Clinical Edge Journal Scan Commentary

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

The study by Huang and colleagues investigates the long-term effects and potential mechanisms of action of transcutaneous electrical acustimulation (TEA) in patients with IBS with constipation (IBS-C) experiencing colonic transit issues and visceral hypersensitivity. Patients with IBS-C receiving TEA had increased frequency of spontaneous bowel movements and significant improvements in analog pain score compared with the placebo group. This supports the benefit of TEA for improving constipation and the concomitant symptoms by accelerating colonic transit and reducing rectal sensation. It can be inferred that the improvement of these symptoms will lead to enhanced quality of life in patients with IBS-C.

The study by Melchior and colleagues¹ emphasizes the effect that IBS can have on a patient's life. Patients with IBS report reduced disease-specific quality of life. The cumulative impact of the demographic factors and the severity of psychological symptoms, somatic symptoms, and gastrointestinal symptoms are associated with decreased quality of life. The severity of this impact is determined by the combination of these factors and the level of severity at which they occur. This decrease in quality of life can lead to increased anxiety related to gastrointestinal function. It is important for providers to acknowledge the effect that gastrointestinal function has on the patient's life in a broader sense. The appreciation and understanding of the patient experience enhances the therapeutic relationship and shared decision-making between the patient and the healthcare provider.

Additional References

1. Melchior C, Colomier E, Trindade IA, et al. Irritable bowel syndrome: Factors of importance for disease-specific quality of life. United European Gastroenterol J. 2022 Jul 13. Doi: 10.1002/ueg2.12277  

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003). The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd. These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.

Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues, this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.

Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues, 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).

In summary, the phase 3 IMpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

Patients with hepatitis B virus (HBV) infection and HCC tend to live longer if both their HBV and HCC are treated. Liu and colleagues performed a meta-analysis of trials that addressed the question whether the same is true for patients with hepatitis C virus (HCV) infection and HCC treated with either interferon or direct-acting antivirals (DAA). They included 23, mostly retrospective, cohort studies in the final meta-analysis. Recurrence data were available in 18 studies, with 2013 patients receiving DAA therapy, 1091 patients receiving interferon therapy, and 1571 patients receiving no intervention. There was no significant difference in recurrence between the DAA group and the interferon group. The meta-analysis demonstrated that patients with HCV-related HCC treated with DAA had a lower risk for HCC recurrence (adjusted hazard ratio [HR] 0.55, 95% CI 0.41-0.74, P < .001; I² 66.6%, P < .001) and a better overall survival (OS) (adjusted HR 0.36, 95% CI 0.16–0.83, P = .017; I² 90.7%, P < .001) than patients with no intervention. The authors concluded that DAA therapy can prevent recurrence and improve OS of patients with HCV-related HCC, especially if a sustained virologic response is achieved.

Atezolizumab with bevacizumab is the current first-line standard of care for patients with unresectable HCC, offering an improved OS compared to sorafenib, as demonstrated in the phase 3 IMbrave150 study. Alternate combinations, such as atezolizumab and cabozantinib, are also being investigated in this setting. The COSMIC-312 phase 3 randomized controlled trial evaluated 837 patients with unresectable HCC who had not received previous systemic therapy. They were randomly assigned in a 2:1:1 ratio to receive cabozantinib plus atezolizumab (n = 432), sorafenib (n = 217), or single-agent cabozantinib (n = 188). Although the patients receiving atezolizumab + cabozantinib had a significantly longer median progression-free survival (6.8 vs 4.2 months; HR, 0.63; P = .001) than patients who received sorafenib, both groups had a similar median OS (15.4 vs 15.5 months; HR, 0.90; P = .44). The authors concluded that this combination requires more study in this patient population.

For patients with unresectable HCC who are unable to tolerate combination therapy in the first-line setting, single-agent therapy might be an option. Verset and colleagues reported the results of a phase 2 study evaluating pembrolizumab in this setting. Cohort 2 of the KEYNOTE-224 study evaluated 51 systemic therapy–naive patients with unresectable HCC who received pembrolizumab for up to 2 years. After 27 months of median follow-up, the median progression-free survival was 4 months (95% CI 2-8 months) and the OS was 17 months (95% CI 8-23 months). The objective response rate was 16% (95% CI 7%-29%). Grade ≥ 3 treatment-related adverse events were observed in 16% of patients. In this prospective study, pembrolizumab provided durable antitumor activity, a promising OS, and a safety profile consistent with previous observations.

