Clinical Edge Journal Scan

Key clinical point: In an updated KEYNOTE-177 analysis, first-line pembrolizumab vs chemotherapy did not improve survival in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), but improved progression-free survival (PFS) and led to fewer treatment-related adverse events (TAE).

Major finding: Pembrolizumab vs chemotherapy provided no survival benefit as the one-sided α boundary for superiority (0.025) was not met (hazard ratio [HR] 0.74; P = .036). However, it prolonged median PFS (16.5 vs 8.2 months; HR 0.59; 95% CI 0.45-0.79) and lowered the grade ≥3 TAE rate (22% vs 66%).

Study details: These are the final analysis data from the phase 3 KEYNOTE-177 trial that included 307 adult patients with previously untreated MSI-H or dMMR mCRC who were randomly assigned to receive pembrolizumab or chemotherapy.

Disclosures: Merck Sharp & Dohme (MSD; Merck subsidiary) sponsored the study. Some authors reported serving on the directorial board of, receiving institutional or clinical trial funding, advisory or consultant honoraria, or travel or accommodation expenses from various sources, including MSD. The other authors are MSD employees and Merck shareholders.

Source: Diaz LA Jr et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659-670 (Apr 12). Doi: 10.1016/S1470-2045(22)00197-8

Key clinical point: In an updated KEYNOTE-177 analysis, first-line pembrolizumab vs chemotherapy did not improve survival in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), but improved progression-free survival (PFS) and led to fewer treatment-related adverse events (TAE).

Major finding: Pembrolizumab vs chemotherapy provided no survival benefit as the one-sided α boundary for superiority (0.025) was not met (hazard ratio [HR] 0.74; P = .036). However, it prolonged median PFS (16.5 vs 8.2 months; HR 0.59; 95% CI 0.45-0.79) and lowered the grade ≥3 TAE rate (22% vs 66%).

Study details: These are the final analysis data from the phase 3 KEYNOTE-177 trial that included 307 adult patients with previously untreated MSI-H or dMMR mCRC who were randomly assigned to receive pembrolizumab or chemotherapy.

Disclosures: Merck Sharp & Dohme (MSD; Merck subsidiary) sponsored the study. Some authors reported serving on the directorial board of, receiving institutional or clinical trial funding, advisory or consultant honoraria, or travel or accommodation expenses from various sources, including MSD. The other authors are MSD employees and Merck shareholders.

Source: Diaz LA Jr et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659-670 (Apr 12). Doi: 10.1016/S1470-2045(22)00197-8

Key clinical point: In an updated KEYNOTE-177 analysis, first-line pembrolizumab vs chemotherapy did not improve survival in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), but improved progression-free survival (PFS) and led to fewer treatment-related adverse events (TAE).

Major finding: Pembrolizumab vs chemotherapy provided no survival benefit as the one-sided α boundary for superiority (0.025) was not met (hazard ratio [HR] 0.74; P = .036). However, it prolonged median PFS (16.5 vs 8.2 months; HR 0.59; 95% CI 0.45-0.79) and lowered the grade ≥3 TAE rate (22% vs 66%).

Study details: These are the final analysis data from the phase 3 KEYNOTE-177 trial that included 307 adult patients with previously untreated MSI-H or dMMR mCRC who were randomly assigned to receive pembrolizumab or chemotherapy.

Disclosures: Merck Sharp & Dohme (MSD; Merck subsidiary) sponsored the study. Some authors reported serving on the directorial board of, receiving institutional or clinical trial funding, advisory or consultant honoraria, or travel or accommodation expenses from various sources, including MSD. The other authors are MSD employees and Merck shareholders.

Source: Diaz LA Jr et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): Final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659-670 (Apr 12). Doi: 10.1016/S1470-2045(22)00197-8

Key clinical point: The findings from the C-Cubed study support the extension of sequential treatment (fluoropyrimidines with bevacizumab followed by oxaliplatin at first progression) over combination treatment (fluoropyrimidines and oxaliplatin with bevacizumab) in selected patients with previously untreated metastatic colorectal cancer (mCRC) who do not need an objective response.

Major finding: Sequential vs combination treatment led to a significantly longer time to failure of strategy (15.2 vs 7.8 months; hazard ratio 0.49; P < .0001). However, the median overall survival (P = .61) or time between randomization and the first progressive disease (P = .12) was not significantly different between the treatment groups.

Study details: Findings are from a phase 3 trial, C-Cubed Study, which included 300 patients aged ≥20 years with previously untreated mCRC who were randomly assigned to receive sequential (n = 151) or combination (n = 149) treatment.

Disclosures: The study was sponsored by Chugai Pharmaceutical, Co., Ltd. Some authors reported receiving grants or personal fees from various sources, including Chugai Pharmaceutical.

Source: Inada R et al. Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study. Eur J Cancer. 2022;169:166-178 (May 12). Doi: 10.1016/j.ejca.2022.04.009

Key clinical point: The findings from the C-Cubed study support the extension of sequential treatment (fluoropyrimidines with bevacizumab followed by oxaliplatin at first progression) over combination treatment (fluoropyrimidines and oxaliplatin with bevacizumab) in selected patients with previously untreated metastatic colorectal cancer (mCRC) who do not need an objective response.

Major finding: Sequential vs combination treatment led to a significantly longer time to failure of strategy (15.2 vs 7.8 months; hazard ratio 0.49; P < .0001). However, the median overall survival (P = .61) or time between randomization and the first progressive disease (P = .12) was not significantly different between the treatment groups.

Study details: Findings are from a phase 3 trial, C-Cubed Study, which included 300 patients aged ≥20 years with previously untreated mCRC who were randomly assigned to receive sequential (n = 151) or combination (n = 149) treatment.

Disclosures: The study was sponsored by Chugai Pharmaceutical, Co., Ltd. Some authors reported receiving grants or personal fees from various sources, including Chugai Pharmaceutical.

Source: Inada R et al. Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study. Eur J Cancer. 2022;169:166-178 (May 12). Doi: 10.1016/j.ejca.2022.04.009

Key clinical point: The findings from the C-Cubed study support the extension of sequential treatment (fluoropyrimidines with bevacizumab followed by oxaliplatin at first progression) over combination treatment (fluoropyrimidines and oxaliplatin with bevacizumab) in selected patients with previously untreated metastatic colorectal cancer (mCRC) who do not need an objective response.

Major finding: Sequential vs combination treatment led to a significantly longer time to failure of strategy (15.2 vs 7.8 months; hazard ratio 0.49; P < .0001). However, the median overall survival (P = .61) or time between randomization and the first progressive disease (P = .12) was not significantly different between the treatment groups.

Study details: Findings are from a phase 3 trial, C-Cubed Study, which included 300 patients aged ≥20 years with previously untreated mCRC who were randomly assigned to receive sequential (n = 151) or combination (n = 149) treatment.

Disclosures: The study was sponsored by Chugai Pharmaceutical, Co., Ltd. Some authors reported receiving grants or personal fees from various sources, including Chugai Pharmaceutical.

Source: Inada R et al. Phase 3 trial of sequential versus combination treatment in colorectal cancer: The C-cubed study. Eur J Cancer. 2022;169:166-178 (May 12). Doi: 10.1016/j.ejca.2022.04.009

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

Clinicians everywhere are excited to have more options, but they are also reeling from trying to keep up with the enormous amount of data. We are fortunate to have a lot of information for these therapies published in the past month, which provides important insight into how to best use them.

Let's start with some new data on dupilumab, which has emerged as a first-line systemic therapy for moderate to severe AD in the US. Patients who were enrolled in the phase 1-3 randomized clinical trials for dupilumab were allowed to enroll in a long-term open-label extension study where they received 300 mg dupilumab weekly. Beck and colleagues published the interim analysis of the ongoing international, multicenter, long-term extension study of 2677 adults with up to 4 years of dupilumab exposure. They found no major increases in adverse event rates, with high durable efficacy and high rates of drug persistence over time. It is important to note that this was an open-label study without a control group — that is, patients knew exactly what treatment they were receiving. In addition, the analysis presented efficacy among those patients who remained in the study over time, which may not adequately account for loss of efficacy over time in patients who dropped out of the study. Nevertheless, the results suggest that dupilumab can be a good long-term treatment option for patients with chronic AD, with no new major safety concerns.

