EGFR L858R + EGFR exon 19 deletion

HLA-A subtypes did not correlate with prognostic outcomes in sensitized EGFR mutations. The diverse binding affinity with EGFR peptides was not translated into the TIME patterns.

This study supports the effectiveness and tolerable safety profile of osimertinib as first-line treatment for patients with aNSCLC in a real-world setting. Exon 19 deletion appears to be a strong predictor of greater effectiveness in patients with aNSCLC.

P2, N=125, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Mar 2026

Subgroup analyses also showed similar tendency that 21 L858R had more clinical benefit compared to 19 Del no matter whether IO monotherapy or IO combination. For advanced EGFR mutant NSCLC patients, 21 L858R had superior IO efficacy compared with 19 Del.

This case demonstrates the efficacy of osimertinib for rare EGFR mutations, aligning with literature suggesting its potential for managing such variants. Although large-scale trials are impractical due to the rarity of these mutations, this report adds valuable evidence supporting osimertinib's use, highlighting the need for comprehensive genomic profiling in NSCLC.

Conclusions Our study reveals a high frequency of occult EGFR mutations (Exon 19 deletion and Exon 21 L858R mutation) in non-small cell lung cancer (NSCLC) patients, particularly among male smokers and female non-smokers. These findings emphasize the importance of routine EGFR mutation testing to identify patients who may benefit from targeted therapies, ultimately improving treatment outcomes.

This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.

P2, N=125, Active, not recruiting, National Cancer Institute (NCI)

Further inhibition of phosphorylated RB with cyclin-dependent kinase (CDK) 4/6 inhibitors, combined with the EGFR-TKI osimertinib, enhanced G0/G1 cell cycle accumulation and growth inhibition of the EGFR-mutant NSCLC in both in vitro and in vivo models...Our study demonstrated that the CDK4/6-RB signal axis, maintained by the MAPK pathway, attenuates the efficacy of EGFR-TKIs in EGFR-mutant NSCLC, and targeting CDK4/6 enhances this efficacy. Thus, combining CDK4/6 inhibitors and EGFR-TKI could be a novel treatment strategy for TKI-naïve EGFR-mutant NSCLC.

Given that osimertinib is often the best available therapy, rechallenging with osimertinib often favors benefit over risk. Safe rechallenge with osimertinib is demonstrated in this case.

Although first-generation tyrosine kinase inhibitors have been the standard front-line treatment option for advanced EGFR mutated NSCLC, newer studies have shown improved survival outcomes with osimertinib therapy when compared to other tyrosine kinase inhibitors like gefitinib or erlotinib. While the difference in PFS between exon 19 deletion and exon 21 L858R mutation NSCLC patients was statistically insignificant, the decrease in PFS of patients with an exon 20 mutation treated with osimertinib was significant, suggesting a different treatment may benefit these patients. For the patients with a coexisting EGFR and PDL mutation, the NCCN guidelines (ref: NCCN 2023) state the treatment for PDL > 50% is pembrolizumab. This opens further prospective for research on co-existing PDL mutations with EGFR and associated treatment outcomes.

In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC patients with Ex19del and exon 21 L858R EGFR mutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversible EGFR TKI, in patients with Ex19del and exon 21 L858R EGFR mutation-positive advanced NSCLC in Indian settings.