Pharmacology

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

BOSTON – The combination of nivolumab and ipilimumab provided a “robust” clinical benefit and had manageable hepatic adverse events in a phase 2 study of sorafenib-treated patients with advanced hepatocellular carcinoma (HCC), an investigator said at the annual meeting of the American Association for the Study of Liver Diseases.

Response rates for the combination treatment exceeded 30% in CheckMate 040, with median overall survival approaching 23 months in one arm of this randomized trial, said Bruno Sangro, MD, PhD, of Clinica Universidad de Navarra, Pamplona, Spain.

The combination had a manageable safety profile with no new safety signals, and most immune-mediated adverse events resolved, including hepatic events, Dr. Sango said in an oral abstract session.

“The favorable benefit/risk profile observed we believe warrants further investigation in patients with HCC,” Dr. Sangro said in his presentation to attendees, adding that a phase 3 study of the combination is already ongoing.

On Nov. 11, 2019, Bristol-Myers Squibb announced its application for nivolumab plus ipilimumab for previously treated advanced HCC had been accepted for priority review by the Food and Drug Administration, which had furthermore granted breakthrough therapy designation for that potential indication.

In September 2017, the FDA approved nivolumab as monotherapy for patients with HCC previously treated with sorafenib. That action was based on results from CheckMate 040 showing on overall response rate of 14% and a median overall survival of 15 months, Dr. Sangro said.

The combination of the programmed death–1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab, which has shown durable responses in other tumor types, may promote synergistic immune activity in HCC through their distinct but complementary mechanisms, according to the investigator.

The first report on the combination of nivolumab plus ipilimumab in CheckMate 040, reported earlier this year at the annual meeting of the American Society of Clinical Oncology, indicated that the combination produced responses that were robust and durable.

Dr. Sangro reported data on 148 patients with advanced HCC previously treated with sorafenib randomized to one of three different dosing regimens with nivolumab plus ipilimumab.

Response rates ranged from 31% to 32% in the three arms, while one particular dosing regimen given every 3 weeks for four cycles had a median overall survival of 22.8 months.

“Just to give a perspective, let me remind you that patients receiving placebo post sorafenib in a number of phase 3 trials have very consistently shown median overall survivals of around 8 months,” Dr. Sangro told attendees.

Hepatic treatment-related adverse events of any grade reported within 30 days of the last dose were seen in 39% of patients in that arm, Dr. Sangro said.

Hepatic events thought to be immune mediated were typically managed with a short course of high-dose corticosteroids, according to Dr. Sangro, who said no patients rechallenged with treatment experienced a recurrence of the event.

Most of the hepatic adverse events occurred early, with a median time to onset of 5.6-8.1 weeks, he said, and most resolved at a median of 6.1-7.9 weeks.

In the ongoing phase 3 CheckMate 9DW study, patients with advanced HCC who are naive to systemic therapy are being randomized to the combination of nivolumab plus ipilimumab, or to the investigators’ choice of either sorafenib or lenvatinib, with a primary endpoint of overall survival, Dr. Sangro said.

The study was supported by Bristol-Myers Squibb and ONO Pharmaceutical. Dr. Sangro reported disclosures related to Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, Terumo, H3 Biomedicine, Ipsen, Lilly, Exelixis, Roche, and Ipsen.

SOURCE: Sangro B et al. The Liver Meeting 2019, Abstract 200.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.

“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.

The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.

To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).

In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.

Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.

Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
 

Results

Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).

Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.

The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).

Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.

The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.

“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”

This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.

SOURCE: Lizee G et al. SITC 2019. Abstract O18.

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

The tyrosine kinase inhibitor (TKI) lorlatinib showed deep responses and intracranial activity in both TKI-pretreated and TKI-naive patients with advanced ROS1-positive non–small cell lung cancer (NSCLC), according to results from a phase 1-2 trial.

“We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive NSCLC,” wrote Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, and colleagues. Their report is in The Lancet Oncology.

The single-arm, open-label study included 69 patients with advanced ROS1-positive disease with or without CNS involvement. The effects of lorlatinib were evaluated across 28 institutions in 12 different countries around the globe.

