Cancer is the leading cause of death in Korea. Statistics show that cancer accounted for 27.5 percent of death's total causes (158.2 per 100,000 population) in 2019. Among the cancer-caused deaths, those by lung cancer had the highest proportion – 36.2 per 100,000 people died of lung cancer.

From the early 2000s, researchers have developed various anticancer drugs targeting oncogenes such as EGFR, ALK, and ROS1 that can cause genetic mutations in lung cancer.

​Professor Park Keun-chil of the Hematology-Oncology Division at Samsung Medical Center​
​Professor Park Keun-chil of the Hematology-Oncology Division at Samsung Medical Center​

These treatments have helped extend the survival of lung cancer patients significantly.

Still, the medical needs for various lung cancer treatment options remain unmet.

KRAS is an oncogene that easily mutates in several types of cancer. The KRAS gene mutation is the second most common in Asian non-small cell lung cancer (NSCLC) patients. Pharmaceutical firms and researchers have continuously challenged to develop a KRAS-targeting treatment for the past 40 years. However, the development of KRAS targeted therapy has remained incomplete so far.

Korea Biomedical Review has met with Professor Park Keun-chil of the Hematology-Oncology Division at Samsung Medical Center to learn about the unmet needs for KRAS-mutated NSCLC, treatment development progress, and expected changes in the treatment environment.

In November, Park presented the results of a phase-1 study on sotorasib, a KRAS G12C inhibitor, at the European Society for Medical Oncology (ESMO) Asia Congress 2020.

Question: Among oncogenes, KRAS had already been discovered decades ago, but researchers have not been able to develop any KRAS-inhibiting drug. Why is it so difficult to develop one?

Answer: KRAS is a protein that acts like a switch that regulates the activation and deactivation of GTP/GDP enzymes. KRAS involves in cell differentiation, proliferation, and survival.

So, researchers have studied to block the binding of GTP, the characteristic of KRAS, to prevent GTP activation and proliferation of cancerous cells.

While the concentration of a specific enzyme is nanomolar (nM, 1 billionth of a molar), a KRAS-GTP concentration is picomolar (pM, one-thousandth of nM), meaning it has a much higher affinity. In other words, it has not been easy to develop a drug with affinity 1,000 times stronger than that of GTP.

Due to KRAS structure, it has been difficult to develop a substance that directly binds to it and blocks its mechanism for the past 40 years.

Q: Can you tell us about the prevalence of KRAS-mutated cancer, patient trends, and treatment development progress?

A: KRAS shows more genetic mutations in patients in the West than those in Asia. In lung cancer, EGFR mutations are the highest in Asian patients and relatively low in Western patients.

In contrast, KRAS gene mutations appear about two to three times more in Western patients than Asian patients. Local data, including those of Samsung Medical Center, shows that about 7 to 8 percent of lung cancer patients have KRAS mutations. On the other hand, in Western cases, KRAS gene mutations appear in 15 to 30 percent of lung cancer patients.

Among KRAS gene variants, KRAS G12C mutation is most common. It appears in about 13 percent of patients with lung adenocarcinoma. KRAS G12C causes cancer when glycine is mutated into cysteine and activated at the codon 12 of the KRAS gene.

One of the representative investigational treatments is Amgen’s sotorasib (AMG510).

Sotorasib does not directly compete with GTP/GDP but binds to the mutated cysteine of KRAS G12C. The treatment candidate then makes the mutated cysteine inactivated and blocks signal transmission, which is an anti-cancer mechanism.

Q: You presented the results of a study on a KRAS G12C-mutation targeted therapy at the ESMO Asia 2020 in November. Can you explain it briefly?

A: As I mentioned earlier, it has not been easy to develop a KRAS-targeting drug. But Amgen developed sotorasib and confirmed very encouraging results in a pre-clinical study. Based on this, the company began the phase-1 trial. The phase-1 study that I presented last year was on NSCLC and other solid cancer patients who have failed in standard chemotherapy. We published the results of the 59 NSCLC patients among them. This was not a small number, given the early-stage trial.

The results showed that the treatment candidate had an objective response rate of 32.2 percent. This is a very encouraging outcome, considering that the standard therapy response rate like docetaxel was only about 7 to 10 percent in patients who have failed in cisplatin. The phase-1 trial aims to determine the appropriate dose of the therapeutic agent. We found in the study that sotorasib 960mg was the appropriate dose. Based on this, we are considering a phase-2 study.

Q: KRAS G12C-mutated NSCLC patients can receive immunotherapies, too. Some immunotherapies can be used as the first-line treatment for patients with advanced cancer. If sotorasib is to become a standard therapy like EGFR-inhibiting or ALK-inhibiting TKIs, it should show better efficacy than immunotherapies. What’s your view on this?

A: In the phase-1 study, sotorasib’s ORR was 32.2 percent in NSCLC patients. ORR of the standard chemotherapy and that of immunotherapy alone can not exceed this number. If a specific biomarker can be developed, sotorasib’s effect will get even better. Then, sotorasib will sufficiently beat the standard therapy or immunotherapy.

Professor Park’s presentation on the results of the phase-1 study on sotorasib at the ESMO Asia Congress 2020
Professor Park’s presentation on the results of the phase-1 study on sotorasib at the ESMO Asia Congress 2020

Q: Amgen’s portfolio signaled that the company might develop sotorasib in combination with immunotherapy. What’s your opinion on this?

A: As cancer cells are also living organisms, they have an instinct to preserve themselves. If we block their activation by using KRAS-inhibiting therapy, cancer cells will find a second and a third way, such as additional mutations to survive. Then, like other anticancer treatments, it might face resistance. To prevent or delay this, it is possible to consider using sotorasib in combination with other drugs.

In the pre-clinical trial, the combination of sotorasib and immunotherapy showed a significant synergy effect in treatment efficacy. What’s interesting is that the injection of the oncogene to an animal treated with the sotorasib plus immunotherapy combo did not cause a relapse of cancer. We can say that the combo of sotorasib and immunotherapy helped create a natural immune healing ability. Of course, it was a pre-clinical study, and we have to confirm it in a clinical study.

Q: Lastly, if investigational KRAS inhibitors are successfully developed, what kind of role will they play in lung cancer treatment in the future?

A: There has been a sea change in lung cancer treatment in the last 20 years. Many therapies have arrived, but researchers are working on a new weapon to overcome lung cancer.

Early-stage lung cancer patients can be cured with local treatment such as surgery or radiation. But many lung cancer patients visit a hospital only after finding out that their disease has progressed to a certain extent. Still, many patients, who thought their cancer was cured with local treatment, end up returning to the hospital due to cancer recurrence with a limited lifetime.

If physicians could sub-categorize more patients for customized treatment strategies by considering genetic changes and immunological characteristics, they can not only raise the treatment rate but reduce side effects. I hope these treatments could help lung cancer live a longer and healthier life.

Compared to the past, the survival of lung cancer patients has significantly improved.

However, as an oncologist on a long-term treatment journey with a patient, I’ve long been wishing that patients’ lifespan could be extended by 10 or 20 years and fully cured at the end.

I also anticipate good treatment results of sotorasib, with a discovery of a biomarker that can select patients with a higher probability of treatment or with the use of another immunotherapy.

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