Pharmacology

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

Reassuring news for women who receive a diagnosis of breast cancer during pregnancy: Pregnancy-induced alterations in the pharmacokinetics of chemotherapy do not appear to compromise outcomes for the mother.

That’s according to investigators who reviewed registry data on 662 pregnant women and 2,081 nonpregnant women with a diagnosis of breast cancer. After a median follow-up of 66 months, there were no significant differences in either disease-free survival (DFS) or overall survival (OS), and women who received more than 60% of their chemotherapy doses during pregnancy had survival comparable to that of nonpregnant women, reported Frédéric Amant, MD, PhD, of University Hospitals Leuven (Belgium).

“These results support initiation of chemotherapy for breast cancer during pregnancy where indicated for oncological reasons,” they reported in a poster discussion session at the American Society of Clinical Oncology annual meeting. (Abstract 515).

Although in general a diagnosis of breast cancer during pregnancy does not appear to affect the mother’s prognosis when standard therapy is used, “caution is warranted as gestational changes in pharmacokinetics with respect to the distribution, metabolism, and excretion of drugs may lead to reduced chemotherapy concentration in pregnant patients,” the authors wrote.

To get a better picture of the prognosis for women diagnosed with breast cancer during pregnancy, the investigators created a cohort of patients from two multicenter registries: the International Network of Cancer, Infertility, and Pregnancy and the German Breast Group. Both registries collect data retrospectively and prospectively,

They used propensity scoring to smooth out differences in the baseline characteristics of pregnant women and nonpregnant controls.

The median age at diagnosis was 34 year for pregnant women, and 38 years for controls. Pregnant women were more likely than were controls to have stage II disease (60.1% vs. 56, 1%, P = .035), grade 3 tumors (74% vs. 62.2%, P < .001), hormone receptor–negative breast tumors (48.4% vs. 30%), and triple-negative breast cancer (38.9% vs. 26.9%, P < .001).

In Cox proportional hazard regression analysis controlling for age, stage, grade, hormone receptor status, HER2 status and histology, there were no significant differences between pregnant women and controls in either DFS (hazard ratio [HR] 1.02, P = .83) or OS (HR 1.08, P = .57).

As noted before, a subgroup analysis of 339 women who received more than 60% of their assigned chemotherapy doses during pregnancy also showed that survival was not significantly different from that of nonpregnant women (HR for DFS 0,71, P = .13; HR for OS 0.85, P = .39).
 

Termination does not benefit the mother

“Thanks to the important work of Dr. Amant in the INCIP [International Network on Cancer, Infertility, and Pregnancy] network and others around the world, we now have sufficient data to know that it’s safe to treat breast cancer during pregnancy, and that the prognosis of breast cancer during pregnancy is comparable to nonpregnant controls if we adjust for certain characteristics such as age and others,” said Fatima Cardoso, MD, of Champalimaud Clinical Center in Lisbon, Portugal, the invited discussant.

­­“With this and other studies, we can come to the conclusion that pregnancy-induced alterations in the chemotherapy concentration due to altered pharmacokinetics does not seem to affect maternal prognosis, and therefore we should initiate treatment of breast cancer during wherever it’s indicated for oncological reasons, knowing that you can only use chemotherapy during the second or third trimester,” she said.

Dr. Cardoso emphasized that breast cancer during pregnancy is a rare situation requiring that treatment be given in a specialized center by an experienced multidisciplinary team, and that interrupting the pregnancy does not improve the mother’s prognosis.

“We have to spread the word to all health professionals who come across these women to stop advising them to immediately terminate pregnancy. For the children, the most important take-home message is avoid prematurely delivery,” she said.

Treatment for women with a diagnosis of breast cancer during pregnancy should be similar to that for nonpregnant women, with the exception of endocrine therapy and anti-HER2 agents, which should be withheld until after delivery, she added.

The study was supported by the European Research Council, Research Foundation Flanders, and Kom op tegen kanker (Stand Up to Cancer). Dr. Amant disclosed a consulting or advisory role for AstraZeneca and Clovis Oncology. Dr. Cardoso disclosed consulting or advisory roles and travel support from multiple companies.

The first KRAS inhibitor approved for the treatment of lung cancer provided a clinically meaningful overall survival benefit in an updated analysis of a phase 2 study.

Treatment with sotorasib yielded a median overall survival (OS) of 12.5 months in patients with previously treated KRAS p.G12C-mutated non-small cell lung cancer (NSCLC), according to an analysis of the phase 2 CodeBreaK 100 trial data presented at the American Society of Clinical Oncology Annual Meeting.

Median progression-free survival (PFS) was 6.8 months in this update, which included a median follow-up of more than 15 months, according to investigator Ferdinandos Skoulidis, MD, PhD, assistant professor of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

Efficacy responses

The confirmed objective response rate was 37.1%, including a 3.2% complete response rate and a median duration of response of 11.1 months, according to the report by Dr. Skoulidis.

In exploratory analyses, the benefit of sotorasib was consistent across patient subgroups, Dr. Skoulidis said in his presentation (Abstract 9003).

In particular, efficacy was observed in subgroups with co-occurring mutations in TP53, STK11, and KEAP1, which are molecular indicators of suboptimal outcomes on standard systemic treatments, according to Dr. Skoulidis.

This update on the registrational phase 2 CodeBreaK100 trial, published concurrently in the New England Journal of Medicine , came just one week after the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib.

Sotorasib was approved for the treatment of patients with previously treated KRAS G12C‑mutated locally advanced or metastatic NSCLC on the basis of previously reported results from CodeBreaK100.

This sotorasib indication represents a “historic milestone,” Dr. Skoulidis said in an interview.

No previously studied selective KRAS inhibitor has been approved despite scientific research efforts that stretch back nearly four decades, he explained.

“In a way, one can say that we have dealt KRAS-mutant lung cancer a knockdown blow, however, I should point out that the fight is not over,” he added.

“These clinical results will no doubt spearhead and galvanize further efforts to develop even more effective therapeutic combinations in the future, as well as identify and either forestall or overcome the eventual development of acquired resistance,” he said.
 

Only 1 out of 8 patients

The KRAS p.G12C mutation is present in about 13% of lung adenocarcinomas, or about one in every eight patients with nonsquamous NSCLC, Dr. Skoulidis said in the interview.

“We are estimating that this is in the region of 13,000 patients newly diagnosed every year in the U.S., and approximately 13,000 patients or so that are currently being treated in the second- or third-line setting,” he said.

The CodeBreaK100 trial included 126 patients with locally advanced or metastatic NSCLC and KRAS p.G12C mutation who had progressed on prior systemic therapies. About 43% had one prior line of treatment, while 35% had two lines, and 22% had three lines. A total of 81% had previously received both platinum-based chemotherapy and PD-1/PD-L1 axis inhibitors.

Most treatment-related adverse events in the study were grade 1-2 and generally manageable, according to Dr. Skoulidis. About 20% of patients experienced grade 3 treatment-related adverse events, which were mostly diarrhea or increases in aspartate aminotransferase and alanine aminotransferase levels. A grade 4 treatment-related adverse event, pneumonitis and dyspnea, was reported in one patient or approximately 1%.
 

