Pharmacology

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

BARCELONA – Nivolumab was associated with improved overall survival and a favorable safety profile, compared with chemotherapy, in patients with previously treated advanced esophageal squamous cell carcinoma (ESCC) in the open-label phase 3 ATTRACTION-3 study.

The overall survival (OS) benefit was observed regardless of tumor programmed death-ligand 1 (PD-L1) expression, Byoung Chul Cho, MD, reported at the European Society for Medical Oncology Congress.

The findings were reported online simultaneously in The Lancet Oncology.

Median OS at a minimum follow-up of 17.6 months was 10.9 vs. 8.4 months in 210 patients randomized to receive treatment with the PD-1 inhibitor nivolumab and 209 who received chemotherapy, respectively (hazard ratio, 0.77), said Dr. Cho of Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

“Notably, there was a 13% and 10% improvement in overall survival rates at 12 months (47% vs. 34%) and 18 months (31% vs. 21%), respectively,” he said, also noting that the HRs for death favored nivolumab vs. chemotherapy across multiple prespecified subgroups, including those based on tumor PD-L1 expression (HRs, 0.69 and 0.84 for PD-L1 of 1% or greater and less than 1%, respectively).

No meaningful difference was seen in progression-free survival between the nivolumab and chemotherapy groups (12% vs. 7%; HR, 1.08), or in objective response rates (19% vs. 22%), he said.

“However, responses were substantially more durable with nivolumab, compared to chemotherapy; duration of response was 6.9 months with nivolumab vs. 3.9 months in the chemotherapy arm,” he said. “Notably, 21% of patients in the nivolumab arm were still in response, compared to only 6% in the chemotherapy arm.”

Patients enrolled in the open label study had unresectable advanced or recurrent ESCC refractory or intolerant to one prior fluoropyrimidine/platinum-based therapy. They were randomized 1:1 to receive 240 mg of nivolumab every 2 weeks or investigators’ choice of paclitaxel or docetaxel.

Fewer treatment-related adverse events (TRAEs) were reported with nivolumab, Dr. Cho said.

Any grade TRAEs occurred in 66% vs. 95% of patients in the groups, respectively, and grade 3-4 TRAEs occurred in 18% vs. 63%. The majority of select TRAEs – defined as those with potential immunologic etiology, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin effects – were grade 1 or 2, and the only difference between the nivolumab and chemotherapy groups with respect to those was in endocrine effects, which affected 11% vs. less than 1% of patients, respectively.

Grade 3/4 select TRAEs occurred in less than 2% of patients, Dr. Cho noted.

An exploratory analysis further showed significant overall improvement in health-related quality of life with nivolumab through week 42 on treatment, he added.

The findings are of note, because metastatic esophageal cancer has a 5-year relative survival rate of less than 8%, and ESCC accounts for about 90% of cases worldwide, he said, adding that current second-line chemotherapy options for ESCC offer poor long-term survival and are associated with toxicity.

Nivolumab, which showed promising antitumor activity and manageable toxicity for advanced ESCC in patients who were refractory to or intolerant of standard chemotherapies in the phase 2 ATTRACTION-1 study, is the first immune checkpoint inhibitor to demonstrate a statistically significant, clinically meaningful improvement in OS vs. chemotherapy in this setting, he said.

The findings of this final analysis of ATTRACTION-3, which shows a 23% reduction in the risk of death, a 2.5-month improvement in median OS, benefit across PD-L1 subgroups, and a favorable safety profile, suggest that nivolumab represents a new standard second-line treatment option for patients with advanced ESCC, he concluded.

ATTRACTION-3 was funded by Ono Pharmaceutical Co., in collaboration with Bristol-Myers Squibb. Dr. Cho reported relationships with Bristol-Myers Squibb, Ono Pharmaceutical, and others. He also reported stock ownership and/or patents with TheraCanVac and Champions Oncology.

SOURCE: Cho B et al. ESMO 2019, Abstract LBA11.

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.

He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.

In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.

“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.

Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).

Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.

HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.

Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.

[email protected]

Postmenopausal women who received a probiotic treatment of three Lactobacillus strains had significantly less lumbar spine bone loss, compared with women in a placebo group, according to recent research published in The Lancet Rheumatology.

CharlieAJA/Thinkstock

“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.

Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 10¹⁰ colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.

Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm²; 95% CI, 0.38 to 14.50).

In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).

Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).

Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”

The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.

In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.

In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.

“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.

This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.

SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2

Postmenopausal women who received a probiotic treatment of three Lactobacillus strains had significantly less lumbar spine bone loss, compared with women in a placebo group, according to recent research published in The Lancet Rheumatology.

CharlieAJA/Thinkstock

“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.

Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 10¹⁰ colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.

Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm²; 95% CI, 0.38 to 14.50).

In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).

Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).

Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”

The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.

In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.

In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.

“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.

This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.

SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2

Postmenopausal women who received a probiotic treatment of three Lactobacillus strains had significantly less lumbar spine bone loss, compared with women in a placebo group, according to recent research published in The Lancet Rheumatology.

CharlieAJA/Thinkstock

“The menopausal and early postmenopausal lumbar spine bone loss is substantial in women, and by using a prevention therapy with bacteria naturally occurring in the human gut microbiota we observed a close to complete protection against lumbar spine bone loss in healthy postmenopausal women,” Per-Anders Jansson, MD, chief physician at the University of Gothenburg (Sweden), and colleagues wrote in their study.

