EGFR exon 20 insertion

P2, N=46, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Jun 2025 --> Jun 2027

With high sensitivity and multiplexing capabilities, this assay operates at a low reaction temperature (around 37 °C) and requires a short processing time, ≈70 min post-cell-free DNA extraction. These features make the chip a valuable tool for easy and widespread cancer screening.

P2, N=100, Active, not recruiting, Allist Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Apr 2024 --> Sep 2025

To develop treatment for EGFR-related NSCLC, several tyrosine kinase inhibitors (TKIs) were designed: gefitinib, erlotinib, as first-generation; neratinib, dacomitinib as second-generation; osimertinib, lazertinib as third-generation, as examples. Although structures obtained so far for the EGFR family provide meaningful insights into the mechanisms, the quality and the quantity of the EGFR family structures are insufficient to elucidate the complete structures and functions to overcome NSCLC. This review evaluates the structures of EGFR-HER2 and investigates their relation to NSCLC.

Furthermore, new molecules recently developed, some of them still under investigation, are shown promising results in the clinical management of ex20ins patients. This review aims to give an update of the landscape of EGFR ex20ins, focusing on their molecular and clinical implications as well as on new treatment strategies emerging in clinical trials.

P1, N=30, Active, not recruiting, Allist Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Aug 2025 | Trial primary completion date: Mar 2023 --> Dec 2024

P1, N=176, Not yet recruiting, Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences); Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sci

EGFR-TKIs may be considered as an alternative treatment option for patients with EGFR exon 20 insertions in cases where the currently recommended therapies, such as chemotherapy with or without amivantamab, are either unavailable or intolerable. The potential use of afatinib for specific patients in this context depends on the precise characteristics of their mutation and remains to be determined.

For instance, amivantamab has been approved as a treatment for epidermal growth factor receptor (EGFR)-mutant NSCLC, including those with EGFR exon 20 insertion mutations. Additionally, antibody-drug conjugates (ADCs), including HER2-targeting trastuzumab deruxtecan, TROP2-targeting ADCs, HER3-targeting patritumab deruxtecan, and MET-targeting telisotuzumab vedotin, have demonstrated promising outcomes in several clinical trials. This review summarizes the recent advancements and challenges associated with the evolving NSCLC therapeutic landscape.

For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

No abstract available

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Sep 2025 | Trial primary completion date: Jun 2025 --> Sep 2025

The median progression-free survival (PFS) of any-line therapy of ICI-combined regimen was 11.5 months, which were significantly longer than that of traditional targeted therapy (4.5 months, P = .026) and chemotherapy (5.0 months, P = .013).ConclusionsICI-combined regimen may be superior compared to targeted therapy and chemotherapy for advanced NSCLC with near-loop insertions of EGFR exon 20. Further exploration is warranted to confirm the efficacy of ICI-combined regimen.

P3, N=354, Active, not recruiting, Takeda | Trial completion date: Jul 2025 --> Sep 2026 | Trial primary completion date: Dec 2024 --> Sep 2026

Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to other TKIs.

No abstract available

No abstract available

Thus, we identified EGFR exon 20 mutations at a novel hotspot in a sizeable number of sinonasal squamous neoplasms, both IPs and SCCs, suggesting that they play a significant role in their pathogenesis. Exon 19 mutations were uncommon.

Our findings suggest that the combination of afatinib and bevacizumab may offer long-term clinical benefits for LUAC patients harboring the novel and rare EGFR Q787L mutation. This case highlights a potential therapeutic strategy warranting further investigation in clinical studies.

A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

P1/2, N=334, Active, not recruiting, Takeda | Trial completion date: Mar 2025 --> Oct 2026 | Trial primary completion date: Mar 2025 --> Oct 2026

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Oct 2025

P1, N=701, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Feb 2025 --> Jun 2026

Different toxicity profiles and sequential strategies were considered, together with efficacy results, to reach common considerations for the front-line treatment strategies in EGFR mutant NSCLC, however clinical research should be prioritized to identify further selection features.

Data suggest that combining chemotherapy with EGFR inhibitors offers promise for EGFR ex20ins-mutated NSCLC. REZILIENT3 is an ongoing phase III study evaluating the efficacy and safety of zipalertinib (an orally available, irreversible EGFR-TKI) plus first-line standard-of-care platinum-based chemotherapy with chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations.Clinical Trial Registration: NCT05973773 (ClinicalTrials.gov).