There is now a large body of evidence generated by phase 4 studies showing the real-world effectiveness of dupilumab. Stingeni and colleagues published the results of a prospective study of 139 adolescents (aged 12-17 years) with moderate-to-severe AD who received dupilumab for 16 weeks. They found significant improvement in AD signs and quality of life overall and across different clinical phenotypes of AD, with robust endpoints achieved most in the diffuse eczema subtype. Despite the previously demonstrated heterogeneity of AD,^1,2 these results suggest that dupilumab can be effective across a variety of patient subtypes.

The JAK inhibitors are new additions to our therapeutic armamentarium for AD. Given how new they are to dermatology, we are always craving more data to inform clinical decision-making. Several recent studies provide additional insights into how we can use the JAK inhibitors in clinical practice.

One major question is how well they work in patients in whom dupilumab previously failed. Shi and colleagues published the results of an interesting and clinically relevant phase 3 study (JADE EXTEND), which included 203 patients with moderate-to-severe AD who were randomly assigned to receive 200 mg or 100 mg once-daily abrocitinib after previously receiving dupilumab for 14 weeks in the JADE COMPARE study. They found that at week 12, the majority of dupilumab nonresponders had high Eczema Area and Severity Index (EASI-75) responses with both doses of abrocitinib. Patients who previously had a good clinical response with dupilumab had even higher treatment responses on abrocitinib than those who were dupilumab nonresponders. These data provide important information to support the use of abrocitinib, and perhaps by extension other JAK inhibitors, in patients who previously had inadequate response to dupilumab.

Another major question is how to differentiate the JAK inhibitors from biologics in AD. One consideration is that patients taking JAK inhibitors may achieve more robust clinical responses compared with those on biologics. Stander and colleagues performed a post hoc analysis of pooled phase 2B/3 studies of abrocitinib (942 patients). They found that, at week 12, a higher proportion of patients receiving 200 mg and 100 mg abrocitinib achieved more robust endpoints, such as EASI-90 and EASI-100 scores, compared with placebo recipients. Of note, these data did not include any comparison data with dupilumab. However, on the basis of cross-study comparison, it would seem that abrocitinib, particularly at the higher 200 mg dose, may lead to more robust clinical responses than dupilumab. However, it is very important to acknowledge that this study focused on 12-week data and maximal efficacy with dupilumab may take longer to achieve.

Additional References

1.         Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-176. Doi:  10.36849/JDD.6408

2.         Yew YW, Thyssen JP, Silverberg JI. A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics. J Amer Acad Dermatol. 2019;80(2):390-401. Doi: 10.1016/j.jaad.2018.09.035

Clinicians everywhere are excited to have more options, but they are also reeling from trying to keep up with the enormous amount of data. We are fortunate to have a lot of information for these therapies published in the past month, which provides important insight into how to best use them.

Let's start with some new data on dupilumab, which has emerged as a first-line systemic therapy for moderate to severe AD in the US. Patients who were enrolled in the phase 1-3 randomized clinical trials for dupilumab were allowed to enroll in a long-term open-label extension study where they received 300 mg dupilumab weekly. Beck and colleagues published the interim analysis of the ongoing international, multicenter, long-term extension study of 2677 adults with up to 4 years of dupilumab exposure. They found no major increases in adverse event rates, with high durable efficacy and high rates of drug persistence over time. It is important to note that this was an open-label study without a control group — that is, patients knew exactly what treatment they were receiving. In addition, the analysis presented efficacy among those patients who remained in the study over time, which may not adequately account for loss of efficacy over time in patients who dropped out of the study. Nevertheless, the results suggest that dupilumab can be a good long-term treatment option for patients with chronic AD, with no new major safety concerns.