Dr. Jansson and colleagues performed a double-blind trial at four centers in Sweden in which 249 postmenopausal women were randomized during April-November 2016 to receive probiotics consisting of three Lactobacillus strains or placebo once per day for 12 months. Participants were healthy women, neither underweight nor overweight, and were postmenopausal, which was defined as being 2-12 years or less from last menstruation. The Lactobacillus strains, L. paracasei 8700:2 (DSM 13434), L. plantarum Heal 9 (DSM 15312), and L. plantarum Heal 19 (DSM 15313), were equally represented in a capsule at a dose of 1 x 10¹⁰ colony-forming unit per capsule. The researchers measured the lumbar spine bone mineral density (LS-BMD) at baseline and at 12 months, and also evaluated the safety profile of participants in both the probiotic and placebo groups.

Overall, 234 participants (94%) had data available for analysis at the end of the study. There was a significant reduction in LS-BMD loss for participants who received the probiotic treatment, compared with women in the control group (mean difference, 0.71%; 95% confidence interval, 0.06%-1.35%), while there was a significant loss in LS-BMD for participants in the placebo group (percentage change, –0.72%; 95% CI, –1.22% to –0.22%) compared with loss in the probiotic group (percentage change, –0.01%; 95% CI, –0.50% to 0.48%). Using analysis of covariance, the researchers found the probiotic group had reduced LS-BMD loss after adjustment for factors such as study site, age at baseline, BMD at baseline, and number of years from menopause (mean difference, 7.44 mg/cm²; 95% CI, 0.38 to 14.50).

In a subgroup analysis of women above and below the median time since menopause at baseline (6 years), participants in the probiotic group who were below the median time saw a significant protective effect of Lactobacillus treatment (mean difference, 1.08%; 95% CI, 0.20%-1.96%), compared with women above the median time (mean difference, 0.31%; 95% CI, –0.62% to 1.23%).

Researchers also examined the effects of probiotic treatment on total hip and femoral neck BMD as secondary endpoints. Lactobacillus treatment did not appear to affect total hip (–1.01%; 95% CI, –1.65% to –0.37%) or trochanter BMD (–1.13%; 95% CI, –2.27% to 0.20%), but femoral neck BMD was reduced in the probiotic group (–1.34%; 95% CI, –2.09% to –0.58%), compared with the placebo group (–0.88%; 95% CI, –1.64% to –0.13%).

Limitations of the study included examining only one dose of Lactobacillus treatment and no analysis of the effect of short-chain fatty acids on LS-BMD. The researchers noted that “recent studies have shown that short-chain fatty acids, which are generated by fermentation of complex carbohydrates by the gut microbiota, are important regulators of both bone formation and resorption.”

The researchers also acknowledged that the LS-BMD effect size for the probiotic treatment over the 12 months was a lower magnitude, compared with first-line treatments for osteoporosis in postmenopausal women using bisphosphonates. “Further long-term studies should be done to evaluate if the bone-protective effect becomes more pronounced with prolonged treatment with the Lactobacillus strains used in the present study,” they said.

In a related editorial, Shivani Sahni, PhD, of Harvard Medical School, Boston, and Connie M. Weaver, PhD, of Purdue University, West Lafayette, Ind., reiterated that the effect size of probiotics is “of far less magnitude” than such treatments as bisphosphonates and expressed concern about the reduction of femoral neck BMD in the probiotic group, which was not explained in the study (Lancet Rheumatol. 2019 Nov;1[3]:e135-e137. doi: 10.1016/S2665-9913(19)30073-6). There is a need to learn the optimum dose of probiotics as well as which Lactobacillus strains should be used in future studies, as the strains chosen by Jansson et al. were based on results in mice.

In the meantime, patients might be better off choosing dietary interventions with proven bone protection and no documented negative effects on the hip, such as prebiotics like soluble corn fiber and dried prunes, in tandem with drug therapies, Dr. Sahni and Dr. Weaver said.

“Although Jansson and colleagues’ results are important, more work is needed before such probiotics are ready for consumers,” they concluded.

This study was funded by Probi, which employs two of the study’s authors. Three authors reported being coinventors of a patent involving the effects of probiotics in osteoporosis treatment, and one author is listed as an inventor on a pending patent application on probiotic compositions and uses. Dr. Sahni reported receiving grants from Dairy Management. Dr. Weaver reported no relevant conflicts of interest.

SOURCE: Jansson P-A et al. Lancet Rheumatol. 2019 Nov;1(3):e154-e162. doi: 10.1016/S2665-9913(19)30068-2

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

CHICAGO – Current dosing recommendations for thyroid replacement during immune checkpoint inhibitor therapy may overshoot the mark, both for patients with preexisting and de novo hypothyroidism.

Kari Oakes/MDedge News

The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.

Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.

Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.

The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.

The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.

However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.

To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.

The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.

At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.

For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.

The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.

For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).

Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.

For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.

However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.

Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.

The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.

Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.

Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
 

SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.

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.




 

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Adding levofloxacin to antimyeloma therapy improved survival and reduced infections in patients with newly diagnosed myeloma, findings from a phase 3 trial suggest.

Wikimedia Commons/KGH/Creative Commons License

The advantages of levofloxacin prophylaxis appear to offset the potential risks in patients with newly diagnosed disease, explained Mark T. Drayson, MBChB, PhD, of the University of Birmingham (England) and colleagues. The study was published in the Lancet Oncology.

The randomized, placebo-controlled, phase 3 TEAMM study enrolled 977 patients with newly diagnosed myeloma. The effects of antimicrobial prophylaxis on infection risk and infection-related mortality were evaluated across 93 hospitals throughout the United Kingdom.

Study patients were randomly assigned to receive 500 mg of oral levofloxacin once daily or placebo for a total of 12 weeks. If applicable, dose adjustments were made based on estimated glomerular filtration rate.

