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Here comes bimekizumab, the newest IL-17 inhibitor
KAUAI, HAWAII –
And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
lthough Dr. Leonardi is a distinguished psoriasis clinical trialist, he wasn’t involved in the BE ABLE study. Only top line results have been announced to date, although publication of the BE ABLE, BE AGILE, and BE ACTIVE results and presentations at major medical meetings are pending.
Bimekizumab is a humanized IgG1 monoclonal antibody which uniquely neutralizes both IL-17A and IL-17F. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit IL-17A, while brodalumab (Siliq) is a pan-IL-17 receptor antagonist, inhibiting the IL-17 A, A/F, E, F, and C receptors. The impressive clinical outcomes of the three BE phase 2b studies validate the notion that IL-17F is an important cytokine in tissue inflammation across a range of dermatologic and rheumatologic diseases.
A long-term extension of BE ABLE is ongoing. In addition, a phase 3 randomized trial of bimekizumab versus adalimumab (Humira) versus placebo in 450 psoriasis patients is now recruiting, as is a separate phase 3 placebo-controlled head to head comparison of bimekizumab versus ustekinumab (Stelara).
The BE ACTIVE study included 206 psoriatic arthritis patients. At the top dose of bimekizumab, the week 12 rate of at least a 50% improvement in joint symptoms, or ACR 50 response, was 46%, compared with 7% in placebo-treated controls. Patients with concomitant psoriasis over at least 3% of their body surface area demonstrated a 65% PASI 90 response rate at 12 weeks.
BE AGILE included 303 patients with ankylosing spondylitis. Forty-seven percent of those randomized to the top-performing dose of bimekizumab had at least a 40% improvement in their Ankylosing Spondylitis Activity Score, or ASAS 40, at week 12, as did 13% in the placebo arm.
Bimekizumab is being developed by UCB, which is planning additional studies advancing the biologic in all three diseases studied in the phase 2b trials.
Dr. Leonardi reported receiving research grants from well over a dozen pharmaceutical companies and serving as a consultant to UCB and others.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
KAUAI, HAWAII –
And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
lthough Dr. Leonardi is a distinguished psoriasis clinical trialist, he wasn’t involved in the BE ABLE study. Only top line results have been announced to date, although publication of the BE ABLE, BE AGILE, and BE ACTIVE results and presentations at major medical meetings are pending.
Bimekizumab is a humanized IgG1 monoclonal antibody which uniquely neutralizes both IL-17A and IL-17F. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit IL-17A, while brodalumab (Siliq) is a pan-IL-17 receptor antagonist, inhibiting the IL-17 A, A/F, E, F, and C receptors. The impressive clinical outcomes of the three BE phase 2b studies validate the notion that IL-17F is an important cytokine in tissue inflammation across a range of dermatologic and rheumatologic diseases.
A long-term extension of BE ABLE is ongoing. In addition, a phase 3 randomized trial of bimekizumab versus adalimumab (Humira) versus placebo in 450 psoriasis patients is now recruiting, as is a separate phase 3 placebo-controlled head to head comparison of bimekizumab versus ustekinumab (Stelara).
The BE ACTIVE study included 206 psoriatic arthritis patients. At the top dose of bimekizumab, the week 12 rate of at least a 50% improvement in joint symptoms, or ACR 50 response, was 46%, compared with 7% in placebo-treated controls. Patients with concomitant psoriasis over at least 3% of their body surface area demonstrated a 65% PASI 90 response rate at 12 weeks.
BE AGILE included 303 patients with ankylosing spondylitis. Forty-seven percent of those randomized to the top-performing dose of bimekizumab had at least a 40% improvement in their Ankylosing Spondylitis Activity Score, or ASAS 40, at week 12, as did 13% in the placebo arm.
Bimekizumab is being developed by UCB, which is planning additional studies advancing the biologic in all three diseases studied in the phase 2b trials.
Dr. Leonardi reported receiving research grants from well over a dozen pharmaceutical companies and serving as a consultant to UCB and others.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
KAUAI, HAWAII –
And that’s not all: Much the same was true in patients with psoriatic arthritis in the parallel phase 2b BE ACTIVE study and for ankylosing spondylitis in the BE AGILE study. BE ABLE was a double-blind, 12-week, multicenter, five-arm, placebo-controlled, dose-ranging study of 250 psoriasis patients randomized to various doses of subcutaneous bimekizumab or placebo every 4 weeks. The primary outcome – the PASI 90 response rate at 12 weeks, rather than the lower-bar PASI 75 endpoint more typically used in clinical trials – was 79% at the optimal dose. The PASI 100 rate – complete clearance of disease – at 12 weeks was 60%, Craig L. Leonardi, MD, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
lthough Dr. Leonardi is a distinguished psoriasis clinical trialist, he wasn’t involved in the BE ABLE study. Only top line results have been announced to date, although publication of the BE ABLE, BE AGILE, and BE ACTIVE results and presentations at major medical meetings are pending.
Bimekizumab is a humanized IgG1 monoclonal antibody which uniquely neutralizes both IL-17A and IL-17F. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit IL-17A, while brodalumab (Siliq) is a pan-IL-17 receptor antagonist, inhibiting the IL-17 A, A/F, E, F, and C receptors. The impressive clinical outcomes of the three BE phase 2b studies validate the notion that IL-17F is an important cytokine in tissue inflammation across a range of dermatologic and rheumatologic diseases.
A long-term extension of BE ABLE is ongoing. In addition, a phase 3 randomized trial of bimekizumab versus adalimumab (Humira) versus placebo in 450 psoriasis patients is now recruiting, as is a separate phase 3 placebo-controlled head to head comparison of bimekizumab versus ustekinumab (Stelara).
The BE ACTIVE study included 206 psoriatic arthritis patients. At the top dose of bimekizumab, the week 12 rate of at least a 50% improvement in joint symptoms, or ACR 50 response, was 46%, compared with 7% in placebo-treated controls. Patients with concomitant psoriasis over at least 3% of their body surface area demonstrated a 65% PASI 90 response rate at 12 weeks.
BE AGILE included 303 patients with ankylosing spondylitis. Forty-seven percent of those randomized to the top-performing dose of bimekizumab had at least a 40% improvement in their Ankylosing Spondylitis Activity Score, or ASAS 40, at week 12, as did 13% in the placebo arm.
Bimekizumab is being developed by UCB, which is planning additional studies advancing the biologic in all three diseases studied in the phase 2b trials.
Dr. Leonardi reported receiving research grants from well over a dozen pharmaceutical companies and serving as a consultant to UCB and others.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM SDEF HAWAII DERMATOLOGY SEMINAR
Virtual reality–based CBT may improve social participation in psychosis
Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.
Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.
Similarly, the group that received virtual reality therapy showed significantly larger decreases in momentary anxiety, compared with those in the control group. Those decreases remained significant at follow-up.
Researchers also observed a significant drop in safety behaviors – such as lack of eye contact – in the group who received the virtual reality therapy. At follow-up, this group showed less paranoid ideation in the form of lower levels of ideas of persecution and social reference.
The treatment also was associated with a small increase in time spent with others at the 6-month follow-up; a decrease was seen in the control group. Patients who underwent virtual reality therapy also showed improvements in self-stigmatization and social functioning.
The authors noted that the benefits for social functioning might take some time to emerge after therapy, as patients in symptomatic remission do not immediately start spending more time with other people.
“When patients increasingly feel more comfortable in social situations and learn that other people are less threatening than anticipated, they might try and succeed to make and maintain social contacts and find hobbies and jobs,” the authors wrote.
However, no significant differences were found between the two groups in terms of depression and anxiety, or in quality of life measurements posttreatment and at follow-up.
