Uncommon EGFR Mutations Research Articles

MO29-3 A database of 1023 patients with NSCLC and uncommon EGFR mutations treated with afatinib: focus on Asian patients

We developed a database of 1023 pts with NSCLC and uncommon EGFR mutations treated with afatinib (afa) in clinical trials and real-world practice. Here, we focus on outcomes in Asian pts, pts with ex20ins mutations and pts with osimertinib (osi) resistance mutations.

Abstract 5768: Genomic characteristics of classic and uncommon EGFR activating mutations explains different responses to first-generation EGFR-TKIs

Abstract Background: Classic sensitizing mutations of epidermal growth factor receptor (cEGFR) (i.e., exon 19 deletions and exon 21 L858R) have shown positive responses to first-generation TKIs in non-small cell lung cancer (NSCLC). For patients with uncommon EGFR mutations (uEGFR), such as G719X, S768I, L861Q and exon 20 insertions, first-generation TKIs might still be one of the mainstay choices in clinic. However, they exhibited heterogeneity in treatment responses. Here, we aimed to elucidate different genomic profiles of tumors carrying uncommon EGFR activating mutations to explain differential treatment responses. Method: We screened 6669 NSCLC patients that underwent targeted NGS of 416 cancer-related genes. Total 2280 EGFR-positive NSCLCs were selected for analysis. We compared somatic mutations, tumor mutation burden (TMB), mutational signature and canonical oncogenic pathways between cEGFR and uEGFR. A validation set of 159 NSCLCs from the Cancer Genome Atlas (TCGA) was used. Adjusted p value less than 0.1 were considered statistically significant. Results: Only patients carrying known EGFR activating mutations and without complex mutations were included. The final cohort comprised 1022 patients with L858R (44.8%), 973 with exon 19 deletion (42.7%), 139 with exon 20 insertion (6.1%), 59 with G719X (2.6%), 51 with L861Q (2.2%), and 36 with S768I (1.6%). In general, clinical features were equally distributed except for higher prevalence of G719X and S768I in male. Most frequently co-mutated genes were similar between cEGFR and uEGFR subgroups, including TP53 (56% vs 60%), PIK3CA (8% vs 11%), and RB1 (8% vs 9%). Despite these, we found enrichment of EPHA3 and MED12 with S768I(both 5/36, 14%)as compared to with cEGFR (2% vs 3%, padj<0.1), while GATA6 predominantly co-occurred with L861Q (4/51, 8%,). Overall, patients carrying uEGFR had significantly higher TMB than those with cEGFR (median TMB 5.07 vs 3.80, p=0.0076), indicating more complicated clonal backgrounds that potentially led to the poor TKI response. Among the ten oncogenic pathways, the hippo pathway markedly more altered more in those with uEGFR than with cEGFR (p=0.0025). Moreover, we found higher fraction of immunoglobulin-related signature (signature 9) and BRCA1/2-associated signature (signature 3) in tumors with cEGFR than with uEGFR (p = 0. 0003 and 0. 02, respectively). Importantly, smoking induced mutations (signature 4) were enriched in uEGFR subgroup (p = 0. 0015), which was also verified in TCGA samples. Further, 28 patients had confirmed treatment with first-generation TKIs, where uEGFR were associated with poor outcomes (HR = 1.43, 95% CI 0.81-2.52). Conclusion: This comprehensive analysis of EGFR-positive mutational landscape revealed specific genomic characteristics associated with uncommon EGFR mutations that might explain their poor response to first-generation TKIs. Citation Format: Xue Wu, Junli Zhang, Jingwen Liu, Yedan Chen, Yang Shao. Genomic characteristics of classic and uncommon EGFR activating mutations explains different responses to first-generation EGFR-TKIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5768.

Abstract 3343: Durable response to osimertinib monotherapy as first line treatment in stage IVB lung adenocarcinoma with atypical EGFR L747P mutation

