Guidelines for Preventing Opportunistic Infections Among Hematopoietic Stem Cell Transplant Recipients
Inhaled Amikacin Shows Promise For Untreated MAC Lung Infections
SAN DIEGO -- Adding amikacin liposome inhalation suspension (ALIS; Arikayce) to a macrolide-based regimen appeared to reduce respiratory symptoms and improve culture conversion rates in patients with newly diagnosed or recurrent Mycobacterium avium complex (MAC) lung infections, the randomized ARISE trial showed.
As measured by the nine-item Quality of Life-Bronchiectasis Respiratory Domain (QOL-B RD), 43.8% of patients in the ALIS arm achieved a meaningful improvement in symptoms from baseline to 7 months, as compared with 33.3% of those assigned to the macrolide-based regimen plus placebo, reported Charles Daley, MD, of National Jewish Health and the University of Colorado School of Medicine in Denver.
Culture conversion rates were numerically higher in the ALIS arm both following the 6-month period of daily treatment (80.6% vs 63.9% P=0.071) and at 7 months, a month after stopping treatment (78.8% vs 47.1%, nominal P=0.001), according to findings presented here at the American Thoracic Society annual meeting.
The main goal of the ARISE study was to validate patient-reported-outcome (PRO) tools using modern psychometric methods for key symptoms of MAC lung disease -- with respiratory symptoms and fatigue previously established as the most prevalent and bothersome to patients.
"It turns out there's no currently validated fit-for purpose PRO instrument for people with MAC lung disease," said Daley. "The symptoms that are most important to our patients are covered in two instruments" -- the QOL-B RD and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a.
Daley's presentation focused on the validation of the QOL-B RD (against the Patient Global Impression of Severity-Respiratory scale); the impact of ALIS on patients' respiratory symptoms using the QOL-B RD; and microbiologic outcomes with ALIS as part of a macrolide-based regimen for this patient population.
The QOL-B RD is a self-administered questionnaire with nine items to assess sputum, coughing, congestion, wheezing, chest pain, and other symptoms -- with eight of the items scored on a Likert Scale (a lot, a moderate amount, a little, not at all) and the sputum question requiring a descriptive answer.
Each score is standardized on a 0-100 scale, with 100 indicating no symptoms. Ultimately a 14.8-point change in an individual patient was deemed to be a meaningful difference on the QOL-B RD, said Daley.
While the study was not powered to show a significant difference between arms, the least-squares mean change from baseline to 7 months on the QOL-B RD favored the ALIS arm (12.24 vs 7.76, P=0.1073).
Results of the ARISE trial are "a significant step toward an area of unmet need in patients with non-cavitary [MAC lung disease]," said Sarah Taimur, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the study.
"It provides much-needed evidence for validation of a self-administered, patient-reported outcome measure that has been previously lacking in this patient population, and could serve as a critical tool that patients and their medical teams can use to gauge response to treatment," Taimur told MedPage Today.
ALIS is currently approved only for patients with MAC lung infections that do not respond to traditional treatments; the validated QOL-B RD instrument will help support the evaluation of the inhaled therapy in an ongoing phase III registrational study (ENCORE) testing a macrolide-based regimen plus either ALIS versus placebo in patients with newly diagnosed or recurrent MAC lung infections who have not received antibiotics for their current infection.
Daley presented findings from ARISE (Validation of Patient-Reported Outcome Measures in Participants With Nontuberculous Mycobacterial Lung Infection Caused by Mycobacterium Avium Complex), which randomized 99 adults with newly diagnosed or recurrent MAC lung infections and non-cavitary disease who had not yet been treated with antibiotics for their current infection. Patients were enrolled at 76 sites across 15 countries, including the U.S.
All patients received azithromycin and ethambutol as their macrolide-based regimen and were randomized 1:1 to ALIS or an empty liposomal control (placebo) once daily for 6 months, followed by a month off of treatment for follow-up. All patients had a mean QOL-B RD score of 85 or less. Patients with mixed infections were allowed in the trial so long as MAC was the dominant species present.
Exclusion criteria included refractory or relapsed MAC infections, more than three previous MAC lung infections, prior ALIS exposure, a smoking history, and certain comorbidities (cystic fibrosis, prior lung transplant, active malignancy).
Participants had a median age of 67-72 years, three-fourths were women, and 81% were white. Most were enrolled from either North America (39%) or Europe (38%). Concurrent respiratory illnesses included bronchiectasis in 49%, asthma in 21%, chronic obstructive pulmonary disease in 16%, cough in 16%, and allergic rhinitis in 11%.
For 73% of the patients, this was their initial MAC infection. Overall, 32% had M. Avium infections, 43% had M. Intracellulare infections, and the rest had other or unspecified MAC infections.
Culture conversion was defined as no growth of MAC in sputum cultures on agar and broth media. Four sputum samples were collected from patients at each monthly visit during the study.
Patients in the ALIS arm achieved culture conversions a median 1 month earlier than those in the comparator arm. Overall, 12.8% of patients who achieved culture conversion in the ALIS arm experienced recurrence at any point in the study compared with 50% of those in the placebo arm. No patients in either group developed MAC isolates with resistance to ALIS.
Treatment-emergent adverse events (TEAEs) were reported in 92% of patients in the ALIS arm and 80% of those in the placebo arm, the most common of which included dysphonia (42% vs 4%, respectively), cough (27% vs 8%), diarrhea (27% vs 25%), and COVID-19 (13% vs 10%). Treatment discontinuation of ALIS specifically occurred in 19%, as compared with 6% with the placebo.
Serious TEAEs were reported in 15% of the ALIS arm and 6% of the comparator arm. No deaths were reported.
Adverse events of special interest included dizziness (4.2% in the ALIS arm vs 9.8% in the placebo arm), tinnitus (4.2% vs 7.8%, respectively), vertigo (4.2% vs 2%), deafness (2.1% vs 2%), dyspnea (10.4% vs 7.8%) or dyspnea on exertion (2.1% vs none), wheezing (6% vs none), hemoptysis (10.4% vs 5.9%), exacerbation of an underlying pulmonary disease (none vs 3.9%), and neuromuscular disorders (2% in each arm).
Elizabeth Short is a staff writer for MedPage Today. She often covers pulmonology and allergy & immunology. Follow
Disclosures
The study was funded by Insmed.
Daley reported relationships with Insmed, AN2 Therapeutics, Bugworks, Paratek Pharmaceuticals, Juvabis, AstraZeneca, Cepheid, Hyfe, MannKind, Matinas Biopharma, Nob Hill Therapeutics, Spero Therapeutics, Zambon, Genentech, Pfizer, Otsuka Pharmaceutical, Eli Lilly, and the Bill and Melinda Gates Foundation.
Taimur reported no disclosures.
Primary Source
American Thoracic Society
Source Reference: Daley CL "Change in patient reported respiratory symptoms in a randomized, double-blind, trial of amikacin liposome inhalation suspension in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease: the ARISE study" ATS 2024; Abstract A1032.
Secondary Source
American Thoracic Society
Source Reference: Daley CL "Microbiologic outcomes from a randomized, double-blind trial of amikacin liposome inhalation suspension in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease: the ARISE study" ATS 2024; Abstract A1033.
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How Targeted Therapies Changed Lung Cancer Treatment
ConferenceEducated Patient® Lung Cancer Summit
One expert explains why "the future of precision medicine" has arrived in lung cancer at the CURE® Educated Patient® Lung Cancer Summit.
When it comes to targeted therapies for the treatment of lung cancer, "the future of precision medicine is here," as Dr. Ravi Salgia explained during the CURE® Educated Patient® Lung Cancer Summit.
Salgia is a medical oncologist who serves as professor and chair in the Department of Medical Oncology and Therapeutics Research as well as the Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope Comprehensive Cancer Center in Duarte, California.
He explained his view that lung cancer is not just one disease, but rather one that encompasses a variety of genetic abnormalities — differences that are now targeted by various modern therapies.
"Lung cancer is no longer lung cancer in my mind," he said. "It's a cancer that arises in the lung that has various characteristics … [and] so all of that has to factor into our decision making, we must make sure that molecular analysis is done. And targeted therapeutics, I'm very happy to say, have revolutionized our treatment. But we need to continue to strive to be better and better. And precision medicine will help us deliver better care."
MORE FROM THE SUMMIT: Understanding Immunotherapy and Side Effects in Advanced Lung Cancer
The revolution, Salgia said, has already arrived.
"You can have EGFR mutations, KRAS alterations, but you can also have MET mutations, MET amplification, MET fusions, BRAF alterations … [and] you have medications such as Tagrisso [osimertinib] and others for EGFR, for ALK rearrangement you have Lobrena [lorlatinib] and other medications, [treatments for] ROS1 [rearrangements] and so forth. And it is important to talk to your physician and health care provider about which medication is the right one for you. At the same time, what are the toxicities?"
Xalkori (crizotinib), approved in 2013, was found to confer a median progression-free survival (the time a patient lives without their disease spreading or worsening) of 10.9 months. By contrast, Lorbrena, approved in 2021, resulted in a median progression-free survival of 33.2 months, according to Salgia's presentation.
Xalkori and Lorbrena are both ALK inhibitors, drugs that inhibit the growth of tumor cells that overexpress ALK, a protein that controls cell growth.
MORE FROM THE SUMMIT: Combining Drugs, Radiation Is 'Practice-Changing' for Some Lung Cancer Subsets
Earlier this year, the FDA approved the ALK inhibitor Alecensa for the treatment of patients with ALK-positive non-small cell lung cancer that was at least 4 centimeters and had been surgically removed — making it, according to Alecensa manufacturer Genentech, the first ALK inhibitor approved for patients with early-stage NSCLC that underwent surgical resection, or removal.
Such treatments are part of the future of precision medicine, as Salgia explained.
"We can take serum or plasma samples and fluid samples, [we can] take tumor tissue, we're working on stool and urine sample as well," said Salgia. "Then, you do this biopsy analysis and or the liquid biopsy analysis such as [of] the blood or even CSF or cerebrospinal fluid [and you] look at the various mutations that can happen, that is the genetic and the non-genetic mechanisms, then ultimately try to look at what are the various medications that one will respond to, and I think, then, ultimately come up with the drug matching [the disease]. That's really what we're committed to being in terms of the future of precision medicine."
For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.
Why Many People With Lung Cancer Who Have Never Smoked Don't Respond Well To Treatments
Non-smokers who develop non-small cell lung cancer (NSCLC) can be unusually resistant to treatment for the disease.
Researchers say they think genetic mutations may be the cause.
Their findings were published today in the journal Nature Communications.
Smoking is the leading cause of lung cancer, but not all people who get lung cancer are smokers. In fact, 10% to 20% of people who get lung cancer have never smoked, according to the U.S. Centers for Disease Control and Prevention (CDC).
The causes of lung cancer among people who have never smoked remain unclear, but experts suspect a combination of environmental, genetic, and lifestyle-related factors play a role.
Lung cancer among non-smokers is the fifth leading cause of death in the world, according to Dr. Eric Singhi, an assistant professor of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center.
"All you need to be at risk for lung cancer is to have lungs," Singhi, who was not involved in the study, told Medical News Today.
Targeted treatment is available for non-small cell lung cancer.
However, researchers from University College London, the Francis Crick Institute, and drugmaker AstraZeneca found that the combination of two genetic mutations may explain why standard treatment is often ineffective among non-smokers.
Targeted treatment fails in 10% to 15% patients, depending upon what kind of NCSLC is being treated, Dr. Manmeet Singh Ahluwalia of the Baptist Health Miami Cancer Institute who was not involved in the study told Medical News Today
In their new study, researchers reported that a mutation in the epidermal growth factor receptor gene (EGFR) — present in up to half of non-smokers with NCSLC — combined with a mutation in the p53 gene resulted in the development of drug-resistant tumors.
Researchers said that the only about a third of people with stage IV NSCLC and an EGFR mutation survive for up to three years.
EGFR enables cancer cells to grow more quickly, whereas the p53 gene plays a role in tumor suppression.
Typically, NSCLC is treated with drugs called EGFR inhibitors, but the study found while tumors in people with just the EGFR mutations got smaller in response to treatment, some tumors actually grew after treatment among those with both the EGFR and p53 mutations.
Lab and animal studies found that these growing, drug-resistant tumors had more cancer cells that had doubled their genome, giving them extra copies of all their chromosomes. In addition, cells with both the double mutation and double genomes were more likely to multiply into new drug-resistant cells.
"We've shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling," said Charles Swanton, PhD, a study co-author and a professor at the UCL Cancer Institute and deputy clinical director at the Francis Crick Institute, said in a statement. "This increases the risk of drug-resistant cells developing through chromosomal instability."
"While whole genome doubling itself may not always cause cancer, it can contribute to cancer growth and disease progression in various ways," added Singh.
Researchers noted that while non-small cell lung cancer patients are tested for EGFR and p53 mutations, there is no test currently available that can detect this dangerous genome doubling.
Work on such a test is under way, however.
"Once we can identify patients with both EGFR and p53 mutations whose tumors display whole genome doubling, we can then treat these patients in a more selective way," said Crispin Hiley, PhD, a study co-author and an associate professor at the UCL Cancer Institute. "This might mean more intensive follow-up, early radiotherapy or ablation to target resistant tumors, or early use of combinations of EGFR inhibitors, such as (AstraZeneca's) osimertinib, with other drugs including chemotherapy."
"Treatment strategies such as combination therapies (targeted therapy plus another treatment) have begun to emerge, aimed at preventing the emergence of resistance to a treatment," said Singhi.
He noted that these include using osimertinib in combination with conventional chemotherapy or amivantamab, an bispecific antibody targeting EGFR and MET, a gene that manufactures a protein involved in cellular signaling, growth, and survival.
"These trials are looking to prove whether two types of treatments together and upfront, offer better clinical outcomes for our patients than one targeted therapy alone," he said. "A very valid concern, however, is that combination therapies tend to be more toxic for our patients, and it can be difficult to discern which patient would benefit more one therapy versus another."
Dr. Shuresh Ramalingam, an executive director of the Winship Cancer Institute of Emory University in Georgia and a non-small cell lung cancer expert who was not involved in the study, told Medical News Today that new therapies can be tailored to address NSCLC cases where EGFR inhibitors are ineffective.
"When targeted treatments stop working, it is not uncommon for physicians to conduct molecular testing to determine if there are new mutations in the tumor," said Ramalingam, who is currently working on a new intervention for treating Stage III NSCLC tumors that cannot be removed surgically. "This knowledge informs appropriate interventions that could overcome the resistance mechanism. For example, for patients with EGFR mutation, a known resistance mechanism with targeted therapy is a new mutation known as the C797S mutation. There are new experimental drugs that are capable of overcoming this specific resistance mechanism in clinical trials."
The proportion of lung cancers occurring in individuals who have never smoked has increased in the past several decades, particularly among women and in younger age groups, said Ahluwalia.
"Approximately two-thirds of [these] cases occur in women, making women who have not smoked more than twice as likely to develop lung cancer than men who have not smoked," he said.
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