At baseline, the team collected stool samples and nasal swabs, and follow-up assessment occurred every 4 weeks for up to 1 year. The primary endpoint was time to death (all causes) or first febrile event from the start of prophylactic therapy to 12 weeks.

After a median follow-up of 12 months, first febrile episodes or deaths were significantly lower for patients in the levofloxacin arm (19%), compared with the placebo arm (27%) for a hazard ratio for time to first event of 0.66 (95% confidence interval, 0.51-0.86; P = .0018).

With respect to safety, the rates of serious adverse events were similar between the study arms, with the exception of tendinitis in the levofloxacin group (1%). Among all patients, a total of 597 serious toxicities were observed from baseline to 16 weeks (52% in the levofloxacin arm vs. 48% in the placebo arm).

“To our knowledge, this is the first time that the use of prophylactic antibiotics has shown a survival benefit in patients with newly diagnosed myeloma,” the researchers reported.

One key limitation of the study was the younger patient population relative to the general population. As a result, differences in survival estimates could exist between the trial and real-world populations, they noted.

“Patients with newly diagnosed myeloma could benefit from levofloxacin prophylaxis, although local antibiotic resistance proportions must be considered,” the researchers cautioned.

The study was funded by the National Institute for Health Research in the United Kingdom. The authors reported financial affiliations with Actelion, Astellas, Celgene, Gilead, Janssen, Pfizer, Takeda, and other companies.

SOURCE: Drayson MT et al. Lancet Oncol. 2019 Oct 23. doi: 10.1016/S1470-2045(19)30506-6.

Neither cognitive behavioral therapy nor second-generation antidepressant medications was more cost effective than the other for treating patients with major depressive disorder, according to a recent study published in Annals of Internal Medicine.

Michail_Petrov-96/Thinkstock

“In the absence of clear superiority of either treatment, shared decision making incorporating patient preferences is critical,” Eric L. Ross, MD, of Massachusetts General Hospital, Boston, and colleagues wrote in their study.

Dr. Ross and colleagues created a decision-analytic model for adults with major depressive disorder in the United States using age and gender data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, and simulated a cohort consisting of 62.2% women with a mean age of 40.7 years. Patients underwent cognitive behavioral therapy (CBT) or received a second-generation antidepressant (SGA) as first-line therapy, and the model calculated risks and benefits of each therapy as well as likelihood of remission and response using data from meta-analyses.

The researchers calculated the average quality-adjusted life-years (QALY) of both treatments at 1 years and 5 years. The incremental cost-effectiveness ratio (ICER) was set at $100,000 or less per QALY for cost effectiveness, and the results were adjusted to 2014 U.S. dollars. Researchers also calculated the net monetary benefit of each treatment based on health and economic outcomes.

At 1 year, Dr. Ross and colleagues found quality-adjusted survival in patients who received CBT increased by 3 days (QALY, 0.008; 95% confidence interval, 0.013-0.025) compared with SGA, but there was a higher mean cost to the health care sector ($900; 95% CI, $500-$1,400) and to society ($1,500; 95% CI, $500-$2,500). CBT was not cost effective at 1 year, with incremental cost-effectiveness ratios in the health care sector of $119,000 per QALY and $186,000 per QALY to society, but the net monetary benefit confidence intervals in the health care sector ($2,400-$1,600) and in society ($3,400-$1,600) appear to show some cost effectiveness for CBT at 1 year, the researchers said.

Compared with SGA, there was an increase of 20 quality-adjusted life days in patients who received CBT at 5 years (QALY, 0.055; 95% CI, 0.044-0.160), and the cost for CBT treatment was reduced by $2,000. While CBT appeared to be cost saving in the base-case analysis, the researchers said there was some uncertainty in the cost effectiveness of CBT when they calculated the incremental net monetary benefit of CBT for the health care sector ($8,100-$21,700) and to society ($10,400-$25,300). In a sensitivity analysis, preference for SGA as a first-line therapy at 1 year was between 64% and 77%, while CBT became more preferred between 1.5 and 2 years, and had between a 73% and 87% preference range at 5 years.

In a related editorial, Mark Sinyor, MD, of Sunnybrook Health Sciences Centre in Toronto, said that although more longitudinal data are needed comparing outcomes in patients with major depressive disorder undergoing treatment with psychotherapy or medication, clinicians should act on what the current evidence shows about the effectiveness of CBT and SGA.

“It is increasingly evident that differences in effectiveness between CBT and SGAs are not substantial and that CBT has some advantages, including potentially lower long-term costs. These must be balanced with the advantages of SGAs, such as potentially more rapid action as well as efficacy across the full [major depressive disorder] severity spectrum,” he said.

Dr. Sinyor also called for CBT and SGA to be made available to all patients with major depressive disorder.

“Antidepressants for [major depressive disorder] are widely accessible in developed countries and that is important for our patients. If we are serious about providing evidence-based care, CBT must become equally available,” he said.

Neil Skolnik, MD, professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health, echoed the sentiment that CBT should be offered alongside antidepressants for treatment of major depressive disorder.

“CBT works as well or better than antidepressant medication, and since people learn skills that they can continue to use, it often has a long-lasting effect. In my experience, for people for whom CBT works – that is, for people who are seeing a therapist who use CBT as their technique and who are willing to put in the work it takes – CBT can be life changing,” he said in an interview. “So, I am not surprised, but I am happy to see the results of this study showing that CBT is cost effective.”

Dr. Skolnik emphasized that not every therapist offers CBT, so health care providers should be aware of the type of therapy they are referring their patients for and monitor that therapy when possible.