At baseline, the median age of study participants was 54 years (range, 44-61 years), and 57% were positive for brain metastases.

Study participants received 100 mg of oral lorlatinib once daily in repeated 21-day cycles. Drug therapy was continued until death, disease progression, unacceptable toxicity, or withdrawal of consent.

The primary outcome measured was intracranial and overall response. Activity outcomes were evaluated in subjects given a minimum of one dose of lorlatinib.

A total of 58% of patients were previously treated with crizotinib, while 30% of patients were TKI-naive. Among 40 crizotinib-pretreated patients, 14 patients (35%) had an objective response, with a median duration of response and PFS of 13.8 and 8.5 months, respectively.

Among 21 TKI-naive patients, 13 patients (62%) had an objective response, with a median duration of response and PFS of 25.3 and 21 months, respectively.

“Intracranial responses were achieved in seven (64%) of 11 TKI-naive patients and 12 (50%) of 24 previous crizotinib-only patients,” they reported.

With respect to safety, serious lorlatinib-related adverse events were observed in 7% of patients, with no therapy-related deaths reported. The most frequently seen grade 3-4 TEAEs were hypertriglyceridemia (19%) and hypercholesterolemia (14%).

The researchers noted a key limitation of the study was the small sample size; however, due to the rare nature of ROS1 rearrangements in patients with NSCLC, increasing enrollment for future studies could be challenging.

“Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent,” they concluded.

Pfizer funded the study. The authors reported financial affiliations with Ariad, Blueprint Medicines, Chugai Pharmaceutical, Daiichi Sankyo, EMD Serono, Pfizer, KSQ Therapeutics, Servier, TP Therapeutics, and other companies.

SOURCE: Shaw AT et al. Lancet Oncol. 2019 Oct 25. doi: 10.1016/S1470-2045(19)30655-2.

The tyrosine kinase inhibitor (TKI) lorlatinib showed deep responses and intracranial activity in both TKI-pretreated and TKI-naive patients with advanced ROS1-positive non–small cell lung cancer (NSCLC), according to results from a phase 1-2 trial.

“We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive NSCLC,” wrote Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, and colleagues. Their report is in The Lancet Oncology.

The single-arm, open-label study included 69 patients with advanced ROS1-positive disease with or without CNS involvement. The effects of lorlatinib were evaluated across 28 institutions in 12 different countries around the globe.

At baseline, the median age of study participants was 54 years (range, 44-61 years), and 57% were positive for brain metastases.

Study participants received 100 mg of oral lorlatinib once daily in repeated 21-day cycles. Drug therapy was continued until death, disease progression, unacceptable toxicity, or withdrawal of consent.

The primary outcome measured was intracranial and overall response. Activity outcomes were evaluated in subjects given a minimum of one dose of lorlatinib.

A total of 58% of patients were previously treated with crizotinib, while 30% of patients were TKI-naive. Among 40 crizotinib-pretreated patients, 14 patients (35%) had an objective response, with a median duration of response and PFS of 13.8 and 8.5 months, respectively.

Among 21 TKI-naive patients, 13 patients (62%) had an objective response, with a median duration of response and PFS of 25.3 and 21 months, respectively.

“Intracranial responses were achieved in seven (64%) of 11 TKI-naive patients and 12 (50%) of 24 previous crizotinib-only patients,” they reported.

With respect to safety, serious lorlatinib-related adverse events were observed in 7% of patients, with no therapy-related deaths reported. The most frequently seen grade 3-4 TEAEs were hypertriglyceridemia (19%) and hypercholesterolemia (14%).

The researchers noted a key limitation of the study was the small sample size; however, due to the rare nature of ROS1 rearrangements in patients with NSCLC, increasing enrollment for future studies could be challenging.

“Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent,” they concluded.

Pfizer funded the study. The authors reported financial affiliations with Ariad, Blueprint Medicines, Chugai Pharmaceutical, Daiichi Sankyo, EMD Serono, Pfizer, KSQ Therapeutics, Servier, TP Therapeutics, and other companies.

