Research Spotlight

Chapagain, M., T. Gumbo, S. K. Heysell and S. Srivastava (2020). “Comparison of a novel regimen of rifapentine, tedizolid, and minocycline with standard regimens for treatment of the pulmonary Mycobacterium kansasii.” Antimicrob Agents Chemother 2020 Jul 20;AAC.00810-20. [Epub ahead of print.].

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The combination of isoniazid, rifampin and ethambutol, is recommended by the American Thoracic Society (ATS) for treatment of pulmonary Mycobacterium kansasii (Mkn) while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. Here, we administered tedizolid, minocycline, clarithromycin, and rifapentine, as monotherapy as well as novel combinations in the intracellular hollow fiber model system of Mkn (HFS-Mkn) in a 28 days study. The ATS and BTS regimens were used as comparator. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in Mkn burden. As monotherapy, at observed tedizolid AUC(0-24)/MIC of 5.85 and minocycline AUC(0-24)/MIC of 5.77 failed to kill the bacteria below day 0 [stasis], clarithromycin AUC(0-24)/MIC of 2.4 held the bacterial burden at stasis, but the rifapentine AUC(0-24)/MIC of 140 killed 2 log(10) cfu/mL below stasis. The BTS regimen kill slope was -0.083±0.035 cfu/mL/day which was significantly superior to the ATS regimen slope of -0.038±0.038 cfu/mL/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119±0.031 cfu/mL/day, superior to the ATS regimen and comparable with the BTS regimen.Summary Statement. BTS and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS-Mkn However, the efficacy of the new combination regimen remains to be tested in clinical settings.

Catenacci, D. V. T., Y. K. Kang, H. Park, H. E. Uronis, K. W. Lee, M. C. H. Ng, P. C. Enzinger, S. H. Park, P. J. Gold, J. Lacy, H. S. Hochster, S. C. Oh, Y. H. Kim, K. A. Marrone, R. J. Kelly, R. A. Juergens, J. G. Kim, J. C. Bendell, T. Alcindor, S. J. Sym, E. K. Song, C. E. Chee, Y. Chao, S. Kim, A. C. Lockhart, K. L. Knutson, J. Yen, A. Franovic, J. L. Nordstrom, D. Li, J. Wigginton, J. K. Davidson-Moncada, M. K. Rosales and Y. J. Bang (2020). “Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.” Lancet Oncol 21(8): 1066-1076.

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BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). FUNDING: MacroGenics.

Bendel, E. C., K. Sniderman, C. Shaw, R. T. Frederick, F. Wong, A. Sanyal, S. K. Asrani, P. S. Kamath, J. Capel and Z. J. Haskal (2020). “Feasibility and Procedural Safety of alfapump System Implantation by IR: Experience from the MOSAIC Study, a Multicenter, Open-Label Prospective Study in Cirrhotic Patients with Refractory Ascites.” J Vasc Interv Radiol 31(8): 1256-1262.e1253.

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PURPOSE: To evaluate feasibility, procedural outcomes, and safety aspects of implantation of the alfapump system for management of refractory ascites by interventional radiology (IR) methods. MATERIALS AND METHODS: The multicenter open-label prospective MOSAIC study included 29 patients (mean age 60.0 y ± 9.9; range, 32-72 y, 17 [56.7%] male) with cirrhotic refractory ascites who received an alfapump system implanted by IR. The fully subcutaneous alfapump system consists of a pump and 2 silicone catheters, whose distal ends are inserted in the peritoneum and the bladder, respectively. The device moves ascites from the peritoneum to the bladder, reducing the requirement of paracentesis. Pumped volume and speed can be customized as required. The implant procedure was performed under general or local anesthesia. Both catheters were placed under ultrasound guidance. The pump was inserted in a subcutaneous pocket on the upper abdomen. Incidence and severity of procedure-related serious adverse events up to 3 months after implantation were recorded. RESULTS: Technical success was achieved in 29 (100%) IR implant procedures. The pump was usually implanted on the right abdomen (76.7%). In 5 patients, deviation from the Instructions for Use was required. Adverse events (requirement of additional incisions, postoperative bleed) occurred in 3 patients. At 3 months after implantation, 3 possibly procedure-related serious adverse events (ascites leakage, bacterial peritonitis, postoperative bleeding) had occurred. Two explantations (2/29; 6.8%) (cellulitis, pump pocket infection) and 4 reinterventions (pump or catheter replacement) were required, corresponding to an adverse event incidence rate of 9/29 (31.0%). CONCLUSIONS: Placement of the alfapump using IR methods is both feasible and technically successful.

Allaix, M. E., F. Rebecchi and A. Fichera (2020). “ASO Author Reflections: Minimally Invasive Surgery for Colorectal Cancer: Where Do We Stand?” Ann Surg Oncol 2020 Aug 5. [Epub ahead of print.].

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The use of robotic platforms and the transanal transabdominal bottom-up approaches recently have been proposed to overcome the technical limitations of laparoscopy. Large RCTs are needed to define their role for rectal cancer patients.
In conclusion, current evidence supports the routine use of laparoscopy for colon and rectal cancer. [No abstract; excerpt from article.].

Allaix, M. E., F. Rebecchi and A. Fichera (2020). “The Landmark Series: Minimally Invasive (Laparoscopic and Robotic) Colorectal Cancer Surgery.” Ann Surg Oncol 2020 Jul 9. [Epub ahead of print.].

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Current high-quality evidence supports the routine use of the laparoscopic approach for patients with colon cancer. Laparoscopic colectomy is associated with earlier resumption of gastrointestinal function and shorter hospital stay, with no increased morbidity or mortality. Pathology and long-term oncologic outcomes are similar to those achieved with open surgery. The absolute benefits of laparoscopic resection for rectal cancer are still under evaluation. While its safety in terms of early postoperative clinical outcomes has been confirmed, two recent randomized controlled trial (RCTs) have questioned its routine use even in expert hands, since its non-inferiority has not been demonstrated when compared with the gold standard of open surgery. Furthermore, the impact of robotic technology is still unclear, since the only RCT available so far failed to demonstrate any benefits compared with standard laparoscopic rectal resection.