EGFR L861Q + EGFR G719X

During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

Our results suggest that ERBB2 plays a previously unrecognized role in EGFR L861Q-driven tumorigenesis, and pan-ERBB inhibitors are likely to be more effective than selective EGFR tyrosine kinase inhibitors in this setting.

Afatinib is effective in pts with NSCLC with major uncommon and compound EGFR mutations, with broad activity against other uncommon EGFR mutations and some Ins20 mutations, unaffected by ethnicity. Asian pts appeared to have a high proportion of major uncommon mutations, known to be highly sensitive to afatinib.

Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively. Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.

Treatment with afatinib (40 mg/day) produced a partial response, which was maintained for 17 months with continued treatment. A literature review revealed that lung cancer with G719X/S768I compound mutation exhibited good response to EGFR-TKIs, even better than that of lung cancers with single uncommon mutations.

We report osimertinib inhibits signalling pathways and cellular growth in G719X mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of PDX harboring the G719X mutation alone or in combination with L861Q and S768I. Together this data supports clinical testing of osimertinib in patients with uncommon EGFR NSCLC.

Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.

Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors. Implications: TAS6417/CLN-081 is a potent EGFR TKI with a wide therapeutic window and may be effective in lung cancer patients with clinically relevant EGFR mutations.

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: Boehringer Ingelheim. Clinical trial identification: N/A

In clinical practice, afatinib was active in patients with u-EGFRm NSCLC, particularly in complex and single mutations. Further strategies are needed for patients with ins20, a subgroup u-EGFRm with a lower clinical benefit with afatinib.

This study’s findings reveal that different EGFR mutation subtypes display heterogeneous immunotherapeutic features, and EGFR G719X was associated with an increased TMB, a higher proportion of TMB-H/PD-L1 positive patients, and fewer concurrent copy number amplification GAs. This suggests that GAs of G719X may have implications as a biomarker for guiding ICI treatment in EGFR-mutated NSCLC.

Patients with this type of NSCLC may obtain long-term survival with afatinib.

There were marked differences between individuals regarding the efficacy of EGFR-TKI treatment and the survival time of patients with uncommon EGFR mutations, second-line EGFR-TKIs had a lower ORR and DCR while had a longer mPFS. All of these could provide a basis for the exploration of different regimens for patients with different types of uncommon mutations.

"The Idylla system provides a rapid, accurate and user-friendly solution to EGFR characterization, especially in time-sensitive scenarios where special expertise and staff training could be a challenge. Research Funding: None"

The first-line treatment was afatinib in 47.5%, erlotinib in 21.5% and gefitinib in 31%. We concluded that the clinical characteristics of the patients of the OPH study are consistent with the previous reported in the Caucasian population and the subgroups with the worst prognosis include the squamous histology, the G719X mutation and the liver metastasis. Research Funding: BOEHRINGER INGELHEIM

In this largest known clinically annotated dataset of patients with atypical EGFR-mutations treated with osi, activity was noted, though 1L clinical benefit on osi appears lower in this multicenter US cohort than in E19del or L858R. These results are comparable to the recently published prospective phase II trial (Cho et al, 2019) conducted in Korea. Patients with L861Q and Exon 19 insertion appeared to benefit the most from osi in this time on treatment retrospective analysis.