Treatment for EGFR-Mutant NSCLC Varies by Driver

Nicolas Girard, MD, PhD

For patients with EGFR-mutant non–small cell lung cancer (NSCLC), the availability of targeted therapy depends on the subgroup of EGFR they belong to, according to Nicholas Girard, MD. Many EGFR tyrosine kinase inhibitor (TKIs) exist for MET-driven tumors, but those with exon 20 insertions and other rare mutations only have chemotherapy.

Platinum-based chemotherapy is the mainstay of treatment for rare EGFR subtypes, said Girard, professor of Respiratory Medicine, Versailles Saint Quentin University, professor, head, at the Curie-Montsouris Thorax Institute, Institut Curie in an interview with Targeted Oncology™. Patients who develop resistance to EGFR TKIs will also encounter platinum-based chemotherapy as their next line of treatment. These standards come from the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, as well as the European Society of Medical Oncology (ESMO) Clinical Practice Guidelines.

“For these patients with common EGFR mutations, we have a well-established standard-of-care right now, which are the EGFR TKIs, and we have an unmet need, which is second-line, where innovative strategies are being developed,” Girard stated.

In the interview, Girard reviews 3 key abstracts presented at the European Lung Cancer Congress (ELCC) 2023, in which different targeted therapies were administered to patients with EGFR-mutant NSCLC in clinical trial and real-world settings.

Targeted Oncology: What is the current picture of EGFR-mutant NSCLC treatment landscape?

Girard: In patients with advanced metastatic non–small cell lung cancer, we have a subgroup of patients that have EGFR mutations, which is a driver alteration that is observed from the beginning until the the development of the tumor, in the primary tumor, and older metastatic sites. We have covert EGFR mutations, which are the frequent ones, like L858R, or exon 19 deletions. These are found in about 90% of patients with EGFR-mutant non–small cell lung cancer. We also have the uncommon EGFR mutations. Among those, EGFR exon 20 insertion mutations are the most prevalent.

Currently, for the management of these patients, we have EGFR TKIs. First-generation TKIs have demonstrated a benefit in terms of PFS [progression-free survival] and OS [overall survival] as compared to second-generation EGFR TKIs. But challenges for these patients are after acquired resistance to EGFR TKI delivered in the first-line setting: What is the best treatment option? In the current clinical practice guidelines from NCCN or ESMO, platinum-based chemotherapy is a standard-of-care. Those patients do not have a benefit from the addition of immunotherapy to chemotherapy. What has been recently demonstrated in randomized trials is repeating a biopsy the tumor to see if it is helpful in in some patients to identify molecular mechanism of resistance, which may be MET activation. There are several studies that are ongoing that are comparing innovative agents after the failure of 1 line of EGFR TKI vs platinum-based chemotherapy. These include MET targeted agents such as selumetinib [Koselugo] and capmatinib [Tabrecta], or it may be antibodies, such as amivantamab [Rybrevant], which is a bispecific EGFR-MET antibody, and randomized phase 3 studies are going to compare these agents with chemotherapy. Additionally, EGFR mutations bypass to other signaling pathways. There are some antibody-drug conjugates that have been developed in the setting of EGFR TKI failure.

For these patients with common EGFR mutations, we have a well-established standard-of-care right now, which are the EGFR TKIs, and we have an unmet need, which is second-line, where innovative strategies are being developed.

Can you discuss the CHRYSALIS trial [NCT02609776], which you presented data on at ELCC 2023?

The long-term results of the CHRYSALIS trial for patients with EGFR exon 20 insertion mutations were presented. It’s an important study because we have had previous reports including a replication of these results, but obviously with targeted agents, what we expect is long-term control of the disease and long-term survival, and it is important to look at the follow-up of the patients enrolled in in such a study. The study is focusing on amivantamab, which is inducing a deep inhibition of the EGFR signaling pathway, what is needed for the treatment of tumors harboring EGFR exon 20 insertion mutations.