Confirmatory trial

Although CodeBreak100 is not a randomized trial, the median OS of 12.5 months compares favorably to median OS times in the range of 7.9-10.3 months reported in randomized phase 3 clinical trials and subgroup analysis of randomized phase 3 trials of docetaxel for patients with KRAS-mutant lung adenocarcinoma, Dr. Skoulidis said in a question-and-answer session.

A confirmatory phase 3 CodeBreaK200 trial of sotorasib versus docetaxel in patients with previously treated KRAS p.G12C-mutated NSCLC is underway. That trial is evaluating PFS as a primary endpoint and OS as a secondary endpoint.

“If the same magnitude of benefit, 12.5 months median overall survival, is confirmed in the larger phase 3 clinical trial, as a clinician I would consider that beneficial for patients, compared to the standard of care,” Dr. Skoulidis said during the session.
 

Mature data

The updated analysis of the phase 2 CodeBreaK100 study is notable for its mature OS data, updated safety and the first molecular subgroup analyses, according to discussant Christine Marie Lovly, MD, PhD, of the division of hematology-oncology at Vanderbilt University Medical Center in Nashville.

“The objective response rate was 37.1%,” she added. “This is a little bit lower than we’re used to for targeted therapies, but remember, this is a different mutation and a very different class of drugs.”

The KRAS G12C inhibitors, several of which are under clinical development, are not tyrosine kinase inhibitors (TKIs), but rather allele-specific inhibitors that target mutant KRAS, trapping it in an inactive conformation, she explained.

Dr. Lovly referenced the exploratory analyses demonstrating efficacy in molecularly defined subgroups, calling it “interesting” that there was no difference in objective response rate between TP53 wild type and mutant tumors.

“We do have data that mutant TP53 seems to confer inferior outcomes for EGFR TKI-directed therapy in patients with EGFR-mutant lung cancer,” she said.

CodeBreaK100 was supported by Amgen, Inc. and partly by a National Institutes of Health Cancer Center Support Grant at Memorial Sloan Kettering Cancer Center.

Dr. Skoulidis reported honoraria from Bristol-Myers Squibb; research funding from AIMM Therapeutics and Amgen; and travel, accommodations, or expenses from Tango Therapeutics. Dr. Lovly reported disclosures related to Amgen, AstraZeneca, Genentech, Novartis, and Pfizer, among others.

The first KRAS inhibitor approved for the treatment of lung cancer provided a clinically meaningful overall survival benefit in an updated analysis of a phase 2 study.

Treatment with sotorasib yielded a median overall survival (OS) of 12.5 months in patients with previously treated KRAS p.G12C-mutated non-small cell lung cancer (NSCLC), according to an analysis of the phase 2 CodeBreaK 100 trial data presented at the American Society of Clinical Oncology Annual Meeting.

Median progression-free survival (PFS) was 6.8 months in this update, which included a median follow-up of more than 15 months, according to investigator Ferdinandos Skoulidis, MD, PhD, assistant professor of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

Efficacy responses

The confirmed objective response rate was 37.1%, including a 3.2% complete response rate and a median duration of response of 11.1 months, according to the report by Dr. Skoulidis.

In exploratory analyses, the benefit of sotorasib was consistent across patient subgroups, Dr. Skoulidis said in his presentation (Abstract 9003).

In particular, efficacy was observed in subgroups with co-occurring mutations in TP53, STK11, and KEAP1, which are molecular indicators of suboptimal outcomes on standard systemic treatments, according to Dr. Skoulidis.

This update on the registrational phase 2 CodeBreaK100 trial, published concurrently in the New England Journal of Medicine , came just one week after the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib.

Sotorasib was approved for the treatment of patients with previously treated KRAS G12C‑mutated locally advanced or metastatic NSCLC on the basis of previously reported results from CodeBreaK100.

This sotorasib indication represents a “historic milestone,” Dr. Skoulidis said in an interview.

No previously studied selective KRAS inhibitor has been approved despite scientific research efforts that stretch back nearly four decades, he explained.

“In a way, one can say that we have dealt KRAS-mutant lung cancer a knockdown blow, however, I should point out that the fight is not over,” he added.

“These clinical results will no doubt spearhead and galvanize further efforts to develop even more effective therapeutic combinations in the future, as well as identify and either forestall or overcome the eventual development of acquired resistance,” he said.
 

Only 1 out of 8 patients

The KRAS p.G12C mutation is present in about 13% of lung adenocarcinomas, or about one in every eight patients with nonsquamous NSCLC, Dr. Skoulidis said in the interview.

“We are estimating that this is in the region of 13,000 patients newly diagnosed every year in the U.S., and approximately 13,000 patients or so that are currently being treated in the second- or third-line setting,” he said.

The CodeBreaK100 trial included 126 patients with locally advanced or metastatic NSCLC and KRAS p.G12C mutation who had progressed on prior systemic therapies. About 43% had one prior line of treatment, while 35% had two lines, and 22% had three lines. A total of 81% had previously received both platinum-based chemotherapy and PD-1/PD-L1 axis inhibitors.

Most treatment-related adverse events in the study were grade 1-2 and generally manageable, according to Dr. Skoulidis. About 20% of patients experienced grade 3 treatment-related adverse events, which were mostly diarrhea or increases in aspartate aminotransferase and alanine aminotransferase levels. A grade 4 treatment-related adverse event, pneumonitis and dyspnea, was reported in one patient or approximately 1%.
 

Confirmatory trial

Although CodeBreak100 is not a randomized trial, the median OS of 12.5 months compares favorably to median OS times in the range of 7.9-10.3 months reported in randomized phase 3 clinical trials and subgroup analysis of randomized phase 3 trials of docetaxel for patients with KRAS-mutant lung adenocarcinoma, Dr. Skoulidis said in a question-and-answer session.

A confirmatory phase 3 CodeBreaK200 trial of sotorasib versus docetaxel in patients with previously treated KRAS p.G12C-mutated NSCLC is underway. That trial is evaluating PFS as a primary endpoint and OS as a secondary endpoint.

“If the same magnitude of benefit, 12.5 months median overall survival, is confirmed in the larger phase 3 clinical trial, as a clinician I would consider that beneficial for patients, compared to the standard of care,” Dr. Skoulidis said during the session.
 

Mature data

The updated analysis of the phase 2 CodeBreaK100 study is notable for its mature OS data, updated safety and the first molecular subgroup analyses, according to discussant Christine Marie Lovly, MD, PhD, of the division of hematology-oncology at Vanderbilt University Medical Center in Nashville.

“The objective response rate was 37.1%,” she added. “This is a little bit lower than we’re used to for targeted therapies, but remember, this is a different mutation and a very different class of drugs.”

The KRAS G12C inhibitors, several of which are under clinical development, are not tyrosine kinase inhibitors (TKIs), but rather allele-specific inhibitors that target mutant KRAS, trapping it in an inactive conformation, she explained.

Dr. Lovly referenced the exploratory analyses demonstrating efficacy in molecularly defined subgroups, calling it “interesting” that there was no difference in objective response rate between TP53 wild type and mutant tumors.

“We do have data that mutant TP53 seems to confer inferior outcomes for EGFR TKI-directed therapy in patients with EGFR-mutant lung cancer,” she said.

CodeBreaK100 was supported by Amgen, Inc. and partly by a National Institutes of Health Cancer Center Support Grant at Memorial Sloan Kettering Cancer Center.