Abstract Background: Targeted therapy plays a critical role in NSCLC with a certain type of mutation. Osimertinib is a third generation EGFR tylosine kinase inhibitor (TKI) which is primarily indicated for NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations. Although use of osimertinib is currently limited to patients with common EGFR mutations, it has been reported that patients with NSCLC harboring uncommon EGFR mutations demonstrated response to EGFR TKIs. Herein, we present a case of advanced adenocarcinoma of the lung with atypical EGFR L747P mutation that revealed a noteworthy durable response to osimertinib monotherapy as first line treatment. Case presentation: A 47-year-old woman with no smoking history presented with new-onset hemoptysis and cough. A chest CT scan showed a lobulated, spiculated 38 mm left upper lung mass with innumerable bilateral pulmonary nodules. CT-guided biopsy demonstrated adenocarcinoma of lung with PD-L1 1-2%. Subsequent PET-CT scan revealed hypermetabolic neoplasm in the left lower lobe with scattered area of abnormal focal FDG uptake within the liver. Brain MRI showed unremarkable findings. The patient was diagnosed with stage IVB adenocarcinoma of lung with multiple hepatic metastases. Circulating tumor DNA (ctDNA) NGS assay showed EGFR L747P [0.3% of variant allele frequency (VAF)] and tissue NGS assay revealed EGFR L747P missense variant c.2239_2240delinsCC (22.8% of VAF). The patient was started on osimertinib 80 mg daily. Follow up CT scan in six week demonstrated decrease in size of the left lower lobe lung mass to 32 mm. She has maintained durable SD for six months without any adverse effects. Most recent follow-up CT scan after eight months from the treatment demonstrated SD of the mass in the left lower lobe and less prominent numerous pulmonary nodules. Discussion: It has not been reported that osimertinib monotherapy is used as first line therapy in NSCLC with EGFR L747P mutation. We report the case of durable response to osimertinib in patients with advanced NSCLC with EGFR L747P mutation. Our case highlights the potential efficacy of osimertinib to NSCLC with atypical EGFR mutation. Although there was a clinical trial to explore clinical activity of osimertinib in patients with NSCLC harboring uncommon EGFR mutation, EGFR L747R mutation was not investigated at that time. To date, there are no ongoing clinical trials on the use of osimertinib in NSCLC with EGFR L747P mutation. Further investigations are warranted to confirm the efficacy of osimertinib in this type of mutation. Citation Format: Horyun Choi, Yeun Ho Lee, Jinah Kim, Leeseul Kim, Na Hyun Kim, Young Kwang Chae. Durable response to osimertinib monotherapy as first line treatment in stage IVB lung adenocarcinoma with atypical EGFR L747P mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3343.

A case of syndrome of inappropriate anti-diuretic hormone during treatment for lung cancer with uncommon EGFR mutations

Syndrome of inappropriate anti-diuretic hormone (SIADH) sometimes occurs in patients with lung cancer, and it has been reported as a complication after chemotherapy with platinum agents. A 55-yearold woman relapsed after right lower lobectomy for adenocarcinoma harboring uncommon EGFR mutations (G719A in exon 18 and L861Q in exon 21). Brain metastases were found seven months after the operation, and subsequent whole brain irradiation followed by oral treatment with afatinib maintained her status for one year. She was subsequently administered erlotinib with bevacizumab as the third-line treatment for refractory meningeal carcinomatosis, but she developed altered consciousness and was transported to the hospital by ambulance. Laboratory evaluation showed a decrease in serum sodium concentration from 142 to 122 mEq/L. Her altered consciousness was improved by the administration of hypertonic saline; however, the patient died 2 months post-treatment. Although SIADH is sometimes seen before or after treatment for lung cancer, this is the first report of the occurrence of SIADH in a patient with uncommon EGFR-mutated lung cancer.

NSCLC with uncommon EGFR mutations treated with atezolizumab plus bevacizumab and chemotherapy.

e21076 Background: Results of IMpower-150 and Orient-31 have demonstrated a favorable effect of combining anti-angiogenic therapy and checkpoint inhibition for refractory NSCLC patients with EGFR mutations. However, both studies included only very few patients with uncommon EGFR mutations, not allowing further analysis. For those patients, representing about 10% of EGFR mutant NSCLCs, treatment options are still limited. Methods: 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. EGFR mutations were detected by NGS (n = 15) or COBAS-PCR (n = 1). PFS was evaluated from start of ABCP and OS from time of initial diagnosis of stage IV. Results: 5 men and 11 women received ABCP therapy in first (n = 4), second (n = 9) or further line (n = 3). Mean age was 56 (36-77) years. Patients had either an Exon 20 insertion (n = 9) or point mutation (n = 2, S768I), an Exon 18 mutation (n = 3, G719X or E709A), an Exon 21 mutation (L861Q) or a compound mutation (G719C/S768I). 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). Median number of full ABCP cycles were 4 (1-6), with 3 patients (23.1%) requiring a dose reduction of chemotherapy and 4 patients (30.8%) suffering from grade 3 or 4 toxicity (one immune related pneumonitis). 13 patients (84.6%) received a maintenance with AB and the median follow-up after initial diagnosis was 19.6 months (2.3-38.4). ORR was 81.3% with 2 CR, 11 PR, 1 SD and 1 PD (not available = 1). Median PFS by Kaplan-Meier analysis was 13.0 months for both the entire cohort (95%-CI: 8.4-17.6) and for Exon 20 insertions (95%-CI: 9.3-16.7). Corresponding median OS was either not reached or 30.7 months (95%-CI: 13.8-47.6). Landmark analysis at 12 months gave a PFS of 42.8% and an OS of 93.3%. Univariate Cox regression showed no association of PFS or OS with patient or treatment parameters, including PD-L1 expression, type of mutation or prior TKI treatment. 4 patients were rechallenged with ABCP while progressing under AB maintenance and responded again. 4 patients received mobocertinib as further treatment, but only one showed a clinical benefit. Conclusions: 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.

