Skylar Kenney, Assistant Editor

The FDA has approved pembrolizumab (Keytruda, Merck), an anti-programmec cell death protein 1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication has received accelerated approval based on tumor response rate and durability of response, though the results of confirmatory trials may change the approval status.

According to a press release from Merck, the approval for this indication is based on data from the ongoing phase 3 KEYNOTE-811 trial, in which pembrolizumab was combined with trastuzumab and either 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin. KEYNOTE-811 is a multicenter, randomized, double-blind, placebo-controlled trial that was designed to enroll 692 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients were randomized into treatment arms containing either pembrolizumab or placebo alongside trastuzumab and investigator’s choice of chemotherapy regimen.

The pembrolizumab combinations demonstrated a statistically significant objective response rate of 74% for patients who received the regimen with pembrolizumab versus 52% for those who received trastuzumab and chemotherapy alone (

<.0001). For patients on the regimen containing pembrolizumab, the complete response rate was 11% and the partial response rate was 63%, whereas the patients receiving trastuzumab and chemotherapy alone had a complete response rate of 3.1% and a partial response rate of 49%.

“Today’s approval marks an important milestone, as this is the first time an anti-PD-1 therapy has been approved in combination with anti-HER2 therapy and chemotherapy as a first-line treatment for these patients,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development at Merck, in the release.

According to the trial, pembrolizumab and placebo were discontinued due to adverse effects (AEs) in 6% of patients in each arm, with pneumonitis being the most common AE leading to discontinuation in the pembrolizumab arm. AEs led to temporary interruption of pembrolizumab in 58% of patients, with the most common AEs being neutropenia, thrombocytopenia, diarrhea, anemia, hypokalemia, fatigue/asthenia, decreased appetite, increased aspartate aminotransferase, increased blood bilirubin, pneumonia, increased alanine aminotransferase, and vomiting. There were no clinically meaningful differences in the incidence of grade 3-4 toxicity between the 2 arms.

FDA Approves Merck’s KEYTRUDA® (pembrolizumab) Combined With Trastuzumab and Chemotherapy as First-line Treatment in Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma [news release]. Merck; May 5, 2021. Accessed May 5, 2021. 

https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-combined-with-trastuzumab-and-chemotherapy-as-first-line-treatment-in-locally-advanced-unresectable-or-metastatic-her2-positive-gastric-or-g/

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This indication has received accelerated approval based on tumor response rate and durability of response, though the results of confirmatory trials may change the approval status.

FDA Approves Pembrolizumab, Trastuzumab and Chemotherapy as First-Line Treatment for Certain Adenocarcinomas

Rates of in-hospital mortality among COVID-19 patients fell 38% between March 2020 and May 2020, but there was little further decline through November 2020, according to a study published in 

. The study is most comprehensive analysis to date of changes in hospital mortality throughout the pandemic, reviewing data on more than 20,000 patients admitted to hospitals for COVID-19 over 9 months, according to the Institute for Health Metrics and Evaluation at the University of Washington.

“Understanding why mortality rates changed is important for clinicians working to improve outcomes for patients hospitalized with COVID-19,” said Gregory Roth, MD, MPH, the study's lead author and an associate professor of medicine at the Institute for Health, in a press release. “Further analysis is needed to understand the drivers more precisely, but it speaks to a crucial need for information sharing and identifying hospital best practices that can prevent mortality rates from increasing again, particularly during possible future waves of COVID-19 infections.”

The investigators analyzed records from the American Heart Association's COVID-19 Cardiovascular Disease Registry, which include 107 hospitals in 31 states. They found mortality rates for patients in the registry were 19.1% in March and April, 11.9% in May and June, 11% in July and August, and 10.8% from September through November. Nearly one-third of patients were admitted to intensive care, and 1 in 5 were placed on mechanical ventilation.

The study was intended to uncover the most likely cause of the observed trend by controlling for patient age, sex, comorbidities, and severity of disease when the patient was admitted. However, they found that none of these factors fully explained the decline in mortality rates. They also found only small changes in patient characteristics during the observed period, including a small decrease in age, an increase in proportion of women, and an increase in BMI.

“Our findings suggest that the decline in mortality could be due to overloaded hospitals and changes in treatment,” Roth said in the release. “With more variants circulating, and many countries still struggling with overloaded hospitals and scarce resources, the more we know about this the better.”

Researchers publish most comprehensive study yet of COVID-19 hospital mortality [news release]. EurekAlert; May 3, 2021. Accessed May 4, 2021. 

https://eurekalert.org/pub_releases/2021-05/ifhm-rpm050321.php

The study is most comprehensive analysis to date of changes in hospital mortality throughout the pandemic, reviewing data on more than 20,000 patients admitted to hospitals for COVID-19 over 9 months, according to the Institute for Health Metrics and Evaluation at the University of Washington.

COVID-19 Hospital Mortality Rates in 2020 Remained Stable Over 6 Months After Initial Decline

The symptom burdens experienced by breast cancer survivors after the end of treatment are widely variable, according to a study presented at the ESMO Breast Cancer 2021 Virtual Congress. This has revealed an unmet need for personalized follow-up care addressing the experiences of individual patients, according to the researchers.

