EGFR exon 20 insertion

Further large-scale studies are needed to establish links between these mutations and clinical features at baseline and following treatment. Furthermore, moving forward, the development of novel drugs will be essential to fulfill the clinical unmet needs.

After four cycles of platinum‒paclitaxel chemotherapy plus immunotherapy with pembrolizumab (a PD-1 blockade), significant primary tumor shrinkage and the disappearance of oligometastasis in the right adrenal gland were discovered via CT scans. No evidence of disease relapse or immune-related adverse events occurred after a post-surgery follow-up time of 9.4 months. This case highlights the potential value and challenges of immunotherapy plus chemotherapy as conversion therapy strategy in treating patients with non-small cell lung cancer (NSCLC) harboring rare EGFR exon 20 insertions.

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

This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.

The assay shows good performance in detecting hotspot SNVs and small indels in ctDNA, and is suitable for clinical use. The limitation of bioinformatics pipelines in variant calling should be noted, and consideration can be given to run multiple pipelines in parallel to avoid missing out variants.

Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies.

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

In the tumor-bearing mouse model, mobocertinib boosted the antitumor effect of paclitaxel and topotecan, resulting in tumor regression. In summary, our study uncovers a novel potential for repurposing mobocertinib as a dual inhibitor of ABCB1 and ABCG2, and suggests the combination of mobocertinib with substrate drugs as a strategy to counteract MDR.

Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutantselective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.

P2, N=46, Recruiting, National Cancer Institute (NCI) | N=20 --> 46

P1, N=701, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting | N=460 --> 701

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.

P2, N=51, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

No abstract available

In conclusion, MD simulations can effectively predict patient outcomes by connecting computational results with clinical data and advancing our understanding of EGFR mutations and their therapeutic responses.

Firstly Mobocertinib and Amivantamab obtained approval from U.S. Food and Drug Administration (FDA) for EGFR ex20ins mutant NSCLC patients, then other drugs, such as Sunvozertinib, made breakthroughs and combination therapies also obtained gains. As mentioned above, it's definitely important to gain deeper understanding of molecular mechanism of EGFR ex20ins and assess effect and difference between novel drugs. This review is devoted to make a summary about newest achievement so to provide valuable reference about precise therapy for patients with EGFR ex20ins..

Most IRRs occurred during the infusion, were low grade, and were manageable with intervention strategies or treatment modifications. Advanced practitioners are critical in preventing, diagnosing, and managing IRRs, including educating patients and families, accurately administering infusions, prescribing premedications, and closely monitoring for IRRs.

P2, N=117, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

Furthermore, our results demonstrated that LB showed potential anti-Ex20ins cancer activity through suppression of the EGFR and ERK1/2 signaling pathway in Ba/F3 cells bearing two to three amino acid insertion mutations. These findings suggested that LB might be valuable for further investigation as a potential candidate in the treatment of associated diseases.

P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Dec 2024 --> Apr 2025

Conclusions Our analysis revealed that this CGP assay can detect actionable and rare alterations with expected frequency with a median TAT of 13 days. Biomarker detection was feasible even when TC<20%.

Sponsored By Johnson and Johnson International (Singapore) Pte Ltd,

Conclusions : This pilot study using a unique cohort of EGFR ex20+ NSCLC patients treated with high dose Osimertinib highlights the complexity of variant dynamics during treatment and disease progression, suggesting a potential link between changed levels of variants detected at progression. Potential resistance mechanisms were shown in 11/18 patients using ctDNA.

Conclusions : The integration of ODxTT alongside single gene tests provides significant additional information without compromising the performance of single gene tests. With ODxTT's high success rate, this integration expands the scope of comprehensive therapeutic strategies for advanced lung cancer.

We also studied preclinical Ba/F3 models expressing EGFR -K745_E746insIPVAIK (Ba/F3-IPVAIK) and EGFR -delE746_A750 (Ba/F3-Del19) to investigate the sensitivity to 1st-generation (gen) (gefitinib and erlotinib), 2nd-gen (afatinib, dacomitinib, and poziotinib), 3rd-gen (osimertinib), and EGFR exon 20 insertion active TKIs (mobocertinib, sunvozertinib, and zipalertinib). The preclinical therapeutic window of Ba/F3-IPVAIK and Ba/F3-Del19 for all the 2nd generation TKIs were similarly favorable, whereas Ba/F3-IPVAIK had much unfavorable therapeutic windows to other EGFR-TKIs compared to Ba/F3-Del19. Conclusions : Our clinical and preclinical findings indicate 2nd-gen EGFR-TKIs are more effective than 1st and 3rd-gen EGFR-TKIs in patients with EGFR exon 19 insertions.

High ERBB3 expression was associated with better survival. These data support the role of HER3 as a viable therapeutic target across multiple molecular subsets.

In PAPILLON (NCT04538664), amivantamab plus carboplatin-pemetrexed (amivantamab-chemotherapy) demonstrated significantly longer progression-free survival (PFS) versus chemotherapy (hazard ratio [HR], 0.395 [95% confidence interval [CI], 0.30-0.53]; P <0.0001). Consistent benefit favoring amivantamab-chemotherapy was seen across all Ex20ins sites. Amivantamab-chemotherapy is the first-line, standard of care for Ex20ins advanced NSCLC.

Although novel EGFR-TKIs are expected to treat EGFR ex20ins mutations in patients with NSCLC, they face many challenges. The main focus of this review is on emerging therapies that target NSCLC with EGFR ex20ins and highlight major ongoing clinical trials while also providing an overview of the associated challenges and research advancements in this area.

P1, N=160, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

While afatinib, a second-generation EGFR-TKI, has received FDA approval for patients with these uncommon EGFR mutations, the approval was based on a post-hoc analysis of randomized clinical trials. By synthesizing these findings, we aim to guide oncologists towards more informed decisions in employing TKIs for NSCLC with uncommon EGFR mutations other than exon 20 insertion. Additionally, we explore potential treatment strategies tailored to these patient populations to address the challenges posed by these mutations.

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

P1/2, N=315, Active, not recruiting, Dizal Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Oct 2023 --> Jul 2024

P2, N=100, Active, not recruiting, Vestre Viken Hospital Trust | Trial completion date: Aug 2023 --> Dec 2025 | Trial primary completion date: Aug 2023 --> Jun 2025

P3, N=8, Terminated, EQRx International, Inc. | Phase classification: P3b --> P3

This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.

In 2021, two drugs, amivantamab and mobocertinib each received FDA accelerated approval for second line use after platinum based therapy. The PAPILLON regimen received subsequent FDA approval. In this commentary, we review the details of PAPILLON and also discuss why the rival trial, EXCLAIM2, may have failed.

After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

In this real-world AI-generated dataset, survival post-osimertinib was poor in patients with cEGFR mutations. Patients with ex20ins in this cohort had improved outcomes, possibly due to ex20ins targeting treatment, highlighting the need for more effective treatments for patients with advanced EGFRm NSCLC.

This pharmacovigilance study systematically explored the cardiovascular adverse events of amivantamab and provided new safety signals based on past safety information. Early and intensified monitoring is crucial, and attention should be directed towards high-risk signals.

The study proved the potential efficacy of 160mg furmonertinib in patients with advanced NSCLC with EGFR ex20ins. Meanwhile, 160mg furmonertinib had a good safety profile.

We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.