Targeting KRAS gene mutation reduces tumors.

New results from early clinical trials of a drug that targets a cancer-causing mutation in the KRAS gene have shown that it can shrink tumours and is well-tolerated by patients.

In two presentations on Sunday at the 32nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online, researchers involved in the KRYSTAL-1 phase I/II clinical trial said that adagrasib (MRTX849) showed clinical activity and manageable adverse side effects in patients with non-small cell lung cancer (NSCLC), colorectal cancer and other solid tumours such as pancreatic, endometrial and ovarian cancer.

Scientists have been trying to develop new drugs that target the KRAS mutation for decades as the gene is one of the most common mutations in cancer. Adagrasib targets a KRAS mutation called G12C; patients who have cancer with this mutation have a poor prognosis and the tumours are resistant to standard treatments. The KRAS G12C mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC; it is also present in 4% of colorectal cancers and 2% of pancreatic cancers. This means it affects well over 100,000 people each year worldwide and represents an unmet need.

Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its signalling to other cells and preventing tumour cell growth and proliferation; this leads to cancer cell death.

Until 2018, no KRAS inhibitor had moved beyond preclinical testing, but in 2018 adagrasib was among the KRAS inhibitors given permission by the US Food and Drug Administration (FDA) to be investigated in clinical trials that started in January 2019. The KRYSTAL-1 phase I/II clinical trial of adagrasib is being conducted in more than 50 sites in the USA and Mirati Therapeutics, the company that has rights to and is developing the drug, is planning to expand clinical developments to other regions, starting in early 2021.

Patients with advanced NSCLC, colorectal cancer and other solid tumours with the KRAS G12C mutation were enrolled in the phase I and Ib part of the KRYSTAL-1 trial and, as the trial progressed, further patients were enrolled in the phase II part. All patients had advanced cancer and had previously received standard treatment for their disease, including chemotherapy and immunotherapy. While they were in the KRYSTAL-1 trial, they received 600mg of adagrasib taken orally twice a day.

Dr Pasi A. Jänne, Director of the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, USA, presented the results for 79 NSCLC patients up to 30 August 2020 to the Symposium. He said: “Among 51 patients for whom we had information on the clinical activity of adagrasib, 45% had an objective response, meaning that their tumours shrank by 30% or more and did not grow or spread to other parts of the body. This includes five patients who had an unconfirmed partial response by 30 August and who were subsequently confirmed as having a partial response in later scans. The disease control rate was 96%, meaning that 49 out of the 51 patients showed a partial or complete response or had stable disease.”

Among the 14 patients in the phase I/Ib part of the trial who had been followed for a longer period of time (median time of 9.6 months), an objective response was seen in six (43%) and in four out of these six patients the duration of treatment has lasted for more than 11 months.

The researchers also analysed the treatment-related adverse side effects in all 110 patients included in the phase I/Ib and II parts of the trial, including those with colorectal cancer and other solid tumours, as well as those with NSCLC. Side effects included nausea (54%), diarrhoea (51%), vomiting (35%), fatigue (32%) and increased levels of an enzyme that indicates minor liver irritation (20%). The only serious adverse side effect to occur in more than one patient was low sodium in the blood, which occurred in two patients.

Prof Jänne said: “KRAS G12C patients are a population where there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, the treatment options are limited. The fact we are seeing responses in 45% of patients, which indicates that adagrasib may be an effective therapy, is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients.

“I’m thrilled to see how well adagrasib is working. Having been involved in multiple other studies of targeted therapies for lung cancer patients, the fact that we now have ones that are showing clinical activity in patients with KRAS G12C mutant cancers is super exciting and wonderful news for lung cancer patients.”

Dr Melissa L. Johnson, Associate Director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology, Nashville, USA, presented updated results for 31 patients with colorectal cancer and other solid tumours up to the data cut-off point of 30 August 2020.

Out of 18 colorectal cancer patients who could be evaluated, three (17%) had a confirmed objective response and two of them continue to receive treatment. Disease control was seen in 17 of the patients (94%) and 12 of these patients continue to be treated.

Among the six patients with other solid tumours who could be evaluated, a partial response was confirmed in a patient with endometrial cancer and in a patient with pancreatic cancer. Unconfirmed partial responses occurred in one patient with ovarian cancer and one with cancer of the bile duct (cholangiocarcinoma). All six patients remain on the treatment.

“I think the clinical activity of adagrasib is highly encouraging in these patients,” said Dr Johnson. “In some patients, the tumour size decreased and this shrinkage was durable, with some evaluable patients still on treatment after 11 months. The unique molecular structure of adagrasib means it takes about 24 hours for concentrations of the drug to reduce by a half, and most of the drug is distributed to the tissues of the body, which appears to result in deep and durable responses.”

Adagrasib’s long half-life enables it to inhibit KRAS continuously between doses. This helps to prevent what is known as a feedback loop, which occurs when the KRAS pathway is not completely inhibited and becomes hyperactive, leading to tumour regrowth.

“We believe that preventing feedback loops may lead to more durable responses in the tumour over a longer period of time and better tumour shrinkage,” said Dr Johnson.

“Adagrasib is generally well tolerated and the adverse side effects are manageable. While 32% of treatment-related adverse events were significant, only 7% of these led to treatment discontinuation,” she said.

The KRYSTAL-1 trial continues and the researchers are also looking at combining adagrasib with other targeted therapies, such as cetuximab for colon cancer and afatinib or pembrolizumab for lung cancer.

William R. Sellers, Professor of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School, USA, is co-chair of the EORTC-NCI-AACR Symposium on behalf of the NCI and was not involved with the research. He commented: “Finding drugs that successfully and selectively inhibit the action of mutant versions of the KRAS gene has been an important goal in cancer drug discovery for years. Mutations in KRAS are common in a number of major cancers that are often hard to treat. Although preliminary, the results of the KRYSTAL-1 trial so far look very promising. Certainly I look forward to the peer review of these data and to the longer-term follow-up of treated patients so we can evaluate the durability of the benefit. It will also be interesting to see how adagrasib performs in combination with other existing therapies. These data also suggest that targeting other forms of mutant KRAS will be clinically important.”


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