There is now a large body of evidence generated by phase 4 studies showing the real-world effectiveness of dupilumab. Stingeni and colleagues published the results of a prospective study of 139 adolescents (aged 12-17 years) with moderate-to-severe AD who received dupilumab for 16 weeks. They found significant improvement in AD signs and quality of life overall and across different clinical phenotypes of AD, with robust endpoints achieved most in the diffuse eczema subtype. Despite the previously demonstrated heterogeneity of AD,^1,2 these results suggest that dupilumab can be effective across a variety of patient subtypes.

The JAK inhibitors are new additions to our therapeutic armamentarium for AD. Given how new they are to dermatology, we are always craving more data to inform clinical decision-making. Several recent studies provide additional insights into how we can use the JAK inhibitors in clinical practice.

One major question is how well they work in patients in whom dupilumab previously failed. Shi and colleagues published the results of an interesting and clinically relevant phase 3 study (JADE EXTEND), which included 203 patients with moderate-to-severe AD who were randomly assigned to receive 200 mg or 100 mg once-daily abrocitinib after previously receiving dupilumab for 14 weeks in the JADE COMPARE study. They found that at week 12, the majority of dupilumab nonresponders had high Eczema Area and Severity Index (EASI-75) responses with both doses of abrocitinib. Patients who previously had a good clinical response with dupilumab had even higher treatment responses on abrocitinib than those who were dupilumab nonresponders. These data provide important information to support the use of abrocitinib, and perhaps by extension other JAK inhibitors, in patients who previously had inadequate response to dupilumab.

Another major question is how to differentiate the JAK inhibitors from biologics in AD. One consideration is that patients taking JAK inhibitors may achieve more robust clinical responses compared with those on biologics. Stander and colleagues performed a post hoc analysis of pooled phase 2B/3 studies of abrocitinib (942 patients). They found that, at week 12, a higher proportion of patients receiving 200 mg and 100 mg abrocitinib achieved more robust endpoints, such as EASI-90 and EASI-100 scores, compared with placebo recipients. Of note, these data did not include any comparison data with dupilumab. However, on the basis of cross-study comparison, it would seem that abrocitinib, particularly at the higher 200 mg dose, may lead to more robust clinical responses than dupilumab. However, it is very important to acknowledge that this study focused on 12-week data and maximal efficacy with dupilumab may take longer to achieve.

Additional References

1.         Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-176. Doi:  10.36849/JDD.6408

2.         Yew YW, Thyssen JP, Silverberg JI. A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics. J Amer Acad Dermatol. 2019;80(2):390-401. Doi: 10.1016/j.jaad.2018.09.035

Clinicians everywhere are excited to have more options, but they are also reeling from trying to keep up with the enormous amount of data. We are fortunate to have a lot of information for these therapies published in the past month, which provides important insight into how to best use them.

Let's start with some new data on dupilumab, which has emerged as a first-line systemic therapy for moderate to severe AD in the US. Patients who were enrolled in the phase 1-3 randomized clinical trials for dupilumab were allowed to enroll in a long-term open-label extension study where they received 300 mg dupilumab weekly. Beck and colleagues published the interim analysis of the ongoing international, multicenter, long-term extension study of 2677 adults with up to 4 years of dupilumab exposure. They found no major increases in adverse event rates, with high durable efficacy and high rates of drug persistence over time. It is important to note that this was an open-label study without a control group — that is, patients knew exactly what treatment they were receiving. In addition, the analysis presented efficacy among those patients who remained in the study over time, which may not adequately account for loss of efficacy over time in patients who dropped out of the study. Nevertheless, the results suggest that dupilumab can be a good long-term treatment option for patients with chronic AD, with no new major safety concerns.

There is now a large body of evidence generated by phase 4 studies showing the real-world effectiveness of dupilumab. Stingeni and colleagues published the results of a prospective study of 139 adolescents (aged 12-17 years) with moderate-to-severe AD who received dupilumab for 16 weeks. They found significant improvement in AD signs and quality of life overall and across different clinical phenotypes of AD, with robust endpoints achieved most in the diffuse eczema subtype. Despite the previously demonstrated heterogeneity of AD,^1,2 these results suggest that dupilumab can be effective across a variety of patient subtypes.

