Research Spotlight

Testa, G., Wall, A., Lee, S. H. and Fine, R. (2022). “Executive orders prohibiting vaccine mandates: implications for transplant patients and physicians.” Am J Transplant.

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There is ongoing discussion within the transplant community, lay press and US government leaders about the appropriateness for vaccine mandates for transplant patients. In Texas, transplant centers are faced with the reality of having an executive order widely interpreted by hospitals administrations as prohibiting vaccine mandates in the provision of medical care.1 This policy is based on the laudable goal of providing all citizens access to life-saving medical care without discrimination based on their personal choices or personal responsibility for their medical problems. However, applying the executive order to ignore vaccination status to patients awaiting an organ transplant submits patients to a perfectly avoidable risk and puts transplant programs in a difficult predicament. The efficacy of the vaccine is inferior when it is given after the transplant and the severity of illness and mortality due to COVID -19 infection are significantly higher in unvaccinated transplant recipients.2-3 This translates into a higher risk of graft loss and patient death following transplantation which leads to a negative impact on outcomes for transplant programs that cannot consider vaccination status as part of their evaluation for listing or transplantation.

Taylor, M. H., Betts, C. B., Maloney, L., Nadler, E., Algazi, A., Guarino, M. J., Nemunaitis, J., Jimeno, A., Patel, P., Munugalavadla, V., Tao, L., Adkins, D., Goldschmidt, J. H., Cohen, E. E. W. and Coussens, L. M. (2022). “Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study.” Clin Cancer Res 28(5): 903-914.

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PURPOSE: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton’s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. PATIENTS AND METHODS: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. RESULTS: Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4-6.8] months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size. CONCLUSIONS: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.

Shih, E., DiMaio, J. M., Squiers, J. J., Banwait, J. K., Meyer, D. M., George, T. J. and Schwartz, G. S. (2022). “Venovenous extracorporeal membrane oxygenation for patients with refractory coronavirus disease 2019 (COVID-19): Multicenter experience of referral hospitals in a large health care system.” J Thorac Cardiovasc Surg 163(3): 1071-1079.e1073.

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BACKGROUND: The benefit of extracorporeal membrane oxygenation (ECMO) for patients with severe acute respiratory distress from coronavirus disease 2019 refractory to medical management and lung-protective mechanical ventilation has not been adequately determined. METHODS: We reviewed the clinical course of 37 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection supported by venovenous ECMO at 4 ECMO referral centers within a large health care system. Patient characteristics, progression of hemodynamics and inflammatory markers, and clinical outcomes were evaluated. RESULTS: The patients had median age of 51 years (interquartile range, 40-59), and 73% were male. Peak plateau pressures, vasopressor requirements, and arterial partial pressure of carbon dioxide all improved with ECMO support. In our patient population, 24 of 37 patients (64.8%) survived to decannulation and 21 of 37 patients (56.8%) survived to discharge. Among patients discharged alive from the ECMO facility, 12 patients were discharged to a long-term acute care or rehabilitation facility, 2 were transferred back to the referring hospital for ventilatory weaning, and 7 were discharged directly home. For patients who were successfully decannulated, median length of time on ECMO was 17 days (interquartile range, 10-33.5). CONCLUSIONS: Venovenous ECMO represents a useful therapy for patients with refractory severe acute respiratory distress syndrome from coronavirus disease 2019.

Schmid, P., Cortes, J., Dent, R., Pusztai, L., McArthur, H., Kümmel, S., Bergh, J., Denkert, C., Park, Y. H., Hui, R., Harbeck, N., Takahashi, M., Untch, M., Fasching, P. A., Cardoso, F., Andersen, J., Patt, D., Danso, M., Ferreira, M., Mouret-Reynier, M. A., Im, S. A., Ahn, J. H., Gion, M., Baron-Hay, S., Boileau, J. F., Ding, Y., Tryfonidis, K., Aktan, G., Karantza, V. and O’Shaughnessy, J. (2022). “Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.” N Engl J Med 386(6): 556-567.

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BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Safadi, R., Rahimi, R. S., Thabut, D., Bajaj, J. S., Ram Bhamidimarri, K., Pyrsopoulos, N., Potthoff, A., Bukofzer, S., Wang, L., Jamil, K. and Devarakonda, K. R. (2022). “Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes.” Clin Transl Sci.

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Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours’ standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented ~50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE.