P = .17).

The unstratified HR for PFS favored the veliparib-doublet arm but did not reach statistical significance (0.75; P = .06). After stratifying patients by sex and serum lactate dehydrogenase levels, the HR for PFS favored veliparib-doublet chemotherapy (0.63; P = .01). However, veliparib showed a much stronger effect in the subgroup of men with abnormal lactate dehydrogenase levels (adjusted HR, 0.34; P less than .001), which violated the “proportional hazards within strata assumption” on which this model was based, rendering the overall stratified HR uninterpretable, the researchers wrote.

They added that, before pursuing a larger definitive clinical trial, they await results from the ongoing phase 2 M14-361 study, in which patients with extensive-stage NSCLC are receiving platinum doublet therapy with carboplatin-etoposide plus either veliparib or placebo.

Funders included the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and the National Cancer Institute. Dr. Owonikoko reported ties to Novartis, Astellas Pharma, Celgene, and several other pharmaceutical companies.

SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.

Adding the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to platinum doublet chemotherapy modestly improved progression-free survival in a randomized, placebo-controlled, phase 2 trial of 128 patients with extensive-stage non–small cell lung cancer.

Improved progression-free survival (PFS) “did not translate into reduction in overall mortality for patients treated with veliparib. However, the improvement in the point estimate of PFS was quite modest at 6.1 months, compared with 5.5 months [in the placebo control arm],” wrote Taofeek K. Owonikoko, MD, PhD, of Emory University, Atlanta, together with his coinvestigators in the Journal of Clinical Oncology.

Preclinical studies suggest that veliparib helps potentiate standard chemotherapy of non–small cell lung cancer (NSCLC), but clinical trials have yielded mixed results for PARP inhibition in this cancer. Patients in this study had untreated, extensive-stage NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. They received four 3-week cycles of cisplatin-etoposide (75 mg/m² intravenously on day 1 and 100 mg/m² on days 1-3) plus either veliparib (100 mg orally twice per day on days 1-7) or placebo.

Grade 3 or higher lymphopenia and neutropenia were more common in the veliparib arm but did not reduce treatment delivery. After a median follow-up time of 18.5 months, overall response rate was 72% in the veliparib arm versus 66% in the control arm (P =.57). Median overall survival times were 10.3 months and 8.9 months, respectively (hazard ratio, 0.83; P = .17).

The unstratified HR for PFS favored the veliparib-doublet arm but did not reach statistical significance (0.75; P = .06). After stratifying patients by sex and serum lactate dehydrogenase levels, the HR for PFS favored veliparib-doublet chemotherapy (0.63; P = .01). However, veliparib showed a much stronger effect in the subgroup of men with abnormal lactate dehydrogenase levels (adjusted HR, 0.34; P less than .001), which violated the “proportional hazards within strata assumption” on which this model was based, rendering the overall stratified HR uninterpretable, the researchers wrote.

They added that, before pursuing a larger definitive clinical trial, they await results from the ongoing phase 2 M14-361 study, in which patients with extensive-stage NSCLC are receiving platinum doublet therapy with carboplatin-etoposide plus either veliparib or placebo.

Funders included the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and the National Cancer Institute. Dr. Owonikoko reported ties to Novartis, Astellas Pharma, Celgene, and several other pharmaceutical companies.

SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Advanced fibrosis affected 5.9% of adults with low-normal thyroid function or subclinical hypothyroidism – more than double the prevalence among adults with strict-normal thyroid function (2.8%; P less than .001), according to the results of a large survey study.

Based on these findings, therapy to improve low thyroid function might help prevent advanced fibrosis secondary to nonalcoholic fatty liver disease, wrote Donghee Kim, MD, PhD, of Stanford University (Calif.), together with his associates in Clinical Gastroenterology and Hepatology.

Prior research has linked low-normal thyroid function with obesity, cardiometabolic diseases, and fractures. For this study, Dr. Kim and his coinvestigators analyzed data from 7,259 adults who lacked major etiologies of chronic liver disease and were included in the National Health and Nutrition Examination Survey between 2007 and 2012.

After accounting for demographic, socioeconomic, and clinical variables, the odds of biopsy-confirmed advanced fibrosis were 100% higher in adults with low-normal thyroid function or subclinical hypothyroidism, compared with adults with strict-normal thyroid function (odds ratio, 2.0; 95% confidence interval, 1.2-3.3). The prevalence and odds of advanced fibrosis was similar in each of these two subgroups. Furthermore, low thyroid function remained strongly linked with advanced fibrosis after accounting for insulin resistance using data from fasting subjects (OR, 2.3; 95% CI, 1.2-4.4).

Previously, Dr. Kim and his coinvestigators found a strong link between biopsy-proven advanced fibrosis and low-normal thyroid function or subclinical hypothyroidism among adults in Korea. “These [new] results are consistent with our previous observations in [an] Asian population, and show their generalizability to the Western world across all ethnicities.”

The researchers did not acknowledge external funding sources. They reported having no conflicts of interest.

SOURCE: Kim D et al. Clin Gastroenterol Hepatol. 2018 Nov 17. doi: 10.1016/j.cgh.2018.11.024.

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Adverse events limited the dose intensity or schedule of chemotherapy when added to nivolumab in patients with treatment-naive advanced gastric cancer, according to results from a small, phase 2 trial.

Fully 95% of patients delayed or reduced the dose of chemotherapy because of adverse events. Serious (grade 3 or higher) treatment-related adverse events affected 15% of patients and 13% of patients stopped treatment because of adverse events, said Narikazu Boku, MD, PhD, of National Cancer Center Hospital in Tokyo, together with his associates. The findings were published in Annals of Oncology.

Nivolumab (Opdivo) is not approved for treating gastric cancer in the United States but is approved as third-line or later therapy in several other countries. In the phase 2 ATTRACTION-4 trial, 39 patients with previously untreated, unresectable, advanced, or recurrent gastric or gastroesophageal junction cancer received nivolumab (360 mg intravenously every 3 weeks), plus either S-1 (40 mg/m² orally twice daily for 14 days followed by 7 days off) or capecitabine (1000 mg/m² orally twice daily for 14 days followed by 7 days off), plus oxaliplatin (130 mg/m² intravenously on day 1 every 3 weeks).

For the regimen containing S-1, the most common serious adverse events requiring delays or reductions in chemotherapy were thrombocytopenia (57%), neutropenia (48%), and nausea (19%), followed by diarrhea, vomiting, abdominal pain, peripheral sensory neuropathy, and fatigue (14% each). For the regimen containing capecitabine, the most common of these adverse events were neutropenia (44%), decreased appetite (28%), and palmar-plantar erythrodysesthesia syndrome (22%), followed by nausea, vomiting, diarrhea, and peripheral sensory neuropathy (17% each). There were no treatment-related deaths.

Efficacy endpoints were secondary and limited by small sample size. Nonetheless, regardless of which of the two chemotherapy regimens patients received, about two-thirds had a complete or partial treatment response, which is “numerically higher” than that reported for either chemotherapy regimen alone, the researchers wrote. After a median follow-up of 13.2 months, median overall survival was not reached, while median progression-free survival was 9.7 months for the S-1-based regimen and 10.6 months for the capecitabine-based regimen. Antitumor response appeared to be unrelated to programmed death–ligand 1 status.

Based on the findings, both nivolumab-chemotherapy regimens have “manageable safety profile and clinically relevant antitumor profile,” Dr. Boku and his coinvestigators stated. The second part of ATTRACTION-4 has recruited a larger group of patients and should shed more light on efficacy.

Ono Pharmaceutical and Bristol-Myers Squibb funded the work. Dr. Boku reported financial ties to both companies and to AstraZeneca and Chugai Pharmaceutical.

SOURCE: Boku N et al. Ann Oncol. 2018 Dec 19. doi: 10.1093/annonc/mdy540.

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Low-dose treatment with plerixafor, a CXC chemokine receptor 4 antagonist, was well tolerated and markedly improved severe presentations of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in three patients who could not receive granulocyte colony-stimulating factor therapy, investigators reported.

“Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus–associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly,” David H. McDermott, MD, of the National Institute of Allergy and Infectious Diseases and his colleagues wrote in the New England Journal of Medicine.

WHIM syndrome is a primary immunodeficiency disorder characterized by panleukopenia and caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Granulocyte colony-stimulating factor (G-CSF) therapy improves neutropenia in these patients, but not other cytopenias.

Previously, the investigators treated three WHIM syndrome patients with plerixafor (Mozobil), which was well tolerated and led to sustained increases in circulating neutrophils, lymphocytes, and monocytes. The current report is of three patients with advanced WHIM syndrome who received open-label plerixafor because they were ineligible for a randomized trial of this drug.

After treatment initiation, infection frequency dropped by 85% in one patient and declined markedly in all three patients. Lymphocyte counts improved the most in two patients while neutrophils were most responsive in the third patient. Warts partially resolved in two patients, of which one patient also experienced partial resolution of head and neck squamous cell carcinoma. This patient later died of a multidrug-resistant Pseudomonas aeruginosa infection after undergoing a 9-hour surgery.

In the third patient, plerixafor therapy led to clearance of TSPyV and 17 human papillomavirus (HPV) infections, with consequent resolution of chronic, progressive, multifocal eczematoid and follicular lesions, the researchers reported. The study dose was relatively low – about 10% of the stem-cell mobilization dose – and did not cause bone pain or other treatment-emergent adverse events, despite the relatively long treatment course (19-52 months).

