Research Spotlight

Shen, L., Jhund, P.S., Anand, I.S., Bhatt, A.S., Desai, A.S., Maggioni, A.P., Martinez, F.A., Pfeffer, M.A., Rizkala, A.R., Rouleau, J.L., Swedberg, K., Vaduganathan, M., Vardeny, O., van Veldhuisen, D.J., Zannad, F., Zile, M.R., Packer, M., Solomon, S.D. and McMurray, J.J.V. (2021). “Incidence and Outcomes of Pneumonia in Patients With Heart Failure.” J Am Coll Cardiol 77(16): 1961-1973.

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BACKGROUND: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials. METHODS: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide). RESULTS: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58). CONCLUSIONS: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).

Bardia, A., Hurvitz, S.A., Tolaney, S.M., Loirat, D., Punie, K., Oliveira, M., Brufsky, A., Sardesai, S.D., Kalinsky, K., Zelnak, A.B., Weaver, R., Traina, T., Dalenc, F., Aftimos, P., Lynce, F., Diab, S., Cortés, J., O’Shaughnessy, J., Diéras, V., Ferrario, C., Schmid, P., Carey, L.A., Gianni, L., Piccart, M.J., Loibl, S., Goldenberg, D.M., Hong, Q., Olivo, M.S., Itri, L.M. and Rugo, H.S. (2021). “Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.” N Engl J Med 384(16): 1529-1541.

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BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Bardia, A., Kaklamani, V., Wilks, S., Weise, A., Richards, D., Harb, W., Osborne, C., Wesolowski, R., Karuturi, M., Conkling, P., Bagley, R.G., Wang, Y., Conlan, M.G. and Kabos, P. (2021). “Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.” J Clin Oncol 39(12): 1360-1370

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PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

Onaca, N., Martinez, E., Bayer, J., Wall, A., Fernandez, H., Ruiz, R., Ma, T.W., Gupta, A., McKenna, G. and Testa, G. (2021). “Selective screening imaging of the aortoiliac arterial system in kidney transplant candidates with non-contrast pelvic computed tomography.” Clin Transplant: e14331.

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Non-contrast pelvic computed tomography (CT) can detect severe iliac artery calcifications that present technical contraindications to kidney transplantation (TCT). We screened 454 asymptomatic patients with a history of any of the following: hemodialysis >10 years, diabetes mellitus >20 years, coronary artery disease (CAD) with percutaneous or surgical interventions, carotid disease, diabetes with below-/above-knee amputations, and heart-kidney transplantation candidacy. Patients with normal dorsalis pedis and/or tibialis posterior pulses were not screened. A total of 8.4% had severe calcifications with TCT; CT determined laterality for implantation in 13.9%. No patients with the following characteristics were classified as TCT: age <40 years, hemodialysis >10 years, carotid arterial disease, prior lower extremity amputation, or heart-kidney transplantation candidacy. CAD was associated with TCT in univariate though not multivariate analysis. Limiting screening to patients >40 years, with DM >20 years, or with CAD, 9.8% had a TCT and CT determined transplant laterality in 14.2%. Screening for severe iliac artery calcifications is useful for selected kidney transplantation candidates over age 40. It can assist with laterality choice or surgeon determination of TCT. Cost and radiation exposure risks should be weighed against the morbidity risks from unnecessary surgery.

Nguyen, A.D. (2021). “Impact of bariatric surgery on gastroesophageal reflux disease and esophageal motility.” Curr Opin Gastroenterol.

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PURPOSE OF REVIEW: Obesity is rapidly increasing in prevalence, and bariatric surgery has become a popular treatment option that can improve all-cause mortality in obese individuals. Gastroesophageal reflux disease (GERD) and esophageal motility disorders are common in the obese population, and the effects of bariatric surgery on these conditions differ depending on the type of bariatric surgery performed. RECENT FINDINGS: Laparoscopic adjustable gastric banding has declined in popularity due to its contributions to worsening GERD symptoms and the development of esophageal dysmotility. Although laparoscopic sleeve gastrectomy (LSG) is the most popular type of bariatric surgery, a comprehensive assessment for acid reflux should be performed as LSG has been linked with worsening GERD. Novel methods to address GERD due to LSG include magnetic sphincter augmentation and concomitant fundoplication. Due to the decreased incidence of postoperative GERD and dysmotility compared to other types of bariatric surgeries, Roux-en-Y gastric bypass should be considered for obese patients with GERD and esophageal dysmotility. SUMMARY: Bariatric surgery can affect esophageal motility and contribute to worsening or development of GERD. A thorough workup of gastrointestinal symptoms before bariatric surgery should be performed with consideration for formal testing with high-resolution manometry and pH testing. Based on these results, the choice of bariatric surgery technique should be tailored accordingly to improve clinical outcomes.