J&J, AbbVie go back to Imbruvica roots in lymphoma. Will lack of survival win matter?

 Back in 2013, AbbVie and Johnson & Johnson’s Imbruvica got its very first FDA go-ahead, which was for previously treated mantle cell lymphoma (MCL). Now, the company is trumpeting a trial win in newly diagnosed patients despite not showing a life-extension advantage.

Adding Imbruvica on top of Teva’s chemotherapy Treanda and Roche’s Rituxan reduced the risk of disease progression or death by 25%. Detailed data from the phase 3 SHINE study are being presented at the 2022 American Society of Clinical Oncology annual meeting.

The study enrolled patients over age 65. These older patients aren’t able to receive intensive chemotherapy or stem cell transplantation because of toxicities, Michael Wang, M.D., of the University of Texas MD Anderson Cancer Center and lead investigator of the study, explained in a statement. MCL is a rare type of blood cancer, accounting for 7% of all non-Hodgkin lymphoma cases.

After a median follow-up of seven years—or 84.7 months to be exact—patients who got the Imbruvica combo went 80.6 months without disease progression, versus 52.9 months for the Treanda-Rituxan group. Patients in both groups also received Rituxan maintenance treatment after six cycles of Treanda and Rituxan.

Although a long time has gone by since the trial started, the regimen used in the control arm is highly relevant and still in use today, Craig Tendler, M.D., vice president of oncology clinical development and global medical affairs at J&J’s Janssen, said in an interview with Fierce Pharma. The more than four years of progression-free period observed in the control arm was also “quite good” compared with real-world experience, he said.

J&J has already submitted the SHINE data to the European Medicines Agency for a potential first-line nod, Tendler said. The company is also speaking with the FDA about filing with this trial, plus support of additional studies including potentially a large ongoing study with the European MCL Network in transplant-eligible patients, he added. The SHINE study was also designed to serve as the confirmatory clinical trial for Imbruvica’s original accelerated approval in second-line MCL.

But there’s one caveat.

Imbruvica didn’t show a benefit in prolonging patients’ lives. At least for now, there is no difference in overall survival between treatment arms, the trial investigators noted.

Tendler shrugged off the lack of a life extension improvement. The overall survival data are still not mature at this point, he noted. Plus, patients also received active treatment after their tumor had progressed.

Among 106 (40.5%) patients who received subsequent therapies in the control arm, 41 got a BTK inhibitor like Imbruvica as a second-line treatment. By comparison, 52 (19.9%) patients in the Imbruvica arm got subsequent treatments. “So it’s not usual or unexpected that it will take more time for survival to mature,” Tendler said.

Even without a definite survival advantage, Tendler said Imbruvica’s ability to induce durable disease control without all the symptoms and complications of disease relapse is “establishing a new benchmark” for these elderly mantle cell lymphoma patients.

Patients in both arms also reported similar quality of life. It’s a positive finding because the addition of Imbruvica didn’t seem to abrogate patients’ ability to go on about their life, Tendler said.

For Imbruvica’s existing indications as well as in the current SHINE study, the BTK inhibitor is dosed repeatedly at least until disease progression. Janssen is working to turn the drug into a fixed-duration combo with Roche and AbbVie’s Venclexta in the all-important chronic lymphocytic leukemia indication. With positive data from the phase 3 GLOW trial and phase 2 CAPTIVATE, J&J has filed that regimen with European authorities and is discussing with the FDA.

https://www.fiercepharma.com/pharma/asco-jj-abbvie-go-back-imbruvicas-roots-lymphoma-will-lack-survival-win-matter

Dario: 3New Studies Demonstrating Improved Health in Users with Multiple Conditions

 The studies demonstrated significant improvement in glucose control and reductions in blood pressure for users managing diabetes and hypertension and improvement in clinical measures for users with diabetes, stress and depression.