A separate, phase 3 trial (NCT02231879) has enrolled 19 patients. Primary results are expected in 2020.

The National Institutes of Health funded the work. Dr. McDermott reported a pending patent to reduce CXCR4 expression and/or function to enhance engraftment of hematopoietic stem cells.

SOURCE: McDermott DH et al. N Engl J Med. 2019;380:163-70.
 

Patients with ankylosing spondylitis whose baseline C-reactive protein (CRP) levels were more than three times the upper limit of normal were significantly more likely to respond to 12 weeks of etanercept therapy than were patients with normal baseline CRP levels, investigators reported.

In a post hoc study of 867 patients who received etanercept during clinical trials, the adjusted odds of achieving 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) at week 12 were 190% higher when CRP levels were “very high” rather than normal at baseline (odds ratio, 2.9; 95% confidence interval, 1.8-4.7). Very-high baseline CRP levels (more than three times the upper limit of normal) also significantly predicted week-12 ASAS50, a change in Ankylosing Spondylitis Disease Activity Score based on CRP (ASDAS-CRP) greater than 1.1 (clinically important improvement), and an ASDAS-CRP less than 1.3 (inactive disease), while a normalization of very-high CRP levels by 2, 4, or 8 weeks of treatment was a significant predictor of achieving week-12 ASDAS inactive disease. “Patient-reported outcomes were less consistent predictors of response,” Xenofon Baraliakos, MD, of Ruhr University Bochum in Herne, Germany, and his coinvestigators wrote in Seminars in Arthritis and Rheumatism.


While the advent of tumor necrosis factor (TNF) antagonists has greatly improved outcomes in ankylosing spondylitis, symptom ambiguity and a lack of objective response criteria still impede early diagnosis and radiographic interpretation. Elevated baseline CRP predicted clinical response to anti-TNF therapy by patients with ankylosing spondylitis in several prior post hoc studies. To further evaluate this finding, the researchers pooled and analyzed data from four randomized, placebo-controlled trials of etanercept in adults with ankylosing spondylitis. In all, 43% of patients had a normal baseline CRP level, 34% had a level that was elevated but did not exceed three times the upper limit of normal, and 23% had a very-high level.

Age of onset, disease duration, and baseline Bath Ankylosing Spondylitis Functional Index also predicted response to etanercept therapy. After controlling for these covariates, a very-high baseline CRP remained a significant predictor for all four week-12 outcomes. This finding points to the value of aggressive, early treatment to normalize CRP in patients with ankylosing spondylitis, the researchers wrote. “Bending the curve of inflammation in the early disease may alter the long-term trajectory of ankylosing spondylitis, which is an opportunity that may not exist in the later stages.”

Thus, CRP, in addition to patient-reported and clinical outcomes, might be useful to help monitor response to anti-TNF therapy, the investigators wrote. It remains unclear whether elevated CRP levels also predict future treatment response in patients who are currently clinically improved or stable.

Pfizer funded the post hoc analysis and acquired the company that had funded the trials (Wyeth). Dr. Baraliakos reported consultancy and speaker fees from Pfizer, AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Merck, Novartis, Sandoz, and UCB. Two coinvestigators were Pfizer employees. A third coinvestigator was contracted by Pfizer to provide statistical support.

SOURCE: Baraliakos X et al. Semin Arthritis Rheum. 2018 Nov 2. doi: 10.1016/j.semarthrit.2018.10.019.

Patients with ankylosing spondylitis whose baseline C-reactive protein (CRP) levels were more than three times the upper limit of normal were significantly more likely to respond to 12 weeks of etanercept therapy than were patients with normal baseline CRP levels, investigators reported.

In a post hoc study of 867 patients who received etanercept during clinical trials, the adjusted odds of achieving 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) at week 12 were 190% higher when CRP levels were “very high” rather than normal at baseline (odds ratio, 2.9; 95% confidence interval, 1.8-4.7). Very-high baseline CRP levels (more than three times the upper limit of normal) also significantly predicted week-12 ASAS50, a change in Ankylosing Spondylitis Disease Activity Score based on CRP (ASDAS-CRP) greater than 1.1 (clinically important improvement), and an ASDAS-CRP less than 1.3 (inactive disease), while a normalization of very-high CRP levels by 2, 4, or 8 weeks of treatment was a significant predictor of achieving week-12 ASDAS inactive disease. “Patient-reported outcomes were less consistent predictors of response,” Xenofon Baraliakos, MD, of Ruhr University Bochum in Herne, Germany, and his coinvestigators wrote in Seminars in Arthritis and Rheumatism.