“We should talk to our patients, present them with options, and then decide together with our patients which approach is best for them,” Dr. Skolnik added. “Medications work, and for many this is a good choice. CBT works, and for many this is a good choice. For some patients, using both CBT and medications is the optimal choice. Both are about equally cost effective. We should discuss the options with our patients and decide the path forward together.”

This study was funded by grants from the U.S. Department of Veterans Affairs Health Services Research and Development and the National Institute of Mental Health. Dr. Ross reported receiving a grant from the National Institute of Mental Health. Two coauthors reported receiving grants from the Department of Veterans Affairs. Dr. Sinyor and Dr. Skolnik reported no conflicts of interest.

SOURCE: Ross EL et al. Ann Intern Med. 2019. doi: 10.7326/M18-1480.

Neither cognitive behavioral therapy nor second-generation antidepressant medications was more cost effective than the other for treating patients with major depressive disorder, according to a recent study published in Annals of Internal Medicine.

Michail_Petrov-96/Thinkstock

“In the absence of clear superiority of either treatment, shared decision making incorporating patient preferences is critical,” Eric L. Ross, MD, of Massachusetts General Hospital, Boston, and colleagues wrote in their study.

Dr. Ross and colleagues created a decision-analytic model for adults with major depressive disorder in the United States using age and gender data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, and simulated a cohort consisting of 62.2% women with a mean age of 40.7 years. Patients underwent cognitive behavioral therapy (CBT) or received a second-generation antidepressant (SGA) as first-line therapy, and the model calculated risks and benefits of each therapy as well as likelihood of remission and response using data from meta-analyses.

The researchers calculated the average quality-adjusted life-years (QALY) of both treatments at 1 years and 5 years. The incremental cost-effectiveness ratio (ICER) was set at $100,000 or less per QALY for cost effectiveness, and the results were adjusted to 2014 U.S. dollars. Researchers also calculated the net monetary benefit of each treatment based on health and economic outcomes.

At 1 year, Dr. Ross and colleagues found quality-adjusted survival in patients who received CBT increased by 3 days (QALY, 0.008; 95% confidence interval, 0.013-0.025) compared with SGA, but there was a higher mean cost to the health care sector ($900; 95% CI, $500-$1,400) and to society ($1,500; 95% CI, $500-$2,500). CBT was not cost effective at 1 year, with incremental cost-effectiveness ratios in the health care sector of $119,000 per QALY and $186,000 per QALY to society, but the net monetary benefit confidence intervals in the health care sector ($2,400-$1,600) and in society ($3,400-$1,600) appear to show some cost effectiveness for CBT at 1 year, the researchers said.

Compared with SGA, there was an increase of 20 quality-adjusted life days in patients who received CBT at 5 years (QALY, 0.055; 95% CI, 0.044-0.160), and the cost for CBT treatment was reduced by $2,000. While CBT appeared to be cost saving in the base-case analysis, the researchers said there was some uncertainty in the cost effectiveness of CBT when they calculated the incremental net monetary benefit of CBT for the health care sector ($8,100-$21,700) and to society ($10,400-$25,300). In a sensitivity analysis, preference for SGA as a first-line therapy at 1 year was between 64% and 77%, while CBT became more preferred between 1.5 and 2 years, and had between a 73% and 87% preference range at 5 years.

In a related editorial, Mark Sinyor, MD, of Sunnybrook Health Sciences Centre in Toronto, said that although more longitudinal data are needed comparing outcomes in patients with major depressive disorder undergoing treatment with psychotherapy or medication, clinicians should act on what the current evidence shows about the effectiveness of CBT and SGA.

“It is increasingly evident that differences in effectiveness between CBT and SGAs are not substantial and that CBT has some advantages, including potentially lower long-term costs. These must be balanced with the advantages of SGAs, such as potentially more rapid action as well as efficacy across the full [major depressive disorder] severity spectrum,” he said.

Dr. Sinyor also called for CBT and SGA to be made available to all patients with major depressive disorder.

“Antidepressants for [major depressive disorder] are widely accessible in developed countries and that is important for our patients. If we are serious about providing evidence-based care, CBT must become equally available,” he said.

Neil Skolnik, MD, professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health, echoed the sentiment that CBT should be offered alongside antidepressants for treatment of major depressive disorder.

“CBT works as well or better than antidepressant medication, and since people learn skills that they can continue to use, it often has a long-lasting effect. In my experience, for people for whom CBT works – that is, for people who are seeing a therapist who use CBT as their technique and who are willing to put in the work it takes – CBT can be life changing,” he said in an interview. “So, I am not surprised, but I am happy to see the results of this study showing that CBT is cost effective.”

Dr. Skolnik emphasized that not every therapist offers CBT, so health care providers should be aware of the type of therapy they are referring their patients for and monitor that therapy when possible.

“We should talk to our patients, present them with options, and then decide together with our patients which approach is best for them,” Dr. Skolnik added. “Medications work, and for many this is a good choice. CBT works, and for many this is a good choice. For some patients, using both CBT and medications is the optimal choice. Both are about equally cost effective. We should discuss the options with our patients and decide the path forward together.”

This study was funded by grants from the U.S. Department of Veterans Affairs Health Services Research and Development and the National Institute of Mental Health. Dr. Ross reported receiving a grant from the National Institute of Mental Health. Two coauthors reported receiving grants from the Department of Veterans Affairs. Dr. Sinyor and Dr. Skolnik reported no conflicts of interest.

SOURCE: Ross EL et al. Ann Intern Med. 2019. doi: 10.7326/M18-1480.