Dr. Skoulidis reported honoraria from Bristol-Myers Squibb; research funding from AIMM Therapeutics and Amgen; and travel, accommodations, or expenses from Tango Therapeutics. Dr. Lovly reported disclosures related to Amgen, AstraZeneca, Genentech, Novartis, and Pfizer, among others.

The first KRAS inhibitor approved for the treatment of lung cancer provided a clinically meaningful overall survival benefit in an updated analysis of a phase 2 study.

Treatment with sotorasib yielded a median overall survival (OS) of 12.5 months in patients with previously treated KRAS p.G12C-mutated non-small cell lung cancer (NSCLC), according to an analysis of the phase 2 CodeBreaK 100 trial data presented at the American Society of Clinical Oncology Annual Meeting.

Median progression-free survival (PFS) was 6.8 months in this update, which included a median follow-up of more than 15 months, according to investigator Ferdinandos Skoulidis, MD, PhD, assistant professor of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

Efficacy responses

The confirmed objective response rate was 37.1%, including a 3.2% complete response rate and a median duration of response of 11.1 months, according to the report by Dr. Skoulidis.

In exploratory analyses, the benefit of sotorasib was consistent across patient subgroups, Dr. Skoulidis said in his presentation (Abstract 9003).

In particular, efficacy was observed in subgroups with co-occurring mutations in TP53, STK11, and KEAP1, which are molecular indicators of suboptimal outcomes on standard systemic treatments, according to Dr. Skoulidis.

This update on the registrational phase 2 CodeBreaK100 trial, published concurrently in the New England Journal of Medicine , came just one week after the U.S. Food and Drug Administration (FDA) granted accelerated approval to sotorasib.

Sotorasib was approved for the treatment of patients with previously treated KRAS G12C‑mutated locally advanced or metastatic NSCLC on the basis of previously reported results from CodeBreaK100.

This sotorasib indication represents a “historic milestone,” Dr. Skoulidis said in an interview.

No previously studied selective KRAS inhibitor has been approved despite scientific research efforts that stretch back nearly four decades, he explained.

“In a way, one can say that we have dealt KRAS-mutant lung cancer a knockdown blow, however, I should point out that the fight is not over,” he added.

“These clinical results will no doubt spearhead and galvanize further efforts to develop even more effective therapeutic combinations in the future, as well as identify and either forestall or overcome the eventual development of acquired resistance,” he said.
 

Only 1 out of 8 patients

The KRAS p.G12C mutation is present in about 13% of lung adenocarcinomas, or about one in every eight patients with nonsquamous NSCLC, Dr. Skoulidis said in the interview.

“We are estimating that this is in the region of 13,000 patients newly diagnosed every year in the U.S., and approximately 13,000 patients or so that are currently being treated in the second- or third-line setting,” he said.

The CodeBreaK100 trial included 126 patients with locally advanced or metastatic NSCLC and KRAS p.G12C mutation who had progressed on prior systemic therapies. About 43% had one prior line of treatment, while 35% had two lines, and 22% had three lines. A total of 81% had previously received both platinum-based chemotherapy and PD-1/PD-L1 axis inhibitors.

Most treatment-related adverse events in the study were grade 1-2 and generally manageable, according to Dr. Skoulidis. About 20% of patients experienced grade 3 treatment-related adverse events, which were mostly diarrhea or increases in aspartate aminotransferase and alanine aminotransferase levels. A grade 4 treatment-related adverse event, pneumonitis and dyspnea, was reported in one patient or approximately 1%.
 

Confirmatory trial

Although CodeBreak100 is not a randomized trial, the median OS of 12.5 months compares favorably to median OS times in the range of 7.9-10.3 months reported in randomized phase 3 clinical trials and subgroup analysis of randomized phase 3 trials of docetaxel for patients with KRAS-mutant lung adenocarcinoma, Dr. Skoulidis said in a question-and-answer session.

A confirmatory phase 3 CodeBreaK200 trial of sotorasib versus docetaxel in patients with previously treated KRAS p.G12C-mutated NSCLC is underway. That trial is evaluating PFS as a primary endpoint and OS as a secondary endpoint.

“If the same magnitude of benefit, 12.5 months median overall survival, is confirmed in the larger phase 3 clinical trial, as a clinician I would consider that beneficial for patients, compared to the standard of care,” Dr. Skoulidis said during the session.
 

Mature data

The updated analysis of the phase 2 CodeBreaK100 study is notable for its mature OS data, updated safety and the first molecular subgroup analyses, according to discussant Christine Marie Lovly, MD, PhD, of the division of hematology-oncology at Vanderbilt University Medical Center in Nashville.

“The objective response rate was 37.1%,” she added. “This is a little bit lower than we’re used to for targeted therapies, but remember, this is a different mutation and a very different class of drugs.”

The KRAS G12C inhibitors, several of which are under clinical development, are not tyrosine kinase inhibitors (TKIs), but rather allele-specific inhibitors that target mutant KRAS, trapping it in an inactive conformation, she explained.

Dr. Lovly referenced the exploratory analyses demonstrating efficacy in molecularly defined subgroups, calling it “interesting” that there was no difference in objective response rate between TP53 wild type and mutant tumors.

“We do have data that mutant TP53 seems to confer inferior outcomes for EGFR TKI-directed therapy in patients with EGFR-mutant lung cancer,” she said.

CodeBreaK100 was supported by Amgen, Inc. and partly by a National Institutes of Health Cancer Center Support Grant at Memorial Sloan Kettering Cancer Center.

Dr. Skoulidis reported honoraria from Bristol-Myers Squibb; research funding from AIMM Therapeutics and Amgen; and travel, accommodations, or expenses from Tango Therapeutics. Dr. Lovly reported disclosures related to Amgen, AstraZeneca, Genentech, Novartis, and Pfizer, among others.

Experiencing an immune-related adverse event during checkpoint inhibitor treatment may predict outcomes in patients with non-small cell lung cancer, exploratory analyses of phase 3 trials suggest.

Immune-related adverse events (irAEs) were tied to longer overall survival (OS) in exploratory pooled analyses of three phase 3 clinical trials evaluating atezolizumab-based regimens, according to investigator Mark A. Socinski, MD, of AdventHealth Cancer Institute, Orlando, Fla.

Median OS approached 26 months for patients who received first-line atezolizumab and experienced an irAE, compared with just 13 months for those who did not experience an irAE, according to results reported at the American Society of Clinical Oncology Annual Meeting (Abstract 9002).

Atezolizumab-treated patients with grade 3 or greater irAEs had the shortest OS, shorter than those atezolizumab-treated patients who experienced grade 1-2 irAEs or no irAEs at all. That short OS may be due to treatment interruptions or discontinuations, said Dr. Socinski.

“Data from these analyses suggest an association between irAEs and efficacy in patients with [non-small cell cancer] NSCLC,” he stated in his presentation of the results.
 

A lot more to learn about irAEs

Similar linkages between irAEs and outcomes were observed in pooled analyses of patients enrolled in the control arms of the phase 3 trials, with a median OS of about 20 months for control patients experiencing an irAE, versus about 13 months for those who did not.

That linkage in the control arm prompted a question from an ASCO attendee about why an effect of irAEs, commonly associated with immune checkpoint inhibitor therapy, would be evident in analyses of patients who did not receive those agents.

