November 2022

KRAS is one of the most frequently mutated oncogenes in cancer, especially colorectal cancer; however, efforts to directly target KRAS have been largely unsuccessful due to its high affinity for GTP/GDP and the lack of a clear binding pocket. MRTX849 as a potent, covalent KRASG12C inhibitor is currently being tested. While treatment which appear to be evident at multiple nodes of the signaling pathway. Several biochemical analyses revealed that KRASG12C exhibits the highest intrinsic GTP hydrolysis rate and highest nucleotide exchange rate among KRAS mutants. Therefore, the nucleotide-bound state of KRASG12C can be shifted toward the GDP-bound state by pharmacologically modulating upstream signaling that increase the activity of KRASG12C inhibitors by introducing a co-mutation that impairs the GTPase activity of KRASG12C.1 

Cetuximab also known as ERBITUX, with MRTX89 is a type of targeted cancer drug in treatment for advanced bowel cancer, commonly in colorectal cancer, as well as head and neck cancers that start in the mouth and throat. It targets KRASG12C to inhibit its dividing mutations. The drug class Cetuximab belongs in, is the monoclonal antibodies (MABs) which are copies of a single antibody. Given this, the only route for it to be effective is intravenous administration as an infusion or slow drip. For patients with thin veins may have severe adverse reactions due to the sensitivity of their veins such as bruising and damaging of the veins.2 

A different option for this patient that would like to receive MRTX89 treatment without IV treatment would be LUMAKRAS also known as Sotorasib. The mechanism of action will still specifically inhibit KRASG12C, but instead as an oral route of administration rather than intravenous. This will offer a more convenient, less painful, but still be an effective option especially in patients with thin veins and would like a different route of administration. Sotorasib is administered in a 960mg tablet that is to be taken only once a day. There are often dose reductions if the patient cannot tolerate the initial potency which again provides patients with safety implementations. It is important to monitor liver functions in these patients especially if they have other prevailing liver disorders, due to LUMAKRAS being able to possibly cause hepatotoxicity now that this is an oral administration rather intravenous.3 

Further studies of LUMAKRAS were performed to analyze the efficacy of the oral dosage form in treating colorectal cancer, as well as pancreatic, endometrial, and appendiceal cancers and melanoma. In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). In conclusion, Sotorasib showed positive anticancer activity in patients with heavily pretreated advanced solid tumors with the KRASG12C mutation. Grade 3 or 4 treatment-related toxic effects only occurred in 11.6% of the patients and is considered very safe overall.4

References 

1 Cetuximab (Erbitux). Cetuximab (Erbitux) | Cancer information | Cancer Research UK. (2019, May 14). https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/cetuximab 

2 Hallin, J., et al The krasg12c inhibitor MRTX849 provides insight toward therapeutic susceptibility of kras-mutant cancers in mouse models and patients. (2020, January). Cancer discovery. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6954325/ 

3 Hong DS, et al KRASG12C inhibition with Sotorasib in advanced solid tumors. The New England journal of medicine. https://pubmed.ncbi.nlm.nih.gov/32955176/ 

4 Learn more about a new oral treatment option for patients with advanced NSCLC. KRAS G12C Mutated NSCLC Oral Therapy. (n.d.) https://www.lumakrashcp.com/sotorasib-dosing#dosing

Camzyos (Mavacamten) has shown some significant improvements in patients with hypertrophic cardiomyopathy (HCM). During clinical trials, 37% of patients had achieved the main goal of the study which was to decrease HCM symptoms (including but not limited to shortness of breath, chest pain, and rapid heartbeat) and increase peak oxygen consumption (the maximal amount of oxygen that can be utilized during exercise). Apart from the patients who met the goal of Camzyos, 27% of patients had some relief in symptoms and improvements in pressure build up in the left ventricle of the heart, which would normally have decreased the blood flow to the rest of the body. Camzyos has been shown to significantly decrease the muscle thickness of the heart which is one of the main causes of HCM.

Although Camzyos has reduced symptoms and improved cardiovascular function in a number of patients, the odds of it becoming a first line therapy in all patients is low. Data shows that two procedures, myectomy and alcohol septal ablation, are more effective in reducing the pressure in the left ventricle and improving symptoms. Myectomy, a surgical procedure which reduces the thickness of the muscles in the heart, decreases symptoms by 95%, whereas Camzyos reduces symptoms by 50%. In the foreseeable future, it is possible for Camzyos to become a first line therapy for patients who are ineligible to receive myectomies or alcohol septal ablations. 

References 

[1] Maron, Martin S. and Ommen, Steve R. “Exploring New and Old Therapies for Obstructive Hypertrophic Cardiomyopathy.” Circulation. 2021;143:1181–1183  https://doi.org/10.1161/CIRCULATIONAHA.120.051330

[2] Keam, S.J. Mavacamten: First Approval. Drugs 82, 1127–1135 (2022). https://doi.org/10.1007/s40265-022-01739-7

Since the rise of COVID-19 cases around the world, efforts have been made to treat and prevent the spread of the virus. According to researchers from Missouri State University, there is a chance sodium pyruvate nasal spray can decrease symptoms, duration, and replication of COVID-19 infection.