SOURCE: Shaw AT et al. Lancet Oncol. 2019 Oct 25. doi: 10.1016/S1470-2045(19)30655-2.

The tyrosine kinase inhibitor (TKI) lorlatinib showed deep responses and intracranial activity in both TKI-pretreated and TKI-naive patients with advanced ROS1-positive non–small cell lung cancer (NSCLC), according to results from a phase 1-2 trial.

“We investigated the antitumour activity and safety of lorlatinib in advanced, ROS1-positive NSCLC,” wrote Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, Boston, and colleagues. Their report is in The Lancet Oncology.

The single-arm, open-label study included 69 patients with advanced ROS1-positive disease with or without CNS involvement. The effects of lorlatinib were evaluated across 28 institutions in 12 different countries around the globe.

At baseline, the median age of study participants was 54 years (range, 44-61 years), and 57% were positive for brain metastases.

Study participants received 100 mg of oral lorlatinib once daily in repeated 21-day cycles. Drug therapy was continued until death, disease progression, unacceptable toxicity, or withdrawal of consent.

The primary outcome measured was intracranial and overall response. Activity outcomes were evaluated in subjects given a minimum of one dose of lorlatinib.

A total of 58% of patients were previously treated with crizotinib, while 30% of patients were TKI-naive. Among 40 crizotinib-pretreated patients, 14 patients (35%) had an objective response, with a median duration of response and PFS of 13.8 and 8.5 months, respectively.

Among 21 TKI-naive patients, 13 patients (62%) had an objective response, with a median duration of response and PFS of 25.3 and 21 months, respectively.

“Intracranial responses were achieved in seven (64%) of 11 TKI-naive patients and 12 (50%) of 24 previous crizotinib-only patients,” they reported.

With respect to safety, serious lorlatinib-related adverse events were observed in 7% of patients, with no therapy-related deaths reported. The most frequently seen grade 3-4 TEAEs were hypertriglyceridemia (19%) and hypercholesterolemia (14%).

The researchers noted a key limitation of the study was the small sample size; however, due to the rare nature of ROS1 rearrangements in patients with NSCLC, increasing enrollment for future studies could be challenging.

“Because crizotinib-refractory patients have few treatment options, lorlatinib could represent an important next-line targeted agent,” they concluded.

Pfizer funded the study. The authors reported financial affiliations with Ariad, Blueprint Medicines, Chugai Pharmaceutical, Daiichi Sankyo, EMD Serono, Pfizer, KSQ Therapeutics, Servier, TP Therapeutics, and other companies.

SOURCE: Shaw AT et al. Lancet Oncol. 2019 Oct 25. doi: 10.1016/S1470-2045(19)30655-2.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, can improve disease biomarkers in patients with primary biliary cholangitis (PBC), based on results of a phase 2 trial.

Will Pass/MDedge News

Compared with placebo, patients treated with cilofexor had significant reductions in serum alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), C-reactive protein (CRP), and primary bile acids, reported lead author Kris V. Kowdley, MD, of Swedish Medical Center in Seattle, and colleagues.

Dr. Kowdley, who presented findings at the annual meeting of the American Association for the Study of Liver Diseases, began by offering some context for the trial.

“There’s a strong rationale for FXR agonist therapy in PBC,” he said. “FXR is the key regulator of bile acid homeostasis, and FXR agonists have shown favorable effects on fibrosis, inflammatory activity, bile acid export and synthesis, as well as possibly effects on the microbiome and downstream in the gut.” He went on to explain that cilofexor may benefit patients with PBC, primary sclerosing cholangitis, or nonalcoholic steatohepatitis (NASH), noting preclinical data that have demonstrated reductions in bile acids, inflammation, fibrosis, and portal pressure.

The present trial involved 71 patients with PBC who lacked cirrhosis and had a serum ALP level that was at least 1.67 times greater than the upper limit of normal, and an elevated serum total bilirubin that was less than 2 times the upper limit of normal. Patients were randomized to receive either cilofexor 30 mg, cilofexor 100 mg, or placebo, once daily for 12 weeks. Stratification was based on use of ursodeoxycholic acid, which was stable for at least the preceding year. Safety and efficacy were evaluated, with the latter based on liver biochemistry, serum C4, bile acids, and serum fibrosis markers.