The JAK inhibitors are new additions to our therapeutic armamentarium for AD. Given how new they are to dermatology, we are always craving more data to inform clinical decision-making. Several recent studies provide additional insights into how we can use the JAK inhibitors in clinical practice.

One major question is how well they work in patients in whom dupilumab previously failed. Shi and colleagues published the results of an interesting and clinically relevant phase 3 study (JADE EXTEND), which included 203 patients with moderate-to-severe AD who were randomly assigned to receive 200 mg or 100 mg once-daily abrocitinib after previously receiving dupilumab for 14 weeks in the JADE COMPARE study. They found that at week 12, the majority of dupilumab nonresponders had high Eczema Area and Severity Index (EASI-75) responses with both doses of abrocitinib. Patients who previously had a good clinical response with dupilumab had even higher treatment responses on abrocitinib than those who were dupilumab nonresponders. These data provide important information to support the use of abrocitinib, and perhaps by extension other JAK inhibitors, in patients who previously had inadequate response to dupilumab.

Another major question is how to differentiate the JAK inhibitors from biologics in AD. One consideration is that patients taking JAK inhibitors may achieve more robust clinical responses compared with those on biologics. Stander and colleagues performed a post hoc analysis of pooled phase 2B/3 studies of abrocitinib (942 patients). They found that, at week 12, a higher proportion of patients receiving 200 mg and 100 mg abrocitinib achieved more robust endpoints, such as EASI-90 and EASI-100 scores, compared with placebo recipients. Of note, these data did not include any comparison data with dupilumab. However, on the basis of cross-study comparison, it would seem that abrocitinib, particularly at the higher 200 mg dose, may lead to more robust clinical responses than dupilumab. However, it is very important to acknowledge that this study focused on 12-week data and maximal efficacy with dupilumab may take longer to achieve.

Additional References

1.         Chovatiya R, Silverberg JI. The heterogeneity of atopic dermatitis. J Drugs Dermatol. 2022;21(2):172-176. Doi:  10.36849/JDD.6408

2.         Yew YW, Thyssen JP, Silverberg JI. A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics. J Amer Acad Dermatol. 2019;80(2):390-401. Doi: 10.1016/j.jaad.2018.09.035

Key clinical point: A diet containing red meat did not have any significant effect on most glycemic and insulinemic risk factors associated with type 2 diabetes (T2D), but it led to a significant reduction in postprandial glucose level compared with a diet containing less or no red meat.

Major finding: A diet with vs without or less meat had no significant effect on insulin sensitivity (standardized mean difference [SMD] −0.11; 95% CI −0.39 to 0.16), insulin resistance (SMD 0.11; 95% CI −0.24 to 0.45), fasting glucose level (SMD 0.13; 95% CI −0.04 to 0.29), and fasting insulin level (SMD 0.08; 95% CI −0.16 to 0.32), but it significantly reduced the postprandial glucose level (SMD −0.44; P < .001).

Study details: Findings are from a meta-analysis of 21 randomized controlled trials that evaluated the association between red meat intake and T2D risk.

Disclosures: This study was funded by the Beef Checkoff. Three authors declared being employees of Midwest Biomedical Research (USA), which received research funding from Beef Checkoff and National Pork Board.

Source: Sanders LM et al. Red meat consumption and risk factors for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2022 (May 5). Doi: 10.1038/s41430-022-01150-1

Key clinical point: A diet containing red meat did not have any significant effect on most glycemic and insulinemic risk factors associated with type 2 diabetes (T2D), but it led to a significant reduction in postprandial glucose level compared with a diet containing less or no red meat.

Major finding: A diet with vs without or less meat had no significant effect on insulin sensitivity (standardized mean difference [SMD] −0.11; 95% CI −0.39 to 0.16), insulin resistance (SMD 0.11; 95% CI −0.24 to 0.45), fasting glucose level (SMD 0.13; 95% CI −0.04 to 0.29), and fasting insulin level (SMD 0.08; 95% CI −0.16 to 0.32), but it significantly reduced the postprandial glucose level (SMD −0.44; P < .001).