After 1 month of chemotherapy with 860 mg of pemetrexed and 480 mg of carboplatin, and immunotherapy with 200 mg of sintilimab, good response to conventional chemotherapy, but a follow-up CT scan showed disease progression...Subsequently, chemotherapy with paclitaxel albumin 400 mg and treatment with pembrolizumab 200 mg were administered, followed by targeted treatment with oral afatinib (PFS: 12 months)...The results indicate that targeted therapy with afatinib and osimertinib for EGFR S7688I/V774M and TP53 mutations has better PFS than targeted therapy with furmonertinib and sunvozertinib. Simultaneously, the combination of platinum-based chemotherapy and immunotherapy may be a potential neoadjuvant therapy for NSCLC IVa stage patients.

Whether first-generation EGFR inhibitors (e.g. icotinib or gefitinib) can sustainably control EGFR-sensitive mutations/C797S NSCLC following third-generation EGFR inhibitor treatment remains insufficiently reported. Our case report discusses a female patient with advanced lung adenocarcinoma carrying an EGFR exon 19 E746_A750delELREA mutation who received almonertinib as first-line treatment and developed C797S resistance during therapy. The patient was subsequently treated with a double dose of icotinib for 8 months until disease progression occurred, along with the development of an EGFR exon 20 T790M point mutation and TP53 mutation. This case provides clinical evidence suggesting that first-generation EGFR-TKIs may be an effective treatment strategy for patients with acquired EGFR 19del/C797S resistance following EGFR TKI therapy.

P2, N=43, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2025 --> Jul 2026 | Trial primary completion date: Jul 2025 --> Jul 2026

Thus, we did not find any significant differences in exon 20 of the EGFR gene between the ISP and OSP groups. In the ISP group, in 48 of 66 cases, multiple and single point mutations were noted, which we characterize as genetic heterogeneity.

The reversibility of amivantamab-related toxicities suggests its promising utility in patients with EGFR exon 20 insertion mutations NSCLC.

No abstract available

Furthermore, amivantamab with lazertinib for first line as well as amivantamab in combination with carboplatin and pemetrexed for second line after osimertinib have both been approved in the treatment of NSCLC harboring EGFR-sensitizing mutations. This work reviews the mechanism of action, pharmacology, clinical trial data, and covers management of toxicities. This guide is designed as a practical reference tool for clinicians, pharmacists, and basic science researchers.

The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.

We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in EGFR-mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs)...Participants were divided into two cohorts: (1) EGFR exon 20 T790M negative (T790M-, progressing on either first-line osimertinib, or on a single line of first/second generation TKI), and (2) T790M positive (T790M+, progressing on greater than or equal to 1 lines of TKI, including osimertinib)...Immune adverse events were not increased with tremelimumab. The clinical registration number of this trial is NCT03994393.

These data illustrate the real-world effectiveness of mobocertinib.

Mobocertinib, an agent with similar properties to amivantamab, served as a control for comparison. Moreover, amivantamab was associated with higher risks of thrombosis events, bone marrow suppression, skin and soft tissue infection, deterioration of respiratory symptoms, and noninfectious pneumonitis. The safety profile of amivantamab requires attention; particularly, monitoring of the adverse drug events described above is necessary during its administration.

STX-721 (53) is a potent, irreversible inhibitor of the majority of EGFR/HER2 ex20ins mutants and demonstrates excellent mutant vs wild-type selectivity both in vitro and in vivo. STX-721 is currently in phase 1/2 clinical trials for EGFR/HER2 ex20ins-driven NSCLC.

Two of 16 patients with EGFR exon 20 insertion mutations were confirmed responders per investigator. Coadministration of mobocertinib decreased the area under the plasma concentration-time curve from time zero to infinity of oral and intravenous midazolam by approximately 32% and 16%, respectively (geometric least-squares mean ratios of 0.676 and 0.837, respectively).

The patient achieved partial response with afatinib for 17 months. Our case highlights the importance of EGFR mutations in the precision targeted treatment of SMARCA4-dNSCLC.

PE cfDNA genotyping has clinical applicability for NSCLC patients and can serve as an additional source for molecular testing. Incorporating PE NGS cfDNA analysis into genetic testing enhances diagnostic yield and aids in identifying actionable mutations in clinical practice.

P2, N=104, Active, not recruiting, Dizal Pharmaceuticals | Trial completion date: May 2024 --> Dec 2025

P2, N=104, Active, not recruiting, Dizal Pharmaceuticals | Trial completion date: May 2024 --> Dec 2025