In his response, Dr. Socinski characterized the finding as “a surprise” and said the finding may either reflect how adverse events are characterized or how chemotherapy impacts the immune system.

“I don’t know that our definition of irAEs is perfect,” he said, “and maybe we don’t understand what impact chemotherapy may have on the immune system, and may actually engender what historically we’ve always seen as an adverse event, but didn’t necessarily classify as an immune-related adverse event.”

More work is needed to better understand the connection between irAES and outcomes, and whether anything can be done as a result of that improved understanding, said discussant Mary Weber Redman, PhD.

“The question is, ‘what is actionable?’” added Dr. Redman, a biostatistician at the Fred Hutchinson Cancer Research Center, Seattle.

A firmer understanding of the relationship between irAEs and outcomes could change how clinicians monitor patients for irAEs, lead to better prediction of which patients may experience higher grade irAEs, and ultimately impact treatment selection potentially to avoid those higher grade events, Dr. Redman said in her remarks.

“Doing these types of analyses are quite important, because we have to look at the breadth of information that we have to be able to interpret that and think about what are future questions,” she said in the question-and-answer session accompanying Dr. Socinski’s presentation.

“I think the key is that we shouldn’t use these analyses to be definitive, but we should use them as to be hypothesis generating,” she added.
 

More evidence to link irAEs and outcomes

Immune-related AEs caused by off-target immune and inflammatory activity have been reported in up to 80% of patients receiving immune checkpoint inhibitors as monotherapy and up to 95% in combination regimens, Dr. Socinski said in his presentation.

“Increasing evidence suggests that the occurrence of immune-related adverse events with PD-L1 or PD-1 inhibitor therapy may be predictive of improved outcomes in cancers such as NSCLC, “ he added.

In their exploratory pooled analyses, Dr. Socinski and co-investigators looked at data from the phase 3 IMpower130 and IMpower132 trials, which evaluated first-line atezolizumab and chemotherapy for NSCLC, and the phase 3 IMpower150 trial, which evaluated atezolizumab plus chemotherapy with or without bevacizumab.

In all, they analyzed data for 1,557 atezolizumab-treated patients, and 900 patients who had been in the control arms of the studies.

Forty-eight percent of atezolizumab-treated patients experienced irAEs of any grade, while 11% experienced irAEs of grade 3-5, according to the presented data. In the control arm, 32% experienced irAEs of any grade and 5% experienced grade 3-5 irAEs.

The most common irAEs of any grade were rash, hepatitis, and hypothyroidism, occurring in 28%, 15%, and 12% of atezolizumab-treated patients, respectively.

Median OS in the atezolizumab arm was 25.7 months for patients with irAEs and 13.0 for patients with no irAEs, with a hazard ratio (HR) of 0.69 using a time-dependent Cox model.

Median OS in the control arm was 20.2 months for patients with irAEs and 12.8 months for patients with no irAEs, with an HR of 0.82.

The overall response rate (ORR) in the atezolizumab arm was 61.1% for patients with irAEs and 37.2% for those without irAEs; in the control arm, ORR was 42.2% for patients with irAEs and 34.0% for those with no irAEs.

Atezolizumab-treated patients who experienced grade 3-5 irAEs had the shortest OS, according to Dr. Socinski. The HRs for OS at 1, 3, 6, and 12 months in atezolizumab-treated patients with grade 3-5 irAEs (compared with those without irAEs) ranged from 1.25 to 0.87. By contrast, HRs at those time points for patients with grade 1-2 irAEs ranged from 0.78 to 0.72, Dr. Socinski said.

Dr. Socinski reported disclosures related to AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen, Lilly, Merck, Novartis, Roche/Genentech, and Spectrum Pharmaceuticals. Dr. Redman reported a consulting or advisory role with AstraZeneca.

Experiencing an immune-related adverse event during checkpoint inhibitor treatment may predict outcomes in patients with non-small cell lung cancer, exploratory analyses of phase 3 trials suggest.

Immune-related adverse events (irAEs) were tied to longer overall survival (OS) in exploratory pooled analyses of three phase 3 clinical trials evaluating atezolizumab-based regimens, according to investigator Mark A. Socinski, MD, of AdventHealth Cancer Institute, Orlando, Fla.

Median OS approached 26 months for patients who received first-line atezolizumab and experienced an irAE, compared with just 13 months for those who did not experience an irAE, according to results reported at the American Society of Clinical Oncology Annual Meeting (Abstract 9002).

Atezolizumab-treated patients with grade 3 or greater irAEs had the shortest OS, shorter than those atezolizumab-treated patients who experienced grade 1-2 irAEs or no irAEs at all. That short OS may be due to treatment interruptions or discontinuations, said Dr. Socinski.

“Data from these analyses suggest an association between irAEs and efficacy in patients with [non-small cell cancer] NSCLC,” he stated in his presentation of the results.
 

A lot more to learn about irAEs

Similar linkages between irAEs and outcomes were observed in pooled analyses of patients enrolled in the control arms of the phase 3 trials, with a median OS of about 20 months for control patients experiencing an irAE, versus about 13 months for those who did not.

That linkage in the control arm prompted a question from an ASCO attendee about why an effect of irAEs, commonly associated with immune checkpoint inhibitor therapy, would be evident in analyses of patients who did not receive those agents.

In his response, Dr. Socinski characterized the finding as “a surprise” and said the finding may either reflect how adverse events are characterized or how chemotherapy impacts the immune system.

“I don’t know that our definition of irAEs is perfect,” he said, “and maybe we don’t understand what impact chemotherapy may have on the immune system, and may actually engender what historically we’ve always seen as an adverse event, but didn’t necessarily classify as an immune-related adverse event.”

More work is needed to better understand the connection between irAES and outcomes, and whether anything can be done as a result of that improved understanding, said discussant Mary Weber Redman, PhD.

“The question is, ‘what is actionable?’” added Dr. Redman, a biostatistician at the Fred Hutchinson Cancer Research Center, Seattle.

A firmer understanding of the relationship between irAEs and outcomes could change how clinicians monitor patients for irAEs, lead to better prediction of which patients may experience higher grade irAEs, and ultimately impact treatment selection potentially to avoid those higher grade events, Dr. Redman said in her remarks.

“Doing these types of analyses are quite important, because we have to look at the breadth of information that we have to be able to interpret that and think about what are future questions,” she said in the question-and-answer session accompanying Dr. Socinski’s presentation.

“I think the key is that we shouldn’t use these analyses to be definitive, but we should use them as to be hypothesis generating,” she added.
 

More evidence to link irAEs and outcomes

Immune-related AEs caused by off-target immune and inflammatory activity have been reported in up to 80% of patients receiving immune checkpoint inhibitors as monotherapy and up to 95% in combination regimens, Dr. Socinski said in his presentation.

“Increasing evidence suggests that the occurrence of immune-related adverse events with PD-L1 or PD-1 inhibitor therapy may be predictive of improved outcomes in cancers such as NSCLC, “ he added.

In their exploratory pooled analyses, Dr. Socinski and co-investigators looked at data from the phase 3 IMpower130 and IMpower132 trials, which evaluated first-line atezolizumab and chemotherapy for NSCLC, and the phase 3 IMpower150 trial, which evaluated atezolizumab plus chemotherapy with or without bevacizumab.