Study details: Findings are from a meta-analysis of 21 randomized controlled trials that evaluated the association between red meat intake and T2D risk.

Disclosures: This study was funded by the Beef Checkoff. Three authors declared being employees of Midwest Biomedical Research (USA), which received research funding from Beef Checkoff and National Pork Board.

Source: Sanders LM et al. Red meat consumption and risk factors for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2022 (May 5). Doi: 10.1038/s41430-022-01150-1

Key clinical point: A diet containing red meat did not have any significant effect on most glycemic and insulinemic risk factors associated with type 2 diabetes (T2D), but it led to a significant reduction in postprandial glucose level compared with a diet containing less or no red meat.

Major finding: A diet with vs without or less meat had no significant effect on insulin sensitivity (standardized mean difference [SMD] −0.11; 95% CI −0.39 to 0.16), insulin resistance (SMD 0.11; 95% CI −0.24 to 0.45), fasting glucose level (SMD 0.13; 95% CI −0.04 to 0.29), and fasting insulin level (SMD 0.08; 95% CI −0.16 to 0.32), but it significantly reduced the postprandial glucose level (SMD −0.44; P < .001).

Study details: Findings are from a meta-analysis of 21 randomized controlled trials that evaluated the association between red meat intake and T2D risk.

Disclosures: This study was funded by the Beef Checkoff. Three authors declared being employees of Midwest Biomedical Research (USA), which received research funding from Beef Checkoff and National Pork Board.

Source: Sanders LM et al. Red meat consumption and risk factors for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2022 (May 5). Doi: 10.1038/s41430-022-01150-1

Key clinical point: Cotadutide vs placebo was safe and effective in reducing body weight, glycated hemoglobin (HbA1c) level, and fasting plasma glucose level in patients with type 2 diabetes mellitus (T2D) and overweight or obesity.

Major finding: Percent decrease in body weight (mean difference [MD] 3.31; 95% CI 2.76-3.38) and glucose area under the plasma concentration curve (MD 30.15; 95% CI 23.18-37.12) and reduction in HbA1c (MD 0.68; 95% CI 0.58-0.79) and fasting plasma glucose (MD 31.31 mg/dL; 95% CI 22.59-40.04) levels over time were higher with cotadutide than placebo. Treatment-emergent serious adverse events were not significantly different between the treatment groups.

Study details: Findings are from a meta-analysis of eight randomized controlled trials including 1259 patients with T2D (body mass index 22-40 kg/m²) who received cotadutide (n = 890), placebo (n = 259), or other interventions (n = 110).

Disclosures: The study was funded by the Science, Technology & Innovation Funding Authority in cooperation with The Egyptian Knowledge Bank. The authors declared no conflicts of interest.

Source: Ali MM et al. Impact of Cotadutide drug on patients with type 2 diabetes mellitus: a systematic review and meta-analysis BMC Endocr Disord. 2022;22:113 (Apr 29). Doi: 10.1186/s12902-022-01031-5

Key clinical point: Cotadutide vs placebo was safe and effective in reducing body weight, glycated hemoglobin (HbA1c) level, and fasting plasma glucose level in patients with type 2 diabetes mellitus (T2D) and overweight or obesity.

Major finding: Percent decrease in body weight (mean difference [MD] 3.31; 95% CI 2.76-3.38) and glucose area under the plasma concentration curve (MD 30.15; 95% CI 23.18-37.12) and reduction in HbA1c (MD 0.68; 95% CI 0.58-0.79) and fasting plasma glucose (MD 31.31 mg/dL; 95% CI 22.59-40.04) levels over time were higher with cotadutide than placebo. Treatment-emergent serious adverse events were not significantly different between the treatment groups.

Study details: Findings are from a meta-analysis of eight randomized controlled trials including 1259 patients with T2D (body mass index 22-40 kg/m²) who received cotadutide (n = 890), placebo (n = 259), or other interventions (n = 110).

Disclosures: The study was funded by the Science, Technology & Innovation Funding Authority in cooperation with The Egyptian Knowledge Bank. The authors declared no conflicts of interest.

