First KRAS based therapy in oncology

With the decision of approval of the first KRAS based therapy a week ago, my news feed was filled with comments about a new era for cancer treatment. I wanted to leverage this moment to learn more about why ‘Sotorasib’, the drug developed for the treatment, was needed, and what it means to the field of oncology.

Let’s start with the target population for this drug and understand why this was needed.

There are various types of cancers, among them the ones that affect the lung are divided into non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC). SCLC is the more aggressive form of lung cancer where treatments for it can only manage the disease and not stop the progression. The drug in consideration targets NSCLC. It is the type of lung cancer which is supposed to be more treatable, where malignant (cancer) cells form in the tissues of the lung. Smoking is a major risk factor for it and the symptoms are centered around breathlessness and chronic cough. There are a lot of different types of NSCLC as well but for most patients with non-small cell lung cancer, current treatments do not cure the cancer.

Sotorasib(Lumakras) has been approved as the first treatment for adult patients with non–non small cell lung cancer whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are one of the most common genomic alterations identified in solid tumors, especially lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non–small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma. Mutant KRAS has been an oncogenic target for decades, but no viable therapeutic agents were developed due to the lack of identification of deep binding pockets for specific small-molecule inhibitors. “Sotorasib represents a major advancement in oncology and changes the treatment paradigm for patients with KRAS G12C–mutated non–small cell lung cancer,” Bob T. Li, MD, PhD, MPH, principal investigator at Memorial Sloan Kettering Cancer Center, said in a press release. “Patients with non–small cell lung cancer who have progressed beyond first-line treatment face a poor prognosis and have limited treatment options available to them. Sotorasib delivers a new option for these patients, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research.”

Let’s now talk about what it means to the field of oncology and what drugs are in the works for personalized treatment of cancer patients.

“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Today’s approval represents a significant step toward a future where more patients will have a personalized treatment approach.”

The drug definitely marked the beginning of a new era for approval of drugs that target these ‘undruggable targets’ and provide personalized treatment for patients with cancer. There are a lot of current trials going on targeting these undruggable targets such as KRAS and p53. To name a few of these clinical trials I am looking forward to along with some of them targeting druggable targets for personalized care are:

• The global, randomized, active-controlled phase 3 CodeBreaK 200 study (NCT04303780) is currently ongoing in patients with previously treated KRAS G12C–mutant NSCLC. The trial will investigate sotorasib compared with docetaxel as treatment for their disease.
• A Phase 2 Study(NCT03668340) of the Wee1 Inhibitor AZD1775 in Women With Recurrent or Persistent Uterine Serous Carcinoma or Uterine Carcinosarcoma is going on. The trial will investigate the progression free survival and toxicities of the inhibitor AZD1775.
• A Phase I/II Study(NCT03634228) of the Oral MDM2 Inhibitor DS-3032b (Milademetan) in Combination With Low Dose Cytarabine (LDAC) in Patients With Newly Diagnosed or Relapsed/Refractory Acute Myeloid Leukemia (AML) has started.
• A Phase 1 Study(NCT03654716) of the Dual MDM2/MDMX Inhibitor ALRN-6924 in Pediatric Cancer is going on.
• A Phase 1/2 Multiple Expansion Cohort Trial(NCT03785249) of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1 is going on.
• A Phase 1 study(NCT04117087) for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic MSS CRC who have progressed on 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab is going on.

I am hoping most of these give us positive results to look forward to and increase the years in the lives of cancer patients!