Across the entire population, baseline median serum bilirubin was 0.6 mg/dL and median serum ALP was 286 U/L. After 12 weeks, compared with placebo, patients treated with cilofexor, particularly those who received the 100-mg dose, showed significant improvements across multiple measures of liver health. Specifically, patients in the 100-mg group achieved median reductions in ALP (–13.8%; P = .005), GGT (–47.7%; P less than .001), CRP (–33.6%; P = .03), and primary bile acids (–30.5%; P = .008). These patients also exhibited trends toward reduced aspartate aminotransferase and aminoterminal propeptide of type III procollagen; Dr. Kowdley attributed the lack of statistical significance to insufficient population size.

Highlighting magnitude of ALP improvement, Dr. Kowdley noted that reductions in ALP greater than 25% were observed in 17% and 18% of patients in the 100-mg and 30-mg cilofexor groups, respectively, versus 0% of patients in the placebo group.

Although the 100-mg dose of cilofexor appeared more effective, the higher dose did come with some trade-offs in tolerability; grade 2 or 3 pruritus was more common in patients treated with the higher dose than in those who received the 30-mg dose (39% vs. 10%). As such, 7% of patients in the 100-mg group discontinued therapy because of the pruritus, compared with no patients in the 30-mg or placebo group.

Responding to a question from a conference attendee, Dr. Kowdley said that ALP reductions to below the 1.67-fold threshold were achieved by 9% and 14% of patients who received the 30-mg dose and 100-mg dose of cilofexor, respectively.

“We believe these data support further evaluation of cilofexor for the treatment of cholestatic liver disorders,” Dr. Kowdley concluded.

The study was funded by Gilead. The investigators disclosed additional relationships with Allergan, Novartis, GlaxoSmithKline, and others.

SOURCE: Kowdley KV et al. The Liver Meeting 2019. Abstract 45.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – For patients with a complete response following treatment for hepatitis C virus (HCV)–related hepatocellular carcinoma (HCC), treatment with direct-acting antiviral therapy was linked to significantly reduced mortality compared with no such treatment, according to results of a large cohort study.

UT Southwestern Medical Center

The mortality benefit associated with direct-acting antiviral (DAA) therapy was consistent across most subgroups, suggesting that the association was driven by achieving sustained virological response (SVR), according to Amit G. Singal, MD, associate professor of medicine at UT Southwestern Medical Center, Dallas.

Those results suggest that DAA therapy in patients with a history of HCC is not only safe, but is also beneficial, Dr. Singal said at the annual meeting of the American Association for the Study of Liver Diseases.

“To be slightly controversial, I think that this changes the paradigm in this subgroup of patients from ‘can be treated’ for their hepatitis C to ‘should be treated,’ ” he concluded in an oral presentation of the results.

While DAA treatment is proven to reduce risk of incident HCC in patients with cirrhosis, the risk-benefit ratio is “less clear” in patients with a history of HCC following complete response, according to Dr. Singal.

Moreover, concerns were raised about the safety of DAA therapy in patients with an HCC history, after early data suggested a potentially higher recurrence risk, he added.

In the current multicenter, retrospective North American cohort study, Dr. Singal and colleagues reviewed data for 797 patients with HCV–related HCC who achieved complete response following ablation, resection, radiotherapy, transarterial chemoembolization, or transarterial radioembolization.

Treatment with DAA therapy was associated with improved overall survival, according to results of multivariable analysis, with a hazard ratio of 0.54 (95% confidence interval, 0.33-0.90). Median time from HCC complete response to death was 25.7 months for the DAA treatment group, versus 11.5 months for the untreated group.

The association between DAA treatment and death was apparently driven by SVR, as reduced mortality was seen in the DAA-treated patients who did achieve SVR, but not in those without SVR, Dr. Singal reported.