Virtual reality–based CBT is intended to get around some of the limitations of exposure-based therapeutic exercises for paranoid ideation. In virtual reality settings, the environment and characters can be completely controlled by the therapist, and the therapy is real time rather than retrospective and therefore not as vulnerable to patient bias.
“Finally, many patients are reluctant or unable to undergo exposure because of strong paranoid fears or negative symptoms,” the authors wrote.
The therapy took place in four virtual social environments – a street, bus, café, and supermarket. The therapist was able to control the characteristics and responses of up to 40 human avatars, enabling personalized treatment exercises for each patient.
“Patients and therapists communicated during virtual reality sessions to explore and challenge suspicious thoughts during social situations, drop safety behaviors during social situations (such as avoiding eye contact with, keeping distance from, and refraining from communication with avatars), and test harm expectancies,” they wrote.
The sessions also were designed to target safety behaviors, such as avoiding eye contact, because such behavior prevents individuals from receiving social information that can improve social cognition and reduce the chance of incorrect paranoid appraisals.
Several limitations were cited. For example, because follow-up was restricted to 6 months, it was not possible to access the long-term effects of virtual reality-based CBT. Also, some of the patients opted not to participate in the study because traveling to the therapy location proved too frightening. “Thus our sample might have been biased, because some of the most paranoid and avoidant patients could not participate,” they wrote.
The study was supported by Fonds NutsOhra and Stichting tot Steun VCVGZ. No conflicts of interest were declared.
SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.
Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.
Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.
Similarly, the group that received virtual reality therapy showed significantly larger decreases in momentary anxiety, compared with those in the control group. Those decreases remained significant at follow-up.
Researchers also observed a significant drop in safety behaviors – such as lack of eye contact – in the group who received the virtual reality therapy. At follow-up, this group showed less paranoid ideation in the form of lower levels of ideas of persecution and social reference.
The treatment also was associated with a small increase in time spent with others at the 6-month follow-up; a decrease was seen in the control group. Patients who underwent virtual reality therapy also showed improvements in self-stigmatization and social functioning.
The authors noted that the benefits for social functioning might take some time to emerge after therapy, as patients in symptomatic remission do not immediately start spending more time with other people.
“When patients increasingly feel more comfortable in social situations and learn that other people are less threatening than anticipated, they might try and succeed to make and maintain social contacts and find hobbies and jobs,” the authors wrote.
However, no significant differences were found between the two groups in terms of depression and anxiety, or in quality of life measurements posttreatment and at follow-up.
Virtual reality–based CBT is intended to get around some of the limitations of exposure-based therapeutic exercises for paranoid ideation. In virtual reality settings, the environment and characters can be completely controlled by the therapist, and the therapy is real time rather than retrospective and therefore not as vulnerable to patient bias.
“Finally, many patients are reluctant or unable to undergo exposure because of strong paranoid fears or negative symptoms,” the authors wrote.
The therapy took place in four virtual social environments – a street, bus, café, and supermarket. The therapist was able to control the characteristics and responses of up to 40 human avatars, enabling personalized treatment exercises for each patient.
“Patients and therapists communicated during virtual reality sessions to explore and challenge suspicious thoughts during social situations, drop safety behaviors during social situations (such as avoiding eye contact with, keeping distance from, and refraining from communication with avatars), and test harm expectancies,” they wrote.
The sessions also were designed to target safety behaviors, such as avoiding eye contact, because such behavior prevents individuals from receiving social information that can improve social cognition and reduce the chance of incorrect paranoid appraisals.
Several limitations were cited. For example, because follow-up was restricted to 6 months, it was not possible to access the long-term effects of virtual reality-based CBT. Also, some of the patients opted not to participate in the study because traveling to the therapy location proved too frightening. “Thus our sample might have been biased, because some of the most paranoid and avoidant patients could not participate,” they wrote.
The study was supported by Fonds NutsOhra and Stichting tot Steun VCVGZ. No conflicts of interest were declared.
SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.
Virtual reality–based cognitive-behavioral therapy could help reduce momentary paranoia and anxiety, and improve social cognition in individuals with psychotic disorders.
Researchers reported the results of a randomized controlled trial of personalized virtual reality-based cognitive-behavioral therapy in 116 patients with a DSM IV–diagnosed psychotic disorder and paranoid ideation in an article published online Feb. 8 in Lancet Psychiatry.
Similarly, the group that received virtual reality therapy showed significantly larger decreases in momentary anxiety, compared with those in the control group. Those decreases remained significant at follow-up.
Researchers also observed a significant drop in safety behaviors – such as lack of eye contact – in the group who received the virtual reality therapy. At follow-up, this group showed less paranoid ideation in the form of lower levels of ideas of persecution and social reference.
The treatment also was associated with a small increase in time spent with others at the 6-month follow-up; a decrease was seen in the control group. Patients who underwent virtual reality therapy also showed improvements in self-stigmatization and social functioning.
The authors noted that the benefits for social functioning might take some time to emerge after therapy, as patients in symptomatic remission do not immediately start spending more time with other people.
“When patients increasingly feel more comfortable in social situations and learn that other people are less threatening than anticipated, they might try and succeed to make and maintain social contacts and find hobbies and jobs,” the authors wrote.
However, no significant differences were found between the two groups in terms of depression and anxiety, or in quality of life measurements posttreatment and at follow-up.
Virtual reality–based CBT is intended to get around some of the limitations of exposure-based therapeutic exercises for paranoid ideation. In virtual reality settings, the environment and characters can be completely controlled by the therapist, and the therapy is real time rather than retrospective and therefore not as vulnerable to patient bias.
“Finally, many patients are reluctant or unable to undergo exposure because of strong paranoid fears or negative symptoms,” the authors wrote.
The therapy took place in four virtual social environments – a street, bus, café, and supermarket. The therapist was able to control the characteristics and responses of up to 40 human avatars, enabling personalized treatment exercises for each patient.
“Patients and therapists communicated during virtual reality sessions to explore and challenge suspicious thoughts during social situations, drop safety behaviors during social situations (such as avoiding eye contact with, keeping distance from, and refraining from communication with avatars), and test harm expectancies,” they wrote.
The sessions also were designed to target safety behaviors, such as avoiding eye contact, because such behavior prevents individuals from receiving social information that can improve social cognition and reduce the chance of incorrect paranoid appraisals.
Several limitations were cited. For example, because follow-up was restricted to 6 months, it was not possible to access the long-term effects of virtual reality-based CBT. Also, some of the patients opted not to participate in the study because traveling to the therapy location proved too frightening. “Thus our sample might have been biased, because some of the most paranoid and avoidant patients could not participate,” they wrote.
The study was supported by Fonds NutsOhra and Stichting tot Steun VCVGZ. No conflicts of interest were declared.
SOURCE: Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.
FROM LANCET PSYCHIATRY
Key clinical point:
Major finding: Patients who received virtual reality–based CBT showed significantly less momentary paranoia and momentary anxiety, and less paranoid ideation, than controls.
Data source: Randomized controlled trial in 116 patients with psychotic disorders.
Disclosures: The study was supported by Fonds NutsOhra and Stichting tot Steun VCVGZ. No conflicts of interest were declared.
Source: Pot-Kolder RMCA et al. Lancet Psychiatry. 2018 Feb 8. doi: 10.1016/S2215-0366(18)30053-1.
Expert shares tips for positioning biologics in IBD patient treatment
LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.
“ and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”
For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.
According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”
A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”
Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”
In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.
He went on to discuss vedolizumab, a monoclonal antibody to alpha4beta7 integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”
Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.
In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.
Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.
Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”
Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”
Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.
*This story was updated on 3/26.
LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.
“ and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”
For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.
According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”
A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”
Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”
In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.
He went on to discuss vedolizumab, a monoclonal antibody to alpha4beta7 integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”
Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.
In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.
Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.
Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”
Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”
Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.
*This story was updated on 3/26.