While the advent of tumor necrosis factor (TNF) antagonists has greatly improved outcomes in ankylosing spondylitis, symptom ambiguity and a lack of objective response criteria still impede early diagnosis and radiographic interpretation. Elevated baseline CRP predicted clinical response to anti-TNF therapy by patients with ankylosing spondylitis in several prior post hoc studies. To further evaluate this finding, the researchers pooled and analyzed data from four randomized, placebo-controlled trials of etanercept in adults with ankylosing spondylitis. In all, 43% of patients had a normal baseline CRP level, 34% had a level that was elevated but did not exceed three times the upper limit of normal, and 23% had a very-high level.

Age of onset, disease duration, and baseline Bath Ankylosing Spondylitis Functional Index also predicted response to etanercept therapy. After controlling for these covariates, a very-high baseline CRP remained a significant predictor for all four week-12 outcomes. This finding points to the value of aggressive, early treatment to normalize CRP in patients with ankylosing spondylitis, the researchers wrote. “Bending the curve of inflammation in the early disease may alter the long-term trajectory of ankylosing spondylitis, which is an opportunity that may not exist in the later stages.”

Thus, CRP, in addition to patient-reported and clinical outcomes, might be useful to help monitor response to anti-TNF therapy, the investigators wrote. It remains unclear whether elevated CRP levels also predict future treatment response in patients who are currently clinically improved or stable.

Pfizer funded the post hoc analysis and acquired the company that had funded the trials (Wyeth). Dr. Baraliakos reported consultancy and speaker fees from Pfizer, AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Merck, Novartis, Sandoz, and UCB. Two coinvestigators were Pfizer employees. A third coinvestigator was contracted by Pfizer to provide statistical support.

SOURCE: Baraliakos X et al. Semin Arthritis Rheum. 2018 Nov 2. doi: 10.1016/j.semarthrit.2018.10.019.

Patients with ankylosing spondylitis whose baseline C-reactive protein (CRP) levels were more than three times the upper limit of normal were significantly more likely to respond to 12 weeks of etanercept therapy than were patients with normal baseline CRP levels, investigators reported.

In a post hoc study of 867 patients who received etanercept during clinical trials, the adjusted odds of achieving 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) at week 12 were 190% higher when CRP levels were “very high” rather than normal at baseline (odds ratio, 2.9; 95% confidence interval, 1.8-4.7). Very-high baseline CRP levels (more than three times the upper limit of normal) also significantly predicted week-12 ASAS50, a change in Ankylosing Spondylitis Disease Activity Score based on CRP (ASDAS-CRP) greater than 1.1 (clinically important improvement), and an ASDAS-CRP less than 1.3 (inactive disease), while a normalization of very-high CRP levels by 2, 4, or 8 weeks of treatment was a significant predictor of achieving week-12 ASDAS inactive disease. “Patient-reported outcomes were less consistent predictors of response,” Xenofon Baraliakos, MD, of Ruhr University Bochum in Herne, Germany, and his coinvestigators wrote in Seminars in Arthritis and Rheumatism.


While the advent of tumor necrosis factor (TNF) antagonists has greatly improved outcomes in ankylosing spondylitis, symptom ambiguity and a lack of objective response criteria still impede early diagnosis and radiographic interpretation. Elevated baseline CRP predicted clinical response to anti-TNF therapy by patients with ankylosing spondylitis in several prior post hoc studies. To further evaluate this finding, the researchers pooled and analyzed data from four randomized, placebo-controlled trials of etanercept in adults with ankylosing spondylitis. In all, 43% of patients had a normal baseline CRP level, 34% had a level that was elevated but did not exceed three times the upper limit of normal, and 23% had a very-high level.

Age of onset, disease duration, and baseline Bath Ankylosing Spondylitis Functional Index also predicted response to etanercept therapy. After controlling for these covariates, a very-high baseline CRP remained a significant predictor for all four week-12 outcomes. This finding points to the value of aggressive, early treatment to normalize CRP in patients with ankylosing spondylitis, the researchers wrote. “Bending the curve of inflammation in the early disease may alter the long-term trajectory of ankylosing spondylitis, which is an opportunity that may not exist in the later stages.”

Thus, CRP, in addition to patient-reported and clinical outcomes, might be useful to help monitor response to anti-TNF therapy, the investigators wrote. It remains unclear whether elevated CRP levels also predict future treatment response in patients who are currently clinically improved or stable.

Pfizer funded the post hoc analysis and acquired the company that had funded the trials (Wyeth). Dr. Baraliakos reported consultancy and speaker fees from Pfizer, AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Merck, Novartis, Sandoz, and UCB. Two coinvestigators were Pfizer employees. A third coinvestigator was contracted by Pfizer to provide statistical support.

SOURCE: Baraliakos X et al. Semin Arthritis Rheum. 2018 Nov 2. doi: 10.1016/j.semarthrit.2018.10.019.

Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.

megaflopp/Thinkstock

Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.

The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.


To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.

Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.

“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.

Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.

SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112

Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.

megaflopp/Thinkstock

Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.

The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.


To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.

Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.

“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.

Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.

SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112

Only 15% of patients prescribed dextromethorphan hydrobromide plus quinidine sulfate had pseudobulbar affect due to multiple sclerosis or amyotrophic lateral sclerosis, the condition for which this drug is labeled, according to an analysis of two national commercial insurance claims databases published online Jan. 7 in JAMA Internal Medicine.

megaflopp/Thinkstock

Conversely, 57% of patients prescribed dextromethorphan-quinidine (Nuedexta) had a diagnosis of Parkinson’s disease or dementia. Furthermore, according to Medicare Part D data, prescriptions for dextromethorphan-quinidine rose 15-fold during a recent 6-year period, with a concurrent 50-fold rise in reimbursement. “In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination,” Michael Fralick, MD, and his associates at Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote in their paper.

The Food and Drug Administration approved Nuedexta in 2010 for the treatment of pseudobulbar affect after it produced modest improvements in laughing or crying episodes in a 12-week, placebo-controlled trial of patients with multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS). The initial FDA label noted: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.” Then, in 2015, patients with Alzheimer’s disease showed modest improvements in agitation scores when they received dextromethorphan-quinidine in a 10-week, placebo-controlled, industry-designed and sponsored trial. Although the dextromethorphan-quinidine arm also had higher rates of falls, urinary tract infections, and serious adverse events, the prescribing information was updated in 2015 to remove the statement about patients with dementia.


To assess real-world prescribing patterns for dextromethorphan-quinidine, Dr. Fralick and his associates analyzed data from 12,858 patients who filled a prescription for this medication between 2010 and 2017 and were recorded in the Optum Clinformatics Data Mart or Truven Health MarketScan databases. Only 8.4% of patients had a diagnosis of MS and only 6.8% had ALS, while 57% had dementia and/or Parkinson’s disease and 28% had an unknown diagnosis. The number of patients prescribed dextromethorphan-quinidine rose from nearly 3,300 in 2011 to more than 50,000 in 2016, while spending on this medication by the Centers for Medicare & Medicaid Services increased from $3.9 million to $200.4 million during the same time period.

Current treatments for behavioral symptoms of dementia “are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients,” the researchers wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.

“Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used,” the authors suggested.

Study funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program. One author disclosed grants from the Food and Drug Administration Office of Generic Drugs and Division of Health Communication unrelated to the study topic.

SOURCE: Fralick M et al. JAMA Inter Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6112

Pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, showed promising safety and efficacy in a phase 2 trial of 15 adults with HER2-mutant non–small cell lung cancer and also topped afatinib in in vitro and murine studies, investigators reported.

In the phase 2 trial, objective response rate was 53%, a median overall survival was 12.9 months, and median progression-free survival was 6.4 months, wrote Yan Wang of Tongji University, Shanghai, China, together with associates. Pyrotinib showed superior antitumor activity, compared with afatinib, in a patient-derived organoid (P = .004) and xenograft mouse model (P = .0471), they reported in Annals of Oncology.

About 2% to 3% of patients with non–small cell lung cancer (NSCLC) have HER2 mutations, which most often involve an exon 20 insertion. Because HER2-targeting agents such as afatinib, dacomitinib, neratinib, and trastuzumab have limited activity against these cancers, patients usually receive chemotherapy, even though it is less effective than in lung cancers with ALK or ROS1 rearrangements.

To seek a better treatment option, the researchers created a HER2YVMA insertion patient-derived organoid model and a patient-derived xenograft mouse model, both of which confirmed the superior antitumor activity of pyrotinib, compared with afatinib or T-DM1 (ado-trastuzumab emtansine). For example, tumor burdens in mice fell by an average of 52% with pyrotinib but rose by 25% on afatinib and by 11% on T-DM1.

Accordingly, the researchers conducted a phase 2 trial of oral pyrotinib (400 mg daily) in 15 adults with NSCLC characterized by HER2 mutations in exon 20 or exon 19, the tyrosine kinase domain. Patients had an Eastern Cooperative Oncology Group performance status of 0-2, lacked symptomatic brain metastases, and had progressed on standard therapy.

In all, nine patients (60%) developed adverse events, the most common of which were grade 1 or 2 diarrhea, decreased hemoglobin levels, and hypocalcemia. There were no grade 3 or 4 events. Progression-free survival ranged from 1.7 to 23.4 months and one-third of patients stayed on pyrotinib for more than 1 year. Among two patients with asymptomatic brain metastases, one stopped pyrotinib at 4 weeks because of primary tumor progression but the other achieved stable disease on treatment. Three (23%) patients developed incident brain metastases on pyrotinib. The sole patient who progressed on a prior HER2-targeted therapy (afatinib) responded to pyrotinib.

