MedNess: bite-size biopharma and medtech news

BI and Amgen to collaborate for KRAS inhibitors
On 16^th September, Boehringer Ingelheim announced that it will collaborate with Amgen for a Phase 1 clinical trial of Lumakras, a KRAS G12C selective inhibitor in combination with BI 1701963, a SOS1::pan-KRAS inhibitor for the treatment of locally advanced or metastatic NSCLC and CRC.
Background: KRAS has remained a difficult therapeutic target for many decades and tumors harbouring KRAS mutations are associated with poor prognosis. Apart from efficacy, targeting KRAS also involves considerable safety issues. KRAS G12C mutations are present in ~13% of non-squamous NSCLC, 3-4% of CRC and in subsets of various other tumors.
In May 2021, the US FDA granted accelerated approval to Lumakras as the first and only treatment option for KRAS G12C mutated locally advanced or metastatic NSCLC.
Details: The Phase 1 trial will evaluate the potential synergistic anti-tumour activity of the drug combination in NSCLC and CRC. Preclinical data suggest that the combination of KRAS G12C and SOS1:pan-KRAS inhibition can lead to increased inhibition in KRAS G12C-driven cancers based on the complementary mechanisms of assets.
BI 1701963 prevents the formation of KRAS(ON) state and shifts the equilibrium towards the KRAS(OFF) state exposing and sensitizing KRAS G12C mutant tumors to KRAS G12C inhibitors, like Lumakras, that covalently bind to cytosine 12 within the switch II pocket of GDP-KRAS G12C (KRAS(OFF)). This also prevents the activation of downstream RAF/MEK/ERK signalling pathway by GTP-KRAS.
Under the non-exclusive collaboration, Amgen will sponsor the clinical trial while both BI and Amgen will share costs and co-supervise clinical development for the combination therapy.
Amgen’s key rival Mirati is also advancing its KRAS G12C inhibitor, Adagrasib in clinical development. Last year, BI announced a similar collaboration with Mirati’s Adagrasib.

EXKIVITY™ (mobocertinib) Approved by U.S. FDA as the First Oral Therapy Specifically Designed for Patients with EGFR Exon20 Insertion+ NSCLC
“The approval of EXKIVITY introduces a new and effective treatment option for patients with EGFR Exon20 insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president, Global Oncology Business Unit, Takeda. “EXKIVITY is the first and only oral therapy specifically designed to target EGFR Exon20 insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

U.S. FDA Accepts Biologics License Application for Tislelizumab in Esophageal Squamous Cell Carcinoma
“Our uniquely designed anti-PD-1 antibody tislelizumab has been shown to significantly improve survival compared to chemotherapy for people with a variety of solid tumors and hematologic malignancies. We previously shared the compelling results at ASCO 2021 with tislelizumab significantly prolonging survival and demonstrating a favorable safety profile over chemotherapy in patients with locally advanced or metastatic ESCC, a devastating disease with an average five-year survival rate of just five percent. This BLA acceptance brings us closer to potentially providing tislelizumab as a treatment for these patients in the United States,” said Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. “Tislelizumab is already approved in five indications in China and has the potential to become a preferred immunotherapy option there. We look forward to continued collaboration with Novartis to work to bring access to tislelizumab to patients around the world.”

Non-invasive test identifies stress as a determining factor in heart disease
According to the American Heart Society (AHS), stress arising from SDH (Social Determinants of Heath) factors can aid in the development of heart disease. In a recent study by Kosuke Inoue, MD, PhD, it was indicated that cumulative exposure to daily stressors or traumatic stress, as well as individual’s mental well-being can positively or negatively influence the cardiovascular health. According to Dr. Inoue, “The stress hormones norepinephrine, epinephrine, dopamine, and cortisol can increase with stress from life events, work, relationships, finances, and more. And we confirmed that stress is a key factor contributing to the risk of hypertension and cardiovascular events.” The study exclusively focuses on examining adults without hypertension, which sets it apart from the past studies. The study included 6000 men and women, looking at the risk factors of atherosclerosis through a Multi-Ethnic Study of Atherosclerosis (MESA) Stress 1 study. Four stress hormones, norepinephrine, epinephrine, dopamine, and cortisol were analyzed in a 12h urine test. The study results showed that in a median follow-up period of 6.5-years, participants had a 21- 31 percent increased chance of developing hypertension with a doubling of the 4 stress hormones. Additionally, in a median follow-up period of 11.2-years, there was a 90 percent increased risk of cardiovascular events each time cortisol levels doubled. Dr. Inoue hopes that by utilizing this non-invasive test and measuring the stress hormones more frequently, more individuals at risk can be identified.

Novocure and Roche to Evaluate Tumor Treating Fields as Part of a Novel Combination for the First-line Treatment of Metastatic Pancreatic Cancer
“We are pleased to collaborate with Roche, a global leader in oncology, to explore the efficacy of TTFields together with atezolizumab immunotherapy in pancreatic cancer,” said William Doyle, Novocure’s Executive Chairman. “The immune-shielded environment of the pancreas has proved challenging for immunotherapies alone to provide benefit. Our phase 2 pilot trial with Roche will study the ability of TTFields together with atezolizumab to improve clinical outcomes for patients with this deadly disease.”