LAS VEGAS – In the clinical opinion of Edward V. Loftus Jr., MD, biologics for inflammatory bowel disease (IBD) patients are best positioned based on age, personal medical history, and the presence of extraintestinal manifestations.
“ and is the way to go if you’re trying to change the trajectory of illness,” Dr. Loftus said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
In general, patients who are younger at diagnosis are going to have more severe disease than patients diagnosed older, said Dr. Loftus, professor of medicine at the Mayo Clinic, Rochester, Minn. “For CD [Crohn’s disease], the presence of fistulizing disease, especially internal fistulas, and to a lesser extent perianal fistulas, and then the presence of small-bowel disease or proximal GI disease, are all harbingers of more aggressive disease,” he said. “Multiple studies show that the time interval between diagnosis and development of intestinal complications is shorter in patients with small-bowel disease relative to colonic disease. When you add up those factors, you’re talking about 70% of CD patients, if not more. Most Crohn’s patients are going to be high-risk patients.”
For ulcerative colitis (UC), being male is a risk factor for hospitalization, surgery, and for developing colon cancer. On average, males are twice as likely as females to require surgery, and they’re twice as likely to develop colon cancer. Other predictors in UC for high-risk disease include early need for hospitalization, early need for corticosteroids, and extensive colitis at diagnosis. “You’re thinking about these things because how you’re going to treat these patients is going to differ,” he said.
According to Dr. Loftus, aminosalicylate (5-ASA) drugs are the frontline drugs of choice for low-risk UC patients with mild symptoms. “If they’re having moderate symptoms, you might initially start with a corticosteroid taper,” he noted. “That can be either prednisone or budesonide MMX. In a patient with really active symptoms, they’re going to go to IV steroids or maybe directly to anti-TNF [tumor necrosis factor] therapy.” For low-risk CD patients, consider budesonide taper then observation. “If they don’t flare again, maybe monitor that patient periodically,” he advised. “For high-risk patients, consider biologic therapy with or without thiopurine or methotrexate.”
A recent analysis of Medicare and Medicaid data from 2006 to 2013 found a significantly higher rate of mortality in IBD patients treated with prolonged corticosteroids than that seen in those treated with anti-TNF therapy (Am J Gastroenterol. Jan 16, 2018. doi: 10.1038/ajg2017.479). “That should give you pause,” Dr. Loftus said. “Don’t just put your patient on prednisone because you think it’s the easiest and safest thing to do. It’s not. It’s much more dangerous and has implications [for] the patient’s life expectancy.”
Some data are beginning to emerge about the use of biosimilars in IBD, mostly from Europe. Investigators of one randomized, controlled trial of biosimilar CT-P13 vs. originator infliximab in CD presented at the 2017 Digestive Disease Week meeting; they found in their trial that at week 6 all clinical endpoints were similar between the two agents. “If you’re forced to change your patient to this particular biosimilar, I wouldn’t be too worried about it,” Dr. Loftus said. “Of course, I’m not necessarily going to switch unless my institution or a particular third-party payer mandate it.”
In a published study funded by the Norwegian government, researchers conducted a prospective trial of switching from infliximab to CT-P13 in patients with a variety of conditions (Lancet. 2017;389:2304-16). Overall, the clinical failure rate was the same for both agents. Among CD patients, the researchers observed a nonsignificant trend toward disease worsening among those on the biosimilar, “but there was essentially no difference,” Dr. Loftus said.
He went on to discuss vedolizumab, a monoclonal antibody to alpha4beta7 integrin approved in 2014 for patients with moderate to severely active UC or CD. Phase 3 data from GEMINI I in moderate to severe UC found that relevant clinical endpoints were met by week 6 and they persisted at week 52 at both doses (N Engl J Med. 2013;369[8]:699-710). “For CD, the use of vedolizumab is a bit of a mixed picture,” Dr. Loftus said. “In GEMINI II, some of the primary endpoints were met at week 6, but at least one was missed (N Engl J Med. 2013;369[8]:711-21). The same thing was seen in GEMINI III. There’s a sense here that vedolizumab takes a little bit longer to work in CD.”
Integrated safety analyses of the GEMINI trials found no signal for increased rates of serious adverse events, and no cases of progressive multifocal leukoencephalopathy have been reported (J Crohns Colitis. 2017;11[2]:185-90). “The risk factors for serious infections were prior anti-TNF failure and opioid analgesic use in UC patients and younger age, steroid use, and opioid analgesic use in CD patients,” Dr. Loftus said.
In a trial of CD patients failing anti-TNF therapy, researchers observed a robust clinical response with ustekinumab, compared with placebo, at week 6 (N Engl J Med. 2016;375:1946-60). Even greater effects were observed in UNITI-2, a trial of ustekinumab in CD patients who hadn’t failed anti-TNFs.
Dr. Loftus cautioned that elderly and immunocompromised patients face an increased risk for infections when they’re placed on anti-TNF therapy. At the same time, researchers used a French database to determine the risk of lymphoma in IBD patients stratified by medication. For patients unexposed to such therapies, the risk of lymphoma was 1:4,000. For patients on thiopurine monotherapy, the risk was about 1:2,000; it was about 1:2,500 for those on anti-TNF monotherapy and about 1:1,000 for those on combination therapy (JAMA. 2017;318:1679-86). “One of the messages in this study is we can reassure our more risk-averse patients that the absolute risk of lymphoma is very low, even among patients on combination therapy,” he said.
Dr. Loftus called for head-to-head trials comparing the individual biologic agents and shared his recommendations on how to position currently available therapies. “I would say that for the average ‘bread and butter’ Crohn’s patient, anti-TNF therapy is the way to go,” he said. “For perianal fistulizing patients, I’m going to go with anti-TNF therapy, such as infliximab or adalimumab. For a patient with active extraintestinal manifestations, such as spondyloarthropathy, uveitis, and pyoderma, anti-TNF therapy is the way to go. However, with an elderly or immunosuppressed patient, consider vedolizumab or ustekinumab. For patients with a personal history of malignancy, an anti-TNF is very reasonable, but it may be easier to convince them to consider vedolizumab or ustekinumab.”
Recommendations for UC are largely similar, he continued. “However, I think we have enough data from GEMINI I and the integrated safety data with vedolizumab to say that, for the average ‘bread and butter’ UC patient, anti-TNF therapy or vedolizumab are appropriate. For a patient with extraintestinal manifestations I would avoid vedolizumab initially and try anti-TNF therapy. For patients with acute severe colitis, we have the bulk of evidence for efficacy resting with infliximab, so I would go with that. For the elderly or immunosuppressed patient, I would go with vedolizumab. For the person with a history of malignancy, an anti-TNF agent is reasonable, but consider vedolizumab.”
Dr. Loftus disclosed that he has consulted for AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Eli Lilly, Celltrion Healthcare, Napo Pharmaceuticals. He has also received research support from AbbVie, Takeda Pharmaceutical, Janssen Pharmaceutica, UCB, Pfizer, Amgen, Genentech, Seres Pharmaceuticals, MedImmune, Allergan, and Robarts Clinical Trials.
*This story was updated on 3/26.
EXPERT ANALYSIS FROM THE CROHN’S & COLITIS CONGRESS
Enzalutamide shines in nonmetastatic castration-resistant prostate cancer
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.
“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”
The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).
With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.
Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.
Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.
Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”
The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.
Weighing the evidence
The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”
Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).
“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.
“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.
It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
Study details
Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.
Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.
Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).
Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).
“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).
The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.
Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
SOURCE: Hussain M et al. Abstract 3.
REPORTING FROM GUCS 2018
Key clinical point:
Major finding: Metastasis-free survival was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001).
Data source: A phase 3 randomized trial among 1,401 men with nonmetastatic castration-resistant prostate cancer and rapidly rising PSA level (PROSPER trial).
