Research Spotlight

Lai, J. C., J. L. Dodge, M. R. Kappus, M. A. Dunn, M. L. Volk, A. Duarte-Rojo, D. R. Ganger, R. S. Rahimi, C. E. McCulloch, C. E. Haugen, M. McAdams-DeMarco, D. Ladner, D. L. Segev and E. C. Verna (2020). “Changes in frailty are associated with waitlist mortality in patients with cirrhosis.” J Hepatol Mar 30. pii: S0168-8278(20)30191-4. [Epub ahead of print].

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BACKGROUND & AIMS: Frailty is predictive of death in patients with cirrhosis, but studies to date have been limited to assessments at a single time point. We aimed to evaluate changes in frailty over time (DeltaLFI) and its association with death/delisting for sickness. METHODS: Adults with cirrhosis listed for liver transplantation without hepatocellular carcinoma at 8 U.S. centers underwent ambulatory longitudinal frailty testing with the Liver Frailty Index (LFI). We used multilevel linear mixed effects regression to model and predict DeltaLFI per 3 months based on age, gender, MELDNa, ascites, and hepatic encephalopathy (HE) and categorize patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted DeltaLFI on death/delisting, with transplantation as the competing risk. RESULTS: We analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe frailty worsening had worse baseline LFI and were more likely to have NAFLD, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted for sickness. The cumulative incidence of death/delisting increased by worsening DeltaLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELDNa, and albumin, a 0.1 unit change in DeltaLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI, 1.35-3.09). CONCLUSION: Changes in frailty were significantly associated with death/delisting independent of baseline frailty and MELDNa. Notably, patients who experienced improvements in frailty over time had a lower risk of death/delisting than those who experienced worsening frailty. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.

Bajaj, J. S., M. Lauridsen, E. B. Tapper, A. Duarte-Rojo, R. S. Rahimi, P. Tandon, D. L. Shawcross, D. Thabut, R. K. Dhiman, M. Romero-Gomez, B. C. Sharma and S. Montagnese (2020). “Important Unresolved Questions in the Management of Hepatic Encephalopathy: An ISHEN Consensus.” Am J Gastroenterol Mar 30. [Epub ahead of print].

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Management of hepatic encephalopathy (HE) remains challenging from a medical and psychosocial perspective. Members of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recognized 5 key unresolved questions in HE management focused on (i) driving, (ii) ammonia levels in clinical practice, (iii) testing strategies for covert or minimal HE, (iv) therapeutic options, and (v) nutrition and patient-reported outcomes. The consensus document addresses these topical issues with a succinct review of the literature and statements that critically evaluate the current science and practice, laying the groundwork for future investigations.

Abou-Alfa, G. K., V. Sahai, A. Hollebecque, G. Vaccaro, D. Melisi, R. Al-Rajabi, A. S. Paulson, M. J. Borad, D. Gallinson, A. G. Murphy, D. Y. Oh, E. Dotan, D. V. Catenacci, E. Van Cutsem, T. Ji, C. F. Lihou, H. Zhen, L. Feliz and A. Vogel (2020). “Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.” Lancet Oncol Mar 20. pii: S1470-2045(20)30109-1. [Epub ahead of print].

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BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13.5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17.8 months (IQR 11.6-21.3). 38 (35.5% [95% CI 26.5-45.4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.

Schmid, P., J. Cortes, L. Pusztai, H. McArthur, S. Kummel, J. Bergh, C. Denkert, Y. H. Park, R. Hui, N. Harbeck, M. Takahashi, T. Foukakis, P. A. Fasching, F. Cardoso, M. Untch, L. Jia, V. Karantza, J. Zhao, G. Aktan, R. Dent and J. O’Shaughnessy (2020). “Pembrolizumab for Early Triple-Negative Breast Cancer.” New England Journal of Medicine 382(9): 810-821.

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BACKGROUND: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. RESULTS: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. CONCLUSIONS: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy. (Funded by Merck Sharp & Dohme [a subsidiary of Merck]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Makkar, R. R., V. H. Thourani, M. J. Mack, S. K. Kodali, S. Kapadia, J. G. Webb, S. H. Yoon, A. Trento, L. G. Svensson, H. C. Herrmann, W. Y. Szeto, D. C. Miller, L. Satler, D. J. Cohen, T. M. Dewey, V. Babaliaros, M. R. Williams, D. J. Kereiakes, A. Zajarias, K. L. Greason, B. K. Whisenant, R. W. Hodson, D. L. Brown, W. F. Fearon, M. J. Russo, P. Pibarot, R. T. Hahn, W. A. Jaber, E. Rogers, K. Xu, J. Wheeler, M. C. Alu, C. R. Smith and M. B. Leon (2020). “Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.” New England Journal of Medicine 382(9): 799-809.

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BACKGROUND: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk. METHODS: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke. RESULTS: At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery. CONCLUSIONS: Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).