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

The Direct KRAS^G12C Inhibitor Adagrasib in Advanced KRAS^G12C-Mutant NSCLC: Results From a Registrational Phase 2 Study

KRAS mutations are detected in about one quarter of all lung adenocarcinomas and are the most common oncogene driver in non–small-cell lung cancer (NSCLC). KRAS^G12C amino acid substitutions are the most common KRAS mutations in NSCLC, comprising just about half of all KRAS mutations in this tumor type. Despite being the most common and first detected oncogene driver in lung cancer, until recently there were no targeted therapies in KRAS mutant NSCLC. The development of direct KRAS^G12C inhibitors represents an important step forward in targeting KRAS mutations. These inhibitors bind inactive guanosine diphosphate (GDP)–bound RAS and trap it in its inactive state.

Dr Jänne and colleagues recently published a phase 2 registrational trial of the direct KRAS^G12C inhibitor adagrasib. In this study of 112 patients with measurable disease at baseline treated with adagrasib, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months (95% CI 6.2-13.8), and the median progression-free survival (PFS) was 6.5 months (95% CI 4.7-8.4). The median overall survival (OS) was 12.6 months (95% CI 9.2-19.2). Among 33 patients with previously treated, stable central nervous system (CNS) metastases, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0-51.8). Treatment-related adverse events occurred in 97.4% of the patients: grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 events). The most frequent toxicities were fatigue and gastrointestinal-related issues (nausea, vomiting, diarrhea, aspartate transaminase/alanine transaminase elevation). Adagrasib was discontinued in 6.9% of patients.

These results further demonstrate that the KRAS^G12C mutation is an actionable target in NSCLC. Sotorasib, another direct KRAS^G12C inhibitor, is currently US Food and Drug Administration approved after initial systemic treatment. The clinical activity of sotorasib and adagrasib are comparable; for sotorasib the rates are an overall response rate (ORR) of 37.1% (95% CI 28.6-46.2), median PFS of 6.8 months (95% CI 5.1-8.2), and median OS of 12.5 months (95% CI 10.0 to nonestimable). Adagrasib also has published evidence of CNS activity that tracks with its systemic activity. Overall, these direct KRAS^G12C inhibitors represent a major advance in the treatment of KRAS^G12C-mutant NSCLC.

EGFR-Mutated NSCLC: Aumolertinib vs Gefitinib Extends PFS

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved clinical outcomes in EGFR-mutant NSCLC.The current standard of care for first-line treatment of advanced NSCLC with the most frequent EGFR activating mutations (EGFR E19del and L858R)is the third-generation EGFR TKI osimertinib. In the FLAURA trial, patients randomly assigned tofirst-lineosimertinib had a substantial PFS benefit (median PFS 18.9 vs 10.2 months) and OS benefit (median OS 38.6 vs 31.8 months)when receivingosimertinib compared with gefitinib or erlotinib.

In the AENEAS trial, published in the Journal of Clinical Oncologyby Dr Lu and colleagues, 420 patients from China with advanced NSCLC harboring EGFR E19del or L858R activating mutations and naive to systemic treatment were enrolled. Patients were randomly assigned to the next-generation EGFR TKI aumolertinib or the first-generation EGFR TKI gefitinib with the primary endpoint of PFS by investigator assessment.Of note, patients with asymptomatic, untreated brain metastases were allowed into the trial. Upon disease progression, patients in the gefitinib group who acquired an EGFR T790M mutation were eligible to crossover to aumolertinib.

The study met its primary endpoint: Patients treated with aumolertinib compared with those treated with gefitinib had a significantly longer median PFS (19.3 vs 9.9 months; hazard ratio [HR] 0.46; P< .0001). This PFS advantage of aumolertinib over gefitinib was also present in the subgroup of patients with CNS metastases (15.3 vs 8.2 months; HR 0.38; P< .0001). The objective response rate was similar inthe aumolertinib and gefitinib groups (objective response rate 73.8% and 72.1%, respectively). The median duration of response was 18.1 months (95% CI 15.2 to not reached) with aumolertinib vs 8.3 months (95% CI 6.9-11.1) with gefitinib. Treatment-emergent adverse events of grade 3 or more were similar in the aumolertinib and gefitinib groups (36.4% vs 35.8%, respectively). There was less rash and diarrhea as well as transaminitis in the aumolertinib arm compared with the gefitinib arm. However, 35.5% of patients developed an elevation in creatinine phosphokinase (CPK), including 7% with grade 3 CPK elevation. However, no rhabdomyolysis was observed.

Overall, the AENEAS study showed comparable median PFS for first-line aumolertinib comparedwith what was observed with osimertinib in the FLAURA study. We still await the OSdata on aumolertinib compared with gefitinib. In the FLAURA study, investigators could choose between erlotinib or gefitinib in the control arm, whereas in AENEAS only gefitinib was allowed, which may have less CNS activity than erlotinib. Moreover, the FLAURA trial was conducted worldwide, whereas the AENEAS trial only enrolled patients in China. This study provides further support for the use of third-generation EGFR TKI over first-generation EGFR TKI as first-line treatment in advanced/metastatic NSCLC harboring EGFR E19del or L858R mutations.