In all, they analyzed data for 1,557 atezolizumab-treated patients, and 900 patients who had been in the control arms of the studies.

Forty-eight percent of atezolizumab-treated patients experienced irAEs of any grade, while 11% experienced irAEs of grade 3-5, according to the presented data. In the control arm, 32% experienced irAEs of any grade and 5% experienced grade 3-5 irAEs.

The most common irAEs of any grade were rash, hepatitis, and hypothyroidism, occurring in 28%, 15%, and 12% of atezolizumab-treated patients, respectively.

Median OS in the atezolizumab arm was 25.7 months for patients with irAEs and 13.0 for patients with no irAEs, with a hazard ratio (HR) of 0.69 using a time-dependent Cox model.

Median OS in the control arm was 20.2 months for patients with irAEs and 12.8 months for patients with no irAEs, with an HR of 0.82.

The overall response rate (ORR) in the atezolizumab arm was 61.1% for patients with irAEs and 37.2% for those without irAEs; in the control arm, ORR was 42.2% for patients with irAEs and 34.0% for those with no irAEs.

Atezolizumab-treated patients who experienced grade 3-5 irAEs had the shortest OS, according to Dr. Socinski. The HRs for OS at 1, 3, 6, and 12 months in atezolizumab-treated patients with grade 3-5 irAEs (compared with those without irAEs) ranged from 1.25 to 0.87. By contrast, HRs at those time points for patients with grade 1-2 irAEs ranged from 0.78 to 0.72, Dr. Socinski said.

Dr. Socinski reported disclosures related to AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen, Lilly, Merck, Novartis, Roche/Genentech, and Spectrum Pharmaceuticals. Dr. Redman reported a consulting or advisory role with AstraZeneca.

Experiencing an immune-related adverse event during checkpoint inhibitor treatment may predict outcomes in patients with non-small cell lung cancer, exploratory analyses of phase 3 trials suggest.

Immune-related adverse events (irAEs) were tied to longer overall survival (OS) in exploratory pooled analyses of three phase 3 clinical trials evaluating atezolizumab-based regimens, according to investigator Mark A. Socinski, MD, of AdventHealth Cancer Institute, Orlando, Fla.

Median OS approached 26 months for patients who received first-line atezolizumab and experienced an irAE, compared with just 13 months for those who did not experience an irAE, according to results reported at the American Society of Clinical Oncology Annual Meeting (Abstract 9002).

Atezolizumab-treated patients with grade 3 or greater irAEs had the shortest OS, shorter than those atezolizumab-treated patients who experienced grade 1-2 irAEs or no irAEs at all. That short OS may be due to treatment interruptions or discontinuations, said Dr. Socinski.

“Data from these analyses suggest an association between irAEs and efficacy in patients with [non-small cell cancer] NSCLC,” he stated in his presentation of the results.
 

A lot more to learn about irAEs

Similar linkages between irAEs and outcomes were observed in pooled analyses of patients enrolled in the control arms of the phase 3 trials, with a median OS of about 20 months for control patients experiencing an irAE, versus about 13 months for those who did not.

That linkage in the control arm prompted a question from an ASCO attendee about why an effect of irAEs, commonly associated with immune checkpoint inhibitor therapy, would be evident in analyses of patients who did not receive those agents.

In his response, Dr. Socinski characterized the finding as “a surprise” and said the finding may either reflect how adverse events are characterized or how chemotherapy impacts the immune system.

“I don’t know that our definition of irAEs is perfect,” he said, “and maybe we don’t understand what impact chemotherapy may have on the immune system, and may actually engender what historically we’ve always seen as an adverse event, but didn’t necessarily classify as an immune-related adverse event.”

More work is needed to better understand the connection between irAES and outcomes, and whether anything can be done as a result of that improved understanding, said discussant Mary Weber Redman, PhD.

“The question is, ‘what is actionable?’” added Dr. Redman, a biostatistician at the Fred Hutchinson Cancer Research Center, Seattle.

A firmer understanding of the relationship between irAEs and outcomes could change how clinicians monitor patients for irAEs, lead to better prediction of which patients may experience higher grade irAEs, and ultimately impact treatment selection potentially to avoid those higher grade events, Dr. Redman said in her remarks.

“Doing these types of analyses are quite important, because we have to look at the breadth of information that we have to be able to interpret that and think about what are future questions,” she said in the question-and-answer session accompanying Dr. Socinski’s presentation.

“I think the key is that we shouldn’t use these analyses to be definitive, but we should use them as to be hypothesis generating,” she added.
 

More evidence to link irAEs and outcomes

Immune-related AEs caused by off-target immune and inflammatory activity have been reported in up to 80% of patients receiving immune checkpoint inhibitors as monotherapy and up to 95% in combination regimens, Dr. Socinski said in his presentation.

“Increasing evidence suggests that the occurrence of immune-related adverse events with PD-L1 or PD-1 inhibitor therapy may be predictive of improved outcomes in cancers such as NSCLC, “ he added.

In their exploratory pooled analyses, Dr. Socinski and co-investigators looked at data from the phase 3 IMpower130 and IMpower132 trials, which evaluated first-line atezolizumab and chemotherapy for NSCLC, and the phase 3 IMpower150 trial, which evaluated atezolizumab plus chemotherapy with or without bevacizumab.

In all, they analyzed data for 1,557 atezolizumab-treated patients, and 900 patients who had been in the control arms of the studies.

Forty-eight percent of atezolizumab-treated patients experienced irAEs of any grade, while 11% experienced irAEs of grade 3-5, according to the presented data. In the control arm, 32% experienced irAEs of any grade and 5% experienced grade 3-5 irAEs.

The most common irAEs of any grade were rash, hepatitis, and hypothyroidism, occurring in 28%, 15%, and 12% of atezolizumab-treated patients, respectively.

Median OS in the atezolizumab arm was 25.7 months for patients with irAEs and 13.0 for patients with no irAEs, with a hazard ratio (HR) of 0.69 using a time-dependent Cox model.

Median OS in the control arm was 20.2 months for patients with irAEs and 12.8 months for patients with no irAEs, with an HR of 0.82.

The overall response rate (ORR) in the atezolizumab arm was 61.1% for patients with irAEs and 37.2% for those without irAEs; in the control arm, ORR was 42.2% for patients with irAEs and 34.0% for those with no irAEs.

Atezolizumab-treated patients who experienced grade 3-5 irAEs had the shortest OS, according to Dr. Socinski. The HRs for OS at 1, 3, 6, and 12 months in atezolizumab-treated patients with grade 3-5 irAEs (compared with those without irAEs) ranged from 1.25 to 0.87. By contrast, HRs at those time points for patients with grade 1-2 irAEs ranged from 0.78 to 0.72, Dr. Socinski said.

Dr. Socinski reported disclosures related to AstraZeneca/MedImmune, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Janssen, Lilly, Merck, Novartis, Roche/Genentech, and Spectrum Pharmaceuticals. Dr. Redman reported a consulting or advisory role with AstraZeneca.

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Dr. Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Dr. Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Dr. Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Dr. Raghav is an advisor and researcher for the company; Dr. Beg had no relationships with it.

[email protected]

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

A version of this article first appeared on Medscape.com.

This article was updated 6/7/21.

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

A version of this article first appeared on Medscape.com.

This article was updated 6/7/21.

