EGFR G719C

EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001)...Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.

Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations...The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.

The present study describes the case of a patient diagnosed with lung adenocarcinoma (LUAD) carrying two rare EGFR exon 18 indel/G719C and exon 19 L747S mutations, in which persistent lesion shrinkage was exhibited within 16 months of osimertinib treatment. Given the paucity of clinical trials for the treatment of LUAD harboring complex EGER mutations, the present detailed case description may provide clinicians with effective clinical experience in treating patients.

In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.

Twenty-one patients received prior osimertinib, n=5 with erlotinib and n=2 with afatinib before detection of acquired BRAF alteration...The most common EGFR TKI with RAF and/or MEK inhibitors were osimertinib+trametinib+vemurafenib (n=1), osimertinib+trametinib (n=5), osimertinib+dabrafenib (n=2), osimertinib+selumetinib (n=3) and erlotinib+trametinib (n=4)... Our study of patients with EGFR-mutant NSCLC with acquired BRAF alteration patients provides insight into the clinical and treatment outcomes. Further exploration of drug combinations is warranted to investigate the tolerability of treatment for patients with EGFR-mutant with acquired BRAF alteration.

Comparable efficacy was observed across EGFR mutant (EGFRm) models previously treated with single or multiple lines of first- (gefitinib, erlotinib), second- (afatinib), and/or third-generation (osimertinib) EGFR TKIs. Additionally, TR was observed in 3/3 (100%) of models previously treated with an EGFR TKI in combination with the cMET TKI savolitinib; high cMET expression by IHC was seen in >90% of the cells in these three models. Notably, 4/5 (80%) of models with prior exposure to the ALK TKI crizotinib demonstrated TR... In vivo efficacy of AZD9592 was demonstrated in PDX models across a broad spectrum of NSCLC molecular profiles. These included EGFRwt and EGFRm tumours harbouring varied EGFR mutations; groups with and without prior chemotherapy; and groups with and without prior treatment with ALK, EGFR, and/or cMET TKI. These observations suggest that AZD9592 may provide clinical benefit in areas of unmet need, including in patients previously treated with chemotherapy or targeted agents.

P3, N=200, Active, not recruiting, National Cancer Institute, Naples | Trial completion date: Jul 2022 --> Jul 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

CSF ctDNA detected using NGS had a high sensitivity for NSCLC-LM, showing high potential in detecting driver and drug-resistant gene mutations. Genomic profiles, combined with clinically relevant prognostic factors, will guide individualised treatments and improve the outcomes of NSCLC-LM patients.

Our results demonstrate that molecular profiling on DNA obtained from separately microdissected foci in heterogeneous tumors can prove helpful in separating true tumor heterogeneity from synchronous/collision tumors. This separation could be of utmost clinical importance to guide appropriate treatment management.

Our results demonstrate that molecular profiling on DNA obtained from separately microdissected foci in heterogeneous tumors can prove helpful in separating true tumor heterogeneity from synchronous/collision tumors. This separation could be of utmost clinical importance to guide appropriate treatment management.

While two EGFR ex20ins-targeting drugs were recently approved by the US Food and Drug Administration (amivantamab and mobocertinib), neither have established CNS activity. Phase 2 will enroll patients in 3 cohorts (n=18 each): patients treated with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients treated with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases treated with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned to enroll at approximately 40 centers in North America, the Asia-Pacific region, and/or Europe.

This real-world study indicates that dacomitinib is potent and well-tolerated in NSCLC patients harboring uncommon EGFR mutations in multi-line settings, and has favourable activity for brain metastases.Data are n (%). AEs, adverse events. There were no grade 4-5 treatment-emergent AEs.

Analysis included 16 stage IV NSCLC patients with uncommon EGFR mutations from 9 different German centers which started treatment in first or further line with Atezolizumab, Bevacizumab, Carboplatin and (nab-)Paclitaxel (ABCP) between October 2018 and January 2022...9 patients received a TKI therapy in first line (4x Afatinib; 5x Osimertinib) with an ORR of 66.7% (CR = 1; PR = 5; SD = 1; PD = 2) and a median time-to-next-treatment of 6.7 months (range: 2.1-39.1 months)... In this retrospective analysis, ABCP achieves an encouraging outcome for patients with uncommon EGFR mutations, comparable to results for common EGFR mutations in IMpower150 (ORR 71%, mPFS: 9.7 months, mOS 29.4 months). This in contrast to immunotherapy alone which shows poor ORR and PFS. Together with new targeted treatment options for Exon 20 insertions like amivantamab (ORR 40%, mPFS 8.3 months) or mobocertinib (ORR 28%, mPFS 7.3 months), ABCP is a valuable option in the early course of treatment for this patient cohort.

