A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m² or higher.
 

inTandem with sotagliflozin

Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.

SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.

Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.

In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m²; average mean, 24 kg/m² at baseline), and 916 had a higher weight (BMI of 27 kg/m² or higher; average mean, 32 kg/m² at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.

Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m²; n = 298, BMI 27 kg/m² or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m²; n = 305, BMI 27 kg/m² or higher) or 400 mg (n = 212; BMI less than 27 kg/m²; n = 313, BMI 27 kg/m² or higher).
 

Glycemic control and body weight

Greater reductions in glycated hemoglobin (HbA_1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m² or higher. At week 24, the least-squares mean difference in HbA_1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).

In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).

“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A_1c,” Dr. Danne said.

He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m² or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.

“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
 

Risk for DKA

“The big charm of these drugs is that not only do you improve A_1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m² [versus BMI of less than 27 kg/m²].”

The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.

“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
 

Body weight and composition

Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.

She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.

SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.

Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).

For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.

The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.

The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.

Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
 

DEPICT with dapagliflozin

In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m²; greater than 23 kg/m² to less than or equal to 25 kg/m²; greater than 25 kg/m² to less than or equal to 27 kg/m²; greater than 27 kg/m² to less than or equal to 30 kg/m²; and greater than 30 kg/m².

The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.

The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m²) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m²) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.

Odds ratios for achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.

“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.

The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m²); 6 versus 1 (BMI greater than 23 kg/m² to less than or equal to 25 kg/m²); 7 versus 1 (BMI greater than 25 kg/m² to less than or equal to 27 kg/m²); 3 versus 1 (BMI greater than 27 kg/m² to less than or equal to 30 kg/m²); and 2 versus 1 (BMI greater than 30 kg/m²).

In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.

The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.

SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.

BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m² or higher.
 

inTandem with sotagliflozin

Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.

SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.

Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.

In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m²; average mean, 24 kg/m² at baseline), and 916 had a higher weight (BMI of 27 kg/m² or higher; average mean, 32 kg/m² at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.

Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m²; n = 298, BMI 27 kg/m² or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m²; n = 305, BMI 27 kg/m² or higher) or 400 mg (n = 212; BMI less than 27 kg/m²; n = 313, BMI 27 kg/m² or higher).
 

Glycemic control and body weight

Greater reductions in glycated hemoglobin (HbA_1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m² or higher. At week 24, the least-squares mean difference in HbA_1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).

In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).

“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A_1c,” Dr. Danne said.

He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m² or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.

“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
 

Risk for DKA

“The big charm of these drugs is that not only do you improve A_1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m² [versus BMI of less than 27 kg/m²].”

The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.

“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
 

Body weight and composition

Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.

She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.

SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.

Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).

For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.

The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.

The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.

Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
 

DEPICT with dapagliflozin

In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m²; greater than 23 kg/m² to less than or equal to 25 kg/m²; greater than 25 kg/m² to less than or equal to 27 kg/m²; greater than 27 kg/m² to less than or equal to 30 kg/m²; and greater than 30 kg/m².

The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.

The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m²) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m²) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.

Odds ratios for achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.

“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.

The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m²); 6 versus 1 (BMI greater than 23 kg/m² to less than or equal to 25 kg/m²); 7 versus 1 (BMI greater than 25 kg/m² to less than or equal to 27 kg/m²); 3 versus 1 (BMI greater than 27 kg/m² to less than or equal to 30 kg/m²); and 2 versus 1 (BMI greater than 30 kg/m²).

In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.

The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.

SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.

BARCELONA – Individuals with type 1 diabetes and a high body mass index gain the most benefit with the least risk when sodium-glucose cotransporter 2 (SGLT2) inhibitors are added to insulin therapy, according to data presented at the annual meeting of the European Association for the Study of Diabetes.

Sara Freeman/MDedge News

Results from new analyses of the inTandem 1 and inTandem 2 trials with sotagliflozin (Zynquista), and the DEPICT-1 and DEPICT-2 trials with dapagliflozin (Farxiga), support the recent decision of the European Medicines Agency to license the use of the drugs only in patients with a BMI of 27 kg/m² or higher.
 

inTandem with sotagliflozin

Weight gain is a challenge in patients with type 1 diabetes, said Thomas Danne, MD, who presented post hoc data from the two inTandem studies. “It’s a little bit counterintuitive,” he acknowledged, “but you have to realize, particularly in patients who have hypoglycemia, that they have to take in extra carbohydrates,” which may tip them to becoming overweight or obese.

SGLT2-inhibitor therapy with sotagliflozin or dapagliflozin added to insulin therapy has been shown to reduce body weight in individuals with type 1 diabetes, but there is an increased risk for diabetic ketoacidosis (DKA). That risk, however, seems to be lower in the higher body-weight categories.

Dr. Danne, director of the department of general pediatrics, endocrinology, and diabetology, and clinical research at the Auf der Bult Hospital for Children and Adolescents, at the Hannover (Germany) Medical School, presented data looking at the outcomes of patients treated with sotagliflozin or placebo based on their BMI.

In all, 1,575 patients were included in the analysis, of whom 659 were of normal weight (BMI of less than 27 kg/m²; average mean, 24 kg/m² at baseline), and 916 had a higher weight (BMI of 27 kg/m² or higher; average mean, 32 kg/m² at baseline). The mean age of patients at study entry was 42 years for those with the lower BMI, and 45 years for those with the higher BMI.

Patients in the two inTandem trials had been treated with insulin plus placebo (n = 228, BMI less than 27 kg/m²; n = 298, BMI 27 kg/m² or higher), or insulin plus sotagliflozin at a dose of 200 mg (n = 219, BMI less than 27 kg/m²; n = 305, BMI 27 kg/m² or higher) or 400 mg (n = 212; BMI less than 27 kg/m²; n = 313, BMI 27 kg/m² or higher).
 

Glycemic control and body weight

Greater reductions in glycated hemoglobin (HbA_1c) were seen with sotagliflozin versus placebo, and even more so, if the BMI was 27 kg/m² or higher. At week 24, the least-squares mean difference in HbA_1c comparing sotagliflozin 200 mg and placebo was –0.32 in patients with the lower BMI, compared with –0.39 in those with the higher BMI. Corresponding values for the 400-mg sotagliflozin group in the higher-BMI group were –0.27 and –0.45, respectively (P less than .001 for all comparisons).

In the lower-BMI group, week 24 least-squares mean differences in body weight comparing sotagliflozin and placebo were –2.06 kg for the 200-mg group and –2.55 kg for the 400-mg group, and –2.27 kg and 3.32 kg in the higher-BMI group (P less than .001 for all comparisons).

“This is why this class of drugs holds so much of a promise, [because] it’s not only one good effect regarding improvement of glycemia judged by A_1c,” Dr. Danne said.

He also reported that treatment with sotagliflozin was associated with an increased time in range, compared with placebo, again, with greater effects seen in the higher- versus lower-BMI groups. In those with a BMI of 27 kg/m² or more, there was an additional 1 hour 58 minutes time in range for the 200-mg dose, and 3 hours 37 minutes for the 200-mg dose, compared with an extra 24 minutes and 1 hour 31 minutes, respectively, in the lower-BMI category.

“We also see a trend to improved reduction in systolic blood pressure in those with the higher BMI,” Dr. Danne said.
 

Risk for DKA

“The big charm of these drugs is that not only do you improve A_1c and all the other good things, but also you do this without increasing the risk of hypoglycemia,” said Dr. Danne. “Again, you can see a trend of a lower risk of severe hypoglycemia for both sotagliflozin doses [compared with placebo] in the group with the body mass index of greater than 27 kg/m² [versus BMI of less than 27 kg/m²].”

The risk of DKA was higher than placebo in both BMI groups, but the number of DKA events was very small when comparing the low and high body weight categories (0 and 1 events, respectively, in the placebo groups; 7 and 9, in the sotagliflozin 200-mg group; and 9 and 11, in the 400-mg group. The absolute risk difference in the exposure adjusted incidence rate was slightly lower in the lower-BMI group, he said, but the numbers were so small that it is difficult to draw conclusions from that finding.

“There is no doubt that we have an increase for the risk of DKA with this class of drugs in general ... but it is futile to discuss whether or not, just on the basis of a body mass index or something else, we will be able to reduce it in a big fashion,” Dr. Danne suggested.
 

Body weight and composition

Other data on the long-term effect of sotagliflozin on body weight and composition were presented by Sangeeta Sawhney, MD, vice-president of clinical development at Lexicon Pharmaceuticals, Chapel Hill, North Carolina.

She presented data from the DEXA substudy of the inTandem phase 3 studies in which 243 patients underwent fat mass and bone density scanning.

SGLT2 inhibitors are associated with weight loss through glycuresis and net caloric loss, Dr. Sawhney reminded the audience. As sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, however, it is important to estimate the contribution of changes in fat mass and lean mass to the weight loss that could be achieved with the drug.