The U.S. Food and Drug Administration has approved a 2.4 mg/week subcutaneous dose of the glucagonlike peptide–1 (GLP-1) receptor agonist semaglutide (Wegovy, Novo Nordisk) for weight loss.

Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m²) or are overweight (BMI ≥ 27 kg/m²) with at least one weight-related comorbidity.

Semaglutide “induces weight loss by reducing hunger, increasing feelings of fullness, and thereby helping people eat less and reduce their calorie intake,” according to a company statement.

Novo Nordisk plans to launch Wegovy later this month in the United States. The prescribing information can be found here.

This weight-loss drug is currently under review by the European Medicines Agency.

Several experts told Medscape that they believe the approval of this drug – as long as it is reimbursed – has the potential to change the paradigm of care when it comes to weight loss.


 

‘Game changer’ drug tested in STEP clinical trial program

The favorable FDA ruling is based on results from the Semaglutide Treatment Effect in People With Obesity (STEP) program of four phase 3 clinical trials that tested the drug’s safety and efficacy in more than 4,500 adults with overweight or obesity obesity who were randomized to receive a reduced a calorie meal plan and increased physical activity (placebo) or this lifestyle intervention plus semaglutide.

The four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo were published in February and March 2021.

As previously reported by this news organization, all trials were in adults with overweight or obesity:

•  was in 1,961 adults (N Engl J Med. 2021 March 18;384:989-1002).
•  was in 1,210 adults who also had diabetes (Lancet. 2021 Mar 13;397;971-84).
•  was in 611 adults, where those in the treatment group also underwent an intensive lifestyle intervention (JAMA. 2021 Feb 24;325:1403-13.
•  was in 803 adults who had reached a target dose of 2.4 mg semaglutide after a 20-week run-in (and the trial examined further weight loss in the subsequent 48 weeks) (JAMA 2021 Mar 23;325:1414-25).

In the STEP 1, 2, and 4 trials of individuals with overweight and obesity, those in the semaglutide groups attained a 15%-18% weight loss over 68 weeks.

The dosage was well-tolerated. The most common side effects were gastrointestinal, and they were transient and mild or moderate in severity.

The side effects, contraindications, and a black box warning about thyroid C-cell tumors are spelled out in the prescribing information.

A coauthor of the STEP 1 trial, Rachel Batterham, MBBS, PhD, of the Centre for Obesity Research at University College London, said at the time of publication: “The findings of this study represent a major breakthrough for improving the health of people with obesity.”

“No other drug has come close to producing this level of weight loss – this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery,” she added.
 

Welcome Addition, But Will Insurance Coverage, Price Thwart Access?

Thomas A. Wadden, PhD, from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and lead author of STEP 3, commented in an email to this news organization that “semaglutide 2.4 mg appears to be the breakthrough in weight management that healthcare providers and their patients with obesity have been waiting for.”

The mean 15% weight loss at 68 weeks is nearly twice what is seen with other FDA-approved anti-obesity medications, he noted, and moreover, 70% of patients taking semaglutide lost at least 10% of their initial weight, which is associated with clinically meaningful improvements in obesity-related type 2 diabetes, hypertension, obstructive sleep apnea, and impaired quality of life.

And “nearly one-third of users are likely to lose 20% or more of their starting weight, an outcome which eludes traditional diet and exercise interventions and which approaches weight losses produced by the most widely performed bariatric surgery, sleeve gastrectomy (with mean losses of 25% of initial weight at 1 year).” Dr. Wadden stressed.

Thus “the efficacy of semaglutide 2.4 mg, combined with its favorable safety profile, makes this medication a potential game changer,” he summarized, echoing Dr. Batterham.

However, insurance coverage and price could block uptake.

“I hope that the millions of people – in the U.S. and worldwide – who could benefit from this medication eventually will have access to it,” said Dr. Wadden. “In the U.S., the coverage of anti-obesity medications by insurers and employers will need to improve to ensure this happens, and the medication must be reasonably priced. These changes are critical to making this medication the game changer it could be.”

“This approval is an important development,” Scott Kahan, MD, director of the National Center for Weight and Wellness, Washington, who was not involved in the clinical trials of this drug, similarly wrote in an email.

“In a field with relatively few medication options, the availability of additional obesity pharmacotherapy agents is welcome,” he said. “In particular, semaglutide has shown impressive efficacy and safety data; as such it should be a valuable clinical option for many patients.”

However, it is concerning that “access to obesity treatments has traditionally been a challenge,” Dr. Kahan warned. “Novo Nordisk’s other obesity medication, Saxenda, has been a valuable tool, but one that exceedingly few patients are able to utilize due to minimal insurance reimbursement and very high cost.”

“It remains to be seen how accessible semaglutide will be for patients,” according to Dr. Kahan, “Still, if the challenge of limited coverage and high cost can be mitigated, this medication has a chance to significantly change the current paradigm of care, which until till now has included minimal use of pharmacotherapy outside specialty clinics,” he maintains.

Subcutaneous semaglutide at doses up to 1 mg/week (Ozempic, Novo Nordisk), which comes as prefilled pens at doses of 0.5 mg or 1.0 mg, is already approved for the treatment of type 2 diabetes.

The company is also applying for approval for a higher dose of semaglutide, 2 mg/week, for use in type 2 diabetes, and has just resubmitted its label expansion application to the FDA, after the agency issued a refusal to file letter in March.

And in September 2019, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), in doses of 7 and 14 mg/day, to improve glycemic control in type 2 diabetes, making it the first GLP-1 receptor agonist available in tablet form.
 

CVOT and oral format trials for obesity on the horizon

The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial will shed light on cardiovascular outcomes after 2.5-5 years in patients with cardiovascular disease and overweight or obesity but without type 2 diabetes. Participants will receive semaglutide in doses up to a maximum of 2.4 mg/week, or placebo, as an adjunct to lifestyle recommendations focused on cardiovascular risk reduction. The study is expected to complete in 2023.

And Novo Nordisk plans to initiate a global 68-week phase 3 trial in the second half of 2021 on the efficacy and safety of oral semaglutide 50 mg compared with placebo in 1000 people with obesity or overweight and comorbidities.

A version of this article first appeared on Medscape.com.

This article was updated 6/7/21.

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

A version of this article first appeared on Medscape.com.

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

A version of this article first appeared on Medscape.com.

A subcutaneous dose of the second-generation glycoprotein IIb/IIIa inhibitor RUC-4 achieved rapid dose-dependent platelet inhibition in patients with ST-segment elevation MI (STEMI) undergoing stenting in the CEL-02 study.

Platelet inhibition occurred within 15 minutes among the 27 patients, and wore off rapidly, with almost 50% of platelet function recovered within 122 minutes.

The drug was well tolerated, with no thrombocytopenia in the first 72 hours after administration, one injection-site reaction, and two major bleeds likely caused by catheter-based trauma to the proximal radial artery, reported Jurrien ten Berg, MD, PhD, St. Antonius Hospital, Nieuwegein, the Netherlands.

The results were reported during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions (EuroPCR 2021) and published simultaneously in EuroIntervention.