Advanced ALK+ NSCLC With Brain Metastases: Lorlatinib Boosts PFS, Reduces CNS Progression

The CROWN trial was a pivotal randomized phase 3 trial that demonstrated an impressive improvement in PFS in patients treated with the third-generationALK inhibitor lorlatinib compared with the first-generation ALK inhibitor crizotinib as initial treatment for advanced ALK-postive (ALK+) NSCLC (HR for disease progression or death0.28; 95% CI0.19-0.41; P≤ .001). A major driver of this PFS benefit in ALK+ NSCLC in the CROWN study is the superior CNS penetration of lorlatinib compared with crizotinib. Obtaining CNS control in ALK+ lung cancers is important because up to 40% of patients with ALK+ NSCLC have brain metastases at initial evaluation, and CNS progression is often observed in patients with ALK+ lung cancer whether it be intracranial metastases or leptomeningeal carcinomatosis. A potential challenge in treating patients with lorlatinib is a unique side effect profile including neurocognitive side effects from lorlatinib. In a recently published study in the Journal of Clinical Oncology, Dr Solomon and colleagues conducted a post hoc exploratory analysis of intracranial efficacy and safety of lorlatinib in ALK+ NSCLC from a phase 3 trial. PFS by blinded independent central review was improved with lorlatinib vs crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% vs 22% and 78% vs 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression compared with crizotinib in patients with (7.4% vs 72%) and without (1% vs 18%) brain metastases at baseline. Complete CNS responses with lorlatinib were seen in 23/38(61%) patients with any brain metastases at baseline compared with 6/40 (15%) with crizotinib. In total, 35% of patients had CNS adverse events with lorlatinib: grade 1 (21%), grade 2 (10%), and grade 3 (3%)in severity. These included cognitive (21%), mood (16%), speech (5%), and psychotic effects (3%), some of which overlapped. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification. Dose reductions of lorlatinib did not appear to affect PFS on the basis of a landmark analysis. Overall, this study demonstrates the exceptional CNS activity of lorlatinib in ALK+ NSCLC and that the neurocognitive side effects can often be managed. There are several next-generation ALK inhibitors now approved in the first-line setting —alectinib, lorlatinib, and brigatinib — notably all with enhanced CNS penetration and improved PFS compared with crizotinib. This posthoc study further supports the impressive CNS activity of lorlatinib in ALK+ NSCLC and supports the use of lorlatinib as a first-line treatment option in these patients, particularly those with ALK+ NSCLC diagnosed with baseline CNS disease.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

In keeping with other studies suggesting that lower-than-standard doses of rituximab (for example, two 500 mg doses every 6 months) are effective in the treatment of rheumatoid arthritis (RA), Bertsias and colleagues evaluated the efficacy of low-dose rituximab (1 g every 6 months) in a cohort of patients with RA. Of 361 patients in the initial registry, 81 achieved sustained low disease activity or remission on standard rituximab regimens and were transitioned to the low-dose regimen; their outcomes were compared with the 280 patients in the registry who received a standard-dose regimen. Only 7.5% experienced flares of RA (compared with 5.9% in the standard-dose group), and patients in the low-dose group had fewer serious adverse events, infections, and hospitalizations. Tapering biologic disease-modifying antirheumatic drugs (DMARD) may thus be a reasonable strategy for some patients with RA, with an eye to their prior results with the medication.

The prospect of achieving sustained DMARD-free remission (SDFR) in people with RA has seemed increasingly feasible in recent studies, although it seems to be affected by anti-citrullinated protein/peptide antibody (ACPA) positivity. That is, people who are ACPA-negative are more likely to reach this target. Verstappen and colleagues examined MRI patterns of joint inflammation in the Leiden Early Arthritis Clinic cohort, as well as another cohort of patients with RA, but only included patients with an RA duration > 1 year to reduce the likelihood of misclassification. Interestingly, ACPA-positive patients who achieved SDFR tended to have lower baseline evidence of joint inflammation (including erosions, synovitis, and osteitis), which was persistent throughout follow-up, whereas ACPA-negative patients who achieved SDFR had similar joint inflammation at baseline to those who did not, but had a better initial response to DMARD therapy. Further study of the potential impact of treatment based on ACPA status would be helpful.