Taken together, these findings support further study of pyrotinib in patients with NSCLC with HER2 exon 20 mutations, the researchers wrote. They have initiated a multicenter, phase 2 trial, which is currently in progress.

Funders included the National Natural Science Foundation of China, the “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the Science and Technology Commission of Shanghai Municipality, the Development Fund for Shanghai Talents, the University of Iowa Start-up Funds, and the American Cancer Society. The investigators reported having no conflicts of interest.

SOURCE: Wang Y et al. Ann Oncol. 2018 Dec 31. doi: 10.1093/annonc/mdy542.

Pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, showed promising safety and efficacy in a phase 2 trial of 15 adults with HER2-mutant non–small cell lung cancer and also topped afatinib in in vitro and murine studies, investigators reported.

In the phase 2 trial, objective response rate was 53%, a median overall survival was 12.9 months, and median progression-free survival was 6.4 months, wrote Yan Wang of Tongji University, Shanghai, China, together with associates. Pyrotinib showed superior antitumor activity, compared with afatinib, in a patient-derived organoid (P = .004) and xenograft mouse model (P = .0471), they reported in Annals of Oncology.

About 2% to 3% of patients with non–small cell lung cancer (NSCLC) have HER2 mutations, which most often involve an exon 20 insertion. Because HER2-targeting agents such as afatinib, dacomitinib, neratinib, and trastuzumab have limited activity against these cancers, patients usually receive chemotherapy, even though it is less effective than in lung cancers with ALK or ROS1 rearrangements.

To seek a better treatment option, the researchers created a HER2YVMA insertion patient-derived organoid model and a patient-derived xenograft mouse model, both of which confirmed the superior antitumor activity of pyrotinib, compared with afatinib or T-DM1 (ado-trastuzumab emtansine). For example, tumor burdens in mice fell by an average of 52% with pyrotinib but rose by 25% on afatinib and by 11% on T-DM1.

Accordingly, the researchers conducted a phase 2 trial of oral pyrotinib (400 mg daily) in 15 adults with NSCLC characterized by HER2 mutations in exon 20 or exon 19, the tyrosine kinase domain. Patients had an Eastern Cooperative Oncology Group performance status of 0-2, lacked symptomatic brain metastases, and had progressed on standard therapy.

In all, nine patients (60%) developed adverse events, the most common of which were grade 1 or 2 diarrhea, decreased hemoglobin levels, and hypocalcemia. There were no grade 3 or 4 events. Progression-free survival ranged from 1.7 to 23.4 months and one-third of patients stayed on pyrotinib for more than 1 year. Among two patients with asymptomatic brain metastases, one stopped pyrotinib at 4 weeks because of primary tumor progression but the other achieved stable disease on treatment. Three (23%) patients developed incident brain metastases on pyrotinib. The sole patient who progressed on a prior HER2-targeted therapy (afatinib) responded to pyrotinib.

Taken together, these findings support further study of pyrotinib in patients with NSCLC with HER2 exon 20 mutations, the researchers wrote. They have initiated a multicenter, phase 2 trial, which is currently in progress.

Funders included the National Natural Science Foundation of China, the “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the Science and Technology Commission of Shanghai Municipality, the Development Fund for Shanghai Talents, the University of Iowa Start-up Funds, and the American Cancer Society. The investigators reported having no conflicts of interest.

SOURCE: Wang Y et al. Ann Oncol. 2018 Dec 31. doi: 10.1093/annonc/mdy542.

Pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, showed promising safety and efficacy in a phase 2 trial of 15 adults with HER2-mutant non–small cell lung cancer and also topped afatinib in in vitro and murine studies, investigators reported.

In the phase 2 trial, objective response rate was 53%, a median overall survival was 12.9 months, and median progression-free survival was 6.4 months, wrote Yan Wang of Tongji University, Shanghai, China, together with associates. Pyrotinib showed superior antitumor activity, compared with afatinib, in a patient-derived organoid (P = .004) and xenograft mouse model (P = .0471), they reported in Annals of Oncology.

About 2% to 3% of patients with non–small cell lung cancer (NSCLC) have HER2 mutations, which most often involve an exon 20 insertion. Because HER2-targeting agents such as afatinib, dacomitinib, neratinib, and trastuzumab have limited activity against these cancers, patients usually receive chemotherapy, even though it is less effective than in lung cancers with ALK or ROS1 rearrangements.

To seek a better treatment option, the researchers created a HER2YVMA insertion patient-derived organoid model and a patient-derived xenograft mouse model, both of which confirmed the superior antitumor activity of pyrotinib, compared with afatinib or T-DM1 (ado-trastuzumab emtansine). For example, tumor burdens in mice fell by an average of 52% with pyrotinib but rose by 25% on afatinib and by 11% on T-DM1.