Dr. ten Berg noted that there is a need for drugs like RUC-4 in the early treatment of STEMI because oral P2Y12 inhibitors have a “seriously delayed” onset by about 2-4 hours. Prehospital use of the glycoprotein inhibitor (GPI) tirofiban was shown to improve reperfusion and late outcomes in the ON-TIME 2 trial, but GPIs require continuous intravenous administration and are associated with thrombocytopenia.

“Since RUC-4 is unique among small-molecule GPI in not inducing the receptor to undergo a major conformational change that has been implicated in the development of thrombocytopenia, it is possible that RUC-4 may be associated with fewer episodes of thrombocytopenia than current GPI,” the authors wrote.

RUC-4, also called zalunfiban, can be delivered with a single subcutaneous dose and, in a phase 1 study, demonstrated platelet inhibition within 15 minutes and was well tolerated up to a dose of 0.075 mg/kg among healthy volunteers and patients with stable coronary artery disease on aspirin.

In the CEL-02 study, 27 STEMI patients received a weight-adjusted subcutaneous injection of RUC-4 before primary percutaneous coronary intervention (PCI) in escalating doses of 0.075 mg/kg, 0.090 mg/kg, and 0.110 mg/kg. Patients were given standard treatment in the ambulance, which included aspirin (93%), ticagrelor (93%), and unfractionated heparin (96%). The activated clotting time was less than 200 seconds in 92% of patients who received additional heparin during cardiac catheterization.

The patients’ mean age was 62 years, 26% were women, and 96% were White. Pharmacodynamic data were available for 24 patients.

The average platelet inhibition 15 minutes after the injection was 77.5%, 87.5%, and 91.7%, respectively, for the three escalating doses (P = .002 for trend).

The primary endpoint of at least 77% inhibition of the iso-TRAP channel – which corresponds to 80% inhibition of light transmission aggregometry stimulated by 20 mcM adenosine diphosphate within 15 minutes – was achieved in three of eight patients at the lowest dose and in seven of eight patients at the middle and highest doses.

“Single-dose subcutaneous RUC-4 induces a fast, potent dose-dependent response of platelet inhibition in patients with STEMI presenting for primary PCI,” Dr. ten Berg concluded. “It is therefore promising for prehospital platelet inhibition in STEMI patients, and the results support further research on clinical benefit.”

The double-blind, randomized phase 2b CELEBRATE trial is underway, evaluating 1,668 STEMI patients treated with a 0.110 mg/kg or 0.130 mg/kg dose of RUC-4 or placebo in the ambulance. The coprimary outcomes are restoration of coronary artery blood flow and resolution of ST-segment deviation post-PCI/angiography. Primary completion is set for March 2023.

MDedge News

Marco Valgimigli, MD, who was not involved in the study, said in an interview that RUC-4 has “some theoretical advantages, compared with conventional IIb/IIIa inhibitors, namely the absence of thrombocytopenia which is, however, relatively rare, especially with tirofiban or eptifibatide.”

The subcutaneous approach may also offer an advantage. Yet, if the administration of RUC-4 is “to happen in the ambulance – a setting where an IV line is usually established – whether the subcutaneous versus IV administration of the treatment proves to be advantageous remains to be seen,” said Dr. Valgimigli, from Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland.

“We would need to see the results of large randomized trials embracing this treatment option before a clinical decision can be made, especially considering that IIb/IIa inhibitors in the ambulance have been tested in the past but ultimately abandoned,” he said.

Limitations of the study are its open-label design, the fact that iso-TRAP channel assay data were not reported by the VeryifyNow instrument and had to be calculated from the raw data, and the fact that the timing of the RUC-4 injection immediately before PCI does not fully resemble the expected use of RUC-4 in clinical practice, where RUC-4 would be administered at the same time as the aspirin, ticagrelor, and heparin, and about an hour before PCI, ten Berg and colleagues wrote.

CeleCor Therapeutics sponsored the study and provided study materials. Dr. ten Berg reported receiving lecture or consultancy fees from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, AccuMetrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and Idorsia, and institutional research grants from ZonMw and AstraZeneca. Coauthor Barry S. Coller is an inventor of RUC-4 and a founder, equity holder, and consultant to CeleCor. He also receives royalties from Centocor/Janssen and the VerifyNow assays. Dr. Valgimigli has received grants from Abbott, Terumo, Medicure, and AstraZeneca, and personal fees from Abbott, Chiesi, Bayer, Daiichi Sankyo, Amgen, Terumo, Alvimedica, AstraZeneca, Biosensors, and Idorsia.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved a once-daily oral medication, which is a combination of olanzapine and samidorphan (Lybalvi, Alkermes), for the treatment of schizophrenia and bipolar I disorder.

The drug is approved for the treatment of adults with schizophrenia and for adults with bipolar I disorder as a maintenance monotherapy or to treat acute manic or mixed episodes, as either monotherapy or an adjunct to lithium or valproate.

An atypical antipsychotic, the drug is a combination of olanzapine, an established antipsychotic medication, and samidorphan, a new chemical entity.

“Schizophrenia and bipolar I disorder are complex, chronic diseases, and there remains a persistent need for new medications with proven efficacy and safety. Olanzapine, a highly efficacious atypical antipsychotic, is associated with significant side effects, including weight gain that may impact patients’ treatment experiences and limit its use. With the efficacy of olanzapine and evidence of less weight gain in patients with schizophrenia, Lybalvi brings a welcome new addition to our medication arsenal,” René S. Kahn, MD, PhD, Esther and Joseph Klingenstein professor & chair, department of psychiatry and Behavioral Health System at the Icahn School of Medicine at Mount Sinai, New York, said in a company press release.

In a clinical development program, the drug demonstrated antipsychotic efficacy, safety, and tolerability, including significantly less weight gain than olanzapine in patients with schizophrenia in the ENLIGHTEN-2 study.

The FDA approved Lybalvi under the 505(b)(2) regulatory pathway based on data from 27 clinical studies, including 18 studies evaluating Lybalvi and nine studies evaluating samidorphan alone and the FDA’s findings of the safety and effectiveness of olanzapine in the treatment of bipolar I disorder and schizophrenia. Data suggest that olanzapine-associated weight gain is disease independent, the company reports.

“People living with schizophrenia or bipolar I disorder must evaluate both efficacy and tolerability when making treatment decisions,” Paul Gionfriddo, president and CEO of Mental Health America, said in the same company press release. “We are grateful that companies like Alkermes are driven to continue developing new treatment options in psychiatry that seek to address unmet needs of our community, and we applaud the FDA for considering the experiences of individuals living with these conditions.” 

Alkermes expects to make Lybalvi available for patients in the fourth quarter of 2021.

A version of this article first appeared on Medscape.com.

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has granted breakthrough therapy designation for Boehringer Ingelheim’s experimental agent for the treatment of cognitive impairment associated with schizophrenia (CIAS).

The drug, known as BI 425809, is a novel glycine transporter-1 inhibitor.

The company announced it will start the CONNEX phase 3 clinical trial program to assess the safety and efficacy of the drug for improving cognition for adults with schizophrenia.

The breakthrough therapy designation and the initiation of phase 3 testing are based on results from a phase 2 clinical trial published in The Lancet Psychiatry.

In the phase 2 trial, oral BI 425809, taken once daily, improved cognition after 12 weeks for patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo.

Impairment of cognitive function is a major burden for people with schizophrenia, and no pharmacologic treatments are currently approved for CIAS.

