KRAS inhibitor pancreatic cancer data released!

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On February 14, Amgen announced efficacy and safety data from the Phase I/II CodeBreaK 100 study of Lumakras (sotorasib) in KRAS-mutant advanced pancreatic cancer

Among 38 patients with advanced pancreatic cancer who had received severe treatment (about 80% had received second-line and later-line therapy), the confirmed ORR assessed by BICR after sotorasib treatment was 21% (8/38), and the disease control rate ( DCR) was 84%

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On January 21 this year, Mirati Therapeutics, another star company that is leading the way in the development of KRAS inhibitors, also announced the positive results of its KRAS G12C inhibitor adagrasib (MRTX849) in the Phase II KRYSTAL-1 study in pancreatic cancer

The data show that as of September 10, 2021, among 10 evaluable pancreatic cancer patients, the objective response rate was 50% (all PR), including 1 unconfirmed partial response (PR), with a median mDOR of 7.

Only from the current small sample data, adagrasib is better for pancreatic cancer patients

Pancreatic cancer is a malignant tumor with an extremely poor prognosis and the fourth leading cause of cancer death in the United States.

The KRAS mutation in pancreatic cancer is much higher than that in lung adenocarcinoma (30% vs 90%), but the KRAS G12C mutation is less common in pancreatic cancer, about 1–2% (14% vs 2%)

Sotorasib is the world's first KRAS G12C inhibitor approved for second-line treatment of KRAS G12C-mutated advanced or metastatic non-small cell lung cancer (NSCLC) in May 2021, with global sales of $90 million in 2021

Adagrasib and sotorasib, while showing encouraging clinical data in pancreatic cancer patients with KRAS G12C mutation, also differ slightly

In terms of efficacy data, Adagrasib has shown certain advantages in all aspects

In addition, sotorasib appeared to show a longer trend for the duration of treatment, but Adagrasib still dominated the DoR

It can be seen that for patients with pancreatic cancer KRAS G12C mutation, both Adagrasib and sotorasib have shown early encouraging clinical data and are expected to become new treatment options

In 2021, a study of KRAS G12C acquired resistance mechanisms was published in the New England Journal of Medicine.

Dr.

Continuous testing of patients during treatment, as well as thinking about how to prevent drug resistance, can lead to more effective pancreatic cancer treatment

Sotorasib is also conducting several clinical studies of combination therapy, including in pancreatic cancer
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Pancreatic tumor cells can promote the activation of surrounding stromal cells and immunosuppressive cells, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and secrete a series of cells Factors and chemokines cause these cells to cluster to the tumor site
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On the other hand, activated stromal cells generate large amounts of extracellular matrix, forming a fibrous "barrier" around pancreatic tumor cells, preventing effector cells (T cells and NK cells) from infiltrating the tumor, allowing tumor cells to evade immune surveillance
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Therefore, in pancreatic cancer, an immunosuppressive environment is usually manifested, resulting in almost complete annihilation of tumor immunotherapy
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As seen in preclinical data in other malignancies such as lung and colorectal cancer, inhibition of KRAS G12C may result in increased T cell infiltration and activation of memory T cell responses, whether inhibition of KRAS G12C has any effect on the immune microenvironment of pancreatic cancer patients make an impact? Although no similar work has been carried out in pancreatic cancer models, many people have tried to use KRAS inhibitors in combination with anti-PD1 antibodies.
Both sotorasib and adagrasib have research cooperation in this regard, and look forward to further expansion in pancreatic cancer clinical research , to provide better treatment options for pancreatic cancer patients
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