The third study demonstrates that the Dario solution has similar positive impact on diabetes across ethnicities.

https://finance.yahoo.com/news/dariohealth-presents-three-studies-demonstrating-120000733.html

Immutep: Positive Overall Response in Phase II Trial in 1st line NSCLC for PD-L1 All-Comers

 

• TACTI-002 has met its primary objective for 1st line non-small cell lung cancer (NSCLC) patients in a PD-L1 all-comer Phase II clinical trial conducted in collaboration with MSD (N=114)

• Combination of efti plus pembrolizumab shows favourable anti-tumour activity:

  • Improved Overall Response Rate (ORR) by local read of 38.6% (intent to treat, 44/114 patients) and 42.7% (evaluable patients, 44/103) compared with data reported at ASCO 2021 (N=36)

• Encouraging responses observed in all PD-L1 status groups, including those patients with PD-L1 negative (TPS < 1%) and PD-L1 low (TPS 1-49%) expressing tumours who are less likely to respond to anti-PD-1 monotherapy

• Other secondary endpoints including Disease Control Rate (DCR) and interim median Progression Free Survival (PFS) continue to demonstrate improvement across all PD-L1 expression levels

• Safe and well tolerated, with a safety profile that is consistent with that observed in previously reported studies for pembrolizumab monotherapy

• Results support continued late stage clinical development of efti

https://finance.yahoo.com/news/immutep-reports-positive-overall-response-181800507.html

Bristol Pulls Application for Reblozy in Beta Thalassemia

 Bristol Myers Squibb (NYSE: BMY) today announced that the company has withdrawn a supplemental biologics license application (sBLA) for Reblozyl® (luspatercept-aamt) for the treatment of anemia in adults with non-transfusion dependent (NTD) beta thalassemia. The Company could not appropriately address the U.S. Food and Drug Administration’s questions about the benefit-risk profile of Reblozyl in this patient population based on the current dataset from the Phase 2 BEYOND trial.

"While we will not pursue this indication in the U.S., we’re continuing to evaluate Reblozyl in a broad clinical development program to bring this important therapeutic option to more patients living with the burden of anemia," said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb.

Reblozyl, a first-in-class therapeutic option, is currently approved in the United States, European Union and Canada to address transfusion-dependent anemia-associated beta thalassemia and lower-risk myelodysplastic syndromes.

https://finance.yahoo.com/news/bristol-myers-squibb-withdraws-supplemental-205900990.html

Salmonella vaccine for poultry contributed to rise of antibiotic-resistant bacteria: researchers

 An investigation into the evolution of Salmonella bacteria infecting Brazilian poultry shows that the introduction of a Salmonella vaccine, combined with increasing antibiotic usage by Brazilian farmers, has led to the rise of strains that are more antibiotic-resistant, but less likely to cause disease in humans. Andrea Micke Moreno of the University of São Paulo, Brazil, and Alison Mather of Quadram Institute Bioscience, UK, report these findings in a new study publishing June 2nd in the open access journal PLOS Genetics.

The bacterium Salmonella enterica is a common cause of food poisoning in humans that frequently results from contaminated poultry. Brazil is the world's largest exporter of chicken meat globally, and a team led by Micke Moreno and Mather wanted to know if the strains of Salmonella present in Brazil were contributing to food poisoning cases in countries that import their products. The researchers compared the genomes of 183 Salmonella collected from chickens in Brazil and 357 Salmonella genomes collected from humans, domestic poultry, and imported Brazilian poultry products in the United Kingdom. They also looked at more than 1,200 publicly available genomes of the two main types of Salmonella found in Brazil to see what they could learn about the evolution of the Brazilian strains.

The team found that distinct lineages of the two main Salmonella types developed in Brazil in the early 2000s, around the same time that the country introduced a Salmonella vaccine for poultry. These bacteria possess genes that make them resistant to three types of antibiotics. But despite their rise in Brazil, these antibiotic-resistant bacteria have caused very few cases of Salmonella in humans in the UK and have not spread to domestic chickens.

Overall, these findings suggest that the use of the Salmonella vaccine in Brazil, along with greater antibiotic usage, enabled the rise of drug-resistant forms of Salmonella, but that these bacteria have not led to greater numbers of food poisoning cases in the UK. The researchers point out that their evaluation of Salmonella genomes from a range of sources in Brazil and the UK reinforces the importance of taking a "One Health" approach to disease, which involves collaborative, multidisciplinary efforts to improve the health of people, animals, and the environment.

Mather adds, "Through our genomic detective work, we have tracked how changes in chicken rearing in Brazil have changed the profile of Salmonella bacteria found circulating within the poultry industry. Whilst this poses no immediate health risk to importing countries like the UK, the bacteria were resistant to antimicrobial drugs, and this highlights the importance of taking a 'One Health' approach that sees the connections between the health of people, animals and the environment, especially when assessing global food supply chains."

Story Source:

Materials provided by PLOS. Note: Content may be edited for style and length.

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Journal Reference:

1. Nabil-Fareed Alikhan, Luisa Zanolli Moreno, Luis Ricardo Castellanos, Marie Anne Chattaway, Jim McLauchlin, Martin Lodge, Justin O’Grady, Roxana Zamudio, Emma Doughty, Liljana Petrovska, Marcos Paulo Vieira Cunha, Terezinha Knöbl, Andrea Micke Moreno, Alison E. Mather. Dynamics of Salmonella enterica and antimicrobial resistance in the Brazilian poultry industry and global impacts on public health. PLOS Genetics, 2022; 18 (6): e1010174 DOI: 10.1371/journal.pgen.1010174

https://www.sciencedaily.com/releases/2022/06/220602140818.htm

Counting cancerous lymph nodes is best predictor of mortality across most cancers

 Patients newly diagnosed with cancer typically focus on one question, eclipsing all others: "What is my prognosis?"

Determining a cancer patient's prognosis -- the likely course and outcome of their disease -- typically involves staging the lymph nodes, a process that examines factors such as the lymph node's size, location and how far the cancer has extended beyond the node. Lymph node staging, however, currently is highly variable, depending on the cancer site, said Zachary S. Zumsteg, MD, assistant professor of Radiation Oncology at Cedars-Sinai Cancer. Because staging helps determine which treatments patients receive, getting it right should be consistent, accurate and universal, which is not always the case, he added.

A study co-led by Zumsteg, recently published in the Journal of the National Cancer Institute,has confirmed the effectiveness of a universal lymph node staging process that potentially may do just that.

"Count the number of metastatic lymph nodes," Zumsteg said. "We found that this simple process is much better for determining prognoses for solid tumors than all the other factors used today. It should be the backbone of nodal staging because it is the best predictor of mortality, irrespective of the disease site."

To test their hypothesis that metastatic nodal counting could be used to generate objective and reproducible nodal classification systems for all solid tumors, the researchers performed a retrospective analysis of nearly 1.3 million patients from the National Cancer Database who were diagnosed between 2004 and 2015. The researchers also used data from an additional 2 million patients from the Surveillance, Epidemiology, and End Results registry.

Their findings, validated across 16 of the most common solid cancers in the United States, confirmed that the number of cancerous lymph nodes is a dominant predictor of cancer death. Investigators also found that consistently, across disease sites, patient mortality risk increased continuously with the increasing number of metastatic lymph nodes.

"These findings are significant because they can potentially improve and simplify how most solid cancers are staged," said study co-author Anthony Nguyen, MD, PhD, a resident in the Department of Radiation Oncology at Cedars-Sinai Cancer. "Lymph node counting is possible in virtually all medical settings, including resource-poor countries, without increased cost to the provider or patient. It also is objective and concrete -- almost all pathologists can look at lymph nodes and agree about how many are cancerous."

Nguyen added that this nodal staging process may improve treatment and prognostic information for patients, delivering a more accurate report about the course and probable outcome of their disease.

"A patient with 10 or more cancerous lymph nodes will have a dramatically different prognosis than one with one positive lymph node," Nguyen said. "That should be accounted for in their overall staging."

History of Nodal Staging

Historically, physicians have recognized that malignant tumors often spread to local lymph nodes before spreading to other parts of the body. Metastatic lymph nodes also have been associated with worse survival outcomes across nearly all solid cancers, including breast, lung, colorectal, prostate, melanoma, and head and neck cancer.

Although nodal status represents one of the cornerstones upon which modern cancer staging is built, it remains highly variable among different disease sites, Nguyen said. Breast cancer staging, for example, relies heavily on the number of cancerous lymph nodes present, while staging for other cancer types uses tumor size, location and spread outside of the lymph nodes.

"Conventional teaching is that nodal metastases behave differently among different cancer types, which accounts for the different staging systems used for each cancer," Zumsteg said. "While it is true that breast cancer is different from prostate cancer, our study finds that there are more similarities than differences among cancers in terms of lymph node behavior. The study comprehensively examined nodal staging across all common solid cancers, rather than looking at a single cancer type in isolation, as has been done for decades."

Study Limitations

While the study's findings are promising, the researchers also cite its limitations. Key among them is that the data focus only on survival, not on cancer recurrences and metastases, Zumsteg explained.