Neither cognitive behavioral therapy nor second-generation antidepressant medications was more cost effective than the other for treating patients with major depressive disorder, according to a recent study published in Annals of Internal Medicine.

Michail_Petrov-96/Thinkstock

“In the absence of clear superiority of either treatment, shared decision making incorporating patient preferences is critical,” Eric L. Ross, MD, of Massachusetts General Hospital, Boston, and colleagues wrote in their study.

Dr. Ross and colleagues created a decision-analytic model for adults with major depressive disorder in the United States using age and gender data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, and simulated a cohort consisting of 62.2% women with a mean age of 40.7 years. Patients underwent cognitive behavioral therapy (CBT) or received a second-generation antidepressant (SGA) as first-line therapy, and the model calculated risks and benefits of each therapy as well as likelihood of remission and response using data from meta-analyses.

The researchers calculated the average quality-adjusted life-years (QALY) of both treatments at 1 years and 5 years. The incremental cost-effectiveness ratio (ICER) was set at $100,000 or less per QALY for cost effectiveness, and the results were adjusted to 2014 U.S. dollars. Researchers also calculated the net monetary benefit of each treatment based on health and economic outcomes.

At 1 year, Dr. Ross and colleagues found quality-adjusted survival in patients who received CBT increased by 3 days (QALY, 0.008; 95% confidence interval, 0.013-0.025) compared with SGA, but there was a higher mean cost to the health care sector ($900; 95% CI, $500-$1,400) and to society ($1,500; 95% CI, $500-$2,500). CBT was not cost effective at 1 year, with incremental cost-effectiveness ratios in the health care sector of $119,000 per QALY and $186,000 per QALY to society, but the net monetary benefit confidence intervals in the health care sector ($2,400-$1,600) and in society ($3,400-$1,600) appear to show some cost effectiveness for CBT at 1 year, the researchers said.

Compared with SGA, there was an increase of 20 quality-adjusted life days in patients who received CBT at 5 years (QALY, 0.055; 95% CI, 0.044-0.160), and the cost for CBT treatment was reduced by $2,000. While CBT appeared to be cost saving in the base-case analysis, the researchers said there was some uncertainty in the cost effectiveness of CBT when they calculated the incremental net monetary benefit of CBT for the health care sector ($8,100-$21,700) and to society ($10,400-$25,300). In a sensitivity analysis, preference for SGA as a first-line therapy at 1 year was between 64% and 77%, while CBT became more preferred between 1.5 and 2 years, and had between a 73% and 87% preference range at 5 years.

In a related editorial, Mark Sinyor, MD, of Sunnybrook Health Sciences Centre in Toronto, said that although more longitudinal data are needed comparing outcomes in patients with major depressive disorder undergoing treatment with psychotherapy or medication, clinicians should act on what the current evidence shows about the effectiveness of CBT and SGA.

“It is increasingly evident that differences in effectiveness between CBT and SGAs are not substantial and that CBT has some advantages, including potentially lower long-term costs. These must be balanced with the advantages of SGAs, such as potentially more rapid action as well as efficacy across the full [major depressive disorder] severity spectrum,” he said.

Dr. Sinyor also called for CBT and SGA to be made available to all patients with major depressive disorder.

“Antidepressants for [major depressive disorder] are widely accessible in developed countries and that is important for our patients. If we are serious about providing evidence-based care, CBT must become equally available,” he said.

Neil Skolnik, MD, professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington Jefferson Health, echoed the sentiment that CBT should be offered alongside antidepressants for treatment of major depressive disorder.

“CBT works as well or better than antidepressant medication, and since people learn skills that they can continue to use, it often has a long-lasting effect. In my experience, for people for whom CBT works – that is, for people who are seeing a therapist who use CBT as their technique and who are willing to put in the work it takes – CBT can be life changing,” he said in an interview. “So, I am not surprised, but I am happy to see the results of this study showing that CBT is cost effective.”

Dr. Skolnik emphasized that not every therapist offers CBT, so health care providers should be aware of the type of therapy they are referring their patients for and monitor that therapy when possible.

“We should talk to our patients, present them with options, and then decide together with our patients which approach is best for them,” Dr. Skolnik added. “Medications work, and for many this is a good choice. CBT works, and for many this is a good choice. For some patients, using both CBT and medications is the optimal choice. Both are about equally cost effective. We should discuss the options with our patients and decide the path forward together.”

This study was funded by grants from the U.S. Department of Veterans Affairs Health Services Research and Development and the National Institute of Mental Health. Dr. Ross reported receiving a grant from the National Institute of Mental Health. Two coauthors reported receiving grants from the Department of Veterans Affairs. Dr. Sinyor and Dr. Skolnik reported no conflicts of interest.

SOURCE: Ross EL et al. Ann Intern Med. 2019. doi: 10.7326/M18-1480.

SAN DIEGO – Not long before his presentation at Psych Congress 2019, psychiatrist Rakesh Jain, MD, MPH, chatted with a fellow attendee, a nurse practitioner from Tyler, Tex. As Dr. Jain recalled later, his fellow Texan told him that “it’s not unusual to see patients on three benzodiazepines.”

The nurse practitioner “talks to them about how they need to do things differently, and they forget,” Dr. Jain said. “He’s very worried about them.”

Dr. Jain is familiar with the feeling. Like many mental health professionals, he worries about the role of benzodiazepines, which seem to be both widely used and misused. Figuring out their proper place in psychiatry “may require us to raise our game,” said Dr. Jain, of Texas Tech University in Midland.

What to do? Dr. Jain and a colleague offered the same answer – tread carefully, but do not eliminate them as an option – in two separate sessions at the annual Psych Congress.

