Most Read Articles
Natalia Reoutova, 20 May 2020

Cancer patients infected with coronavirus disease 2019 (COVID-19) appear to be at higher risk of severe outcomes, including death, but cancer type and treatment serve as better predictors, according to recent research presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I.

At the time of writing, COVID-19 has spread to more than 200 countries and territories, affecting an estimated 4.5 million people and killing over 300,000. Cancer, on the other hand, is newly diagnosed in 18 million people and takes the lives of 10 million every year.

“We have invited physician scientists who are at the epicentre of the COVID-19 pandemic, taking care of patients with cancer. They gathered prospective information to understand the effects of COVID-19 on patients with cancer, are testing new treatments, and are making this knowledge available to the global research community, so we can all benefit from their experience,” said Professor Antoni Ribas from UCLA Medical Center, Los Angeles, California, US, chairperson of the COVID-19 and cancer plenary session of the meeting.

Natalia Reoutova, 3 days ago

Fasting-mimicking diet (FMD) cycles in combination with endocrine therapy (ET) cause metabolic changes in hormone receptor (HR)-positive breast cancer patients analogous to those observed in animal models, where they are associated with anticancer activity.

Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.
Natalia Reoutova, 2 days ago

Results of the world’s first-in-human phase I clinical trial of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 PD-1–edited T cells, recently published in Nature Medicine, suggest therapy’s feasibility in refractory non-small-cell lung cancer (NSCLC), with no severe treatment-related adverse events (TRAEs).

Updates on proteasome inhibitors in relapsed/refractory multiple myeloma

Dr. Jason Butler
Icon Cancer Care & Royal Brisbane and Women’s Hospital
Australia
01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.

The proteasome complex influences many cellular functions by disposing of short-lived and regulatory proteins, and dysregulation of this activity is implicated in many diseases. [Med Res Rev 2001;21:245-273] Proteasome inhibitors have undergone clinical development for various malignancies, and have become a cornerstone of current therapy for MM. [Cancer Metastasis Rev 2017;36:561-584] Several members of the class are now used routinely in clinical practice; notable examples are bortezomib, a first-generation agent, and the second-generation agents carfilzomib and ixazomib. Within the class, differences between individual agents include the chemical backbone, proteasomal binding sites, reversibility, and efficacy and safety profiles. [Nat Rev Clin Oncol 2017;14:417-433]

Evolution of proteasome inhibitors in R/R MM

The utility of bortezomib in R/R MM was established in the APEX study, which compared the efficacy and safety of bortezomib with high-dose dexamethasone. Bortezomib-treated patients had higher response rates (combined complete response [CR] and partial response [PR], 38 percent vs 18 percent; p<0.001), longer time to disease progression (median, 6.2 months vs 3.5 months; hazard ratio [HR], 0.55; p<0.001), and higher 1-year survival rate (80 percent vs 66 percent; p=0.003) compared with dexamethasone-treated patients. [N Engl J Med 2005;352:2487-2498] Based on the favourable efficacy and safety profile seen in APEX, bortezomib-dexamethasone combination therapy became standard of care in R/R MM. [Cancer Metastasis Rev 2017;36:561-584]

APEX was followed by trials of bortezomib in triple-agent combinations for R/R MM. These included the CASTOR study, in which daratumumab-bortezomib-dexamethasone resulted in significantly longer progression-free survival (PFS) than bortezomib-dexamethasone alone (median PFS, not reached vs 7.2 months at 7.4-month follow-up; HR, 0.39; 95 percent confidence interval [CI], 0.28 to 0.53; p<0.001), and the OPTIMISMM study in which the addition of pomalidomide to bortezomib-dexamethasone significantly improved PFS and response rates compared with bortezomib-dexamethasone (median PFS, 11.2 months vs 7.1 months; HR, 0.61; 95 percent CI, 0.49 to 0.77; p<0.0001). [N Engl J Med 2016;375:754-766; Lancet Oncol 2019;20:781-794]

However, not all studies of triple-agent combinations showed improvements compared with dual-agent regimens. For example, in PANORAMA-1, a study comparing panobinostat-bortezomib-dexamethasone with placebo-bortezomib-dexamethasone, the overall survival (OS) benefit from the addition of panobinostat was modest (median OS, 40.3 months vs 35.8 months; HR, 0.94; 95 percent CI, 0.78 to 1.14; p=0.54), and this combination has not been adopted in routine clinical practice. [Lancet Haematol 2016;3:e506-e515]