“Cognition is a fundamental aspect of everyday life, including problem solving, memory, and attention, which is why finding solutions for cognitive impairment is a key area of Boehringer Ingelheim mental health research,” Vikas Mohan Sharma, MS, with Boehringer Ingelheim, said in a news release.

“This breakthrough therapy designation further highlights the urgent need for novel treatments for people living with schizophrenia. By combining traditional treatment approaches with new and innovative technologies, we are developing targeted therapies that will help to ease the burden of mental health conditions and enable people living with these conditions to create more meaningful connections to their lives, loved ones, and society,” said Mr. Sharma.

The CONNEX clinical trial program is composed of three clinical trials – CONNEX-1, CONNEX-2, and CONNEX-3. All are phase 3 randomized, double-blind, placebo-controlled parallel group trials that will examine the efficacy and safety of BI 425809 taken once daily over a 26-week period for patients with schizophrenia.

The primary outcome measure is change from baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia consensus cognitive battery.

The CONNEX trial program will use VeraSci’s Pathway electronic clinical outcome assessment platform, including VeraSci’s Virtual Reality Functional Capacity Assessment Tool (VRFCAT), which simulates key instrumental activities of daily living in a realistic interactive virtual environment, VeraSci explains in a news release announcing the partnership with Boehringer Ingelheim.

The VRFCAT is sensitive to functional capacity deficits and has been accepted into the FDA’s Clinical Outcome Assessment Qualification Program.

The CONNEX trials will also utilize speech biomarker technology from Aural Analytics, which will provide a “richer picture of trial participants’ cognition alongside more conventional clinical outcome measures,” Boehringer Ingelheim says.

“Several of the symptoms of schizophrenia are generated by cognitive and emotional processes that can be identified through disruptions in the outward flow of speech. Using innovative speech analytics may help to objectively assess the downstream consequences of these disruptions,” said Daniel Jones, Aural Analytics co-founder and CEO.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has granted breakthrough therapy designation for Boehringer Ingelheim’s experimental agent for the treatment of cognitive impairment associated with schizophrenia (CIAS).

The drug, known as BI 425809, is a novel glycine transporter-1 inhibitor.

The company announced it will start the CONNEX phase 3 clinical trial program to assess the safety and efficacy of the drug for improving cognition for adults with schizophrenia.

The breakthrough therapy designation and the initiation of phase 3 testing are based on results from a phase 2 clinical trial published in The Lancet Psychiatry.

In the phase 2 trial, oral BI 425809, taken once daily, improved cognition after 12 weeks for patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo.

Impairment of cognitive function is a major burden for people with schizophrenia, and no pharmacologic treatments are currently approved for CIAS.

“Cognition is a fundamental aspect of everyday life, including problem solving, memory, and attention, which is why finding solutions for cognitive impairment is a key area of Boehringer Ingelheim mental health research,” Vikas Mohan Sharma, MS, with Boehringer Ingelheim, said in a news release.

“This breakthrough therapy designation further highlights the urgent need for novel treatments for people living with schizophrenia. By combining traditional treatment approaches with new and innovative technologies, we are developing targeted therapies that will help to ease the burden of mental health conditions and enable people living with these conditions to create more meaningful connections to their lives, loved ones, and society,” said Mr. Sharma.

The CONNEX clinical trial program is composed of three clinical trials – CONNEX-1, CONNEX-2, and CONNEX-3. All are phase 3 randomized, double-blind, placebo-controlled parallel group trials that will examine the efficacy and safety of BI 425809 taken once daily over a 26-week period for patients with schizophrenia.

The primary outcome measure is change from baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia consensus cognitive battery.

The CONNEX trial program will use VeraSci’s Pathway electronic clinical outcome assessment platform, including VeraSci’s Virtual Reality Functional Capacity Assessment Tool (VRFCAT), which simulates key instrumental activities of daily living in a realistic interactive virtual environment, VeraSci explains in a news release announcing the partnership with Boehringer Ingelheim.

The VRFCAT is sensitive to functional capacity deficits and has been accepted into the FDA’s Clinical Outcome Assessment Qualification Program.

The CONNEX trials will also utilize speech biomarker technology from Aural Analytics, which will provide a “richer picture of trial participants’ cognition alongside more conventional clinical outcome measures,” Boehringer Ingelheim says.

“Several of the symptoms of schizophrenia are generated by cognitive and emotional processes that can be identified through disruptions in the outward flow of speech. Using innovative speech analytics may help to objectively assess the downstream consequences of these disruptions,” said Daniel Jones, Aural Analytics co-founder and CEO.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has granted breakthrough therapy designation for Boehringer Ingelheim’s experimental agent for the treatment of cognitive impairment associated with schizophrenia (CIAS).

The drug, known as BI 425809, is a novel glycine transporter-1 inhibitor.

The company announced it will start the CONNEX phase 3 clinical trial program to assess the safety and efficacy of the drug for improving cognition for adults with schizophrenia.

The breakthrough therapy designation and the initiation of phase 3 testing are based on results from a phase 2 clinical trial published in The Lancet Psychiatry.

In the phase 2 trial, oral BI 425809, taken once daily, improved cognition after 12 weeks for patients with schizophrenia; doses of 10 mg and 25 mg showed the largest separation from placebo.

Impairment of cognitive function is a major burden for people with schizophrenia, and no pharmacologic treatments are currently approved for CIAS.

“Cognition is a fundamental aspect of everyday life, including problem solving, memory, and attention, which is why finding solutions for cognitive impairment is a key area of Boehringer Ingelheim mental health research,” Vikas Mohan Sharma, MS, with Boehringer Ingelheim, said in a news release.

“This breakthrough therapy designation further highlights the urgent need for novel treatments for people living with schizophrenia. By combining traditional treatment approaches with new and innovative technologies, we are developing targeted therapies that will help to ease the burden of mental health conditions and enable people living with these conditions to create more meaningful connections to their lives, loved ones, and society,” said Mr. Sharma.

The CONNEX clinical trial program is composed of three clinical trials – CONNEX-1, CONNEX-2, and CONNEX-3. All are phase 3 randomized, double-blind, placebo-controlled parallel group trials that will examine the efficacy and safety of BI 425809 taken once daily over a 26-week period for patients with schizophrenia.

The primary outcome measure is change from baseline in overall composite T-score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia consensus cognitive battery.

The CONNEX trial program will use VeraSci’s Pathway electronic clinical outcome assessment platform, including VeraSci’s Virtual Reality Functional Capacity Assessment Tool (VRFCAT), which simulates key instrumental activities of daily living in a realistic interactive virtual environment, VeraSci explains in a news release announcing the partnership with Boehringer Ingelheim.

The VRFCAT is sensitive to functional capacity deficits and has been accepted into the FDA’s Clinical Outcome Assessment Qualification Program.

The CONNEX trials will also utilize speech biomarker technology from Aural Analytics, which will provide a “richer picture of trial participants’ cognition alongside more conventional clinical outcome measures,” Boehringer Ingelheim says.

“Several of the symptoms of schizophrenia are generated by cognitive and emotional processes that can be identified through disruptions in the outward flow of speech. Using innovative speech analytics may help to objectively assess the downstream consequences of these disruptions,” said Daniel Jones, Aural Analytics co-founder and CEO.

A version of this article first appeared on Medscape.com.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.