In this cohort of 114 patients, they had to be pretreated with at least 1 prior line of platinum-based chemotherapy. As assessed by the investigator, the response rate was 77% in these patients, and the median duration of response was just above 1 year at 12.5 months. It is very interesting to see that the response rate was similar no matter the patient subgroup in terms of prior response to first-line treatment. Also, it was very interesting to see that we have updated long-term outcomes reported in this presentation, including a median PFS of 6.9 months, and a 14% PFS rate at 2 years, which is remarkable in the setting of aggressive disease. Regarding overall survival, the median was 23 months, and at 1-year, the rate was 73%, and 2 years, the overall survival rate was 47%. This means that at 2 years, we have about 1/3 of patients alive without disease progression, meaning that these patients have this long-term benefit from the exposure to amivantamab. Then, regarding the safety profiles with this long-term follow-up, we did not identify additional safety signals. Management of patients relies on a proactive management of cutaneous toxicities, especially prevention and treatment of rash, which is the most frequent adverse event. Overall, grade 3 and 4 adverse events were infrequent in this group of patients.

Can you talk about the comparison of CHRYSALIS to real-world data, as presented at ELCC 2023?

In a poster that was presented at ELCC, we deal with an indirect comparison between the CHRYSALIS study with real-world data. This means patients with historical controls, patients with EGFR exon 20 insertion mutations, received real-world treatment or the availability of amivantamab, or other targeted agents. This is a very large comparison, which allows you to compare amivantamab and several treatment regimens administered to these patients after the failure of chemotherapy, and this includes common EGFR TKIs, immune checkpoint inhibitors, non-platinum-based chemotherapy, and combination of chemotherapy plus anti-angiogenic agents, or other kind of treatment regimens.

These data were obtained from several sources in Europe and in the [United States] to a cohort that reflects the historical treatment practice for these patients in the setting of third- or first-line. It was interesting to see that all together with amivantamab, we are seeing more than 40% risk of disease progression and risk of deaths in those patients as compared with historical treatments. This is true for historic EGFR TKIs, and this is true for chemotherapy. It was interesting to understand that even if we do not have a randomized phase 3 trial comparing amivantamab with standard-of-care historical treatments in the second-line setting and beyond, these data provide additional evidence of the benefit of amivantamab for those patients. These benefits include higher response rate, more prolonged PFS, more prolonged OS, and it was even reinforced as the standard-of-care for patients with EGFR exon 20 insertion mutations after the failure of chemotherapy. This is part of the current guidelines in Europe, the ESMO Clinical Practice Guidelines in the United States in the NCCN Guidelines, It is important to add this data showing that major progress at ELCC because it brings additional value to the data that we have currently with amivantamab.

Other real-world data were presented at ELCC 2023. What can you share about this research?

A poster was focusing on select patients with cancer with common EGFR mutations who received osimertinib [Tagrisso] as first-line treatment, and this was real-world data. Focusing on treatment beyond osimertininb, this is a challenging clinical situation where standard-of-care relies on chemotherapy, but it’s important also to see what treatment sequencing delivered in those patients. At the end, the overall survival of patients is a result of each line of treatment and the efficacy of each line of treatment.

It was interesting to see that in this in this group of more than 500 patients, we were able to look at some key findings. The first finding is that a quarter of patients died before receiving a second-line treatment. That means that the follow-up of patients who were receiving osimertinib should be optimized, and should lead to an earlier identification of disease progression so that patients can have access to salvage therapy.

We also can combine this data with data from the Flatiron database into a larger database. It was a similar figure. Twenty-three percent of patients died before receiving second-line treatment. Who are those patients? Well, looking in both databases, these patients were older, they had higher comorbidities, and a poor performance status as compared to the others. This is per year. We also looked at prognostic factors overall. At the end, again, ECOG performance status is a major predictor of the outcome. It was also interesting to see that we were able to compare in those patients with good performance stages vs those ECOG performance scores of 2, and also according to age, the duration of treatment, especially with osimertinib in the first-line setting, which is far lower in patients with a lower performance scores. These data show that we have an opportunity on patients with common EGFR mutations receiving osimertinib. It shows that it's still an unmet need,. Osimertinib has completely changed the natural history of EGFR-mutant lung cancer, but still, we have some patients who are rapidly progressing, and we have some patients with limited duration of treatment. There is a need to further optimize first-time treatment of patients with common EGFR mutations.