As Dr. Jain noted, benzodiazepines are popular, and for good reason. “There are many patients, perhaps hundreds of thousands, who are using benzodiazepines chronically, and they’re doing it right. There’s not a CVS in America where benzodiazepines aren’t well stocked. They’re very inexpensive, and the most costly benzodiazepine is still cheaper than Motrin.”

On the other hand, he said, the medications are linked to addiction and physical dependence. “Thirty percent of those who die of opioid overdoses may not have died if they didn’t have benzodiazepines [in their systems].”

Be very cautious about prescribing as needed

“It’s rarely indicated to prescribe benzodiazepine [as needed] when you’re treating people with anxiety,” he said. “The main reason is patients don’t know when they need it. They take their pills either when they’re so anxious that they’ve already been freaking out for a long time, or they take it when they’re first starting to feel at least a bit anxious. That leads to taking it to prevent being anxious.”

Allow an as-needed approach in certain situations

It can be appropriate to prescribe benzodiazepines for specific short-term anxiety-provoking situations, such as speaking in public, Dr. Stein said.

However, he said, advise patients to try the medication beforehand so they understand its effects. “I’ve had one occasion where I thought we had a dose worked out well. Somebody had to do a work presentation, and he took the medicine and got up in front of the group. He wasn’t anxious at all. But he couldn’t remember a single thing.”
 

Don’t use them as patients start SSRIs

Patients can get anxious as they start SSRIs, especially for panic disorders, Dr. Stein said. So it might seem reasonable, as some psychiatrists believe, to add benzodiazepines on a short-term basis.

But Dr. Stein said he is not a fan of this approach. As he noted, benzodiazepines are hard to stop. He prefers to help patients understand possible side effects of SSRIs instead, and he emphasized the importance of being available to help patients get through them.

Dr. Jain and Dr. Stein each reported multiple relationships with industry.

SAN DIEGO – Not long before his presentation at Psych Congress 2019, psychiatrist Rakesh Jain, MD, MPH, chatted with a fellow attendee, a nurse practitioner from Tyler, Tex. As Dr. Jain recalled later, his fellow Texan told him that “it’s not unusual to see patients on three benzodiazepines.”

The nurse practitioner “talks to them about how they need to do things differently, and they forget,” Dr. Jain said. “He’s very worried about them.”

Dr. Jain is familiar with the feeling. Like many mental health professionals, he worries about the role of benzodiazepines, which seem to be both widely used and misused. Figuring out their proper place in psychiatry “may require us to raise our game,” said Dr. Jain, of Texas Tech University in Midland.

What to do? Dr. Jain and a colleague offered the same answer – tread carefully, but do not eliminate them as an option – in two separate sessions at the annual Psych Congress.

As Dr. Jain noted, benzodiazepines are popular, and for good reason. “There are many patients, perhaps hundreds of thousands, who are using benzodiazepines chronically, and they’re doing it right. There’s not a CVS in America where benzodiazepines aren’t well stocked. They’re very inexpensive, and the most costly benzodiazepine is still cheaper than Motrin.”

On the other hand, he said, the medications are linked to addiction and physical dependence. “Thirty percent of those who die of opioid overdoses may not have died if they didn’t have benzodiazepines [in their systems].”

Be very cautious about prescribing as needed

“It’s rarely indicated to prescribe benzodiazepine [as needed] when you’re treating people with anxiety,” he said. “The main reason is patients don’t know when they need it. They take their pills either when they’re so anxious that they’ve already been freaking out for a long time, or they take it when they’re first starting to feel at least a bit anxious. That leads to taking it to prevent being anxious.”

Allow an as-needed approach in certain situations

It can be appropriate to prescribe benzodiazepines for specific short-term anxiety-provoking situations, such as speaking in public, Dr. Stein said.

However, he said, advise patients to try the medication beforehand so they understand its effects. “I’ve had one occasion where I thought we had a dose worked out well. Somebody had to do a work presentation, and he took the medicine and got up in front of the group. He wasn’t anxious at all. But he couldn’t remember a single thing.”
 

Don’t use them as patients start SSRIs

Patients can get anxious as they start SSRIs, especially for panic disorders, Dr. Stein said. So it might seem reasonable, as some psychiatrists believe, to add benzodiazepines on a short-term basis.

But Dr. Stein said he is not a fan of this approach. As he noted, benzodiazepines are hard to stop. He prefers to help patients understand possible side effects of SSRIs instead, and he emphasized the importance of being available to help patients get through them.

Dr. Jain and Dr. Stein each reported multiple relationships with industry.

SAN DIEGO – Not long before his presentation at Psych Congress 2019, psychiatrist Rakesh Jain, MD, MPH, chatted with a fellow attendee, a nurse practitioner from Tyler, Tex. As Dr. Jain recalled later, his fellow Texan told him that “it’s not unusual to see patients on three benzodiazepines.”

The nurse practitioner “talks to them about how they need to do things differently, and they forget,” Dr. Jain said. “He’s very worried about them.”

Dr. Jain is familiar with the feeling. Like many mental health professionals, he worries about the role of benzodiazepines, which seem to be both widely used and misused. Figuring out their proper place in psychiatry “may require us to raise our game,” said Dr. Jain, of Texas Tech University in Midland.

What to do? Dr. Jain and a colleague offered the same answer – tread carefully, but do not eliminate them as an option – in two separate sessions at the annual Psych Congress.

