Targeting EGFR Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer: Changes in Treatment Strategies are Coming.

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most frequent EGFR mutation type, following only exon 19 deletions and exon 21 L858R point mutations. EGFR ex20ins mutations are found in approximately 4%-12% of all EGFR-positive non-small cell lung cancers (NSCLCs). Unlike classical EGFR mutations, EGFR ex20ins mutations display remarkable subtype diversity and heterogeneity. Patients harboring these mutations generally have an inferior prognosis because of insensitivity to conventional treatment approaches such as immunotherapy, chemotherapy, and targeted therapy. Consequently, there remains a significant unmet medical need for efficacious treatments. Recently, amivantamab and sunvozertinib have demonstrated notable efficacy as first-line treatments, and several other promising novel targeted drugs are also challenging the status quo of traditional first-line platinum-based chemotherapy regimens. These developments are anticipated to further improve survival outcomes for NSCLC patients with EGFR ex20ins mutations. Hence, this review summarizes the epidemiology, molecular attributes, detection methodologies, and therapeutic advancements for EGFR ex20ins mutations in NSCLC, and briefly discusses the mechanisms of drug resistance.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19).

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion-specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. METHODS: In this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. RESULTS: Among 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7-5.5) months and 6.5 (95 % CI = 3.9-not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. CONCLUSION: Osimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions. CLINICALTRIALS: govIdentifier: NCT03414814.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer.

BACKGROUND: BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. METHODS: This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. FINDINGS: The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67). CONCLUSION: Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. FUNDING: National Natural Science Foundation of China.

Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer.

Background: Non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertions (EGFRex20ins) is relatively resistant to the existing EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is a novel TKI that selectively targets EGFRex20ins and has demonstrated therapeutic efficacy in pretreated patients with tumors harboring these mutations. Methods: This is a retrospective, non-interventional, multicenter real-world study aimed at assessing the efficacy and safety of mobocertinib in patients with EGFRexon20ins who received 160 mg QD monotherapy as part of expanded access. Data collection was based on patients' records. PET-CT or CT scans were used to measure systemic response, while brain MRIs were used to examine intracranial response as part of the follow-up. Results: 16 patients were included in this report. Mobocertinib was administered to 31.3% (5) of patients as first-line, 50% (8) as second-line, and 18.7% (3) as a later-line therapy. The median age was 65 years (range, 38-83), 75% (12/16) were female, and 50% (8/16) had brain metastases at baseline before mobocertinib treatment. The objective response rate (ORR) to mobocertinib was 25% (4/16) (1/5 for first line and 3/11 for other lines), disease control rate (DCR) was 75% (12/16) with a follow-up period of 11 months. The median duration of treatment (mDoT) was 5.6 months across all patients, and 8.6 months in responders. Based on the presence or absence of brain metastasis, the mDoT was 14.8 and 5.4 months (p=0.01), respectively. Mobocertinib Grade ≥3 treatment-related adverse events (TRAEs) included diarrhea (19%), nausea (6%) and renal failure (6%). Dose reduction was reported in 25% of cases to 80 mg. Conclusion: Mobocertinib in compassionate use exhibited an ORR of 25%, which is very similar to that of the phase 2 EXCLAIM study and clearly better than historical data of monochemotherapy or conventional EGFR inhibitors. The greatest benefit was noted in patients without brain metastases, who showed durable effects with mDoT 14.8 months, while intracranial activity was limited. These findings may assist therapeutic considerations, inasmuch as results from the EXCLAIM cohort-3 dedicated to brain lesions are not available yet.

Case Report: A good response to furmonertinib second-line treatment of an advanced lung adenocarcinoma patient with a rare EGFR exon 20 N771_P772insH mutation: A case report and literature review.

Background: Lung adenocarcinoma with the classical EGFR 19 deletion and exon 21 L858R point mutations has exhibited good responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, the sensitivity of uncommon EGFR exon 20 insertion mutation to third-generation EGFR-TKIs has not been determined. Although emerging targeted therapies for EGFR exon 20 insertion mutation have been reported in recent years, such patients still have a poorer prognosis than those with typical or wild-type EGFR mutations. Case summary: Here, we report the case of a 57-year-old man with advanced non-small cell lung cancer (NSCLC) with a rare EGFR exon 20 N771_P772insH mutation. The patient was treated with furmonertinib as second-line therapy. Although his pleural effusion was more than before that during treatment, various examination results showed that the pleural effusion was closely related to hypoproteinemia; thus, local progression was not considered. His cough was significantly alleviated, and the dose was well tolerated. The patient was evaluated for a remarkable progression-free survival (PFS) of 10.0 months, a duration of response (DOR) of 8.0 months, and an overall survival (OS) of 22.0 months, which had not previously been achieved. Conclusion: The present study indicated that furmonertinib might be a good treatment option for first-line progressive NSCLC patients with EGFR exon 20 insertion mutation.