While two EGFR ex20ins-targeting drugs were recently approved by the FDA (amivantamab and mobocertinib), neither have established CNS activity. Phase 2 will enroll patients in 3 cohorts (n = 18 each): patients with prior platinum-based chemotherapy and an EGFR ex20ins-targeted agent; patients with prior platinum but no EGFR ex20ins-targeted agent; and patients with active asymptomatic brain metastases with prior platinum with or without an EGFR ex20ins-targeted agent. The study is planned for approximately 40 centers in North America, the Asia-Pacific region, and/or Europe.

The patient was started on osimertinib therapy... This case highlights the importance of early sequencing in pancreatic tumors that appear to be the primary site of malignancy. The use of NGS early in the patient's clinical course not only changed the treatment strategy but also drastically altered the prognosis. While metastatic pancreatic adenocarcinoma has with a poor prognosis and survival rate, treatment of EGFR-mutated non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors is associated with high response rates.

P2/3, N=90, Not yet recruiting, The First Affiliated Hospital of Henan University of Science and Technology

ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs.

P3, N=200, Ongoing, ISTITUTO NAZIONALE TUMORI - IRCCS FONDAZIONE PASCALE

The chi-square including the covariates was 14.85 (P<0.01). Conclusion Our data indicated that EGFR uncommon mutations were widely distributed in Brazilian patients with NSCLC and may contribute to new perspectives on precision treatment.

The chi-square including the covariates was 14.85 (P<0.01). Conclusion Our data indicated that EGFR uncommon mutations were widely distributed in Brazilian patients with NSCLC and may contribute to new perspectives on precision treatment.

The chi-square including the covariates was 14.85 (P<0.01). Conclusion Our data indicated that EGFR uncommon mutations were widely distributed in Brazilian patients with NSCLC and may contribute to new perspectives on precision treatment.

The chi-square including the covariates was 14.85 (P<0.01). Conclusion Our data indicated that EGFR uncommon mutations were widely distributed in Brazilian patients with NSCLC and may contribute to new perspectives on precision treatment.

No abstract available

P2, N=170, Recruiting, Fondazione Ricerca Traslazionale

The current study represents the first epidemiological study in Iraq to find EGFR mutations frequency among NSCLC patients that reveals the incidence rate of 27.53%, which is between the higher prevalence rate in Asian populations and lower rates in western countries. These results explain the genetic differences of NSCLC in the world due to ethnic differences of the population, more studies are needed in Arab countries to study the EGFR mutations, find the effect of ethnicity and environmental factors for lung cancer, and the subsequent therapy.

P2, N=189, Ongoing, FONDAZIONE RICERCA TRASLAZIONALE (FORT)

Conclusion More and more uncommon EGFR mutations are identified owing to the development of NGS. This is the largest NGS-based cohort of Chinese lung cancers for investigating uncommon EGFR mutations, and 5.48% patients that with EGFR-TKI-sensitive uncommon mutations alone were found, which should be informative for the clinical therapies.

Overall TAT for the ultra-rapid workflow was reduced by ~50% compared to PCR/CE, and in most cases, results are delivered on the same day as tumor sampling. The lack of nucleic acid extraction and single-slide sample input enables targeted profiling of even scant tumor samples. Although both PCR/CE and the ultra-rapid workflow provide drastic improvement of TAT compared to NGS-based profiling, more comprehensive coverage of actionable EGFR mutations in the ultrarapid workflow allows for faster and more definitive treatment of NSCLC

Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

Despite low sensitivity, combined DS, RFLP, and PCR-HRM was able to detect EGFR mutations in plasma cfDNA with high specificity. Moreover, TKI resistance exon 20 insertions mutation was detected as early as 3 months post TKI treatment.

Funding: Pfizer Pharma GmbH. Clinical trial identification: Study Number 2016/01.

The cartridge-based fully integrated platform with ultra-rapid TAT demonstrated high concordance with the conventional NGS-based platform. The fully-automated and integrated platform has minimized the need for significant molecular expertise and laboratory infrastructure. However, this platform does have its limitations, such as only detecting the most common EGFR mutations.

P2, N=37, Recruiting, SCRI Development Innovations, LLC