"We need more detailed patterns of recurrence and need to understand the intermediate step: Why does the number of positive lymph nodes cause cancer spread and death?" Zumsteg said. "What happens between surgery and death? Do patients with higher positive lymph node counts have more recurrences in the lymph nodes themselves, more recurrences at other distant sites, or both?"

In the short term, the researchers hope to raise awareness across all communities, so the nodal staging system can be implemented, the researchers said.

"Nodal stages inform whether head and neck cancer patients, for example, are treated with surgery, chemotherapy or radiation, or all three," Zumsteg said. "It is a major factor that guides treatments across all cancers. Improving staging can improve these treatment decisions."

Story Source:

Materials provided by Cedars-Sinai Medical Center. Note: Content may be edited for style and length.

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Journal Reference:

1. Anthony T Nguyen, Michael Luu, Vina P Nguyen, Diana J Lu, Stephen L Shiao, Mitchell Kamrava, Katelyn M Atkins, Alain C Mita, Kevin S Scher, Daniel E Spratt, Mark B Faries, Timothy J Daskivich, De-Chen Lin, Michelle M Chen, Jon Mallen-St Clair, Howard M Sandler, Allen S Ho, Zachary S Zumsteg. Quantitative Nodal Burden and Mortality Across Solid Cancers. JNCI: Journal of the National Cancer Institute, 2022; DOI: 10.1093/jnci/djac059

https://www.sciencedaily.com/releases/2022/06/220603100123.htm

Melatonin Poisonings in Kids Jumped 530% in 10 Years

 Pediatric poisoning from the dietary supplement melatonin rose by over 500% from 2012 to 2021, mainly due to an increase among children under age 5, researchers found.

Children ingesting melatonin, which is generally used to treat insomnia and sleep disorders, accounted for 4.9% of all pediatric ingestions reported to poison control centers in 2021, a 530% jump from 0.6% in 2012, reported Karima Lelak, MD, of Children's Hospital of Michigan in Detroit, and colleagues.

In addition, pediatric hospitalizations related to melatonin poisoning rose during the study period. Five children required mechanical ventilation and two died, the authors wrote in the Morbidity and Mortality Weekly Report.

Lelak's team noted that not surprisingly, the largest increase in melatonin ingestion occurred during the COVID pandemic, writing that "this might be related to increased accessibility of melatonin ... as children spent more time at home because of stay-at-home orders and school closures," or that the pandemic might have increased sleep disturbances, which meant it was accessible in more households.

"Public health initiatives should focus on raising awareness of increasing numbers of melatonin ingestions among children and on the development of preventive measures to eliminate this risk," the researchers wrote.

The authors examined data from single-substance melatonin ingestions in individuals 19 or younger which were reported to U.S. poison control centers.

From 2012 to 2021, there were 260,435 pediatric melatonin ingestions reported, which comprised 2.25% of all pediatric ingestions. That number skyrocketed from 8,337 in 2012 to 52,263 in 2021, with the largest increase (+38%) occurring from 2019 to 2020.

Nearly all (94%) were unintentional, occurred in the home (99%), and managed on-site (88%). Most involved boys age 5 or younger.

A large majority (83%) of children were asymptomatic, though gastrointestinal, cardiovascular, and central nervous system symptoms were most common among symptomatic children.

However, 27,795 children required treatment at a healthcare facility. While most (72%) were discharged, 15% were hospitalized and 1% required intensive care. The majority of children who were hospitalized were teenagers with intentional ingestions. Lelak and co-authors added that 4,555 children (1.6%) who ingested melatonin had more serious outcomes.

The two deaths were among children ages 3 months and 13 months; both occurred in the home and one was due to "intentional medication misuse," the authors wrote.

The authors urged healthcare providers to warn parents about potential toxic consequences of melatonin exposure and to report any melatonin-related adverse events to FDA's MedWatch, the agency's medical product safety reporting program.

Disclosures

Lelak disclosed no conflicts of interest. One co-author disclosed being associate editor of Pediatrics, and support from Wolters Kluwer.

Primary Source

Morbidity and Mortality Weekly Report

Source Reference: Lelak K, et al "Pediatric melatonin ingestions -- United States, 2012-2021" MMWR 2022; 71:725-729.

https://www.medpagetoday.com/pediatrics/generalpediatrics/99017