Disclosures: Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
Source: Hussain M et al. Abstract 3.
Next-day discharge after TAVR shows promise
Compared with a longer hospital stay, next-day discharge (NDD) after minimalist transcatheter aortic valve replacement (TAVR) appears safe, according to a recently reported analysis of patients treated at a single center.
The composite endpoint of mortality and readmission at 30 days was similar for NDD, compared with later discharges among patients who had a procedure that met minimalist criteria, defined in this study as transfemoral TAVR under conscious sedation and local anesthesia.
Mortality and readmission at 1 year was lower in the NDD group, mainly because of a lower risk of noncardiovascular readmissions, study authors reported in JACC: Cardiovascular Interventions. “Although superior NDD outcomes are likely attributed to selected patient characteristics, NDD in patients without in-hospital complications may be appropriate after transfemoral balloon-expandable TAVR,” wrote Norihiko Kamioka, MD, division of cardiology, Emory University, Atlanta, and associates.
The retrospective, observational analysis included 663 consecutive patients who underwent elective balloon-expandable TAVR during July 2014–July 2016. Cases with complications after the procedure were excluded.
The final analysis, which included 150 patients who had NDD and 210 discharged later, showed no difference between groups in the composite endpoint of mortality, and that 30-day readmissions were similar between groups (hazard ratio, 0.62; 95% confidence interval, 0.20-1.91).
Mortality and readmission at 1 year, the primary endpoint chosen for the study, favored the NDD group (HR, 0.47; 95% CI, 0.27-0.81), but “this finding probably reflects a healthier cohort in the NDD group,” the investigators noted. Furthermore, “although the reason for the discrepancy in the composite outcome at 1 year is mainly driven by noncardiovascular readmission, other confounding variables cannot be entirely ruled out,” Dr. Kamioka and colleagues said in the report.
Predictors of NDD included male sex, no atrial fibrillation, lower serum creatinine level, and younger age, researchers also found.
A validation cohort would be needed to confirm the findings of this study, including predictors of favorable outcomes, and to apply NDD to a wider population, study authors said.
Dr. Kamioka reported no relationships relevant to the study. Study coauthors reported disclosures related to Edwards Lifesciences, Abbott Vascular, Medtronic, Gore Vascular, and Boston Scientific.
SOURCE: JACC: Cardiovascular Interventions. 2018 Jan 22. doi: 10.1016/j.jcin.2017.10.021.
Researchers at Emory University have been leaders in promoting the so-called minimalist approach to TAVR and helping others understand how to safely reduce the length of stay without reducing the quality of care in these patients; however, the present study has significant shortcomings” that “may raise more questions than answers.
Because of these exclusions, it is difficult to know from this study if this treatment is generalizable to a larger TAVR population.
The conclusion that there was no difference in the composite outcome of death and readmission at 30 days is helpful information, offering reassurance that patient safety is not being compromised with NDD; however, the finding of superior outcomes at 1 year in the NDD group was driven by a significant reduction in noncardiovascular readmissions, which merely reemphasizes that the NDD patients in this study were lower risk rather than that they benefited by NDD.
Molly Szerlip, MD, of the Heart Hospital Baylor Plano (Tex.) made these comments in an accompanying editorial (JACC: Cardiovasc Interven. 2018 Jan 22. doi: 10.1016/j.jcin.2017.12.001). She reported disclosures related to Edwards Lifesciences and Medtronic.
Researchers at Emory University have been leaders in promoting the so-called minimalist approach to TAVR and helping others understand how to safely reduce the length of stay without reducing the quality of care in these patients; however, the present study has significant shortcomings” that “may raise more questions than answers.
Because of these exclusions, it is difficult to know from this study if this treatment is generalizable to a larger TAVR population.
The conclusion that there was no difference in the composite outcome of death and readmission at 30 days is helpful information, offering reassurance that patient safety is not being compromised with NDD; however, the finding of superior outcomes at 1 year in the NDD group was driven by a significant reduction in noncardiovascular readmissions, which merely reemphasizes that the NDD patients in this study were lower risk rather than that they benefited by NDD.
Molly Szerlip, MD, of the Heart Hospital Baylor Plano (Tex.) made these comments in an accompanying editorial (JACC: Cardiovasc Interven. 2018 Jan 22. doi: 10.1016/j.jcin.2017.12.001). She reported disclosures related to Edwards Lifesciences and Medtronic.
Researchers at Emory University have been leaders in promoting the so-called minimalist approach to TAVR and helping others understand how to safely reduce the length of stay without reducing the quality of care in these patients; however, the present study has significant shortcomings” that “may raise more questions than answers.
Because of these exclusions, it is difficult to know from this study if this treatment is generalizable to a larger TAVR population.
The conclusion that there was no difference in the composite outcome of death and readmission at 30 days is helpful information, offering reassurance that patient safety is not being compromised with NDD; however, the finding of superior outcomes at 1 year in the NDD group was driven by a significant reduction in noncardiovascular readmissions, which merely reemphasizes that the NDD patients in this study were lower risk rather than that they benefited by NDD.
Molly Szerlip, MD, of the Heart Hospital Baylor Plano (Tex.) made these comments in an accompanying editorial (JACC: Cardiovasc Interven. 2018 Jan 22. doi: 10.1016/j.jcin.2017.12.001). She reported disclosures related to Edwards Lifesciences and Medtronic.
Compared with a longer hospital stay, next-day discharge (NDD) after minimalist transcatheter aortic valve replacement (TAVR) appears safe, according to a recently reported analysis of patients treated at a single center.
The composite endpoint of mortality and readmission at 30 days was similar for NDD, compared with later discharges among patients who had a procedure that met minimalist criteria, defined in this study as transfemoral TAVR under conscious sedation and local anesthesia.
Mortality and readmission at 1 year was lower in the NDD group, mainly because of a lower risk of noncardiovascular readmissions, study authors reported in JACC: Cardiovascular Interventions. “Although superior NDD outcomes are likely attributed to selected patient characteristics, NDD in patients without in-hospital complications may be appropriate after transfemoral balloon-expandable TAVR,” wrote Norihiko Kamioka, MD, division of cardiology, Emory University, Atlanta, and associates.
The retrospective, observational analysis included 663 consecutive patients who underwent elective balloon-expandable TAVR during July 2014–July 2016. Cases with complications after the procedure were excluded.
The final analysis, which included 150 patients who had NDD and 210 discharged later, showed no difference between groups in the composite endpoint of mortality, and that 30-day readmissions were similar between groups (hazard ratio, 0.62; 95% confidence interval, 0.20-1.91).
Mortality and readmission at 1 year, the primary endpoint chosen for the study, favored the NDD group (HR, 0.47; 95% CI, 0.27-0.81), but “this finding probably reflects a healthier cohort in the NDD group,” the investigators noted. Furthermore, “although the reason for the discrepancy in the composite outcome at 1 year is mainly driven by noncardiovascular readmission, other confounding variables cannot be entirely ruled out,” Dr. Kamioka and colleagues said in the report.
Predictors of NDD included male sex, no atrial fibrillation, lower serum creatinine level, and younger age, researchers also found.
A validation cohort would be needed to confirm the findings of this study, including predictors of favorable outcomes, and to apply NDD to a wider population, study authors said.
Dr. Kamioka reported no relationships relevant to the study. Study coauthors reported disclosures related to Edwards Lifesciences, Abbott Vascular, Medtronic, Gore Vascular, and Boston Scientific.
SOURCE: JACC: Cardiovascular Interventions. 2018 Jan 22. doi: 10.1016/j.jcin.2017.10.021.
Compared with a longer hospital stay, next-day discharge (NDD) after minimalist transcatheter aortic valve replacement (TAVR) appears safe, according to a recently reported analysis of patients treated at a single center.