While these findings together suggest that DAA treatment is linked to reduced mortality after HCC complete response, prospective studies are needed to confirm this association, Dr. Singal said.

Dr. Singal reported disclosures related to AbbVie, Bayer, BMS, Eisai, Exact Sciences, Exelixis, Genentech, Gilead FOCUS, Glycotest, GRAIL, Merck, Roche, TARGET Pharmasolutions, and Wako Diagnostics.
 

SOURCE: Singal AG et al. The Liver Meeting 2019, Abstract 199.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

BOSTON – Kratom, a botanical product with opioid-like activity, is increasingly responsible for cases of liver injury in the United States, according to investigators.

Will Pass/MDedge News

Kratom-associated liver damage involves a mixed pattern of hepatocellular and cholestatic injury that typically occurs after about 2-6 weeks of use, reported lead author Victor J. Navarro, MD, division head of gastroenterology at Einstein Healthcare Network in Philadelphia, and colleagues.

“I think it’s important for clinicians to have heightened awareness of the abuse potential [of kratom], because it is an opioid agonist and [because of] its capacity to cause liver injury,” Dr. Navarro said.

Kratom acts as a stimulant at low doses, while higher doses have sedating and narcotic properties. These effects are attributed to several alkaloids found in kratom’s source plant, Mitragyna speciose, of which mitragynine, a suspected opioid agonist, is most common.

Presenting at the annual meeting of the American Association for the Study of Liver Diseases, Dr. Navarro cited figures from the National Poison Data System that suggest an upward trend in kratom usage in the United States, from very little use in 2011 to 1 exposure per million people in 2014 and more recently to slightly more than 2.5 exposures per million people in 2017, predominantly among individuals aged 20 years and older. According to the Centers for Disease Control and Prevention, more than 90 kratom-associated deaths occurred between July 2016 and December 2017. Because of growing concerns, the Food and Drug Administration has issued multiple public warnings about kratom, ranging from products contaminated with Salmonella and heavy metals, to adverse effects such as seizures and liver toxicity.

The present study aimed to characterize kratom-associated liver injury through a case series analysis. First, the investigators reviewed 404 cases of herbal and dietary supplement-associated liver injury from the Drug-Induced Liver Injury Network prospective study. They found 11 suspected cases of kratom-related liver injury, with an upward trend in recent years. At this time, seven of the cases have been adjudicated by an expert panel and confirmed to be highly likely or probably associated with kratom.

Of these seven cases, all patients were hospitalized, although all recovered without need for liver transplant. Patients presented after a median of 15 days of kratom use, with a 28-day symptom latency period. However, Dr. Navarro noted that some cases presented after just 5 days of use. The most common presenting symptom was itching (86%), followed by jaundice (71%), abdominal pain (71%), nausea (57%), and fever (43%). Blood work revealed a mixed hepatocellular and cholestatic pattern. Median peak ALT was 362 U/L, peak alkaline phosphatase was 294 U/L, and peak total bilirubin was 20.1 mg/dL. Despite these changes, patients did not have significant liver dysfunction, such as coagulopathy.

Following this clinical characterization, Dr. Navarro reviewed existing toxicity data. Rat studies suggest that kratom is safe at doses between 1-10 mg/kg, while toxicity occurs after prolonged exposure to more than 100 mg/kg. A cross-sectional human study reported that kratom was safe at doses up to 75 mg/day. However, in the present case series, some patients presented after ingesting as little as 0.66 mg/day, and Dr. Navarro pointed out wide variations in product concentrations of mitragynine.

“Certainly, we need more human toxicity studies to determine what a safe dose really is, because this product is not going away,” Dr. Navarro said.

The investigators disclosed relationships with Gilead, Bristol-Myers Squibb, Sanofi, and others.

SOURCE: Navarro VJ et al. The Liver Meeting 2019, Abstract 212.

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

Fentanyl was involved in more overdose deaths than any other drug in 2017, and the death rate in New England was 15 times higher than in regions of the Midwest and West, according to the National Center for Health Statistics.