Recent results from the ORAL Surveillance postmarketing safety analysis suggest that tofacitinib is associated with an increased risk for cancer in patients with RA patients who are aged >50 years, compared with anti–tumor necrosis factor (TNF) agents. Khosrow-Khavar and colleagues used insurance claims data to further investigate the risk for cancer with tofacitinib vs anti-TNF agents. They created two cohorts of patients who were new users of anti-TNF agents or tofacitinib: One was a "real-world" cohort including all patients with RA, whereas the other applied the inclusion and exclusion criteria from the ORAL Surveillance trial, including age >50 years, one cardiovascular risk factor, and use of methotrexate. Results from the real-world cohort, including over 10,000 patients who had used tofacitinib, did not show any increase in cancer risk, whereas the trial-simulating conditions did yield higher numbers of cancers in the group exposed to tofacitinib. Though reassuring, these results are limited by the short follow-up duration, and longer-term follow-up studies are necessary for further evaluation.

In another interesting note with respect to medication morbidity and risk, Xu and colleagues performed a meta-analysis looking at the association of methotrexate use and mortality in patients with RA. Only 15 studies were included in the final analysis, though they did encompass a large total number of patients. Overall, methotrexate use in these studies was associated with lower rates of overall mortality as well as mortality due to cardiovascular and interstitial lung disease. However, conclusions as to the direct impact of methotrexate were limited by the heterogeneity of study designs, doses of methotrexate, and additional therapy as well as comparators.

Patients with advanced gastroesophageal adenocarcinoma (GEA) have a poor prognosis. Despite recent improvements in treatments, overall survival (OS) for most of these patients remains < 18 months. Immune checkpoint inhibitors in combination with chemotherapy are now approved for treatment of advanced GEA in the first-line setting (pembrolizumab for esophageal cancers and nivolumab for GEA). These approvals are based on the results of the randomized phase 3 studies KEYNOTE-590 and CheckMate 649.^1,2 However, there remains a need to better define patients who are more likely to benefit from these agents.

KEYNOTE-062 was a phase 3 study of pembrolizumab in patients with advanced gastric and gastroesophageal junctionadenocarcinoma.³ Patients were randomly assignedto receive chemotherapy, chemotherapy plus pembrolizumab, or pembrolizumab alone. This study did not lead to pembrolizumab approval for gastric cancer or GEA, although, consistently with other studies, it suggested that patients whose tumors had higher programmed death-ligand 1 expression were more likely to benefit from immunotherapy treatments.

Lee and colleagues published results of a prespecified exploratory analysis from this study that evaluated the association between tumor mutational burden (TMB) and patient outcomes. Those who had tumors with higher TMB had better outcomes from immunotherapy treatments, but not chemotherapy alone. In patients with TMB ≥10 mut/Mb, pembrolizumab vs chemotherapy significantly improved the objective response rate (ORR; 55.6% vs 41.2%), progression-free survival (PFS; 11.1 vs. 7.0 months; hazard ratio [HR] 0.52) and OS (31.6 vs 13.4 months; HR 0.34). Similarly, pembrolizumab plus chemotherapy vs chemotherapy alone improved ORR (73.3% vs 41.2%), PFS (31.1 vs 7.0 months; HR 0.62), and OS (31.1 vs 13.4 months; HR 0.54). However, after patients with microsatellite instability–high (MSI-H) tumors, who represented 44% of patients (22 of 50), with TMB ≥10 mut/Mb were removed from the analysis, the positive association between TMB and immunotherapy effect on OS and PFS was no longer significant. The small number of patients with high TMB limits the interpretation of these exploratory data. However, the results suggest that TMB is unlikely to emerge as a significant clinically relevant biomarker in patients with microsatellite-stable upper gastrointestinal cancers.

Ultimately, novel therapeutic strategies are needed to improve outcomes. The phase 3 BRIGHTER study reported by Shah and colleagues evaluated the activity of napabucasin, a generator of reactive oxygen species, in advanced GEA. This was a phase 3 study that enrolled 714 patients whose tumors progressed on one prior line of therapy. Patients were randomly assigned in a 1:1 fashion to receive eitherpaclitaxel plus napabucasin or paclitaxel plus placebo. The primary endpoint was OS. Patient characteristics were well balanced between the treatment arms. At the preplanned interim analysis, there was no difference in OS between the two treatment arms (6.97 months with napabucasin vs 7.29 months with placebo; P =.5699).As such, the study was terminated before enrollment completion because it was deemed futile to continue. There were no new safety signals. It is important to note that since the study was launched, ramucirumab and paclitaxel became the new standard treatment in the second-line setting per the phase 3 RAINBOW study.⁴ As such, this combination regimen should be offered to patients who are candidates for systemic treatment in the second-line setting and who have no contraindications to these agents.

To further expand on the use of ramucirumab in GEA, the phase 2 HGCSG1603 study evaluated ramucimumab in combination with irinotecan in the second-line setting. This single-arm phase 2 study conducted in Japan enrolled 35 patients with GEA who progressed on a first-line regimen. The primary endpoint was PFS rate at 6 months. This study demonstrated a 26.5% PFS rate at 6 months. Median PFS was 4.2 months, and OS was 9.6 months. Although the study did not meet its pre-specified primary endpoint of a 39% PFS rate at 6 months, the secondary endpoints of OS and PFS were similar to historical references from the RAINBOW study. These results suggest that irinotecan and ramucirumab is an active combination in GEA and could be offered to patients who are not candidates for paclitaxel, for example those with significant neuropathy. The benefits of an irinotecan chemotherapy backbone in second-line therapy has been previously demonstrated in the phase 2 RAMIRIS study, which found clinically meaningful activity of a leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) and ramucirumab combination, as well as a decreased benefit from paclitaxel in patients with prior taxane exposure.⁵ In summary, ramucirumab in combination with irinotecan-containing chemotherapy (either as a single agent or as part of FOLFIRI) is areasonable second-line treatment option for patients with advanced GEA, and this is already included in National Comprehensive Cancer Network guidelines.

Additional References

              1.           Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40. Doi: 10.1016/S0140-6736(21)00797-2

              2.           Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771. Doi: 10.1016/S0140-6736(21)01234-4

              3.           Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1571-1580. Doi: 10.1001/jamaoncol.2020.3370

              4.           Wilke H, Van Cutsem E, Cheul Oh S, et al. RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors. J Clin Oncol. 2014;32(15 Suppl):4076. Doi: 10.1200/jco.2014.32.15_suppl.4076

5.           Klempner SJ, Maron SB, Chase L, et al. Initial report of second-line FOLFIRi in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi-institutional retrospective analysis. Oncologist. 2019:24:475-482. Doi: 10.1634/theoncologist.2018-0602

Patients with advanced gastroesophageal adenocarcinoma (GEA) have a poor prognosis. Despite recent improvements in treatments, overall survival (OS) for most of these patients remains < 18 months. Immune checkpoint inhibitors in combination with chemotherapy are now approved for treatment of advanced GEA in the first-line setting (pembrolizumab for esophageal cancers and nivolumab for GEA). These approvals are based on the results of the randomized phase 3 studies KEYNOTE-590 and CheckMate 649.^1,2 However, there remains a need to better define patients who are more likely to benefit from these agents.

KEYNOTE-062 was a phase 3 study of pembrolizumab in patients with advanced gastric and gastroesophageal junctionadenocarcinoma.³ Patients were randomly assignedto receive chemotherapy, chemotherapy plus pembrolizumab, or pembrolizumab alone. This study did not lead to pembrolizumab approval for gastric cancer or GEA, although, consistently with other studies, it suggested that patients whose tumors had higher programmed death-ligand 1 expression were more likely to benefit from immunotherapy treatments.

Lee and colleagues published results of a prespecified exploratory analysis from this study that evaluated the association between tumor mutational burden (TMB) and patient outcomes. Those who had tumors with higher TMB had better outcomes from immunotherapy treatments, but not chemotherapy alone. In patients with TMB ≥10 mut/Mb, pembrolizumab vs chemotherapy significantly improved the objective response rate (ORR; 55.6% vs 41.2%), progression-free survival (PFS; 11.1 vs. 7.0 months; hazard ratio [HR] 0.52) and OS (31.6 vs 13.4 months; HR 0.34). Similarly, pembrolizumab plus chemotherapy vs chemotherapy alone improved ORR (73.3% vs 41.2%), PFS (31.1 vs 7.0 months; HR 0.62), and OS (31.1 vs 13.4 months; HR 0.54). However, after patients with microsatellite instability–high (MSI-H) tumors, who represented 44% of patients (22 of 50), with TMB ≥10 mut/Mb were removed from the analysis, the positive association between TMB and immunotherapy effect on OS and PFS was no longer significant. The small number of patients with high TMB limits the interpretation of these exploratory data. However, the results suggest that TMB is unlikely to emerge as a significant clinically relevant biomarker in patients with microsatellite-stable upper gastrointestinal cancers.

Ultimately, novel therapeutic strategies are needed to improve outcomes. The phase 3 BRIGHTER study reported by Shah and colleagues evaluated the activity of napabucasin, a generator of reactive oxygen species, in advanced GEA. This was a phase 3 study that enrolled 714 patients whose tumors progressed on one prior line of therapy. Patients were randomly assigned in a 1:1 fashion to receive eitherpaclitaxel plus napabucasin or paclitaxel plus placebo. The primary endpoint was OS. Patient characteristics were well balanced between the treatment arms. At the preplanned interim analysis, there was no difference in OS between the two treatment arms (6.97 months with napabucasin vs 7.29 months with placebo; P =.5699).As such, the study was terminated before enrollment completion because it was deemed futile to continue. There were no new safety signals. It is important to note that since the study was launched, ramucirumab and paclitaxel became the new standard treatment in the second-line setting per the phase 3 RAINBOW study.⁴ As such, this combination regimen should be offered to patients who are candidates for systemic treatment in the second-line setting and who have no contraindications to these agents.