Osimertinib in non-small cell lung cancer with uncommon EGFR-mutations: a post-hoc subgroup analysis with pooled data from two phase II clinical trials.

BackgroundOsimertinib is standard of care for EGFR-mutated non-small cell lung cancer (NSCLC) patients. The efficacy of the drug in patients with mutations other than the common deletion in exon 19 and L858R in exon 21 is largely unknown.MethodsWe identified patients with uncommon EGFR-mutations from two prospective clinical phase II, single-arm studies for previously treated patients and untreated patients, respectively, and pooled data for this analysis. All patients received treatment with osimertinib 80 mg daily until radiological progression or death. The primary endpoint of both trials was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS) and intracranial efficacy as key secondary endpoints. Circulating tumour DNA (ctDNA) was analysed before and two weeks after treatment initiation in the first line cohort.ResultsOf 299 enrolled patients in the two trials, 21 patients with uncommon mutations were identified; 12 patients had a single mutation (G719X or L861Q), one patient had L861Q and an exon 20 insertion, and 8 patients had compound mutations with G719X and either L861Q or S768I. Three of the 10 pretreated patients had the T790M resistance mutation. ORR was 47.6% and disease control rate (DCR) 85.7%. The median duration of response (DoR) was 7.9 months. Among 11 patients treated with osimertinib in first line, ORR was 63.6% vs. 30.0% of 10 previously treated patients. The median PFS was 5.5 months in both groups. Patients with G719X-compound mutations had a higher response rate (62.5% vs. 38.5%), a longer median PFS (13.7 vs. 3.5 months) and median OS (29.3 vs. 7.5 months) than patients with other mutations. Most first line treated patients (81.8%) displayed a reduction in ctDNA after two weeks of treatment.ConclusionsOsimertinib demonstrates activity in patients with uncommon EGFR-mutations, and especially for G719X-compound mutations.

Treatment pattern and outcomes in patients with uncommon or compound EGFR mutations in India: CRSF 2020-03 study.

e21034 Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resulted in significant improvement in the outcomes of patients with activating EGFR mutations. But the ideal treatment of patients harboring uncommon, or compound mutations is not well defined. This multicentric audit was conducted to study the distribution, treatment pattern, and outcomes of patients with uncommon or compound EGFR mutations. Methods: This was a multicentric retrospective study that included patients with uncommon (mutations other than Exon 19 deletions and Exon 21 L858R) or compound (double or complex) mutations treated during the period of 2017-2020. Statistical analysis was done using SPSS version 20.0. Descriptive statistics were used wherever appropriate. Kaplan Meier Aanlaysis was performed for estimation of PFS and OS. Results: Total 99 patients with uncommon or compound mutations were included in the study. The median age was 55 years (25-82 years). Majority were males (n=65,67%) and 47 (47%) were smokers. Sixty-seven patients (68 %) had a single uncommon mutation and the remaining 32 (32%) had compound mutations. Most common mutations were exon 20 insertion (n=34, 35%) and T790M (N=16,16%). Other frequent mutations observed were exon 18 G719X (n=7,7%) and exon 21 L861Q (n=3,3%). Twenty-three patients (n=23,23%) were eligible only for best supportive care. Thirty-two patients (32%) received first-generation TKI, 30 patients (30%) received palliative chemotherapy and 11 patients (11 %) received Osimertinib. Gefitinib with chemotherapy was used in 2 patients and combination of Gefitinib with Afatinib was used in one patient. Overall response rate and clinical benefit rate with first line treatment was 23% and 35% respectively. Response could not be assessed in 14 patients. Median PFS was 5 months (95% CI 3.4-6.9) and median OS was 8.3 months (95% CI 3.3- 13). In patients who received any form of systemic treatment, median PFS was 6.2 months (95% CI- 3.3-9.1) and OS was 11 months (95% CI -8.9-13.9). Conclusions: The most frequent uncommon mutations in India are exon 20 insertion followed by compound mutations and exon 20 T790M mutation. Outcomes of patients with these rare mutations are dismal in the real world setting with the available treatment options.

Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms.

