The lack of approved therapies to target EGFR exon 20 insertion mutations, the third most common form of EGFR mutations, led to the study of osimertinib in combination with cetuximab in patients with advanced EGFR-mutant non–small cell lung cancer.<br />
Johnathan W. Riess, MD, MS
The lack of approved therapies to targetEGFRexon 20 insertion mutations, the third most common form ofEGFRmutations, led to the study of osimertinib (Tagrisso) in combination with cetuximab (Erbitux) in patients with advancedEGFR-mutant nonsmall cell lung cancer (NSCLC).
The investigators performed genetic editing with CRISPR on various cells with exon 20 insertions. The cells were then used to compare osimertinib plus cetuximab compared with osimertinib alone. In other cohorts, the combination regimen was also compared to afatinib (Gilotrif) gefitinib (Iressa), and erolotinib (Tarceva) (cohort B), osimertinib monotherapy (cohort C), and first-line osimertinib (cohort E).
In comparison with osimertinib alone, the combination of osimertinib and cetuximab showed robust tumor growth inhibition across multiple patient-derived xenograft models (PDXs) (P= .05). One exception was the 763_Y764InsFQEA PDX model, which responded equally to combination therapy and monotherapy. In one case involving a S768_D770dupSVD PDX, there was also an increase in survival.
These promising early results inspired a new cohort to the study (cohort D), which looked at osimertinib plus necitumumab in patients withEGFRexon 20 insertionpositive NSCLC who previously progressed on platinum-based chemotherapy.
Of the 4 patients who were evaluable for response, 2 partial responses have been seen with the combination of osimertinib and necitumumab and the median progression-free survival was 5.3 months. The cohort analysis is ongoing with 6 patients enrolled and plans to accrue up to 18 patients.
In an interview withTargeted Oncology, Johnathan W. Riess, MD, MS, associate professor, UC Davis Comprehensive Cancer Center, discussed preclinical data on osimertinib inEGFR-mutant NSCLC and how it relates to the ongoing phase I study of osimertinib plus cetuximab as a targeted treatment regimen for this patient population.
TARGETED ONCOLOGY: What data do we have of EGFR TKIs that come close to being sufficient for the treatment of patients with EGFR Exon 20 Insertion NSCLC?
Riess: EGFR exon 20 insertions are the third most common group ofEGFR-activated mutations. However, there are no approvedEGFR-directed therapies to treat these insertions. There are some newer-generation EGFR TKIs, like poziotinib and TAK-788, that do seem to have some activity against these insertions. There is also a bifunctional MET/EGFR antibody called JNJ-372, which also has some activity against theseEGFRexon 20 insertions. We're starting to have newer and better therapies come along that are exciting.
TARGETED ONCOLOGY: What drug are you studying for patients with EGFR exon 20 insertion NSCLC?
Riess: At UC Davis, we have an NCS-sponsored trial of osimertinib, which is approved as first-line treatment for the more common EGFR mutations, such as, exon 19 deletions and L858R, as well as T7090m, the most common acquired resistance mechanism to the first- and second-generation TKIs erlotinib (Tarceva), afatinib, and gefitinib. We're studying EGFR exon 20 insertions in combination with necitumumab, which is an EGFR monoclonal antibody. We generated some preclinical data showing evidence of activity and we've translated that to the clinic. We're accruing a cohort of patients who have EGFR exon 20 insertions and are treating them with osimertinib and necitumumab.
TARGETED ONCOLOGY: What role do monoclonal antibodies typically play in the treatment ofEGFR-mutant NSCLC?
Riess: EGFR monoclonal antibodies are used in certain situations to treat NSCLC. There were some data published in squamous NSCLC looking at the addition of necitumumab to platinum-based chemotherapy with cisplatin/gemcitabine that showed an improvement in overall survival with the EGFR monoclonal antibody necitumumab. That's been supplanted by immunotherapy in combination with chemotherapy because the magnitude of the survival benefit with chemoimmunotherapy is so much greater. An example is the KEYNOTE-407 trial, [which looked at] carboplatin and paclitaxel with pembrolizumab (Keytruda). But it has been used in that situation.
InEGFR-mutant NSCLC, we have our phase I study of osimertinib and necitumumab in select settings of EGFR resistance, like the EGFR exon 20 patients. [In these patients] we're studying safety, tolerability, and looking for a signal of activity.
There's also the combination of afatinib, a second-generation EKI, and cetuximab, which is another EGFR monoclonal antibody that's similar to necitumumab. It's been studied in patients who are resistant to earlier EGFR TKIs. The response rate occurs in about one-third of patients, and that's something used in the clinic on occasion. The main adverse events (AEs) to worry about are rash and other potential skin-related AEs that need to be managed.
TARGETED ONCOLOGY: What were the study results?
Riess: Of 4 evaluable patients, we've seen 2 confirmed responses so far with this combination inEGFRexon 20 insertion NSCLC, so we’re excited about that and are continuing to accrue patients.
TARGETED ONCOLOGY: What are the next steps with this research?
Riess: What we'd like to do is complete the accrual of the cohort. We have planned a total of 18 patients to accrue and a goal of seeing 3 or more responses as an early signal of clinical activity. We'll continue to accrue these patients and also examine which insertions may be more sensitive to the combination than others because they are such a heterogeneous group of insertions. We've described of 60 of these insertions that can occur in patients.
TARGETED ONCOLOGY: What are you most excited about with this research?
Riess: It's nice to finally be able bring clinical trials to these patients. Previously, there have been no approved EGFR TKIs [for this population of patients withEGFRexon 20 insertions]. It's nice to finally see drugs where we have early signs of clinical activity.
Riess JW, Floch N, Mack PC, et al. In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC. Presented at: IASLC 20th World Conference on Lung Cancer; Barcelona, Spain. Abstract MA09.02.