Clinical trials have shown sodium pyruvate reduces respiratory inflammation caused by an IL-6 cytokine. This cytokine is also known to cause the negative symptoms experienced by COVID-19 patients. Thus, a two-week double-blind controlled human trial study was performed to showcase the effects of sodium pyruvate nasal spray on COVID-19 symptoms. A self-reported Likert scale of 0-10, 10 being the most severe was used. And the trial observed the effect on viral load in patients using viral titers. In this study, there was a statistically significant decrease in viral RNA copies in patients taking sodium pyruvate compared to the subjects taking the placebo (saline). Regarding the symptoms, there was a statistically significant decrease in coughing and sneezing with the group taking sodium sulfate, but the difference was not by much compared to subjects taking the placebo. There was also a statistically significant decrease in fatigue. In conclusion, based on this study sodium pyruvate nasal spray could potentially reduce symptoms of coughing, sneezing, and fatigue and decrease the viral load.

A cohort study was conducted on this topic by Takeda in 2017 in Tokyo, Japan. The safety and clinical efficacy of Alogliptin and Metformin Hydrochloride combination tablets were measured in 1026 participants who either had hepatic impairment, renal impairment, or were over the age of 65. The study took place over the course of one year and results revealed that about 6% of participants experienced adverse events. Serious adverse events included atrial fibrillation, deep vein thrombosis, and hepatocellular carcinoma. Other less serious adverse events included heart palpations, bundle branch block, hypoglycemia, renal disorder, chronic gastritis, muscle weakness, and dizziness. Over the course of the study, changes in HBA1C, fasting blood glucose, and fasting insulin were measured. From baseline to completion of the study, HBA1C decreased by an average of 0.259%. Fasting blood glucose decreased by an average of 12.08 mg/dL, and fasting insulin level increased by an average of 1.21 mcrU/mL.  

According to the package insert for Alogliptin and Metformin Hydrochloride combination tablets, therapy should generally be avoided in those with hepatic impairment due to the potential risk of lactic acidosis. This is an increased production in lactic acid characterized by stomach discomfort, muscle pain, malaise, and diarrhea. If therapy is continued, more serious symptoms may develop such as hypotension, resistant bradyarrhythmias, and possibly death.  

Alogliptin and Metformin Hydrochloride combination tablets may be used in those with renal impairment, however assessment of renal function must be determined before therapy can be initiated. This is because the risk of metformin accumulation and lactic acidosis increases with the degree of impairment. This therapy is not recommended in patients with eGFR 30 to 60 mL/minute/1.73 m2 and is contraindicated in patients with eGFR <30 mL/minute/1.73 m2.  

Accesspharmacy – pharmacy educational resource. (n.d.). Retrieved November 20, 2022, from https://accesspharmacy.mhmedical.com/drugs.aspx#monoNumber=423630§ionID=243300831&tab=tab0

Specified drug-use survey of Alogliptin and metformin hydrochloride combination tablets "survey on long-term use in type 2 diabetes mellitus patients with renal or hepatic impairment or advanced age" Retrieved November 20, 2022, from https://clinicaltrials.gov/ct2/show/NCT03555565

A phase I/II clinical trial (KRYSTAL-1) assessed the efficacy of MRTX849 (adagrasib) as monotherapy in the treatment of patients with advanced KRAS G12C solid tumors. Results from this study were recently released by Mirati therapeutics on September 7th, 2022. They evaluated adagrasib as a monotherapy and in combination with cetuximab. Of the 76 participants, 44 patients received adagrasib (600 mg twice daily) monotherapy and 32 patients received a combination of adagrasib and cetuximab. The monotherapy treatment resulted in a 19% objective response rate and 86% disease control rate. The median duration of response was 4.3 months and the median progression-free survival was 5.6 months. Combination treatment of adagrasib with cetuximab showed a objective response rate of 46% and a disease control rate of 100%. The median duration of response was 7.6 months and the median progression-free survival was 6.9 months. In both treatments, the majority of treatment-related adverse events were grade 1-2 and there were no grade 5 events observed. 

Overall, this study showed that adagrasib is clinically effective as a monotherapy as well as in combination with cetuximab. As stated previously, the monotherapy caused grade 1-2 adverse effects with the most common being nausea, diarrhea, vomiting and fatigue. These would most likely not impact the patient’s way of life compared to chemotherapy. In conclusion, efficacy of MRTX849 as monotherapy has been tested in a phase I/II clinical trial and has shown antitumor activity in patients with advanced KRAS G12C solid tumors.

References:

[1] Mirati Therapeutics presents late-breaking Adagrasib monotherapy and combination results in advanced colorectal cancer. Mirati Therapeutics Inc. (2022, September 7). https://ir.mirati.com/press-releases/press-release-details/2022/Mirati-Therapeutics-Presents-Late-Breaking-Adagrasib-Monotherapy-and-Combination-Results-in-Advanced-Colorectal-Cancer/default.aspx

It is not a surprise that most of those who require medical attention for chronic diseases or illnesses tend to be racial and ethnic minorities. Yet, despite the insurance coverage they may already be receiving, it can be a challenge for many to access certain healthcare providers. To mitigate this issue, insurers ought to focus and improve on three main areas: variety, distribution, and time.

Variety pertains to the different types of providers. For instance, a bilingual provider should be made available within a network for those whose primary language is not English in order to prevent miscommunication. “Types” of healthcare providers could also refer to those who specialize within a certain field (e.g, a community of people or region in which hypertension is a prevalent issue ought to have their needs addressed by cardiologists to maximize the optimization of their care).

This transitions into the next area of focus, which is distribution. The main problem with Medicaid or other government-funded insurances lies in the unequal geographic spread of providers. Distribution and variety go hand-in-hand in the sense that it is critical that a wide range of healthcare providers be covered to best address the needs of all patients within an area. With regards to the third point of focus, time, it would be ideal to make available a few of these providers outside of regular business hours, in case emergencies were to arise.