publication date: Oct. 2, 2020

Clinical Roundup

Corticosteroids improve survival in critically ill COVID-19 patients

An international team led by clinician-scientists at UPMC and the University of Pittsburgh School of Medicine have pooled data from 121 hospitals in eight countries to find that inexpensive, widely available steroids improve the odds that very sick COVID-19 patients will survive the illness.

The findings were made through the “Randomized Embedded Multifactorial Adaptive Platform-Community Acquired Pneumonia” (REMAP-CAP) trial and are reported in JAMA as part of a four-article package. The World Health Organization is updating its COVID-19 treatment guidance as a result.

REMAP-CAP includes the UPMC-REMAP-COVID19 trial, the only U.S.-based trial to test corticosteroids — a class of drug that lowers inflammation and modulates immune system activity — for treating critically ill COVID-19 patients. An analysis combining the REMAP-CAP data with that from six other randomized controlled trials to test corticosteroids reinforces the results of the UK RECOVERY trial reported in June, which found the steroid dexamethasone reduced deaths by 29% in ventilated COVID-19 patients.

“It is relatively rare in medicine that you find drugs where the evidence of their effectiveness in saving lives is so consistent,” lead author Derek Angus, chief health care innovation officer at UPMC and professor and chair of the Department of Critical Care Medicine at Pitt, said in a statement. “This is, in many respects, the single clearest answer we’ve had so far on how to manage terribly ill COVID-19 patients. People on ventilators or oxygen and under intensive care should definitely be given corticosteroids.”

Between March and June, the REMAP-CAP corticosteroid trial randomized 403 adult COVID-19 patients admitted to an intensive care unit to receive the steroid hydrocortisone or no steroids at all. The trial found a 93% probability that giving patients a seven-day intravenous course of hydrocortisone would result in better outcomes than not giving the steroid. The results were consistent across age, race and sex.

REMAP-CAP and the other corticosteroid trials did not test the drugs in non-hospitalized patients with COVID-19 who did not need respiratory support. Steroids currently are not recommended for these patients because they can dampen the immune system and have serious side effects. In addition, the REMAP-CAP corticosteroid trial was mostly conducted in resource-rich countries across Europe, North America and Australasia, so the findings may not translate to low- and middle-income countries.

Because it is designed to simultaneously test multiple combinations of potential therapies—as opposed to the traditional, slow clinical trial process that tests one therapy at a time—REMAP-CAP is particularly well-suited for rapidly identifying effective treatments during the COVID-19 pandemic. It is currently testing thousands of different treatment regimens, including various doses and combinations of vitamin C, convalescent plasma, blood thinners, antivirals and immune modulators.

“REMAP-CAP and our findings on corticosteroids are possible because of a global community of clinicians and scientists coordinating and sharing data across different languages and countries,” said co-author Christopher Seymour, M.D., UPMC intensivist and director of the Translational and Clinical Science Program at the Clinical Research, Investigation and Systems Modeling of Acute Illness (CRISMA) Center in Pitt’s School of Medicine. “This is how we get definitive answers as fast as possible on how to best treat patients. Outcomes in Amsterdam are helping patients at UPMC Altoona.”

Timothy Girard, M.D., Christopher Horvat, M.D., David Huang, M.D., Kelsey Linstrum, M.S., and Stephanie Montgomery, M.S., all of Pitt’s CRISMA Center, also contributed to this research.

Additional authors on the JAMA publication are from the Raymond Poincaré Hospital – AP-HP (Greater Paris University Hospitals), University of Versailles and University Paris Saclay, all in France; King Saud Bin Abdulaziz University for Health Sciences in Saudi Arabia; Imperial College London, Imperial College Healthcare NHS Trust, University of Oxford, Bristol Royal Informatory, University of Bristol, NHS Blood and Transplant, Queen’s University Belfast, and Intensive Care National Audit & Research Centre, all in the UK; Berry Consultants, LLC, the Global Coalition for Adaptive Research, University of California at Los Angeles and Harbor-UCLA Medical Center, all in the U.S.; St. Michael’s Hospital of Unity Health Toronto, Université de Sherbrooke, University of Toronto, University Health Network, University of British Columbia and University of Manitoba, all in Canada; Jena University Hospital in Germany; Monash University, Alfred Health, Princess Alexandra Hospital University of West Australia, The George Institute for Global Health and St. John of God Hospital, all in Australia; University Medical Center Utrecht, University of Amsterdam and Radboud University Medical Center, all in the Netherlands; Antwerp University Hospital in Belgium; Network for Improving Critical Care Systems and Training in Sri Lanka; Mahidol Oxford Tropical Medicine Research Unit in Thailand; Auckland City Hospital, The Health Research Council of New Zealand and University of Auckland, all in New Zealand; and St. Vincent’s University Hospital and University College Dublin, both in Ireland.

