Research Spotlight

Bardia, A., Messersmith, W.A., Kio, E.A., Berlin, J.D., Vahdat, L., Masters, G.A., Moroose, R., Santin, A.D., Kalinsky, K., Picozzi, V., O’Shaughnessy, J., Gray, J.E., Komiya, T., Lang, J.M., Chang, J.C., Starodub, A., Goldenberg, D.M., Sharkey, R.M., Maliakal, P., Hong, Q., Wegener, W.A., Goswami, T. and Ocean, A.J. (2021). “Sacituzumab Govitecan, a Trop-2-Directed Antibody-Drug Conjugate, for Patients with Epithelial Cancer: Final Safety and Efficacy Results from the Phase 1/2 IMMU-132-01 Basket Trial.” Ann Oncol Mar 16;S0923-7534(21)00883-8. [Epub ahead of print].

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BACKGROUND: Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase 1/2 multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n>10 patients) of small-cell lung (SCLC), colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate (CRPC) cancer. RESULTS: In the OSP (n=495, median age 61 years, 68% female; UGT1A1 *28 homozygous (n=46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n=75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1 *28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1*1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and SCLC (11/62, 17.7% ORR), and one CRPC patient had a complete response (n=1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Auner, H.W., Gavriatopoulou, M., Delimpasi, S., Simonova, M., Spicka, I., Pour, L., Dimopoulos, M.A., Kriachok, I., Pylypenko, H., Leleu, X., Doronin, V., Usenko, G., Hajek, R., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Stevens, D.A., Quach, H., Jagannath, S., Moreau, P., Levy, M., Badros, A., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Mateos, M.V., Cavo, M., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Richardson, P.G. and Grosicki, S. (2021). “Effect of Age and Frailty on the Efficacy and Tolerability of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma.” Am J Hematol Mar 23. [Epub ahead of print].

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Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analyses of the multicenter, prospective, randomised BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, P=0.024), ≥VGPR (OR, 1.68, P=0.027), PFS (HR 0.55, P=0.002), and improved OS (HR 0.63, P=0.030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, P=0.08) and OS (HR 0.62, P=0.062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had lower incidence of grade ≥2 peripheral neuropathy in ≥65 (22% vs 37%; P=0.0060) and frail patients (15% vs 44%; P=0.0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

Asrani, S.K. and Everson, G.T. (2021). “Editorial: stratifying risk of adverse outcomes in cirrhosis-the Hepquant SHUNT test. Authors’ reply.” Aliment Pharmacol Ther 53(8): 941-942.

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Drs Maan and Sonneveld highlighted the link of portal pressure to risk for clinical complications in patients with chronic liver disease, citing the excellent studies from the Barcelona and Yale liver units. These studies, and others, have established linkage between increasing portal pressure, formation of portal‐systemic shunts, varices and clinical outcomes. Portal‐systemic shunting occurs in parallel to rise in portal pressure—providing a rationale for the HepQuant SHUNT test which quantifies portal‐systemic shunting to be considered as a surrogate for portal hypertension.[No abstract; excerpt from article].

Arnold, S.V., Manandhar, P., Vemulapalli, S., Kosinski, A., Desai, N.D., Bavaria, J.E., Carroll, J.D., Mack, M.J., Thourani, V.H. and Cohen, D.J. (2021). “Impact of short-term complications of transcatheter aortic valve replacement on longer-term outcomes: results from the STS/ACC Transcatheter Valve Therapy Registry.” Eur Heart J Qual Care Clin Outcomes 7(2): 208-213.

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AIMS: While complications of transcatheter aortic valve replacement (TAVR) have decreased, they still occur commonly and may negatively impact both short- and long-term outcomes. We sought to examine the association of complications after TAVR with survival and health status in a real-world cohort. METHODS AND RESULTS: Among 45 884 TAVR patients from 513 US sites who survived 30 days, 21.4% had at least one major complication [stroke, bleed, vascular complication, new pacemaker, acute kidney injury (AKI), and moderate/severe paravalvular leak (PVL)]. In multivariable models, Stage 3 AKI [hazard ratio (HR) 3.43, 95% confidence interval (CI) 2.64-4.45], stroke (HR 2.62, 95% CI 2.06-3.32), and bleeding (HR 1.83, 95% CI 1.55-2.16) were independently associated with significantly increased risk of early death (<3 months) with slight attenuation in these hazards between 3 and 12 months. Moderate/severe PVL (HR 1.37, 95% CI 1.21-1.55) and new pacemaker (HR 1.15, 95% CI 1.05-1.25) were associated with more modest risk of excess mortality that was consistent through 12 months. Among surviving patients, stroke (-6.1 points, 95% CI -8.4 to -3.7), moderate/severe PVL (-3.2 points, 95% CI -4.9 to -1.6), and new pacemaker (-2.3 points, 95% CI -3.2 to -1.5) were associated with less improvement in 1-year health status, as assessed by the Kansas City Cardiomyopathy Questionnaire. CONCLUSION: In this study of contemporary TAVR, we found that complications remain common within the first 30 days after TAVR and are associated with worse 1-year survival and health status among survivors. These findings support continued efforts to reduce major complications of TAVR and may also help define quality of care.

Alshehri, A.M., Barner, J.C., Wong, S.L., Ibrahim, K.R. and Qureshi, S. (2021). “Perceptions among Muslims regarding fasting, medication use and provider engagement during Ramadan in the United States.” Int J Health Plann Manage Mar 12. [Epub ahead of print].

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BACKGROUND: Muslims with chronic diseases tend to fast during Ramadan, although Islam allows them not to fast. Therefore, understanding their perceptions and how they manage their health, especially as a minority population, is very important. OBJECTIVE: To examine Muslims’ (1) perceptions of fasting exemptions, (2) medication usage behaviour, (3) perceptions of relationships with healthcare providers and (4) factors impacting health management during Ramadan. METHOD: This was a qualitative study employing four focus groups (two groups of women and two groups of men). Adult Muslims (aged 18 years or more) with chronic diseases were invited to participate. Participants were asked open-ended questions about their fasting ability, medication usage behaviours, healthcare access and collaboration with providers during Ramadan. Trained researchers conducted the focus groups interviews in both English and Arabic. Each focus group was recorded, and three investigators independently transcribed the data and extracted themes and categories. Coding terminology issues were resolved through discussion. RESULTS: Twenty-five Muslims with chronic diseases (e.g., diabetes, hypertension, renal failure and anaemia) participated. The most prominent themes/subthemes were as follows: (1) fasting exemption (e.g., uncontrolled medical conditions), (2) fasting nonexemption (e.g., controlled medical conditions), (3) nonoral medication use during Ramadan, (4) healthcare provider involvement during Ramadan, and (5) factors impacting health management during Ramadan. CONCLUSION: Muslim patients perceive fasting as an important religious practice, so they tend to self-modify their medication-taking behaviours. Educating pharmacists and other healthcare providers about Muslim culture, especially their strong desire to fast, may lead to Muslims better managing their medications and viewing pharmacists and other healthcare providers as knowledgeable healthcare providers.