Source: Ali MM et al. Impact of Cotadutide drug on patients with type 2 diabetes mellitus: a systematic review and meta-analysis BMC Endocr Disord. 2022;22:113 (Apr 29). Doi: 10.1186/s12902-022-01031-5

Key clinical point: Cotadutide vs placebo was safe and effective in reducing body weight, glycated hemoglobin (HbA1c) level, and fasting plasma glucose level in patients with type 2 diabetes mellitus (T2D) and overweight or obesity.

Major finding: Percent decrease in body weight (mean difference [MD] 3.31; 95% CI 2.76-3.38) and glucose area under the plasma concentration curve (MD 30.15; 95% CI 23.18-37.12) and reduction in HbA1c (MD 0.68; 95% CI 0.58-0.79) and fasting plasma glucose (MD 31.31 mg/dL; 95% CI 22.59-40.04) levels over time were higher with cotadutide than placebo. Treatment-emergent serious adverse events were not significantly different between the treatment groups.

Study details: Findings are from a meta-analysis of eight randomized controlled trials including 1259 patients with T2D (body mass index 22-40 kg/m²) who received cotadutide (n = 890), placebo (n = 259), or other interventions (n = 110).

Disclosures: The study was funded by the Science, Technology & Innovation Funding Authority in cooperation with The Egyptian Knowledge Bank. The authors declared no conflicts of interest.

Source: Ali MM et al. Impact of Cotadutide drug on patients with type 2 diabetes mellitus: a systematic review and meta-analysis BMC Endocr Disord. 2022;22:113 (Apr 29). Doi: 10.1186/s12902-022-01031-5

Key clinical point: In patients with type 2 diabetes mellitus (T2D) for ≥10 years, metformin use vs no use was significantly associated with a lower risk for any and early age-related macular degeneration (AMD) but not late AMD.

Major finding: A significant association was observed between metformin use and any AMD (adjusted odds ratio [aOR] 0.24) and early AMD (aOR 0.17; both P < .0001), but not late AMD (P = .0619). Prolonged use (>5 years) and high cumulative dose (>3500 g) of metformin reduced AMD risk (P_trend = .0007).

Study details: This retrospective study included 324 patients aged ≥50 years diagnosed with T2D for ≥10 years, of which 209 were metformin users and 115 were metformin nonusers.

Disclosures: This study was funded by Hospital Youth Research Fund of China-Japan

Friendship Hospital and Beijing University of Chemical Technology-China-Japan Friendship Hospital Biomedical Translational Engineering Research Center Joint Fund. The authors declared no competing interests.

Source: Jiang J et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: A retrospective study. BMJ Open. 2022;12:e054420 (Apr 26). Doi: 10.1136/bmjopen-2021-054420

Key clinical point: In patients with type 2 diabetes mellitus (T2D) for ≥10 years, metformin use vs no use was significantly associated with a lower risk for any and early age-related macular degeneration (AMD) but not late AMD.

Major finding: A significant association was observed between metformin use and any AMD (adjusted odds ratio [aOR] 0.24) and early AMD (aOR 0.17; both P < .0001), but not late AMD (P = .0619). Prolonged use (>5 years) and high cumulative dose (>3500 g) of metformin reduced AMD risk (P_trend = .0007).

Study details: This retrospective study included 324 patients aged ≥50 years diagnosed with T2D for ≥10 years, of which 209 were metformin users and 115 were metformin nonusers.

Disclosures: This study was funded by Hospital Youth Research Fund of China-Japan

Friendship Hospital and Beijing University of Chemical Technology-China-Japan Friendship Hospital Biomedical Translational Engineering Research Center Joint Fund. The authors declared no competing interests.

Source: Jiang J et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: A retrospective study. BMJ Open. 2022;12:e054420 (Apr 26). Doi: 10.1136/bmjopen-2021-054420

Key clinical point: In patients with type 2 diabetes mellitus (T2D) for ≥10 years, metformin use vs no use was significantly associated with a lower risk for any and early age-related macular degeneration (AMD) but not late AMD.