“Follow-up programs are different in each country,” said Kelly de Ligt, PhD, in a press release. “In the Netherlands, for instance, breast cancer survivors have an annual visit with their treating physician for a follow-up period of 5 years, or 10 years if they are young. Previous studies had assessed side-effects experienced after the end of treatment as independent items, but in reality, survivors usually experience multiple symptoms that can add up and weigh heavily on their daily life. We wanted to measure the overall burden on their health-related quality of life and see if any patterns emerged that would better inform us on which individuals require active symptom management.”

The researchers selected 404 participants who had been surgically treated with or without adjuvant treatment for breast cancer stages I to III that were between 1- and 5-years post-diagnosis from the Netherlands Cancer Registry. These patients were questioned about their experienced burden for fatigue, nausea, pain, shortness of breath, insomnia, appetite, constipation, and diarrhea, as well as emotional and cognitive symptoms.

Analysis of these responses allowed the researchers to organize breast cancer survivors into 3 primary categories: low, intermediate, and high symptom burdens.

“In the low-burden group, to which almost a third of patients belonged, women were less affected compared to the average found among a representative sample of 1300 women of the general population in the Netherlands, who filled out the same questionnaire," de Ligt said in the release. “I was pleasantly surprised to find that so many survivors were doing as well or even better than the average Dutch woman.”

Fifty-five percent of study participants were classed in the intermediate-burden subgroup, which had similar results to the general population, though their scores for fatigue, insomnia, and cognitive symptoms were slightly worse. The high-burden subgroup, according to the investigators, confirmed the necessity for personalized approaches to the follow-up of cancer patients, some of whom still required specialized treatment up to 5 years after diagnosis.

“This was the smallest group, only 15% of our population, but nonetheless, 1 in 6 women in our study had worse scores than the general population for all symptoms—and the differences, ranging between 15 and 20 percentage points, were large enough to be considered not just statistically significant, but clinically relevant as well,” de Ligt said in the release.

The study also found that patients with comorbidities such as heart disease and diabetes were more likely to experience a high symptom burden.

“This association was so strong in our analysis that we were not able to link the level of symptom burden patients reported with the type of therapy they had received.,” de Ligt said in the release. “However, because we measured symptom burden and comorbidities at the same time in the study, we cannot draw conclusions from these findings alone. Future research should attempt to measure patients' health-related quality of life through Patient Reported Outcome Measures (PROMs) before the start of treatment for breast cancer and afterwards to allow us to measure the effect of the therapy.”

Personalised follow-up care needed to address varying health burdens in breast cancer pts [news release]. EurekAlert; May 3, 2021. Accessed May 4, 2021. 

https://eurekalert.org/pub_releases/2021-05/esfm-pfc043021.php

Symptom Burdens for Breast Cancer Survivors Largely Variable, Indicating Need for Personalized Care

Fatigue-inducing anemias caused by chronic diseases and inflammation may be treatable with a combination of inexpensive oral medications, according to a study published in 

. The second most common type of anemia, it can act as an added burden for organ-transplant recipients and people with autoimmune disorders, as well as patients battling conditions such as cancer or kidney disease.

Anemia of chronic disease and inflammation is triggered by restricted iron delivery to the bone marrow cells that make red blood cells and can result in severe fatigue, headaches, dizziness, rapid heartbeat, and sweating.

“Not only do these anemias cause unpleasant symptoms, but they are also associated with functional impairment and shorter lifespan,” said Adam Goldfarb, MD, chief of UVA Health's Division of Experimental Pathology, in a press release. “Drawbacks of current therapies include their expense, tendency to lose of effectiveness and risk for serious side effects. This new therapeutic approach has potential to provide a low-cost, highly effective, safe alternative. A further benefit would be its easy applicability to resource-limited areas around the world.”

The investigators found that the inadequate availability of iron in patients with anemia disrupts the Golgi apparatus inside our cells, which is responsible for packaging proteins and lipids vital to cells' healthy operations. By understanding the source of these cellular defects, the team could tailor a targeted approach to reverse the problem in mouse models of anemia. A combination of isocitrate and fumarate allowed ferritin recovery and microtubule regrowth, enabling long-term correction of anemia caused by inflammation.

The study suggests an inexpensive oral medication may also be effective for human patients, according to the authors. Pilot studies in patients with anemia associated with kidney disease are currently being planned.

“The need for new anemia therapies is highlighted by the abundance of new agents currently in early clinical trials,” Goldfarb said in the release. “In defining a novel basic cellular response, our work has opened the door to a safe and simple therapy with unique potential for globally accessibility.”

Anemia discovery points to more effective treatment approaches [news release]. EurekAlert; April 27, 2021. Accessed April 29, 2021. 

https://www.eurekalert.org/pub_releases/2021-04/uovh-adp042721.php

Fatigue-inducing anemias caused by chronic diseases and inflammation may be treatable with a combination of inexpensive oral medications, according to a study published in Nature Communications. 