Treatment selection for patients with EGFR exon 20 insertions in NSCLC

Matthew Fowler: What is the first-line treatment option for patients with EGFR exon 20 positive insertion non-small cell lung cancer?

Zofia Piotrowska, MD: Although we now have 2 targeted therapies approved for these patients, unfortunately none of them are approved as first line. Some clinical trials are underway on first-line treatment options for these patients. But as of 2021, the preferred first-line treatment for these patients remains platinum-based chemotherapy, carboplatin and pemetrexed. The role of immunotherapy for these patients is still an open question as to whether we should give them first-line combinations of chemotherapy and immunotherapy, or whether perhaps patients with EGFR exon 20 insertions may benefit less from immunotherapy. We have seen this in the case of more frequent sensitizing mutations, where immunotherapy alone is certainly less active than in other types of lung cancer. The question remains open whether these patients should receive chemotherapy alone or chemoimmunotherapy, and this is something that needs to be decided at the individual patient level and in discussion with the patients. Both mobocertinib and amivantamab are approved options for second-line or higher treatment, so when your patients progress on this platinum-based chemotherapy regimen, that’s when we start thinking about these new approvals.

Matthew Fowler: With these 2 agents that we have been discussing that have received recent approvals, what are some of the treatment options for patients who may progress with these?

Zofia Piotrowska, MD: Before talking about the treatment options that might be available for patients who have progressed on amivantamab and mobocertinib, many people have asked me, how should we choose between these options? What do we think of mobocertinib and amivantamab, again, both approved for second-line or later treatment? This will be a discussion with patients about some of the differences in the safety profile of these drugs, the logistics and how they are administered, and selecting what is best for patients. Amivantamab is an intravenous [intravenous] therapy. It is given initially weekly for the first 4 weeks of treatment, then every 2 weeks thereafter. This therefore forces patients to come to the clinic regularly. While mobocertinib is an oral therapy, and so often, patients will prefer oral therapy. Although with mobocertinib we are seeing that patients can have frequent and sometimes high grade diarrhea. Both of these are important considerations, so we need to talk to patients and decide which of these factors makes one of these drugs the preferred second-line option for each individual patient?

We are now seeing new drugs in development beyond mobocertinib and amivantamab. We have seen recent data presented at ASCO [American Society of Clinical Oncology annual meeting] last year of a drug from Dizal [Pharmaceuticals], DZD9008; another drug from Cullinan Oncology, CLN-081; and several more in development. In the future, both of these agents are effective, but there is still a long way to go in terms of efficacy and safety. CNS [central nervous system] penetration will be an important issue in the future. Many of these patients have brain metastases, and we are still learning about the activity of these compounds on the CNS. But we are concerned that they may not be as active on the CNS as we would like, so in the future we will need new and better treatments, but it is certainly exciting to have these options at our available today.

Matthew Fowler: Is there a role for mobocertinib and amivantamab sequencing?

Zofia Piotrowska, MD: This is a very important question, and the short answer is that we don’t know yet. The sequencing of these 2 agents probably has a role to play because when we think of patients with stage IV lung cancer, we want to think about using all the options available to us to help control their cancer. But we don’t know what the optimal sequence is, if maybe amivantamab would be effective after mobocertinib, or the other way around, if mobocertinib would be effective after amivantamab. This is something we will have to learn in the future, and it will be an important question as to how we decide how to sequence these agents in the future.

Transcript edited for clarity.

Martin E. Berry