Nationally, fentanyl was involved in 39% of all drug overdose deaths and had an age-adjusted death rate of 8.7/100,000 standard population in 2017. In 2016, when fentanyl also was the most involved drug in the United States, the corresponding figures were 29% and 5.9/100,000, the agency said in a recent report.

Fentanyl was the most involved drug in overdose deaths for 6 of the country’s 10 public health regions in 2017, with a clear pattern of decreasing use from east to west. The highest death rate (22.5/100,000) occurred in Region 1 (New England) and the lowest rates (1.5/100,000) came in Region 6 (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas) and Region 9 (Arizona, California, Hawaii, and Nevada), the researchers said.

A somewhat similar pattern was seen for heroin, which was second nationally on the list of drugs most frequently involved in overdose deaths (23%), except that New England was somewhat below three other regions in the East and upper Midwest. The highest heroin death rate (8.6/100,000) was seen in Region 2 (New Jersey and New York) and the lowest (2.2) occurred in Region 9, they said, based on data from the National Vital Statistics System’s mortality files.

The fentanyl pattern was even more closely repeated with cocaine, third in involvement nationally at 21% of overdose deaths in 2017. The high in overdose deaths (9.5/100,000) came in Region 1 again, and the low in Region 9 (1.3), along with Region 7 (Iowa, Kansas, Missouri, and Nebraska) and Region 10 (Alaska, Idaho, Oregon, and Washington), the report showed.

The regional pattern of overdose deaths for methamphetamine, which was fourth nationally in involvement (13.3%), basically reversed the other three drugs: highest in the West and lowest in the Northeast. Region 9 had the highest death rate (5.2/100,000) and Region 2 the lowest (0.4), with Region 1 just ahead at 0.6.

“Understanding these regional differences in the drugs most frequently involved in drug overdose deaths may help inform prevention and policy efforts,” the investigators wrote.

rfranki@mdedge.com

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

NATIONAL HARBOR, MD. – Sitravatinib may “restore or enhance” the activity of anti-PD-1 therapy in patients with checkpoint inhibitor–refractory urothelial carcinoma, an investigator reported at the annual meeting of the Society for Immunotherapy of Cancer.

Jennifer Smith/MDedge News

Clinical activity was observed with combination sitravatinib and nivolumab in patients with urothelial carcinoma who had disease progression on or after an immune checkpoint inhibitor and were previously treated with platinum-based chemotherapy.

“Up until a few years ago, the only therapies we had [for urothelial carcinoma] were cytotoxic, platinum-based chemotherapies,” said Pavlos Msaouel, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

“Thankfully, since 2016, immune checkpoint therapy has become part of our toolbox. But even with single-agent, approved immune checkpoint therapies, anti-PD-1/anti-PD-L1, the response rates are still low, around 20%, and durable responses are only seen in a subset of patients. So we have to do better, if possible, potentially by combining immune checkpoint therapies with other immunotherapies such as sitravatinib.”

Dr. Msaouel explained that sitravatinib inhibits a spectrum of related receptor tyrosine kinases, including TAM family receptors (TYRO3, Axl, and Mer), split family receptors (VEGFR2/PDGFR and c-KIT), and c-Met. Researchers are investigating sitravatinib in combination with nivolumab in a phase 2 trial of patients with urothelial carcinoma (NCT03606174). Dr. Msaouel presented results from one cohort on this trial – 33 patients who had previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.

At baseline, the patients’ median age was 68 years (range, 47-83 years), and 70% were male. Patients had metastatic (n = 30) or locally advanced (n = 3) disease. They had received a median of two (range, one to four) prior systemic therapies.

For this study, patients received oral sitravatinib at 120 mg daily and intravenous nivolumab at 240 mg every 2 weeks or 480 mg every 4 weeks on continuous 28-day cycles. Tumor assessments were performed every 8 weeks.

Results

Of the 22 patients evaluable for efficacy, 1 patient achieved a complete response, 5 had a partial response, 15 had stable disease, and 1 progressed. Eight patients had tumor regression greater than 30%.

Treatment duration exceeded 26 weeks in six patients. Nine patients, including four responders, were still on study at the data cutoff in mid-October.