The composite endpoint of mortality and readmission at 30 days was similar for NDD, compared with later discharges among patients who had a procedure that met minimalist criteria, defined in this study as transfemoral TAVR under conscious sedation and local anesthesia.
Mortality and readmission at 1 year was lower in the NDD group, mainly because of a lower risk of noncardiovascular readmissions, study authors reported in JACC: Cardiovascular Interventions. “Although superior NDD outcomes are likely attributed to selected patient characteristics, NDD in patients without in-hospital complications may be appropriate after transfemoral balloon-expandable TAVR,” wrote Norihiko Kamioka, MD, division of cardiology, Emory University, Atlanta, and associates.
The retrospective, observational analysis included 663 consecutive patients who underwent elective balloon-expandable TAVR during July 2014–July 2016. Cases with complications after the procedure were excluded.
The final analysis, which included 150 patients who had NDD and 210 discharged later, showed no difference between groups in the composite endpoint of mortality, and that 30-day readmissions were similar between groups (hazard ratio, 0.62; 95% confidence interval, 0.20-1.91).
Mortality and readmission at 1 year, the primary endpoint chosen for the study, favored the NDD group (HR, 0.47; 95% CI, 0.27-0.81), but “this finding probably reflects a healthier cohort in the NDD group,” the investigators noted. Furthermore, “although the reason for the discrepancy in the composite outcome at 1 year is mainly driven by noncardiovascular readmission, other confounding variables cannot be entirely ruled out,” Dr. Kamioka and colleagues said in the report.
Predictors of NDD included male sex, no atrial fibrillation, lower serum creatinine level, and younger age, researchers also found.
A validation cohort would be needed to confirm the findings of this study, including predictors of favorable outcomes, and to apply NDD to a wider population, study authors said.
Dr. Kamioka reported no relationships relevant to the study. Study coauthors reported disclosures related to Edwards Lifesciences, Abbott Vascular, Medtronic, Gore Vascular, and Boston Scientific.
SOURCE: JACC: Cardiovascular Interventions. 2018 Jan 22. doi: 10.1016/j.jcin.2017.10.021.
FROM JACC: CARDIOVASCULAR INTERVENTIONS
Key clinical point: Next-day discharge (NDD) after minimalist TAVR appeared safe, compared with a longer hospital stay.
Major finding: The composite endpoint of mortality and readmission at 30 days was similar between groups (HR, 0.62; 95% CI, 0.20-1.91), and was lower in the NDD arm at 1 year because of fewer noncardiovascular readmissions.
Data source: A single-center, retrospective, nonrandomized observational analysis comprising 663 consecutive patients who underwent elective balloon-expandable TAVR between July 2014 and July 2016.
Disclosures: Study authors reported disclosures related to Edwards Lifesciences, Abbott Vascular, Medtronic, Gore Vascular, and Boston Scientific.
Source: JACC: Cardiovasc Interven. doi: 10.1016/j.jcin.2017.10.021.
Fetal alcohol syndrome: Context matters
Recently, there was a lot of hoopla in the popular press caused by the report by Philip A. May, PhD, and his team showing that the rates of fetal alcohol spectrum disorder (FASD) ran between 1.1 to 5.0% in first graders in four U.S. communities (JAMA. 2018;319[5]:474-82). This publication and the press it received made my heart sing because the findings made national news – meaning the issue would be in the public’s consciousness for a day or two. That is progress.
As psychiatrists, we should know that context is important. For example, I was at the Northeast Conference on Fetal Alcohol Spectrum Disorders in 2017 in Colby, Maine, and heard Larry Burd, PhD, a longstanding expert in the area of FASD, describe the drinking habits of the Native American women who had children with FASD. He described them as being alcoholics. I was floored, because engaged in social drinking during this time, but stopped cold when they realized that they were pregnant. I only saw two of 500 women that I would consider alcoholics, and one went on a 3-day binge with her girlfriends when she learned that she was pregnant. Clearly, context matters.
I continue to maintain that increasing choline in prenatal vitamins is a way out of this mess the United States is in with its hidden epidemic of FASD.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; a clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; a former president/CEO of Community Mental Health Council; and a former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
Recently, there was a lot of hoopla in the popular press caused by the report by Philip A. May, PhD, and his team showing that the rates of fetal alcohol spectrum disorder (FASD) ran between 1.1 to 5.0% in first graders in four U.S. communities (JAMA. 2018;319[5]:474-82). This publication and the press it received made my heart sing because the findings made national news – meaning the issue would be in the public’s consciousness for a day or two. That is progress.
As psychiatrists, we should know that context is important. For example, I was at the Northeast Conference on Fetal Alcohol Spectrum Disorders in 2017 in Colby, Maine, and heard Larry Burd, PhD, a longstanding expert in the area of FASD, describe the drinking habits of the Native American women who had children with FASD. He described them as being alcoholics. I was floored, because engaged in social drinking during this time, but stopped cold when they realized that they were pregnant. I only saw two of 500 women that I would consider alcoholics, and one went on a 3-day binge with her girlfriends when she learned that she was pregnant. Clearly, context matters.
I continue to maintain that increasing choline in prenatal vitamins is a way out of this mess the United States is in with its hidden epidemic of FASD.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; a clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; a former president/CEO of Community Mental Health Council; and a former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
Recently, there was a lot of hoopla in the popular press caused by the report by Philip A. May, PhD, and his team showing that the rates of fetal alcohol spectrum disorder (FASD) ran between 1.1 to 5.0% in first graders in four U.S. communities (JAMA. 2018;319[5]:474-82). This publication and the press it received made my heart sing because the findings made national news – meaning the issue would be in the public’s consciousness for a day or two. That is progress.
As psychiatrists, we should know that context is important. For example, I was at the Northeast Conference on Fetal Alcohol Spectrum Disorders in 2017 in Colby, Maine, and heard Larry Burd, PhD, a longstanding expert in the area of FASD, describe the drinking habits of the Native American women who had children with FASD. He described them as being alcoholics. I was floored, because engaged in social drinking during this time, but stopped cold when they realized that they were pregnant. I only saw two of 500 women that I would consider alcoholics, and one went on a 3-day binge with her girlfriends when she learned that she was pregnant. Clearly, context matters.
I continue to maintain that increasing choline in prenatal vitamins is a way out of this mess the United States is in with its hidden epidemic of FASD.
Dr. Bell is a staff psychiatrist at Jackson Park Hospital Family Medicine Clinic in Chicago; a clinical psychiatrist emeritus in the department of psychiatry at the University of Illinois at Chicago; a former president/CEO of Community Mental Health Council; and a former director of the Institute for Juvenile Research (birthplace of child psychiatry), also in Chicago.
Pediatrician blogs generally provide accurate vaccine information
Pediatrician blogs frequently provide accurate information to parents concerning vaccines, although some blogs do provide information inconsistent with Centers for Disease Control and Prevention guidelines, a study found.
“ However, we identified two exceptions in which pediatrician blogs conveyed extremely inaccurate, antivaccine information,” wrote Mersine A. Bryan, MD, of the University of Washington, Seattle, and her colleagues. “These two extreme blogs were the only blogs that contained any information that was not consistent with CDC information. This finding is important because pediatricians are viewed by parents as a trusted source of information about vaccines.”
Ultimately, the researchers examined 31 blogs with 324 posts related to vaccine content. Most of the information addressed “specific vaccines,” which accounted for 36% of all vaccine-related blog posts. The two most discussed vaccines were MMR (41% of vaccine-specific posts) and influenza (35%). Pediatrician bloggers also commonly addressed “activism against antivaccination,” which was the second most popular topic category.
The analysis revealed that many of the blog posts (91%) on 29 pediatrician blogs provided CDCC information. Only two blogs contained inaccurate vaccine information. Vaccine safety was the most commonly refuted CDCC information, with inaccurate information such as, “We are literally poisoning unborn children with the Tdap now being given to pregnant women with no testing ever done to inject that much aluminum into pregnant animals even!”