Major finding: A significant association was observed between metformin use and any AMD (adjusted odds ratio [aOR] 0.24) and early AMD (aOR 0.17; both P < .0001), but not late AMD (P = .0619). Prolonged use (>5 years) and high cumulative dose (>3500 g) of metformin reduced AMD risk (P_trend = .0007).

Study details: This retrospective study included 324 patients aged ≥50 years diagnosed with T2D for ≥10 years, of which 209 were metformin users and 115 were metformin nonusers.

Disclosures: This study was funded by Hospital Youth Research Fund of China-Japan

Friendship Hospital and Beijing University of Chemical Technology-China-Japan Friendship Hospital Biomedical Translational Engineering Research Center Joint Fund. The authors declared no competing interests.

Source: Jiang J et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: A retrospective study. BMJ Open. 2022;12:e054420 (Apr 26). Doi: 10.1136/bmjopen-2021-054420

Key clinical point: Patients with first-ever stroke and type 2 diabetes mellitus (T2D) who receive metformin treatment (MT) show lower stroke severity, case fatality, and disability rates.

Major finding: MT vs non-MT group had a lower rate of in-hospital case fatality (odds ratio [OR] 0.63; 95% CI 0.47-0.84), 12-month case fatality (OR 0.69; 95% CI 0.50-0.88), and 12-month disability (OR 0.83; 95% CI 0.70-0.95).

Study details: The data come from a prospective, hospital-based cohort study including 7587 patients with first-ever stroke and T2D, of which 3593 (47.36%) received MT (MT group) and 3994 (52.64%) did not receive MT (non-MT group).

Disclosures: This study was supported by the National Major Public Health Service Projects, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Natural Science Foundation of Tianjin, and China Postdoctoral Science Foundation, among others. The authors declared no conflicts of interest.

Source: Tu WJ et al. Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes. Ther Adv Chronic Dis. 2022 (Apr 19). Doi: 10.1177/20406223221076894

Key clinical point: Patients with first-ever stroke and type 2 diabetes mellitus (T2D) who receive metformin treatment (MT) show lower stroke severity, case fatality, and disability rates.

Major finding: MT vs non-MT group had a lower rate of in-hospital case fatality (odds ratio [OR] 0.63; 95% CI 0.47-0.84), 12-month case fatality (OR 0.69; 95% CI 0.50-0.88), and 12-month disability (OR 0.83; 95% CI 0.70-0.95).

Study details: The data come from a prospective, hospital-based cohort study including 7587 patients with first-ever stroke and T2D, of which 3593 (47.36%) received MT (MT group) and 3994 (52.64%) did not receive MT (non-MT group).

Disclosures: This study was supported by the National Major Public Health Service Projects, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Natural Science Foundation of Tianjin, and China Postdoctoral Science Foundation, among others. The authors declared no conflicts of interest.

Source: Tu WJ et al. Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes. Ther Adv Chronic Dis. 2022 (Apr 19). Doi: 10.1177/20406223221076894

Key clinical point: Patients with first-ever stroke and type 2 diabetes mellitus (T2D) who receive metformin treatment (MT) show lower stroke severity, case fatality, and disability rates.

Major finding: MT vs non-MT group had a lower rate of in-hospital case fatality (odds ratio [OR] 0.63; 95% CI 0.47-0.84), 12-month case fatality (OR 0.69; 95% CI 0.50-0.88), and 12-month disability (OR 0.83; 95% CI 0.70-0.95).

Study details: The data come from a prospective, hospital-based cohort study including 7587 patients with first-ever stroke and T2D, of which 3593 (47.36%) received MT (MT group) and 3994 (52.64%) did not receive MT (non-MT group).

Disclosures: This study was supported by the National Major Public Health Service Projects, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Natural Science Foundation of Tianjin, and China Postdoctoral Science Foundation, among others. The authors declared no conflicts of interest.

Source: Tu WJ et al. Metformin use is associated with low risk of case fatality and disability rates in first-ever stroke patients with type 2 diabetes. Ther Adv Chronic Dis. 2022 (Apr 19). Doi: 10.1177/20406223221076894