To further expand on the use of ramucirumab in GEA, the phase 2 HGCSG1603 study evaluated ramucimumab in combination with irinotecan in the second-line setting. This single-arm phase 2 study conducted in Japan enrolled 35 patients with GEA who progressed on a first-line regimen. The primary endpoint was PFS rate at 6 months. This study demonstrated a 26.5% PFS rate at 6 months. Median PFS was 4.2 months, and OS was 9.6 months. Although the study did not meet its pre-specified primary endpoint of a 39% PFS rate at 6 months, the secondary endpoints of OS and PFS were similar to historical references from the RAINBOW study. These results suggest that irinotecan and ramucirumab is an active combination in GEA and could be offered to patients who are not candidates for paclitaxel, for example those with significant neuropathy. The benefits of an irinotecan chemotherapy backbone in second-line therapy has been previously demonstrated in the phase 2 RAMIRIS study, which found clinically meaningful activity of a leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) and ramucirumab combination, as well as a decreased benefit from paclitaxel in patients with prior taxane exposure.⁵ In summary, ramucirumab in combination with irinotecan-containing chemotherapy (either as a single agent or as part of FOLFIRI) is areasonable second-line treatment option for patients with advanced GEA, and this is already included in National Comprehensive Cancer Network guidelines.

Additional References

              1.           Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40. Doi: 10.1016/S0140-6736(21)00797-2

              2.           Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771. Doi: 10.1016/S0140-6736(21)01234-4

              3.           Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1571-1580. Doi: 10.1001/jamaoncol.2020.3370

              4.           Wilke H, Van Cutsem E, Cheul Oh S, et al. RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors. J Clin Oncol. 2014;32(15 Suppl):4076. Doi: 10.1200/jco.2014.32.15_suppl.4076

5.           Klempner SJ, Maron SB, Chase L, et al. Initial report of second-line FOLFIRi in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi-institutional retrospective analysis. Oncologist. 2019:24:475-482. Doi: 10.1634/theoncologist.2018-0602

Patients with advanced gastroesophageal adenocarcinoma (GEA) have a poor prognosis. Despite recent improvements in treatments, overall survival (OS) for most of these patients remains < 18 months. Immune checkpoint inhibitors in combination with chemotherapy are now approved for treatment of advanced GEA in the first-line setting (pembrolizumab for esophageal cancers and nivolumab for GEA). These approvals are based on the results of the randomized phase 3 studies KEYNOTE-590 and CheckMate 649.^1,2 However, there remains a need to better define patients who are more likely to benefit from these agents.

KEYNOTE-062 was a phase 3 study of pembrolizumab in patients with advanced gastric and gastroesophageal junctionadenocarcinoma.³ Patients were randomly assignedto receive chemotherapy, chemotherapy plus pembrolizumab, or pembrolizumab alone. This study did not lead to pembrolizumab approval for gastric cancer or GEA, although, consistently with other studies, it suggested that patients whose tumors had higher programmed death-ligand 1 expression were more likely to benefit from immunotherapy treatments.

Lee and colleagues published results of a prespecified exploratory analysis from this study that evaluated the association between tumor mutational burden (TMB) and patient outcomes. Those who had tumors with higher TMB had better outcomes from immunotherapy treatments, but not chemotherapy alone. In patients with TMB ≥10 mut/Mb, pembrolizumab vs chemotherapy significantly improved the objective response rate (ORR; 55.6% vs 41.2%), progression-free survival (PFS; 11.1 vs. 7.0 months; hazard ratio [HR] 0.52) and OS (31.6 vs 13.4 months; HR 0.34). Similarly, pembrolizumab plus chemotherapy vs chemotherapy alone improved ORR (73.3% vs 41.2%), PFS (31.1 vs 7.0 months; HR 0.62), and OS (31.1 vs 13.4 months; HR 0.54). However, after patients with microsatellite instability–high (MSI-H) tumors, who represented 44% of patients (22 of 50), with TMB ≥10 mut/Mb were removed from the analysis, the positive association between TMB and immunotherapy effect on OS and PFS was no longer significant. The small number of patients with high TMB limits the interpretation of these exploratory data. However, the results suggest that TMB is unlikely to emerge as a significant clinically relevant biomarker in patients with microsatellite-stable upper gastrointestinal cancers.