Vaccine-scheduling CDCC information was another topic that was addressed inaccurately, with statements such as, “Routine administration of hepatitis B vaccine to 1-day-old infants, which began in 1991, is an unwarranted practice that needs to stopped as soon as possible.” Delayed vaccinations also were inaccurately discussed in 5% of blog posts from two bloggers, who recommended that hepatitis B and MMR vaccines be delayed.
The study had several limitations, including how the blogs were selected for analysis; all were identified using common search engines, which may have caused researchers to miss an unknown number of blogs. In addition, information may have been augmented by “hyperbloggers,” who account for a large proportion of blog posts about vaccines, the researchers reported in Vaccine.
“While uncommon, the presentation of inaccurate, antivaccine information on pediatrician blogs may be persuasive to parents reading vaccine information online. Parents who delay immunizations due to safety concerns are more likely to use the Internet to learn more about vaccines,” wrote Dr. Bryan and her colleagues. “While these negative pediatrician bloggers are the exception, their impact may be disproportionate as people exposed to negative vaccine information in blog format have a more negative view of vaccinations than those exposed to positive vaccine information. Half of parents do not cross-check the information they read online with their doctor.”
The authors had no relevant financial disclosures.
SOURCE: Bryan MA et al. Vaccine. 2018 Jan 29;36(5):765-70.
Facebook and Twitter are useful tools for spreading vaccine information to families, but refuting “antivaccine” information can cause pushback.
“I use social media to disseminate information to families in my practice via a practice Facebook page, as well as to a larger audience via Twitter. I also share information with personal comments on my personal Facebook page,” Deborah Greenhouse, MD, said in an interview. “I have definitely run into questions over concerns with specific vaccines, particularly HPV [human papillomavirus] vaccine and MMR vaccine. Most of these originate with anecdotal posts about vaccine adverse effects.”
When addressing vaccine fears, Dr. Greenhouse presents current, fact-based information from credible sources, stressing the fact that correlation does not equal causation. To keep the lines of communication open, she encourages her patients to call with vaccine safety related questions.
While she has had some positive experiences with refuting “antivaccine” information, it also has been unpleasant. “Sometimes my posts and tweets have led to good interactive discussion. But sometimes they have led to extremely hostile and sometimes obscenity-laden responses by antivaccine activists.”
Despite “antivaccine” concern and pushback via social media, “alternative scheduling” is not viewed as “better than nothing,” she said. The vaccine schedule is based on solid science and should be adhered to. Deviating from a recommended vaccine schedule can put a child at unnecessary, and unacceptable, risk.
Dr. Greenhouse has used social media outreach to effectively provide information to her patients, but also has noted that some pediatricians provide inaccurate information online. “They are tougher to refute than the typical layperson because their credentials make them seem credible.”
Dr. Deborah Greenhouse is a board-certified pediatrician at the Palmetto Pediatric and Adolescent Clinic in Columbia, S.C. She is also a fellow of the American Academy of Pediatrics.
Facebook and Twitter are useful tools for spreading vaccine information to families, but refuting “antivaccine” information can cause pushback.
“I use social media to disseminate information to families in my practice via a practice Facebook page, as well as to a larger audience via Twitter. I also share information with personal comments on my personal Facebook page,” Deborah Greenhouse, MD, said in an interview. “I have definitely run into questions over concerns with specific vaccines, particularly HPV [human papillomavirus] vaccine and MMR vaccine. Most of these originate with anecdotal posts about vaccine adverse effects.”
When addressing vaccine fears, Dr. Greenhouse presents current, fact-based information from credible sources, stressing the fact that correlation does not equal causation. To keep the lines of communication open, she encourages her patients to call with vaccine safety related questions.
While she has had some positive experiences with refuting “antivaccine” information, it also has been unpleasant. “Sometimes my posts and tweets have led to good interactive discussion. But sometimes they have led to extremely hostile and sometimes obscenity-laden responses by antivaccine activists.”
Despite “antivaccine” concern and pushback via social media, “alternative scheduling” is not viewed as “better than nothing,” she said. The vaccine schedule is based on solid science and should be adhered to. Deviating from a recommended vaccine schedule can put a child at unnecessary, and unacceptable, risk.
Dr. Greenhouse has used social media outreach to effectively provide information to her patients, but also has noted that some pediatricians provide inaccurate information online. “They are tougher to refute than the typical layperson because their credentials make them seem credible.”
Dr. Deborah Greenhouse is a board-certified pediatrician at the Palmetto Pediatric and Adolescent Clinic in Columbia, S.C. She is also a fellow of the American Academy of Pediatrics.
Facebook and Twitter are useful tools for spreading vaccine information to families, but refuting “antivaccine” information can cause pushback.
“I use social media to disseminate information to families in my practice via a practice Facebook page, as well as to a larger audience via Twitter. I also share information with personal comments on my personal Facebook page,” Deborah Greenhouse, MD, said in an interview. “I have definitely run into questions over concerns with specific vaccines, particularly HPV [human papillomavirus] vaccine and MMR vaccine. Most of these originate with anecdotal posts about vaccine adverse effects.”
When addressing vaccine fears, Dr. Greenhouse presents current, fact-based information from credible sources, stressing the fact that correlation does not equal causation. To keep the lines of communication open, she encourages her patients to call with vaccine safety related questions.
While she has had some positive experiences with refuting “antivaccine” information, it also has been unpleasant. “Sometimes my posts and tweets have led to good interactive discussion. But sometimes they have led to extremely hostile and sometimes obscenity-laden responses by antivaccine activists.”
Despite “antivaccine” concern and pushback via social media, “alternative scheduling” is not viewed as “better than nothing,” she said. The vaccine schedule is based on solid science and should be adhered to. Deviating from a recommended vaccine schedule can put a child at unnecessary, and unacceptable, risk.
Dr. Greenhouse has used social media outreach to effectively provide information to her patients, but also has noted that some pediatricians provide inaccurate information online. “They are tougher to refute than the typical layperson because their credentials make them seem credible.”
Dr. Deborah Greenhouse is a board-certified pediatrician at the Palmetto Pediatric and Adolescent Clinic in Columbia, S.C. She is also a fellow of the American Academy of Pediatrics.
Pediatrician blogs frequently provide accurate information to parents concerning vaccines, although some blogs do provide information inconsistent with Centers for Disease Control and Prevention guidelines, a study found.
“ However, we identified two exceptions in which pediatrician blogs conveyed extremely inaccurate, antivaccine information,” wrote Mersine A. Bryan, MD, of the University of Washington, Seattle, and her colleagues. “These two extreme blogs were the only blogs that contained any information that was not consistent with CDC information. This finding is important because pediatricians are viewed by parents as a trusted source of information about vaccines.”
Ultimately, the researchers examined 31 blogs with 324 posts related to vaccine content. Most of the information addressed “specific vaccines,” which accounted for 36% of all vaccine-related blog posts. The two most discussed vaccines were MMR (41% of vaccine-specific posts) and influenza (35%). Pediatrician bloggers also commonly addressed “activism against antivaccination,” which was the second most popular topic category.
The analysis revealed that many of the blog posts (91%) on 29 pediatrician blogs provided CDCC information. Only two blogs contained inaccurate vaccine information. Vaccine safety was the most commonly refuted CDCC information, with inaccurate information such as, “We are literally poisoning unborn children with the Tdap now being given to pregnant women with no testing ever done to inject that much aluminum into pregnant animals even!”
Vaccine-scheduling CDCC information was another topic that was addressed inaccurately, with statements such as, “Routine administration of hepatitis B vaccine to 1-day-old infants, which began in 1991, is an unwarranted practice that needs to stopped as soon as possible.” Delayed vaccinations also were inaccurately discussed in 5% of blog posts from two bloggers, who recommended that hepatitis B and MMR vaccines be delayed.
