Non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation is a rare disease, which accounts for only 1-3 percent of all NSCLC patients. Still, it has a poor prognosis as existing therapies show only limited effects.
However, a new oral targeted therapy, Exkivity (mobocertinib), has recently drawn the attention of patients and doctors for its effectiveness in treating EGFR exon 20 insertion mutations, a unique and challenging mutation that makes it difficult to treat.
With a median duration of response (mDOR) of 17.5 months and a median overall survival (mOS) of 24 months, Exkivity is recommended as a standard treatment in the NCCN guidelines.
Korea Biomedical Review interviewed Professor Han Ji-yeon of the Department of Hemato-Oncology at the National Cancer Center to learn about the latest developments in treating EGFR exon 20 insertion mutations and the clinical value of Exkivity.
Question: EGFR exon 20 insertion mutation is known to be a rare disease.
Answer: It accounts for 1-3 percent of all NSCLC cases. The rates differ slightly among Western and Asian people, with about 3 percent in Asia and 1 percent in the West. This is due to the nature of the mutation called “EGFR.”. Epidermal growth factor receptor is a gene mutation common in non-smoking lung cancer patients, and one of the characteristics of lung cancer in Asia is the high share of non-smokers. Since EGFR mutations tend to be concentrated in Asian populations, EGFR exon 20 insertion mutations are also more prevalent in Asian patients.
However, this prevalence is based on classical diagnostics, such as PCR (polymerase chain reaction). When more sophisticated tests, including NGS (next-generation sequencing), are used, the prevalence in the West is reported to be 1.8 percent. The prevalence in Asia is also presumed to rise higher if they use NGS testing more aggressively.
Q: EGFR exon 20 insertion mutations are learned to show a poor prognosis. Is it because effective therapies have yet to be developed or if the mutation itself is challenging?
A: The steric hindrance caused by the EGFR exon 20 insertion mutation makes it difficult for drugs to bind and develop effective drugs. There are many EGFR TKIs in development, and several studies have targeted the exon 20 mutation. However, they have all failed. On the other hand, inhibitors that can strongly modulate this mutation were developed and tested in clinical trials. Still, the toxicity was too severe for patients to maintain treatment.
Today, Exkivityi and Rybrevant (amivantamab) have proven efficacy worldwide and are recommended in global guidelines. Both treatments are designed to be effective in patients with reduced toxicity compared to existing agents. The availability of treatment for EGFR exon 20 insertion mutations is very encouraging. Exkivity is also the oral TKI approved among those targeting the EGFR exon 20 insertion mutation.
Q: What are the differences between the two drugs?
A: Exkivity is an oral EGFR inhibitor, while Rybrevant is an injectable “dual antibody” therapy that targets both EGFR and MET. While no studies have directly compared the two drugs, indirect comparisons of published studies suggest they are similar in progression-free survival (PFS). Numerical response rates are slightly higher for Rybrevant. However, Exkivity reports a longer duration of response data. The main advantage of Exkivity is that it is oral.
Q: What does a longer duration of response (DOR) mean?
A: It means that once you start treatment, you stay in response for a long time. It is not yet understood why resistance develops when treating exon 20 insertion mutations, so it is essential to look at the characteristics of a drug that works well and responds for a long time.
Q: In the case of Exkiviti, we've heard that diarrhea is a common adverse event in clinical practice.
A: Diarrhea is the most common adverse event, and while it is distressing for patients, it is manageable.
Another company previously developed a drug targeting the exon 20 insertion variant, but the toxicity caused by the TKI was so severe that patients could not tolerate it. Side effects, such as diarrhea, acne, and canker sores, were so severe that patients could not continue treatment. In comparison, Exkivity’s diarrhea side effects are manageable.
Q: We understand that they can also adjust the doses of Exkivity.
A: That’s possible because it is an oral medication. Doctors can start with a lower dose if a patient has diarrhea side effects, depending on the severity. Physicians can adjust the dose according to the grade if the patient still feels uncomfortable.
Q: In lung cancer, the effect of treatment on brain metastases is also essential. There are no data on brain metastases for the two drugs mentioned earlier.
A: There are no data on intracranial response rates for either Exkivity or Rybrevant. However, there are differences in the proportion of patients with brain metastases in each study. The Rybrevant study included about 22 percent of patients with brain metastases, while the Exkivity study included 35 percent. Nevertheless, brain metastases do not appear to have a significant impact as the data were similar in PFS, OS, and other endpoints. Another limitation of the data is the small number of patients with EGFR exon 20 insertion mutations, as they are rare.
Q: Lastly, what would you like to say to patients in Korea treated for EGFR exon 20 insertion mutations?
A: EGFR exon 20 insertion mutation is an EGFR mutation that is rarely detected but has a poor prognosis. Until now, there were no treatable drugs, but now it can be treated with drugs recognized as effective. So, I would like to see patients have hope. However, we also want to ensure an environment where patients have access to these drugs.