Ultimately, novel therapeutic strategies are needed to improve outcomes. The phase 3 BRIGHTER study reported by Shah and colleagues evaluated the activity of napabucasin, a generator of reactive oxygen species, in advanced GEA. This was a phase 3 study that enrolled 714 patients whose tumors progressed on one prior line of therapy. Patients were randomly assigned in a 1:1 fashion to receive eitherpaclitaxel plus napabucasin or paclitaxel plus placebo. The primary endpoint was OS. Patient characteristics were well balanced between the treatment arms. At the preplanned interim analysis, there was no difference in OS between the two treatment arms (6.97 months with napabucasin vs 7.29 months with placebo; P =.5699).As such, the study was terminated before enrollment completion because it was deemed futile to continue. There were no new safety signals. It is important to note that since the study was launched, ramucirumab and paclitaxel became the new standard treatment in the second-line setting per the phase 3 RAINBOW study.⁴ As such, this combination regimen should be offered to patients who are candidates for systemic treatment in the second-line setting and who have no contraindications to these agents.

To further expand on the use of ramucirumab in GEA, the phase 2 HGCSG1603 study evaluated ramucimumab in combination with irinotecan in the second-line setting. This single-arm phase 2 study conducted in Japan enrolled 35 patients with GEA who progressed on a first-line regimen. The primary endpoint was PFS rate at 6 months. This study demonstrated a 26.5% PFS rate at 6 months. Median PFS was 4.2 months, and OS was 9.6 months. Although the study did not meet its pre-specified primary endpoint of a 39% PFS rate at 6 months, the secondary endpoints of OS and PFS were similar to historical references from the RAINBOW study. These results suggest that irinotecan and ramucirumab is an active combination in GEA and could be offered to patients who are not candidates for paclitaxel, for example those with significant neuropathy. The benefits of an irinotecan chemotherapy backbone in second-line therapy has been previously demonstrated in the phase 2 RAMIRIS study, which found clinically meaningful activity of a leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan (FOLFIRI) and ramucirumab combination, as well as a decreased benefit from paclitaxel in patients with prior taxane exposure.⁵ In summary, ramucirumab in combination with irinotecan-containing chemotherapy (either as a single agent or as part of FOLFIRI) is areasonable second-line treatment option for patients with advanced GEA, and this is already included in National Comprehensive Cancer Network guidelines.

Additional References

              1.           Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40. Doi: 10.1016/S0140-6736(21)00797-2

              2.           Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771. Doi: 10.1016/S0140-6736(21)01234-4

              3.           Shitara K, Van Cutsem E, Bang YJ, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1571-1580. Doi: 10.1001/jamaoncol.2020.3370

              4.           Wilke H, Van Cutsem E, Cheul Oh S, et al. RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors. J Clin Oncol. 2014;32(15 Suppl):4076. Doi: 10.1200/jco.2014.32.15_suppl.4076

5.           Klempner SJ, Maron SB, Chase L, et al. Initial report of second-line FOLFIRi in combination with ramucirumab in advanced gastroesophageal adenocarcinomas: A multi-institutional retrospective analysis. Oncologist. 2019:24:475-482. Doi: 10.1634/theoncologist.2018-0602

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by JAK inhibitors is efficacious in psoriatic arthritis (PsA). On the basis of the results of the pivotal SELECT-PsA 1 and SELECT-PsA 2 trials, upadacitinib, a selective JAK1 inhibitor, was recently approved for the treatment of PsA. However, data on longer-term disease control is still of interest. In a post hoc analysis of SELECT-PsA 1 and SELECT-PsA 2, Mease and colleagues assessed the proportion of patients achieving low disease activity or remission, as defined by validated measures such as the Disease Activity Index in Psoriatic Arthritis, Psoriatic Arthritis Disease Activity Scores, and minimal disease activity at 24 and 56 weeks. They showed that at week 24,a higher proportion of patients receiving 15 mg upadacitinib vs placebo achieved low disease activityon the Disease Activity Index in Psoriatic Arthritis (range, 35%-48% vs 4%-16%; P< .05) and remission (range, 7%-11% vs 0%-3%; P< .05), with the responses sustained until week 56. Thus, upadacitinib provides sustained disease control in PsA and is an effective oral therapy.

Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n=95;PsA,n=69, and axial spondyloarthritis, n=95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.

Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at¹⁸F-fluorodeoxyglucose(FDG) PET-CT uptakeina cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by JAK inhibitors is efficacious in psoriatic arthritis (PsA). On the basis of the results of the pivotal SELECT-PsA 1 and SELECT-PsA 2 trials, upadacitinib, a selective JAK1 inhibitor, was recently approved for the treatment of PsA. However, data on longer-term disease control is still of interest. In a post hoc analysis of SELECT-PsA 1 and SELECT-PsA 2, Mease and colleagues assessed the proportion of patients achieving low disease activity or remission, as defined by validated measures such as the Disease Activity Index in Psoriatic Arthritis, Psoriatic Arthritis Disease Activity Scores, and minimal disease activity at 24 and 56 weeks. They showed that at week 24,a higher proportion of patients receiving 15 mg upadacitinib vs placebo achieved low disease activityon the Disease Activity Index in Psoriatic Arthritis (range, 35%-48% vs 4%-16%; P< .05) and remission (range, 7%-11% vs 0%-3%; P< .05), with the responses sustained until week 56. Thus, upadacitinib provides sustained disease control in PsA and is an effective oral therapy.

Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n=95;PsA,n=69, and axial spondyloarthritis, n=95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.

Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at¹⁸F-fluorodeoxyglucose(FDG) PET-CT uptakeina cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.

Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by JAK inhibitors is efficacious in psoriatic arthritis (PsA). On the basis of the results of the pivotal SELECT-PsA 1 and SELECT-PsA 2 trials, upadacitinib, a selective JAK1 inhibitor, was recently approved for the treatment of PsA. However, data on longer-term disease control is still of interest. In a post hoc analysis of SELECT-PsA 1 and SELECT-PsA 2, Mease and colleagues assessed the proportion of patients achieving low disease activity or remission, as defined by validated measures such as the Disease Activity Index in Psoriatic Arthritis, Psoriatic Arthritis Disease Activity Scores, and minimal disease activity at 24 and 56 weeks. They showed that at week 24,a higher proportion of patients receiving 15 mg upadacitinib vs placebo achieved low disease activityon the Disease Activity Index in Psoriatic Arthritis (range, 35%-48% vs 4%-16%; P< .05) and remission (range, 7%-11% vs 0%-3%; P< .05), with the responses sustained until week 56. Thus, upadacitinib provides sustained disease control in PsA and is an effective oral therapy.

Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n=95;PsA,n=69, and axial spondyloarthritis, n=95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.

Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at¹⁸F-fluorodeoxyglucose(FDG) PET-CT uptakeina cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.

The TRIPLETE study from Italy is a simply designed phase 3 clinical trial in which 435 patients with newly diagnosed RAS and BRAF wild-type metastatic colorectal cancer were randomized in a 1:1 fashionto receive either modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) plus panitumumab or fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) plus panitumumab. In both arms, over 90% of patients were aged ≤70 years old, and 12% had right-sided disease. These factors are critical because older patients are less likely to benefit from multidrug chemotherapy, and patients with right-sided disease would not be expected to respond to epidermal growth factor receptor inhibitors, irrespective of RAS status. The study's primary endpoint was objective response rate (ORR) according to the revised Response Evaluation Criteria in Solid Tumours guidelines (RECIST 1.1). Secondary endpoints included safety and progression-free survival (PFS). ORR was 73% in the experimental arm and 76% in the control arm (odds ratio [OR] 0.87; P = .526). There were no differences in PFS, early tumor shrinkage rate, R0 resection rate, or depth of response either.

Though I would have liked to have seen a leucovorin calcium (folinic acid), fluorouracil,and irinotecan hydrochloride (FOLFIRI) arm as well, I believe that these results are enough to cast significant doubt on the burgeoning belief that in metastatic colorectal cancer, more chemotherapy is better for those who can tolerate it.

AtezoTRIBE, also out of Italy, is a randomized, phase 2 study that randomly selected patients with newly diagnosed metastatic colorectal cancer to receive FOLFOXIRI and bevacizumab with or without atezolizumab. I am less sanguine about this study design, vis-à-vis the TRIPLETE study, as patients in AtezoTRIBE were randomized in a 2:1 fashion, with two thirds therefore receiving treatment on the experimental arm. The 2:1 randomization was rationalized on the basis of the supposition that patients are more likely to enroll on a study if they know they have a greater chance of receiving a novel treatment. However, I have never seen a study supporting that hypothesis with data, and a 2:1 randomization significantly reduces statistical power. Patients were stratified on the basis of tumor mutational burden (TMB) and Immunoscore IC (high or low as determined by CD8 cell density, programmed death ligand 1 cell density, as well as proximity and clustering of the two cell groups). There were similar rates of high TMB (7% control and 8% experimental) and high Immunoscore IC (25% control and 22% experimental) in both arms. The primary endpoint was PFS. At a median follow-up of 19.9 months, the experimental arm had astatistically improved median PFS (13.1 vs 11.5 months; adjusted hazard ratio 0.70; P = .018). Serious adverse events were reported in 27% vs 26% of patients, respectively. Of note, the subgroup analysis shows that PFS improvement was accrued in the experimental arm by patients with either high TMB, high Immunoscore IC, or both. Further studies will be needed in patients prospectively selected for high Immunoscore IC to see whether these observations hold. If so, Immunoscore IC could eventually replace TMB as a marker of potential immune therapy responsiveness in microsatellite-stable metastatic colorectal cancer.