As Dr. Jain noted, benzodiazepines are popular, and for good reason. “There are many patients, perhaps hundreds of thousands, who are using benzodiazepines chronically, and they’re doing it right. There’s not a CVS in America where benzodiazepines aren’t well stocked. They’re very inexpensive, and the most costly benzodiazepine is still cheaper than Motrin.”

On the other hand, he said, the medications are linked to addiction and physical dependence. “Thirty percent of those who die of opioid overdoses may not have died if they didn’t have benzodiazepines [in their systems].”

Be very cautious about prescribing as needed

“It’s rarely indicated to prescribe benzodiazepine [as needed] when you’re treating people with anxiety,” he said. “The main reason is patients don’t know when they need it. They take their pills either when they’re so anxious that they’ve already been freaking out for a long time, or they take it when they’re first starting to feel at least a bit anxious. That leads to taking it to prevent being anxious.”

Allow an as-needed approach in certain situations

It can be appropriate to prescribe benzodiazepines for specific short-term anxiety-provoking situations, such as speaking in public, Dr. Stein said.

However, he said, advise patients to try the medication beforehand so they understand its effects. “I’ve had one occasion where I thought we had a dose worked out well. Somebody had to do a work presentation, and he took the medicine and got up in front of the group. He wasn’t anxious at all. But he couldn’t remember a single thing.”
 

Don’t use them as patients start SSRIs

Patients can get anxious as they start SSRIs, especially for panic disorders, Dr. Stein said. So it might seem reasonable, as some psychiatrists believe, to add benzodiazepines on a short-term basis.

But Dr. Stein said he is not a fan of this approach. As he noted, benzodiazepines are hard to stop. He prefers to help patients understand possible side effects of SSRIs instead, and he emphasized the importance of being available to help patients get through them.

Dr. Jain and Dr. Stein each reported multiple relationships with industry.

MADRID – Psoriasis patients aged 65 years and older are at more than twice the risk of serious bacterial and opportunistic infections, compared with younger patients, but that risk is not further elevated by being on biologic agents, Joseph F. Merola, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

He presented a large, propensity score–matched comparative safety study, which demonstrated that the infection risk of older psoriasis patients on biologics was not significantly different from that of similar patients on nonbiologic systemic medications or phototherapy. The study implications, he said, are clear: When moderate to severe psoriasis warrants consideration of highly effective biologic therapies, that therapeutic option shouldn’t be taken off the table on the basis of a mistaken belief that biologics pose a greater infection risk just because the affected patient is over age 65 years.

“We really think that older patients should be offered treatments at the same level of disease control as all the rest of our psoriasis patients, in the context of shared decision making,” said Dr. Merola, a dermatologist and rheumatologist who is the director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston.

The study utilized longitudinal claims data from a very large U.S. database covering the years 2003-2017. Among the 185 million covered lives were 1.1 million individuals with psoriasis, including 150,000 aged 65 years or older. After excluding older psoriasis patients with comorbid cancer or autoimmune disease, the investigators were left with 11,218 older psoriasis patients initiating systemic therapy for the first time and therefore eligible for propensity score matching using a highly accurate proprietary platform. The final study population consisted of 2,795 older psoriasis patients newly initiating biologic therapy, 2,795 others newly initiating nonbiologic systemic agents, and 2,529 seniors starting phototherapy. The matching was based upon factors including age, sex, prior infections, comorbid psoriatic arthritis, diabetes, and obesity.

The primary study endpoint was the rate of serious bacterial or opportunistic infections requiring hospitalization during the first 6 months of treatment. The bottom line: The rates were closely similar across all three groups, with the most common serious infections being pneumonia and cellulitis.

In contrast, among a population of 115,047 senior psoriasis patients who never used systemic therapy, the risk of serious infection was 12.2 events per 1,000 patients over 6 months, compared with 5.3 events in 120,174 matched controls without psoriasis. That translates to a 2.24-fold increased risk.

One audience member commented that a limitation of the study was that all biologics were lumped together. He would expect that the tumor necrosis factor inhibitors, for example, would be associated with a significantly higher serious infection risk than biologics with other targets.

Dr. Merola conceded the point, adding that the investigators are trying to reanalyze the data in a more granular way to address that shortcoming. Other study limitations included an inability to access the specific doses of systemic treatments used or to stratify patients by disease severity.

Another audience member noted that dermatologists often reassure surgeons that there’s no increased risk of infection associated with psoriasis when in fact there is increased risk in older psoriasis patients, according to these new data.

“We’re not trying to send a message to surgeons to withhold a knee transplant because of a psoriasis plaque over the knee,” Dr. Merola replied. “I think we’ve all been there; we’ve all fought that battle.” Based on the data, he said, he would advise that “our patients who need to be on systemics should remain appropriately on systemics as we see fit.”

The study was entirely funded by Brigham and Women’s Hospital. Dr. Merola reported serving as a consultant to and/or recipient of research grants from nearly two dozen pharmaceutical companies.

[email protected]

MADRID – Psoriasis patients aged 65 years and older are at more than twice the risk of serious bacterial and opportunistic infections, compared with younger patients, but that risk is not further elevated by being on biologic agents, Joseph F. Merola, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

He presented a large, propensity score–matched comparative safety study, which demonstrated that the infection risk of older psoriasis patients on biologics was not significantly different from that of similar patients on nonbiologic systemic medications or phototherapy. The study implications, he said, are clear: When moderate to severe psoriasis warrants consideration of highly effective biologic therapies, that therapeutic option shouldn’t be taken off the table on the basis of a mistaken belief that biologics pose a greater infection risk just because the affected patient is over age 65 years.