Accordingly, the researchers conducted a phase 2 trial of oral pyrotinib (400 mg daily) in 15 adults with NSCLC characterized by HER2 mutations in exon 20 or exon 19, the tyrosine kinase domain. Patients had an Eastern Cooperative Oncology Group performance status of 0-2, lacked symptomatic brain metastases, and had progressed on standard therapy.

In all, nine patients (60%) developed adverse events, the most common of which were grade 1 or 2 diarrhea, decreased hemoglobin levels, and hypocalcemia. There were no grade 3 or 4 events. Progression-free survival ranged from 1.7 to 23.4 months and one-third of patients stayed on pyrotinib for more than 1 year. Among two patients with asymptomatic brain metastases, one stopped pyrotinib at 4 weeks because of primary tumor progression but the other achieved stable disease on treatment. Three (23%) patients developed incident brain metastases on pyrotinib. The sole patient who progressed on a prior HER2-targeted therapy (afatinib) responded to pyrotinib.

Taken together, these findings support further study of pyrotinib in patients with NSCLC with HER2 exon 20 mutations, the researchers wrote. They have initiated a multicenter, phase 2 trial, which is currently in progress.

Funders included the National Natural Science Foundation of China, the “Shuguang Program” supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission, the Science and Technology Commission of Shanghai Municipality, the Development Fund for Shanghai Talents, the University of Iowa Start-up Funds, and the American Cancer Society. The investigators reported having no conflicts of interest.

SOURCE: Wang Y et al. Ann Oncol. 2018 Dec 31. doi: 10.1093/annonc/mdy542.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Children who developed inflammatory bowel disease before the age of 18 had a three- to fivefold increase in risk of death, compared with others in a large, retrospective registry study.

The study, which spanned a recent 50-year period, found “no evidence that [these] hazard ratios have changed since the introduction of immunomodulators and biologics,” wrote Ola Olén, MD, PhD, of Karolinska University Hospital in Sola, Sweden, together with her associates. Malignancy was the most frequent cause of death among patients with childhood-onset inflammatory bowel disease, followed by digestive diseases and infections. Absolute numbers of premature deaths were low, but the increase in relative risk was highest among patients with childhood-onset ulcerative colitis with primary sclerosing cholangitis and patients who had a first-degree relative with ulcerative colitis. The findings were published in the February issue of Gastroenterology.

Inflammatory bowel disease is thought to be more severe when it begins in childhood, but data on mortality for these patients are lacking. Using national Swedish health registries, Dr. Olén and her associates compared deaths among 9,442 children and adolescents with inflammatory bowel disease with those among 93,180 others matched by sex, age, and place of residence. Both groups were typically followed through age 30 years, and the study covered 1964 through 2014.

In all, there were 294 deaths among patients with childhood-onset inflammatory bowel disease (2.1 deaths per 1,000 person-years) and 940 deaths among matched individuals (0.7 deaths per 1,000 person-years), for a statistically significant adjusted hazard ratio of 3.2 (95% confidence interval, 2.8-3.7). For every 694 patients with childhood-onset inflammatory bowel disease who were followed through adulthood, there was one additional death per year, compared with a demographically similar population, the researchers determined.

SOURCE: Olén O et al. Gastroenterology. 2018 Oct 17. doi: 10.1053/j.gastro.2018.10.028.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

Among patients with diminutive (1-5 mm) colonic polyps, multiplicity was a significant risk factor for advanced metachronous colonic neoplasia, while advanced histologic features alone were not, according to the results of a pooled analysis of data from 64,344 patients.

Metachronous advanced neoplasia affected similar proportions of patients with and without high-risk diminutive polyps (17.6% vs. 14.6%, respectively; relative risk, 1.13; 95% confidence interval, 0.79-1.61), reported Jasper L.A. Vleugels, MD, of the University of Amsterdam, together with his associates. However, patients with at least three nonadvanced (diminutive or small) adenomas were at significantly increased risk of metachronous advanced neoplasia, compared with low-risk patients (overall risk ratio, 2.12; 95% CI, 1.89-2.38), the investigators wrote in the February issue of Gastroenterology.

This multicenter study spanned 12 prospectively evaluated cohorts of patients in the United States and Europe. All patients underwent colonoscopy because of a positive fecal immunochemical test result or for the purpose of screening, surveillance, or evaluation of symptoms. The researchers defined low-risk patients as individuals with one or two diminutive or small nonadvanced adenomas. In contrast, “high-risk” patients had a polyp with advanced histology (at least a 25% villous component, high-grade dysplasia, or colonic rectal carcinoma), at least three diminutive (1-5 mm) or small (6-9 mm) nonadvanced adenomas, or an adenomatous or sessile serrated lesion measuring at least 10 mm.