“This ongoing trial continues to show promising clinical activity, including tumor regression and prolonged duration on treatment,” Dr. Msaouel said.

He added that combination sitravatinib and nivolumab has “an acceptable side effect profile, with manageable adverse events.”

Common treatment-related adverse events, in all 33 patients, were fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and alanine aminotransferase increase (21%).

Grade 3 treatment-related adverse events included fatigue (12%), hypertension (12%), diarrhea (9%), lipase increase (9%), decreased appetite (3%), and palmar-plantar erythrodysesthesia syndrome (3%). There were no grade 4 or 5 treatment-related events.

Mirati Therapeutics sponsored the trial. Dr. Msaouel disclosed relationships with Mirati, Bristol-Myers Squibb, Exelixis, Pfizer, and Takeda.

SOURCE: Msaouel P et al. SITC 2019. Abstract O23.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.

BOSTON – A short course of direct-acting antiviral therapy combined with ezetimibe prevented or rapidly cured hepatitis C virus infection in transplant recipients receiving organs from infected donors, results of a recent study show.

The regimen, given right before transplantation and for 7 days afterward, reduced the cost of direct-acting antiviral (DAA) therapy and allowed patients to complete hepatitis C virus (HCV) therapy before hospital discharge, according to authors of the study, which was presented at the annual meeting of the American Association for the Study of Liver Diseases.

If confirmed in subsequent studies, this regimen could become the standard of care for donor-positive, recipient-negative transplantation, said lead study author Jordan J. Feld, MD, R. Phelan Chair in translational liver disease research at the University of Toronto and research director at the Toronto Centre for Liver Disease.

“Transplant recipients are understandably nervous about accepting organs from people with HCV infection,” said Dr. Feld in a press release. “This very short therapy allows them to leave hospital free of HCV, which is a huge benefit. Not only is it cheaper and likely safer, but the patients really prefer not having to worry about HCV with all of the other challenges after a transplant.”

Results of this study come at a time when the proportion of overdose death organ donors is on the rise, from just 1% in 2000 to 15% in 2016, according to Dr. Feld. Overdose deaths account for the largest percentage of HCV-infected donors, most of whom are young and often otherwise healthy, he added.

Recipients of HCV-infected organs can be cured after transplant as a number of studies have previously shown. However, preventing transmission would be better than cure, Dr. Feld said, in part because of issues with drug-drug interactions, potential for relapse, and issues with procuring the drugs after transplant.

Accordingly, Dr. Feld and colleagues sought to evaluate “preemptive” treatment with DAA therapy combined with ezetimibe, which they said has been shown to inhibit HCV entry blockers. The recipients, who were listed for heart, lung, kidney, or kidney-pancreas transplant, were given glecaprevir/pibrentasvir plus ezetimibe starting 6-12 hours prior to transplantation, and then daily for 7 days.

The median age was 36 years for the 16 donors reported, and 61 years for the 25 recipients. Most recipients (12 patients) had a lung transplant, while 8 had a heart transplant, 4 had a kidney transplant, and 1 had a kidney-pancreas transplant.

There were no virologic failures, according to the investigators, with sustained virologic response (SVR) after 6 weeks in 7 patients, and SVR after 12 weeks in the remaining 18. Three recipients did have detectable HCV RNA, though all cleared and had SVR at 6 weeks in one case, and SVR at 12 weeks in the other two, according to the investigators’ report.

Of 22 serious adverse events noted in the study, 1 was considered treatment related, according to the report, and there were 2 deaths among lung transplant patients, caused by sepsis in 1 case to sepsis and subarachnoid hemorrhage in another.

It’s not clear whether ezetimibe is needed in this short-duration regimen, but in any case, it is well tolerated and inexpensive, and so there is “minimal downside” to include it, Dr. Feld and coinvestigators wrote in their report.

Dr. Feld reported disclosures related to Abbvie, Abbott, Enanta Pharmaceuticals, Gilead, Janssen, Merck, and Roche.

SOURCE: Feld JJ et al. The Liver Meeting 2019, Abstract 38.