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February 23, 2022

LUMAKRAS struggles to compete in advanced pancreatic cancer

LUMAKRAS is unlikely to overtake adagrasib to become the first KRAS G12C-targeting agent for advanced pancreatic cancer.

By GlobalData Healthcare

On 14 February, Amgen published a press release announcing efficacy and safety data from the Phase I/II pivotal CodeBreak 100 trial of its small-molecule LUMAKRAS (sotorasib) in patients with KRAS G12C-mutated, advanced pancreatic cancer. Although Amgen believes that these data show clinically meaningful anticancer activity, it is unlikely to overtake its main competitor, Mirati Therapeutic’s adagrasib, in the race to become the first KRAS G12C-targeting agent marketed in this underserved patient population.

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the US in both males and females. Clinical outcomes among patients in the advanced or metastatic settings remain dismal, with a reported median survival of 5–7 months and a five-year survival rate of 10%, one of the lowest of any oncology indications. Composed mainly of chemotherapies, the pancreatic cancer treatment paradigm contains few therapeutic options that demonstrate clinical benefits, especially after second-line therapy. As such, developing novel therapies to improve survival rates in patients with advanced pancreatic cancer remains a high unmet need. The G12C mutation keeps the oncogenic KRAS protein in an activate conformational ‘on’ state that promotes downstream signalling and the aberrant growth of tumour cells in a number of solid tumours. Given that this mutation has historically been undruggable, physicians are keeping a keen eye on the progression of both small molecule inhibitors, LUMAKRAS and adagrasib.

In the CodeBreak 100 trial, in which LUMAKRAS monotherapy is being studied in multiple solid tumours, the cohort of 38 patients with pancreatic cancer demonstrated an overall response rate of 21.1% and a disease control rate (DCR) of 84.2%, along with positive safety results. The median progression-free survival (mPFS) was 4.0 months and overall survival was 6.9 months. The median duration of response was 5.7 months with a median follow-up of 16.8 months. As these patients were heavily pre-treated and nearly 80% of patients received LUMAKRAS as a third-line or later therapy, these results show a significant clinical benefit. Mirati’s adagrasib has, however, already achieved more profound clinical data. Last month, Mirati released data from the Phase I/II, pivotal KRYSTAL-1 trial stating that, after treatment with adagrasib monotherapy, ten patients with KRAS G12C-mutated pancreatic ductal adenocarcinoma (PDAC), which accounts for 80% of all pancreatic cancer diagnoses, showed both partial and objective response rates of 50%. It also demonstrated a disease control rate of 100% and a mPFS of 6.6 months.

Although LUMAKRAS was approved to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC), Amgen has not been able to replicate its success outside of NSCLC. According to David Reese, executive vice-president of research and development at Amgen, the next step is to expand the CodeBreak 100 trial by enrolling ‘more patients with pancreatic and other tumour types to better understand the efficacy and safety of LUMAKRAS in tumours outside of colorectal and NSCLCs’. Despite this, even after data from trials with larger numbers of patients are released, Mirati’s adagrasib is set to remain the clear leader in the race to gain first-to-market advantage in this patient population.

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