The study had several limitations, including how the blogs were selected for analysis; all were identified using common search engines, which may have caused researchers to miss an unknown number of blogs. In addition, information may have been augmented by “hyperbloggers,” who account for a large proportion of blog posts about vaccines, the researchers reported in Vaccine.
“While uncommon, the presentation of inaccurate, antivaccine information on pediatrician blogs may be persuasive to parents reading vaccine information online. Parents who delay immunizations due to safety concerns are more likely to use the Internet to learn more about vaccines,” wrote Dr. Bryan and her colleagues. “While these negative pediatrician bloggers are the exception, their impact may be disproportionate as people exposed to negative vaccine information in blog format have a more negative view of vaccinations than those exposed to positive vaccine information. Half of parents do not cross-check the information they read online with their doctor.”
The authors had no relevant financial disclosures.
SOURCE: Bryan MA et al. Vaccine. 2018 Jan 29;36(5):765-70.
Pediatrician blogs frequently provide accurate information to parents concerning vaccines, although some blogs do provide information inconsistent with Centers for Disease Control and Prevention guidelines, a study found.
“ However, we identified two exceptions in which pediatrician blogs conveyed extremely inaccurate, antivaccine information,” wrote Mersine A. Bryan, MD, of the University of Washington, Seattle, and her colleagues. “These two extreme blogs were the only blogs that contained any information that was not consistent with CDC information. This finding is important because pediatricians are viewed by parents as a trusted source of information about vaccines.”
Ultimately, the researchers examined 31 blogs with 324 posts related to vaccine content. Most of the information addressed “specific vaccines,” which accounted for 36% of all vaccine-related blog posts. The two most discussed vaccines were MMR (41% of vaccine-specific posts) and influenza (35%). Pediatrician bloggers also commonly addressed “activism against antivaccination,” which was the second most popular topic category.
The analysis revealed that many of the blog posts (91%) on 29 pediatrician blogs provided CDCC information. Only two blogs contained inaccurate vaccine information. Vaccine safety was the most commonly refuted CDCC information, with inaccurate information such as, “We are literally poisoning unborn children with the Tdap now being given to pregnant women with no testing ever done to inject that much aluminum into pregnant animals even!”
Vaccine-scheduling CDCC information was another topic that was addressed inaccurately, with statements such as, “Routine administration of hepatitis B vaccine to 1-day-old infants, which began in 1991, is an unwarranted practice that needs to stopped as soon as possible.” Delayed vaccinations also were inaccurately discussed in 5% of blog posts from two bloggers, who recommended that hepatitis B and MMR vaccines be delayed.
The study had several limitations, including how the blogs were selected for analysis; all were identified using common search engines, which may have caused researchers to miss an unknown number of blogs. In addition, information may have been augmented by “hyperbloggers,” who account for a large proportion of blog posts about vaccines, the researchers reported in Vaccine.
“While uncommon, the presentation of inaccurate, antivaccine information on pediatrician blogs may be persuasive to parents reading vaccine information online. Parents who delay immunizations due to safety concerns are more likely to use the Internet to learn more about vaccines,” wrote Dr. Bryan and her colleagues. “While these negative pediatrician bloggers are the exception, their impact may be disproportionate as people exposed to negative vaccine information in blog format have a more negative view of vaccinations than those exposed to positive vaccine information. Half of parents do not cross-check the information they read online with their doctor.”
The authors had no relevant financial disclosures.
SOURCE: Bryan MA et al. Vaccine. 2018 Jan 29;36(5):765-70.
FROM VACCINE
Key clinical point: Pediatricians usually provide accurate information via blogs.
Major finding: 91% of blog posts on 29 pediatrician blogs contained only CDC-consistent information.
Study details: A content analysis of 31 pediatrician blogs from Jan. 1, 2014, to Feb. 28, 2015.
Disclosures: The authors had no relevant financial disclosures.
Source: Bryan MA et al. Vaccine. 2018 Jan 29;36(5):765-70.
Late-breaking research presented at AAD on Saturday February 17
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in San Diego. Look for the latest news and video interviews from the meeting in medical, surgical, and aesthetic dermatology at edermatologynews.com starting Friday February 16.
Coverage will include the late-breaker sessions, which will be presented on Saturday February 17.
Check out another late-breaking session – on basic science, cutaneous oncology, and pathology – which will include presentations on the growing burden of melanoma, the incidence of Merkel cell carcinoma in the United States, and the inverse genetic risk between vitiligo and cutaneous melanoma.
Find out more about these and other sessions at the official 2018 AAD Annual Meeting’s page.
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in San Diego. Look for the latest news and video interviews from the meeting in medical, surgical, and aesthetic dermatology at edermatologynews.com starting Friday February 16.
Coverage will include the late-breaker sessions, which will be presented on Saturday February 17.
Check out another late-breaking session – on basic science, cutaneous oncology, and pathology – which will include presentations on the growing burden of melanoma, the incidence of Merkel cell carcinoma in the United States, and the inverse genetic risk between vitiligo and cutaneous melanoma.
Find out more about these and other sessions at the official 2018 AAD Annual Meeting’s page.
Dermatology News will be on site later this week at the annual meeting of the American Academy of Dermatology in San Diego. Look for the latest news and video interviews from the meeting in medical, surgical, and aesthetic dermatology at edermatologynews.com starting Friday February 16.
Coverage will include the late-breaker sessions, which will be presented on Saturday February 17.
Check out another late-breaking session – on basic science, cutaneous oncology, and pathology – which will include presentations on the growing burden of melanoma, the incidence of Merkel cell carcinoma in the United States, and the inverse genetic risk between vitiligo and cutaneous melanoma.
Find out more about these and other sessions at the official 2018 AAD Annual Meeting’s page.
More time with digital media impacts childhood well-being
In school-aged children, according to Stephanie Ruest, MD, of Hasbro Children’s Hospital, Providence, R.I., and her associates.
In a study surveying parents from the 2011-2012 National Survey of Children’s Health, behavior of 64,464 children aged 6-17 years was examined. Results found that 31% of children were reported to have a combined daily digital media exposure (DME) of less than 2 hours/day, 36% had 2-4 hours, 17% had 4-6 hours, and 16% had at least 6 hours/day of DME. Among the children with less than 2 hours of DME, 38% had access to media devices in their bedroom, compared with 73% in the greater than 6-hour exposure group.
Additionally, children who had 2-4 hours of DME per weekday not related to schoolwork had 22% lower odds of always/usually finishing their homework, compared with children who had less than 2 hours. Children with 4-6 hours/day had 46% lower odds and those with greater than 6 hours/day had 57% lower odds of demonstrating this marker, compared with children with less than 2 hours (P less than .001). “There was a similar decrease in odds seen with each of the remaining four flourishing markers (test for trend P less than .001 for each marker),” Dr. Ruest and her associates said.
“DME, when measured in combined daily hours, is inversely associated with behaviors and attitudes that have been identified as markers of childhood flourishing in a dose-dependent manner,” the researchers concluded. “Future studies should continue to work towards elucidating the complex relationship between total DME time in conjunction with the content of the media and how the interplay affects childhood flourishing.”
SOURCE: Ruest S et al. J Pediatr. 2018 Feb 1. doi: 10.1016/j.jpeds.2017.12.016.
In school-aged children, according to Stephanie Ruest, MD, of Hasbro Children’s Hospital, Providence, R.I., and her associates.
In a study surveying parents from the 2011-2012 National Survey of Children’s Health, behavior of 64,464 children aged 6-17 years was examined. Results found that 31% of children were reported to have a combined daily digital media exposure (DME) of less than 2 hours/day, 36% had 2-4 hours, 17% had 4-6 hours, and 16% had at least 6 hours/day of DME. Among the children with less than 2 hours of DME, 38% had access to media devices in their bedroom, compared with 73% in the greater than 6-hour exposure group.
Additionally, children who had 2-4 hours of DME per weekday not related to schoolwork had 22% lower odds of always/usually finishing their homework, compared with children who had less than 2 hours. Children with 4-6 hours/day had 46% lower odds and those with greater than 6 hours/day had 57% lower odds of demonstrating this marker, compared with children with less than 2 hours (P less than .001). “There was a similar decrease in odds seen with each of the remaining four flourishing markers (test for trend P less than .001 for each marker),” Dr. Ruest and her associates said.
“DME, when measured in combined daily hours, is inversely associated with behaviors and attitudes that have been identified as markers of childhood flourishing in a dose-dependent manner,” the researchers concluded. “Future studies should continue to work towards elucidating the complex relationship between total DME time in conjunction with the content of the media and how the interplay affects childhood flourishing.”
SOURCE: Ruest S et al. J Pediatr. 2018 Feb 1. doi: 10.1016/j.jpeds.2017.12.016.
In school-aged children, according to Stephanie Ruest, MD, of Hasbro Children’s Hospital, Providence, R.I., and her associates.
In a study surveying parents from the 2011-2012 National Survey of Children’s Health, behavior of 64,464 children aged 6-17 years was examined. Results found that 31% of children were reported to have a combined daily digital media exposure (DME) of less than 2 hours/day, 36% had 2-4 hours, 17% had 4-6 hours, and 16% had at least 6 hours/day of DME. Among the children with less than 2 hours of DME, 38% had access to media devices in their bedroom, compared with 73% in the greater than 6-hour exposure group.
Additionally, children who had 2-4 hours of DME per weekday not related to schoolwork had 22% lower odds of always/usually finishing their homework, compared with children who had less than 2 hours. Children with 4-6 hours/day had 46% lower odds and those with greater than 6 hours/day had 57% lower odds of demonstrating this marker, compared with children with less than 2 hours (P less than .001). “There was a similar decrease in odds seen with each of the remaining four flourishing markers (test for trend P less than .001 for each marker),” Dr. Ruest and her associates said.
“DME, when measured in combined daily hours, is inversely associated with behaviors and attitudes that have been identified as markers of childhood flourishing in a dose-dependent manner,” the researchers concluded. “Future studies should continue to work towards elucidating the complex relationship between total DME time in conjunction with the content of the media and how the interplay affects childhood flourishing.”
SOURCE: Ruest S et al. J Pediatr. 2018 Feb 1. doi: 10.1016/j.jpeds.2017.12.016.
FROM THE JOURNAL OF PEDIATRICS
Study explores biological implications of MHC-II expression in tumor cells
SAN FRANCISCO – , and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.
The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
MHC-II
“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.
He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.
The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.
“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.
They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.
“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”
Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.
A closer look at individual genes that were different between class II–negative and positive tumors showed that LAG-3 mRNA was more enriched in the HLA-DR+ tumors, and also in patients who experienced a significant response to anti-PD-1 therapy.
“We also had a small population of samples that were derived from relapsed specimens,” he said. “We performed IHC within a small subset where we had paired tumors from pre-PD-1 response and relapse [to look at] LAG-3+ lymphocytes in the tumor ... and saw significant enrichment of LAG-3 infiltrate in the relapsed specimens. Importantly, all of these tumors were MHC-II+.”
Findings in a mouse model
The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”
Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.
Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.
“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.
This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.
“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”
To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
FCRL6
“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”
An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.
“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.
When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.
In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.
In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.
In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.
“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.
MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
Combined anti-PD-1 and anti-LAG-3 therapy
The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.
In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.
The 20% response rate seen in those with LAG-3 expression suggests “there could be a biomarker for this combined therapy,” he said, noting that while the overall response rate of 13% is low, “it is relevant because it is rescuing some patients who progressed on therapy, and it follows Dr. Balko’s science of why that would be the case.”
Dr. Balko has received research funding from Incyte, and holds a patent on use of HLA-DR/MHC expression to predict response to immunotherapies. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or adviser for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.
sworcester@frontlinemedcom.com
SOURCE: Balko J et al., ASCO-SITC abstract 180
SAN FRANCISCO – , and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.
The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
MHC-II
“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.
He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.
The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.
“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.
They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.
“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”
Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.
A closer look at individual genes that were different between class II–negative and positive tumors showed that LAG-3 mRNA was more enriched in the HLA-DR+ tumors, and also in patients who experienced a significant response to anti-PD-1 therapy.
“We also had a small population of samples that were derived from relapsed specimens,” he said. “We performed IHC within a small subset where we had paired tumors from pre-PD-1 response and relapse [to look at] LAG-3+ lymphocytes in the tumor ... and saw significant enrichment of LAG-3 infiltrate in the relapsed specimens. Importantly, all of these tumors were MHC-II+.”
Findings in a mouse model
The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”
Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.
Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.
“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.
This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.
“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”
To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
FCRL6
“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”
An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.
“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.
When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.
In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.
In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.
In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.
“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.
MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
Combined anti-PD-1 and anti-LAG-3 therapy
The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.
In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.
The 20% response rate seen in those with LAG-3 expression suggests “there could be a biomarker for this combined therapy,” he said, noting that while the overall response rate of 13% is low, “it is relevant because it is rescuing some patients who progressed on therapy, and it follows Dr. Balko’s science of why that would be the case.”
Dr. Balko has received research funding from Incyte, and holds a patent on use of HLA-DR/MHC expression to predict response to immunotherapies. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or adviser for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.
sworcester@frontlinemedcom.com
SOURCE: Balko J et al., ASCO-SITC abstract 180
SAN FRANCISCO – , and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.
The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
MHC-II
“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.
He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.
The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.
“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.
They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.
“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”
Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.
A closer look at individual genes that were different between class II–negative and positive tumors showed that LAG-3 mRNA was more enriched in the HLA-DR+ tumors, and also in patients who experienced a significant response to anti-PD-1 therapy.
“We also had a small population of samples that were derived from relapsed specimens,” he said. “We performed IHC within a small subset where we had paired tumors from pre-PD-1 response and relapse [to look at] LAG-3+ lymphocytes in the tumor ... and saw significant enrichment of LAG-3 infiltrate in the relapsed specimens. Importantly, all of these tumors were MHC-II+.”
Findings in a mouse model
The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”
Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.
Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.
“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.
This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.
“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”
To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
FCRL6
“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”
An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.
“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.
When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.
In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.
In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.
In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.
“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.
MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
Combined anti-PD-1 and anti-LAG-3 therapy
The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.
In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.
The 20% response rate seen in those with LAG-3 expression suggests “there could be a biomarker for this combined therapy,” he said, noting that while the overall response rate of 13% is low, “it is relevant because it is rescuing some patients who progressed on therapy, and it follows Dr. Balko’s science of why that would be the case.”
Dr. Balko has received research funding from Incyte, and holds a patent on use of HLA-DR/MHC expression to predict response to immunotherapies. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or adviser for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.
sworcester@frontlinemedcom.com
SOURCE: Balko J et al., ASCO-SITC abstract 180
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point: MHC-II expression could be useful for stratifying patients to anti-PD-1/anti-LAG-3 and other therapies.
Major finding: The ORR was 75% for class II–positive tumors treated with combined anti-PD-1/anti-LAG-3
Study details: RNA sequencing on 58 patients with anti-PD-1-treated tumors and on matched pretreatment specimens.
Disclosures: Dr. Balko has received research funding from Incyte, and holds a patent on use of HLA-DR/MHC expression to predict response to immunotherapies. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or adviser for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.
Source: Balko J et al. ASCO-SITC abstract 180.