Pooled data from the inTandem 1 and inTandem 2 studies showed that at week 24, there were reductions in body weight of –1.7 kg and –2.6 kg with sotagliflozin 200 mg and 400 mg, respectively, and at 52 weeks, reductions of –1.9 kg and –2.9 kg. However, there was an increase in body weight with placebo (+0.5 and +0.8 kg, respectively).

For the substudy, patients underwent dual-energy x-ray absorptiometry at baseline and weeks 24 and 52. Fat mass was measured at all three time points, and bone density was evaluated at the start and end of the study.

The least-square mean change in total fat mass from baseline to week 24 and week 52 were +0.6 and +0.1 kg, respectively, for placebo, –1.6 and –1.6 kg for the sotagliflozin 200-mg dose; and –1.9 and –2.1 kg for the 400-mg dose, “which really parallels the reduction in total body weight,” Dr. Sawhney observed.

The changes in total lean mass were much smaller for sotagliflozin, she added, at –0.6 kg at week 24 and 0.3 kg at week 52 for the 200-mg dose, and –0.7 kg and –0.4 kg, respectively, for the 400-mg dose, and rises in lean mass of 0.2 kg and 0.4 kg, respectively, in placebo.

Taken together, these data show that “about 80% of the body weight reduction is really from the fat mass, and a much smaller proportion of the total body weight reduction is really coming from the lean fat mass,” said Dr. Sawhney.
 

DEPICT with dapagliflozin

In a poster, Paresh Dandona, MD, PhD, of the State University of New York at Buffalo, and associates presented data from a pooled analysis of the DEPICT-1 and DEPICT-2 studies looking at safety and efficacy outcomes with dapagliflozin according to five BMI categories: less than or equal to 23 kg/m²; greater than 23 kg/m² to less than or equal to 25 kg/m²; greater than 25 kg/m² to less than or equal to 27 kg/m²; greater than 27 kg/m² to less than or equal to 30 kg/m²; and greater than 30 kg/m².

The pooled analysis included 548 patients treated with dapagliflozin 5 mg and 532 who received placebo. The investigators found that patients with higher BMIs who were treated with dapagliflozin had greater weight loss, showed a trend toward achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) or more without the risk of severe hypoglycemia, and had fewer episodes of definite DKA, compared with those with those with lower BMIs.

The adjusted mean percentage change from baseline in body weight in the lowest BMI (less than or equal to 23 kg/m²) group at week 24 was +0.06 kg for placebo and –2.71 kg for dapagliflozin, and at week 52, +0.33 kg and –2.91 kg, respectively. Corresponding values comparing placebo and dapagliflozin at 24 and 52 weeks in the highest BMI group (greater than 30 kg/m²) were –0.30 kg and –3.03 kg, and +0.56 and –3.58 kg.

Odds ratios for achieving an HbA_1c reduction of 5.5 mmol/mol (greater than or equal to 0.5%) without severe hypoglycemia at week 24 with dapagliflozin, compared with placebo, were, in increasing order of BMI groups: 1.85, 1.93, 3.87, 2.91, and 4.20.

“Generally, more events of definite DKA were observed in patients treated with dapagliflozin than in those treated with placebo,” but there were fewer events as BMI increased, Dr. Dandona and associates reported. “These data should be interpreted with caution due to the low number of events in each subgroup,” they added.

The number of adjudicated DKA events comparing dapagliflozin and placebo across the BMI groups were: 4 versus 1 (BMI less than or equal to 23 kg/m²); 6 versus 1 (BMI greater than 23 kg/m² to less than or equal to 25 kg/m²); 7 versus 1 (BMI greater than 25 kg/m² to less than or equal to 27 kg/m²); 3 versus 1 (BMI greater than 27 kg/m² to less than or equal to 30 kg/m²); and 2 versus 1 (BMI greater than 30 kg/m²).

In regard to limitations, “this was a post hoc analysis,” the investigators noted, adding that the studies were not originally powered for comparison between BMI subgroups, so the results should be considered exploratory. Moreover, DKA and hypoglycemia were strictly monitored in the trials, which “may differ from real-world situations,” they said.

The inTandem studies were sponsored by Lexicon and Sanofi. Dr. Danne disclosed receiving research funding and serving as a consultant, advisory board or steering committee member, or speaker for various companies, including Sanofi. Dr. Sawhney is an employee of and holds stoke in Lexicon. The DEPICT studies were sponsored by AstraZeneca. The lead author, Dr. Dandona, disclosed employment or consultancy services for multiple companies, including AstraZeneca.

SOURCE: Danne T et al. EASD 2018, Oral Presentation 2; Dandona P et al. EASD 2019, ePoster 720; Sawhney S et al. EASD 2019, Oral Presentation 3.

