(Focus - Malaysia)
The landscape of lung cancer, with its multifaceted nature, poses a challenge for which a comprehensive treatment approach is imperative. The diversity of lung cancer subtypes in the varying stages at which it's diagnosed, and the interplay of genetic and environmental factors all contribute to the complexity of effective treatment strategies. Among the latest investigations into treatment modalities, one of the subtypes that have gained prominence is the EGFR exon 20 insertion mutation, an uncommon and heterogeneous group of non-small cell lung cancers resistant to conventional EGFR tyrosine kinase inhibitors.
In our recent conversation with Dr. Mohd Arif Mohd Zim, a distinguished Pulmonologist from Malaysia, we delved into complexities and advancements surrounding EGFR exon 20 insertion mutations. Dr. Arif also underscored the critical need for specialized approaches and the significance of education and open communication for patients and caregivers.
Dr. Mohd Arif Mohd Zim is a Consultant Pulmonologist and internal Medicine currently serving at Damansara Specialist Hospital 2, Malaysia.
Gefitinib and erlotinib are use as first-generation TKIs however, studies have showed that patients with exon 20 insertion did not respond well with the 1st generation TKIs. There are limited evidence showing the 2nd generation TKIs effective in treating exon 20 insertion patients.
Although EGFR exon 20 insertion mutations are uncommon compared to other mutations in lung cancer, the survival rate of EGFR exon 20 insertion is worse even with immune checkpoint inhibitors (ICI) [1], [2]. What would be the reason for lower survival rates of EGFR exon 20 insertion patients with ICI monotherapy?
Dr. Mohd Arif - The reason or the problem for the lower survival rate is because those who have exon 20 insertions carry a bad prognosis. They are not responding well to the immunotherapy because patients with exon 20 insertions have low PD-L1 levels
Do you see any role of ICI + chemotherapy in increasing the survival rate of EGFR exon 20 insertion patients?
Dr. Mohd Arif - There are few evidences showing that immunotherapy + chemotherapy use as a second line agent increase the survival rate in patients with exon 20 insertion compared to chemotherapy or other TKI alone.
Is there any clinical evidence to support this?
Dr. Mohd Arif - There are a few ongoing randomized control trials. However there are retrospective studies looking at the evidence of immunotherapy + chemotherapy in patients with exon 20 insertion. The results are promising based on these retrospective studies.
We have heard about TKIs like Gefitinib being one of the treatment options in 1st line EGFR mutated lung cancer patients. However, exon 20 insertion mutation is related to Gefitinib resistance. [3] So, are 2nd generation TKIs effective in treating exon 20 insertion patients?
Dr. Mohd Arif - Gefitinib and erlotinib are use as first-generation TKIs however, studies have showed that patients with exon 20 insertion did not respond well with the 1st generation TKIs. There are limited evidence showing the 2nd generation TKIs effective in treating exon 20 insertion patients. However, 3rd generation TKI have been shown to be effective in patients with exon 20 insertion.
Amivantamab which is a bispecific antibody that targets EGFR and MET mutation was recently approved as a second line treatment for exon 20 insertion.
Could you comment on the anti-tumor activity of Osimertinib monotherapy in treating NSCLC patients having exon 20 insertion mutations?
Dr. Mohd Arif - Osimertinib is a 3rd generation TKI. Some studies revealed that Osimertinib improved progression-free survival rates in patients with exon 20 insertion mutation.
What are the other novel therapies for treating exon 20 insertion mutation in lung cancer patients, doctor?
Dr. Mohd Arif - They are few, but I don't know if they have FDA approval. Some may have FDA approval, like mobocertinib, and some are in trial stages, like poziotinib. Amivantamab which is a bispecific antibody that targets EGFR and MET mutation was recently approved as a second line treatment for exon 20 insertion.
What are the unmet needs with the treatment and management pathway of EGFR exon 20 insertion lung cancer patients?
Dr. Mohd Arif - I think the problem with EGFR exon 20 insertion is that they have a lot of variants. So, it is difficult for us to get the targeted variants for treating these patients. So, we need more studies and targeted therapy for these exon 20 insertions.
We understand that single-gene testing cannot pick up all the exon mutations, especially exon 20 insertion mutations may be missed. According to you, what are the limitations of single-gene testing like PCR in detecting exon 20 insertion mutation?
Dr. Mohd Arif - I think the problem with single gene testing like PCR is that it just detects a single gene. It only detects the known sequencing, which is the limitation of a single gene study. But if you do the new generation sequencing, you will try to look for all the mutations, known or unknown.
Do you face any challenges in implementing the NGS test as a diagnostic test for mNSCLC patients in your practice?
Dr. Mohd Arif - Not all hospitals in Malaysia are currently providing the test and the cost for the test is quite expensive. However some of the hospitals are giving discounts as an encouragement for the doctors to do more NGS test and these really help us to diagnose not just exons 20 insertion but other mutations as well.
As with other diseases, we need to educate the patient and the family regarding the prognosis and limitations of the available medication. I will advise them on the clear evidence of routine conventional chemotherapy. If the patient is not responding with chemotherapy, we can discuss on second-line immunotherapy. I will definitely encourage patients to enroll themselves in clinical trials on medications involving exon 20 insertion.
Is there any other challenge that you face concerning the cost or access to treatments in Malaysia for lung cancer patients?
Dr. Mohd Arif - Cost is not just an issue here but also anywhere in the world. Normally, I will try to get sponsors from the government or non-government organization for patients who can’t afford treatment. If there are clinical trials on new treatment for lung cancers available, we will encourage patients to join the study.
What is the future of lung cancer treatment in Malaysia look like, doctor?
Dr. Mohd Arif - Lung cancer treatment in Malaysia has progressed tremendously. Many years ago, stage 4 lung cancer is like a death sentence to the patient but now we can see many patients with stage 4 lung cancer on TKIs have better survival rate, my uncle himself has been on TKIs for seven years and he is still surviving. So, lung cancer prognosis in Malaysia is now better. We have access to treatment, but cost is the limitation. Now we are involved in many clinical trials on lung cancer treatment, and we can enroll our patients for them to get the latest and better medications.
Doctor, what do you suggest to exon 20 insertion patients and their caregivers to effectively manage this disease?
Dr. Mohd Arif - As with other diseases, we need to educate the patient and the family regarding the prognosis and limitations of the available medication. I will advise them on the clear evidence of routine conventional chemotherapy. If the patient is not responding with chemotherapy, we can discuss on second-line immunotherapy. I will definitely encourage patients to enroll themselves in clinical trials on medications involving exon 20 insertion.
Thank you for your time!
References: