How does the KRAS gene-targeting drug AMG510 control brain lesions?

The KRAS gene mutation in lung cancer is a persistent problem, and there has been a lack of a good targeted drug for this gene mutation until the emergence

The probability of brain metastasis in lung cancer is high, and the current treatment methods for brain metastases include surgery, radiotherapy and chemotherapy, and targeted immunity, but the requirements for surgical benefits are very demanding, and radiotherapy is also restricted by many factors, especially affecting the long-term quality

Ongoing CodeBreak 100 clinical trials have shown that some patients treated with AMG510 have achieved complete or partial remission of brain metastases and achieved a stable state

In the following case, the patient has a G12C mutation in the KRAS gene, and the brain metastases have not been treated before, let's take a look at the efficacy of AMG510 after using this drug.

AMG510 makes brain metastases disappear

In June 2018, a 61-year-old woman was admitted to the hospital for examination

The first treatment performed by the patient was chemotherapy plus the PD-1 inhibitor pabolivizumab, and the chemotherapy drugs were cisplatin and pemetrexed

In September 2018, the patient started maintenance therapy with pemetrexed plus pabolizumab and discontinued ciplatin, but discontinued in March 2019 due to pemetrexed progressive polyneuropathy

In June 2019, the patient's lungs progressed
.

Hemostasis and radiotherapy for hemostasis are required, and the PD-1 inhibitor pabolizumab
is discontinued.

Metastatic lesions in the brain also remain in a state of
continuous remission.

In November 2019, the lesions in the patient's lungs progressed again, and the lesions in the brain also progressed and led to related symptoms
.

There are new metastases in the cerebellar part, and continuous hydrocephalus appears
.

Stereotactic radiation therapy was performed on cerebellar lesions by implantation of a ventricular abdominal shunt tube, as well as radiation therapy
for lesions of the lungs that were enlarged.

Since the condition was stable for more than one year, the patient resumed the use of the
PD-1 inhibitor pabolizumab.

In February 2021, the patient's cerebellum and lungs progressed again, treatment with docetaxel was started, and after four treatment cycles, new lesions
appeared in the brain.

In June 2021, the patient began oral administration of 960 mg of AMG510 per day, and after 6 weeks of administration, the patient's lung lesions and new metastatic lesions of the brain that had not yet been treated showed a good response, which lasted for 5 months
.

Figure 1: Imaging examination treated with AMG510

As shown in the figure above, during the six weeks of AMG510 use, brain imaging showed that the patient's brain lesions had shrunk significantly, achieving a clinical partial remission
.

In November 2021, due to the progression of the disease, the patient began treatment
with gemcitabine.

After a month, the brain progresses and presents with associated symptoms, corresponding behavioral changes and mental atrophy, for which neurosurgical treatment is carried
out.

Treatment of gemcitabine continues until February
2022.

In March 2022, the patient again challenged the use of pemetrexed, and a month later with carboplatin plus paclitaxel, while radiotherapy
for the whole brain was performed.

However, the condition continued to progress, and the patient began palliative care in May 2022
.

Discussion and enlightenment

From 2018 to 2022, the patient's overall treatment lasted a total of more than four years, which is rare for lung cancer patients with KRAS
gene mutations.

During the treatment process, a variety of drug treatment options continue to resist, patients continue to change drugs, again and again to buy themselves time, under the premise of ensuring the quality of life, prolong the time of life (see figure below
).

Figure 2.
A roadmap of the patient's overall treatment process

AMG510 has shown good efficacy for asymptomatic, untreated active brain lesions, with the lesions nearly completely absent
within a few weeks of treatment.

Unfortunately, although tumor foci disappear quickly, recurrence is also rapid
.

However, there are also patients treated with AMG510 and brain metastases are controlled
.

Whether this is related to the type of KRAS gene drive mutation, we have no way of knowing
.

It should be noted that during the treatment of AMG510, close brain MRI examination is required to observe whether there are signs of recurrence of brain metastases in time to take corresponding measures
.

Some clinical trials are evaluating the potential of AMG510 combined with bevacizumab and others to treat brain metastases, and the degree of cancer will be reported
in a timely manner in this regard.

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.

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References:

1、Kira-Lee Koster, et al.
, Sotorasib Shows Intracranial Activity in Patients with KRAS G12C-Mutated Adenocarcinoma of the Lung and Untreated Active Brain Metastases, Case Rep Oncol 2022; 15:720–725

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