Clinical evidence for carfilzomib

ENDEAVOR study

The safety and efficacy of carfilzomib, a second-generation proteasome inhibitor, in R/R MM was established in the phase III ENDEAVOR study, in which patients were randomized to receive carfilzomib-dexamethasone or bortezomib-dexamethasone treatment. The study’s results showed an improvement in PFS in the carfilzomib arm compared with the bortezomib arm, with the risk of disease progression or death halved with carfilzomib-dexamethasone vs bortezomib-dexamethasone (median PFS, 18.7 months vs 9.4 months; HR, 0.53; 95 percent CI, 0.44 to 0.65; p<0.0001). This PFS benefit was observed in most prespecified patient subgroups, including age category and previous treatments, and longer PFS with carfilzomib treatment was observed irrespective of prior bortezomib use. [Lancet Oncol 2016;17:27-38; Leukemia 2017;31:115-122]

In the ENDEAVOR study, twice as many patients treated with carfilzomib-dexamethasone vs bortezomib-dexamethasone achieved CR or better (58 [13 percent] vs 29 [6 percent]; p<0.0010) or very good partial response (VGPR) or better (252 [54 percent] vs 133 [29 percent]; p<0.0001). Adverse events (AEs) observed in the carfilzomib group included dyspnoea, cough and hypertension. [Lancet Oncol 2016;17:27-38]

The cardiovascular safety of carfilzomib was evaluated in an ENDEAVOR substudy, which evaluated echocardiographic data on left ventricular ejection fraction (LVEF), right ventricular function and pulmonary arterial systolic pressure at 12-week intervals and at the end of treatment. In both treatment groups, a slight decline in LVEF was seen during the study, with parameters returning to baseline values upon treatment cessation. [Blood Adv 2018;2:1633-1644] An analysis of real-world data found that the risk of cardiac-related hospitalizations during treatment was similar between patients receiving carfilzomib and non-carfilzomib regimens when adjusted for treatment duration and baseline conditions. (Figure 1) [J Clin Oncol 2018;36 (suppl):abstract 8043]

HK-AMG-119mo1

ASPIRE study

In the phase III ASPIRE study, patients with R/R MM were randomized to receive carfilzomib-lenalidomide-dexamethasone or lenalidomide-dexamethasone treatment (control group). A significant increase in median PFS was seen in the carfilzomib group compared with the control group (26.3 months vs 17.6 months; HR, 0.69; 95 percent CI, 0.57 to 0.83), and significantly more patients in the carfilzomib group achieved CR or better (31.8 percent vs 9.3 percent; p<0.001), with deeper responses being associated with better survival outcomes. [N Engl J Med 2015;372:142-152]

Furthermore, greater PFS improvements with carfilzomib vs controls were seen in patients with one prior line of therapy compared with patients with two or more prior therapies, suggesting greater survival benefit when carfilzomib therapy is given earlier in the course of disease. (Figure 2) [Blood Cancer J 2017;7:e554] The PFS benefit with carfilzomib was seen in every prespecified subgroup, and carfilzomib-treated patients had improved health-related quality of life during 18 cycles of treatment compared with controls (p<0.001). [N Engl J Med 2015;372:142-152]

HK-AMG-119mo2

A.R.R.O.W. study

Twice-weekly intravenous administration of carfilzomib can be burdensome for some patients; therefore, the randomized phase III A.R.R.O.W. study compared once-weekly vs twice-weekly carfilzomib-dexamethasone in patients with R/R MM, with carfilzomib given at 70 mg/m2 and 27 mg/m2 in the once-weekly and twice-weekly arms, respectively, following administration of 20 mg/m2 once or twice weekly in cycle 1 in the respective groups. [Lancet Oncol 2018;19:953-964]

Results of A.R.R.O.W. showed longer median PFS in the once-weekly group compared with the twice-weekly group (11.2 months vs 7.6 months; HR, 0.69; 95 percent CI, 0.54 to 0.83; p=0.0029). (Figure 3) Overall response rate was 22 percent higher in the once-weekly group. While the study was not powered to detect an OS advantage, at 12 months, OS rate was 76.6 percent in the once-weekly group and 71.9 percent in twice-weekly group. The median carfilzomib exposure was longer in the once-weekly group (38.0 weeks; interquartile range [IQR], 14.1–54.1) than in the twice-weekly group (29.1 weeks, IQR, 13.3–46.3), suggesting that the convenience of a once-weekly regimen allows patients to stay on therapy longer. [Lancet Oncol 2018;19:953-964]

HK-AMG-119mo3

Asian patients in ENDEAVOR and A.R.R.O.W.

As the incidence of MM is rising in Asia, a subgroup analysis of the efficacy and safety of carfilzomib in Asian patients (defined by geography) from the ENDEAVOR and A.R.R.O.W. studies was performed. [JAMA Oncol 2018;4:1221-1227; Int J Hematol 2019;110:466-473]

In ENDEAVOR, median OS among Asian patients was 47.6 months vs 38.8 months for carfilzomib-dexamethasone vs bortezomib-dexamethasone (HR, 0.856). Median PFS among Asian patients in A.R.R.O.W. was longer with once-weekly vs twice-weekly carfilzomib-dexamethasone (16.0 months vs 8.4 months; HR, 0.628). The analysis thus concluded that carfilzomib has a favourable risk-benefit profile in Asian patients, consistent with the observations of the parent studies. [Int J Hematol 2019;110:466-473]

Further reassuring data on carfilzomib use in Asian patients with R/R MM were reported in a phase I study conducted in Japan (carfilzomib-dexamethasone, once-weekly), and a phase III study conducted in China (carfilzomib-dexamethasone, twice weekly), which concluded that the carfilzomib regimens evaluated had favourable efficacy and safety profiles in their respective populations. [Cancer Sci 2018;109:3245-3252; Du J, et al, 17th International Myeloma Workshop, 2019, abstract SP-115]

CANDOR study

More recently, the phase III CANDOR study evaluated the addition of daratumumab to carfilzomib-dexamethasone therapy in patients with R/R MM. In an interim analysis, patients randomized to receive daratumumab-carfilzomib-dexamethasone had a 37 percent reduction in the risk of disease progression or death compared with those receiving carfilzomib-dexamethasone alone (HR, 0.630; 95 percent CI, 0.464 to 0.854; p=0.0014), and had not yet reached median PFS at data cut-off date (compared with 15.8 months in the control group). [Usmani SZ, et al, ASH 2019, abstract LBA-6]

Conclusions

The clinical development of proteasome inhibitors has greatly benefited patients with MM. While licensing and reimbursement may limit the use of certain combinations in some regions, the mounting evidence of their benefit appears to be reducing these barriers. Further clinical developments within the class may improve their convenience for patients and further refine understanding of their efficacy and safety.

HK-AMG-119mo4

Related MIMS Drugs

Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Oncology - Hong Kong digital copy today!
Sign In To Download
Editor's Recommendations
Most Read Articles
Natalia Reoutova, 20 May 2020

Cancer patients infected with coronavirus disease 2019 (COVID-19) appear to be at higher risk of severe outcomes, including death, but cancer type and treatment serve as better predictors, according to recent research presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I.

At the time of writing, COVID-19 has spread to more than 200 countries and territories, affecting an estimated 4.5 million people and killing over 300,000. Cancer, on the other hand, is newly diagnosed in 18 million people and takes the lives of 10 million every year.

“We have invited physician scientists who are at the epicentre of the COVID-19 pandemic, taking care of patients with cancer. They gathered prospective information to understand the effects of COVID-19 on patients with cancer, are testing new treatments, and are making this knowledge available to the global research community, so we can all benefit from their experience,” said Professor Antoni Ribas from UCLA Medical Center, Los Angeles, California, US, chairperson of the COVID-19 and cancer plenary session of the meeting.

Natalia Reoutova, 3 days ago

Fasting-mimicking diet (FMD) cycles in combination with endocrine therapy (ET) cause metabolic changes in hormone receptor (HR)-positive breast cancer patients analogous to those observed in animal models, where they are associated with anticancer activity.

Dr. Jason Butler, 01 Apr 2020
Proteasome inhibitors have become a cornerstone of therapy for multiple myeloma (MM). At the Hong Kong Society of Myeloma Annual Scientific Meeting 2019, Dr Jason Butler of the Icon Cancer Care & Royal Brisbane and Women’s Hospital, Brisbane, Australia, reviewed current evidence for the use of proteasome inhibitors in the management of relapsed/refractory MM (R/R MM), with a focus on the efficacy and safety profile of carfilzomib.
Natalia Reoutova, 2 days ago

Results of the world’s first-in-human phase I clinical trial of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 PD-1–edited T cells, recently published in Nature Medicine, suggest therapy’s feasibility in refractory non-small-cell lung cancer (NSCLC), with no severe treatment-related adverse events (TRAEs).