“We really think that older patients should be offered treatments at the same level of disease control as all the rest of our psoriasis patients, in the context of shared decision making,” said Dr. Merola, a dermatologist and rheumatologist who is the director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston.

The study utilized longitudinal claims data from a very large U.S. database covering the years 2003-2017. Among the 185 million covered lives were 1.1 million individuals with psoriasis, including 150,000 aged 65 years or older. After excluding older psoriasis patients with comorbid cancer or autoimmune disease, the investigators were left with 11,218 older psoriasis patients initiating systemic therapy for the first time and therefore eligible for propensity score matching using a highly accurate proprietary platform. The final study population consisted of 2,795 older psoriasis patients newly initiating biologic therapy, 2,795 others newly initiating nonbiologic systemic agents, and 2,529 seniors starting phototherapy. The matching was based upon factors including age, sex, prior infections, comorbid psoriatic arthritis, diabetes, and obesity.

The primary study endpoint was the rate of serious bacterial or opportunistic infections requiring hospitalization during the first 6 months of treatment. The bottom line: The rates were closely similar across all three groups, with the most common serious infections being pneumonia and cellulitis.

In contrast, among a population of 115,047 senior psoriasis patients who never used systemic therapy, the risk of serious infection was 12.2 events per 1,000 patients over 6 months, compared with 5.3 events in 120,174 matched controls without psoriasis. That translates to a 2.24-fold increased risk.

One audience member commented that a limitation of the study was that all biologics were lumped together. He would expect that the tumor necrosis factor inhibitors, for example, would be associated with a significantly higher serious infection risk than biologics with other targets.

Dr. Merola conceded the point, adding that the investigators are trying to reanalyze the data in a more granular way to address that shortcoming. Other study limitations included an inability to access the specific doses of systemic treatments used or to stratify patients by disease severity.

Another audience member noted that dermatologists often reassure surgeons that there’s no increased risk of infection associated with psoriasis when in fact there is increased risk in older psoriasis patients, according to these new data.

“We’re not trying to send a message to surgeons to withhold a knee transplant because of a psoriasis plaque over the knee,” Dr. Merola replied. “I think we’ve all been there; we’ve all fought that battle.” Based on the data, he said, he would advise that “our patients who need to be on systemics should remain appropriately on systemics as we see fit.”

The study was entirely funded by Brigham and Women’s Hospital. Dr. Merola reported serving as a consultant to and/or recipient of research grants from nearly two dozen pharmaceutical companies.

[email protected]

MADRID – Psoriasis patients aged 65 years and older are at more than twice the risk of serious bacterial and opportunistic infections, compared with younger patients, but that risk is not further elevated by being on biologic agents, Joseph F. Merola, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

He presented a large, propensity score–matched comparative safety study, which demonstrated that the infection risk of older psoriasis patients on biologics was not significantly different from that of similar patients on nonbiologic systemic medications or phototherapy. The study implications, he said, are clear: When moderate to severe psoriasis warrants consideration of highly effective biologic therapies, that therapeutic option shouldn’t be taken off the table on the basis of a mistaken belief that biologics pose a greater infection risk just because the affected patient is over age 65 years.

“We really think that older patients should be offered treatments at the same level of disease control as all the rest of our psoriasis patients, in the context of shared decision making,” said Dr. Merola, a dermatologist and rheumatologist who is the director of the Center for Skin and Related Musculoskeletal Diseases at Brigham and Women’s Hospital, Boston.

The study utilized longitudinal claims data from a very large U.S. database covering the years 2003-2017. Among the 185 million covered lives were 1.1 million individuals with psoriasis, including 150,000 aged 65 years or older. After excluding older psoriasis patients with comorbid cancer or autoimmune disease, the investigators were left with 11,218 older psoriasis patients initiating systemic therapy for the first time and therefore eligible for propensity score matching using a highly accurate proprietary platform. The final study population consisted of 2,795 older psoriasis patients newly initiating biologic therapy, 2,795 others newly initiating nonbiologic systemic agents, and 2,529 seniors starting phototherapy. The matching was based upon factors including age, sex, prior infections, comorbid psoriatic arthritis, diabetes, and obesity.

The primary study endpoint was the rate of serious bacterial or opportunistic infections requiring hospitalization during the first 6 months of treatment. The bottom line: The rates were closely similar across all three groups, with the most common serious infections being pneumonia and cellulitis.

In contrast, among a population of 115,047 senior psoriasis patients who never used systemic therapy, the risk of serious infection was 12.2 events per 1,000 patients over 6 months, compared with 5.3 events in 120,174 matched controls without psoriasis. That translates to a 2.24-fold increased risk.

One audience member commented that a limitation of the study was that all biologics were lumped together. He would expect that the tumor necrosis factor inhibitors, for example, would be associated with a significantly higher serious infection risk than biologics with other targets.

Dr. Merola conceded the point, adding that the investigators are trying to reanalyze the data in a more granular way to address that shortcoming. Other study limitations included an inability to access the specific doses of systemic treatments used or to stratify patients by disease severity.

Another audience member noted that dermatologists often reassure surgeons that there’s no increased risk of infection associated with psoriasis when in fact there is increased risk in older psoriasis patients, according to these new data.

“We’re not trying to send a message to surgeons to withhold a knee transplant because of a psoriasis plaque over the knee,” Dr. Merola replied. “I think we’ve all been there; we’ve all fought that battle.” Based on the data, he said, he would advise that “our patients who need to be on systemics should remain appropriately on systemics as we see fit.”

The study was entirely funded by Brigham and Women’s Hospital. Dr. Merola reported serving as a consultant to and/or recipient of research grants from nearly two dozen pharmaceutical companies.

[email protected]