Among more than 50,000 diminutive polyps in the dataset, the prevalence of advanced histologic features was 7.1% among patients who underwent colonoscopy because of a positive fecal immunochemical test and 1.5% among those who had a colonoscopy for other reasons (P = .04). However, statistically similar proportions of patients in each of these subgroups were classified as “high risk” because of advanced histology (0.8% and 0.4%, respectively) or multiplicity (3.8% and 3.0%, respectively). Because metachronous advanced neoplasia was detected in similar proportions of patients with and without diminutive polyps with advanced histologic features (17.6% vs. 14.6%, respectively), the presence of such features did not independently predict metachronous advanced neoplasia, either overall (relative risk, 1.13; 95% CI, 0.79-1.61), or in either subgroup.

SOURCE: Vleugels J et al. Gastroenterology. 2018 Nov 2. doi: 10.1053/j.gastro.2018.10.050.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.

For patients with treatment-refractory ulcerative colitis, accelerated induction with infliximab did not appear to reduce the need for colectomy, while adding a calcineurin inhibitor to vedolizumab safely and effectively induced clinical remission in nearly half of patients, according to the results of two studies published in Clinical Gastroenterology and Hepatology.

The first study retrospectively evaluated 213 patients with acute severe ulcerative colitis who received infliximab rescue therapy at three gastroenterology centers between 2005 and 2017. Rates of subsequent colectomy were similar whether patients received infliximab (5 mg/kg) at weeks 0, 2, and 6, or were on an accelerated schedule (8% vs. 9%, respectively; adjusted odds ratio, 1.35; 95% confidence interval, 0.38-4.82).

However, among patients who received accelerated treatment, those who received a higher initial dose of infliximab (10 mg/kg) were less likely to subsequently undergo colectomy than those who started at 5 mg/kg and received “chaser” 5-mg or 10-mg doses before week 2, reported Niharika Nalagatla, MD, of Massachusetts General Hospital in Boston, with her associates. “While there was no statistically significant difference [between these groups], there were numerically lower rates of in-hospital and long-term colectomy in the 10 mg/kg group, with a trend toward statistical significance at 2 years [OR, 0.44; 95% CI, 0.18-1.12; P = .08],” they added.

They reported similar results from their systematic review and meta-analysis of seven studies of infliximab induction schedules in patients with acute severe ulcerative colitis. Accordingly, they called for prospective studies to identify which patients are most likely to benefit from accelerated infliximab therapy.

The second study, which was prospective, included 11 patients with treatment-refractory ulcerative colitis who initially received vedolizumab immunotherapy and then started on a calcineurin inhibitor (either tacrolimus or cyclosporine) during their first 12 months of treatment. Rates of steroid-free clinical remission (Harvey-Bradshaw index score less than 4 or short clinical colitis activity index score less than 2) were 55% at week 14 and 45% at week 52, reported Britt Christensen, MD, of the University of Chicago and the Royal Melbourne Hospital, with her associates.

Two of these patients were hospitalized for intravenous cyclosporine plus corticosteroid therapy because they failed to respond to 3 months of treatment with vedolizumab plus prednisolone (40 mg), the investigators noted. One patient did not respond and ultimately underwent colectomy, while the other tapered off cyclosporine after 51 days of treatment and remained in steroid-and calcineurin-free clinical remission at 12 months.

Serious adverse events were uncommon, reflecting the relatively good safety profile of vedolizumab. Combination antitumor necrosis factor and calcineurin inhibitor therapy has been linked to severe infections and deaths, and clinical trials of vedolizumab excluded patients with calcineurin inhibitor exposure. However, vedolizumab primarily targets the localized immune system of the gut, so adding an agent “with broad immune-suppressing effects would not [lead to greater] infective and other complications,” the investigators wrote. “Indeed, no significant toxicity was observed in our series, despite the fact that many patients were on quadruple immunosuppressive therapy, at least initially.”

Dr. Nalagatla reported receiving support from the National Institutes of Health and the Crohn’s & Colitis Foundation. She reported having no relevant conflicts of interest. One of her coinvestigators reported ties to AbbVie, Takeda, Gilead, Merck, and Pfizer. Dr. Christensen and her associates reported receiving support from the University of Chicago and the government of Australia. Dr. Christensen reported ties to Janssen, AbbVie, Takeda, and Pfizer, and four of her coinvestigators also reported ties to a number of pharmaceutical companies.

SOURCES: Nalagatla N et al. Clin Gastroenterol Hepatol. 2018 Jun 23. doi: 10.1016/j.cgh.2018.06.031; Christensen B et al. Clin Gastroenterol Hepatol. 2018 May 8. doi: 10.1016/j.cgh.2018.04.060.