This research was funded by The Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) consortium FP7-HEALTH-2013-INNOVATION-1 (#602525), the Australian National Health and Medical Research Council (#APP1101719 and #1116530), the New Zealand Health Research Council (#16/631), the Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant (#158584), the UK National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the UPMC Office of Healthcare Innovation, the Breast Cancer Research Foundation, the French Ministry of Health (PHRC-20-0147), and the Minderoo Foundation.

 

Phase III trial shows Opdivo significantly improves DFS as adjuvant therapy for muscle-invasive urothelial carcinoma

Bristol Myers Squibb said CheckMate -274, a pivotal phase III trial evaluating Opdivo (nivolumab) after surgery in patients with high-risk, muscle-invasive urothelial carcinoma, met its primary endpoints of improving disease-free survival (DFS) versus placebo in both all randomized patients and in patients whose tumor cells express PD-L1 ≥1% (programmed death-ligand 1).

CheckMate-274 is the first and only phase III trial in which immunotherapy has reduced the risk of relapse in the adjuvant setting for these patients.

“With currently available therapies, more than 50% of patients with bladder cancer will experience recurrence after surgery, and each year, the disease takes the lives of nearly 200,000 patients,” said Matthew Galsky, professor of medicine, director of genitourinary medical oncology, director of the novel therapeutics unit, and co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai.

“Advances like immunotherapy have helped bring hope to patients across a growing number of cancer types, including previously treated advanced urothelial carcinoma. The positive results from CheckMate -274 point to the potential for nivolumab to become a new standard of care in the adjuvant setting, extending disease-free survival for post-surgery patients with muscle-invasive urothelial cancer without the use of chemotherapy.”

BMS plans to complete a full evaluation of the CheckMate -274 data, work with investigators to present the results at an upcoming medical conference, and submit the data to health authorities. The CheckMate -274 trial will continue as planned to allow for future analyses of secondary endpoints, including overall survival and disease-specific survival.

 

Yale study reinforces benefit of using targeted therapy for early-stage NSCLC

Treatment with the targeted therapy osimertinib following surgery continues to significantly improve disease-free survival in patients with early-stage, non-small cell lung cancer with epidermal growth factor receptor gene mutation, according to updated findings led by researchers at Yale Cancer Center.

The benefit of osimertinib treatment demonstrated earlier this year in the ADAURA trial was so substantial that the independent data monitoring committee recommended early unblinding of the multinational randomized controlled phase III trial. The latest findings are to be presented September 19 at 12:30 p.m., during the virtual science program at the annual meeting of the European Society for Medical Oncology. The results are also to be published online in the New England Journal of Medicine at the same time.

“These updated results from the ADAURA trial once again demonstrated a statistically significant and clinically meaningful improvement in disease-free survival in the adjuvant treatment of patients with early-stage EGFR mutations for NSCLC,” said Roy S. Herbst, chief of Medical Oncology at YCC and Smilow Cancer Hospital and senior author of the study. “It’s so critical to provide patients with this type of lung cancer a new treatment option.”

ADAURA is a phase III, randomized trial that looked at adjuvant therapy with osimertinib, a third-generation EGFR-TKI, versus placebo, in treating patients with Stage IB through IIIA EGFR-mutated non-small cell lung cancer. The trial results showed that osimertinib offered a two-year, 89% DFS for patients with resected lung cancer (stage IB/II/IIIA) compared to a DFS rate of 52% in patients randomized to treatment with placebo, with manageable side effects.

Disease-free survival measures the time from randomization to first sign of cancer recurrence or death. In this trial, patients treated with osimertinib had a 79% reduction in the risk of their cancer returning or death. The study will continue to follow patients for overall survival outcomes.

“In the past, we haven’t had much success fighting recurrence in the liver, lung and brain of NSCLC in patients with EGFR mutations,” said Herbst. “These study results will hopefully be practice-changing and have a huge impact on patient care.”

This study was funded by AstraZeneca.

Copyright (c) 2020 The Cancer Letter Inc.