The SVS' Community Practice Committee will hold a webinar, Credentialing and Privileging for New Procedures and Technologies, on Tuesday, November 12th from 7-8pm CT. The webinar will focus on critical elements for obtaining privileging, the definition of a new procedure, a proposed process for credentialing and privileging and implementing the proposed process. Dr. Thomas Forbes is presenting the webinar and there will be time for questions. Dr. Forbes will also be joined by several vascular surgeons to answer your privileging and credentialing questions. Register today.

The SVS' Community Practice Committee will hold a webinar, Credentialing and Privileging for New Procedures and Technologies, on Tuesday, November 12th from 7-8pm CT. The webinar will focus on critical elements for obtaining privileging, the definition of a new procedure, a proposed process for credentialing and privileging and implementing the proposed process. Dr. Thomas Forbes is presenting the webinar and there will be time for questions. Dr. Forbes will also be joined by several vascular surgeons to answer your privileging and credentialing questions. Register today.

The SVS' Community Practice Committee will hold a webinar, Credentialing and Privileging for New Procedures and Technologies, on Tuesday, November 12th from 7-8pm CT. The webinar will focus on critical elements for obtaining privileging, the definition of a new procedure, a proposed process for credentialing and privileging and implementing the proposed process. Dr. Thomas Forbes is presenting the webinar and there will be time for questions. Dr. Forbes will also be joined by several vascular surgeons to answer your privileging and credentialing questions. Register today.

With physician distress a top concern of vascular surgeons, the SVS and its Wellness Task Force are launching a member support component of its wellness program, designed to help vascular surgeons enhance their personal resilience/wellness, and continue development of a compassionate and accountable peer community. Beginning in November, an article and a self-awareness exercise will be posted on SVSConnect each month and the group will encourage discussion on the topic. In February, a second phase of the program will offer members the opportunity to join peer support conference calls guided by wellness experts.

With physician distress a top concern of vascular surgeons, the SVS and its Wellness Task Force are launching a member support component of its wellness program, designed to help vascular surgeons enhance their personal resilience/wellness, and continue development of a compassionate and accountable peer community. Beginning in November, an article and a self-awareness exercise will be posted on SVSConnect each month and the group will encourage discussion on the topic. In February, a second phase of the program will offer members the opportunity to join peer support conference calls guided by wellness experts.

With physician distress a top concern of vascular surgeons, the SVS and its Wellness Task Force are launching a member support component of its wellness program, designed to help vascular surgeons enhance their personal resilience/wellness, and continue development of a compassionate and accountable peer community. Beginning in November, an article and a self-awareness exercise will be posted on SVSConnect each month and the group will encourage discussion on the topic. In February, a second phase of the program will offer members the opportunity to join peer support conference calls guided by wellness experts.

The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS Foundation has just published its 2019 Annual Report. This year, the report focuses on how past award recipients have used their grants to impact and improve patient care. More than $13 million in grants over the past three decades have given recipients the support they need to impact the lives of patients and those who provide care. Read about the stories, see the numbers and consider giving to the SVS Foundation in their 2019 Annual Report.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

The SVS, in collaboration with the Vascular and Endovascular Surgery Society (VESS) and the Society for Clinical Vascular Surgery (SCVS), has launched a new leadership development program. Its aim is to help our community of vascular surgeons reach their full potential as leaders and make the most positive impact possible in our specialty, their place of work, their community and other areas of importance in their life. The program is open to academic and community practice vascular surgeons from the US or Canada who are 5-10 years out from training. Learn more here.

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.

That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.

“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
 

The state of the art

Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.

A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.

An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.

Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”

Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.

The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.

“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”

The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.

“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.

When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.

One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.

Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.

“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:

• Combination immunotherapy is necessary.
• Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
• Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
• PD-1 blockade should continue.
• Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.

Clinical and molecular biomarkers

Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.

Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”

“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”

Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.

Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.

TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.

“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.

“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”

IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.

PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.

“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.

In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.

“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.

Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.

In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.

That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”

DDR is also garnering attention.

“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.

The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.

“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.

“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”

At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
 

The SCLC immune microenvironment

The immune microenvironment will be an integral part of that journey, according to Dr. Liu.

“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.

“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.

Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.

Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.

Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.

“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.

Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.

“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).

Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.

“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.

“All of these will need to be accounted for in various patients.”

These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.

In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.

“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.

Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.

“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.

But many questions remain, he said.

For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?

And importantly, “how will we choose between these various molecules we have?” he asked.

“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”

It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.

However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.

“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.

Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.

“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”

As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.

“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”

Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.




 

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.