9109 Background: About 10% of EGFR mutations (EGFRm) are ‘uncommon mutations’ (ucEGFRm). osimertinib is a 3rd generation EGFRi, active against common EGFRm. We aimed to collect real-world data about systemic and brain response and resistance mechanisms to osimertinib for ucEGFRm patients. Methods: This is a multi-center, retrospective study of ucEGFRm mNSCLC treated with osimertinib as first EGFRi. RECIST and RANO-BM response was evaluated by investigators. Progression free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated from initiation of osimertinib. Mutations found at resistance were collected. Results: 62 patients (pts) were identified in 22 centers from 9 countries. Median age was 64 (35-91) years, 74% females, 84% Caucasian, never/former/current smokers were 48%/39%/11% respectively, ECOG PS was 0-1/2/3-4 in 84%/10%/5%. Histology was adenocarcinoma in 97%. The largest subgroups were G719X, de novo T790M and L861Q (Table). Compound EGFR mutations were found in 27 pts (44%), TP53 mutations in 21 pts (34%). In 17 cases (27%), compound mutations included the common L858R/deletion19 and/or de novo T790M. Most frequent metastatic sites were lung/bone/brain in 45%/44%/39%. Most frequent toxicities were gastrointestinal (32 pts, 52%) and skin (24 pts, 39%); 8 pts had grade 3-4 AEs. No grade 5 AE occurred. 3 pts had AEs leading to discontinuation. RECIST response (RR) was available for 53 pts, CR - 4 (8%), PR - 27 (51%), SD - 17 (32%), and PD - 5 (9%). Median DOR (mDOR) was 17.4 months (95% CI 9.1-NA). mPFS was 9.5 months (95% CI 8.5–17.4). mOS was 24.5 months (95% CI 17.4-35.1). See Table for efficacy in the major subgroups. 24 pts (39%) had brain metastasis at presentation, for 12 pts a brain response by RANO-BM was available with 25%/25%/33%/17% CR/PR/SD/PD. For 14 pts, rebiopsy mutation analysis at progression on osimertinib was available: 3 pts with an additional EGFR mutation (C797S,D585Y, E709K), 3 pts with a new TP53 mutation, 1 with c-Met amplification and 1 pt with transformation to neuroendocrine carcinoma. Conclusions: Osimertinib demonstrated activity in ucEGFRm with 91% disease control rate and encouraging PFS and DOR. Brain response was seen in 50% of cases. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRm presented so far. [Table: see text]

Afatinib (AFA) plus bevacizumab (BEV) combination after osimertinib (OSI) resistance in advanced EGFR-mutant NSCLC: A phase II study (ABCD-study).

9117 Background: After OSI failure, various resistant mechanisms such as C797S and uncommon EGFR mutations, or MET amplification have been reported. AFA is an irreversible EGFR-TKI with a potency as pan-HER inhibitor, including high sensitivity to uncommon EGFR mutations. Many clinical studies have also shown a synergy of EGFR-TKIs and VEGF inhibitors. Methods: ECOG PS 0-1 patients (pt) with EGFR-mutant NSCLC were enrolled after OSI resistance. AFA was prescribed at 30-40 mg QD, and BEV was administered at 15 mg/kg tri-weekly until progression. Plasma/histologic rebiopsied samples taken after OSI failure but before enrollment were analyzed to examine resistant mechanisms including gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. Results: Between January 2018 and October 2020, 28 pts were enrolled. Mutation subtypes were: 9 (32%) Del-19; 5 (18%) Del-19+T790M; 5 (18%) L858R; 7 (25%) L858R+T790M; 1 (4%) Del-19+L858R+T790M; and 1 (4%) G719S. Median line of prior OSI was 2 (range, 1-9). CR/PR was obtained by prior OSI in 24 (86%) pts. Regarding AFA+BEV efficacy, one (4%) CR, 4 (14%) PR, and 17 (61%) SD were confirmed, resulting in response rate of 17.9% and disease control rate of 78.6%. Median DoR was 9.0 (range, 4.2-22.3) months. Median PFS and OS were 2.7 (95% CI, 2.0-4.6) months and not reached, respectively. Twenty-eight (100%) plasma and/or 21 (75%) histologic rebiopsies identified: 17 (61%) TP53; 15 (54%) T790M; 9 (32%) uncommon EGFR; 9 (32%) MET; 6 (21%) C797S; 3 (11%) BRAF; 2 (7%) HER2; 2 (7%) KRAS; and 2 (7%) PI3K mutations; or 14 (50%) EGFR; 6 (21%) MET; and 2 (7%) HER2 amplifications. One (4%) small cell transformation was found. Among 6 C797S pts, 1 CR, 4 SD, and 1 PD were confirmed. Three (33%) of 9 uncommon EGFR and 1 (50%) of 2 HER2 mutation positive pts achieved radiographic response. All 15 T790M-positive pts showed no response, but 5 (38%) of 13 T790M-negative pts responded to AFA+BEV. None (0%) of six pts with EGFR downstream signaling mutations such as BRAF, KRAS, or PI3K responded. Five (50%) of 10 pts without T790M/BRAF/KRAS/PIK3 mutations exhibited confirmed response. FAT1 mutation was found in two (40%) of 5 responded pts. Dose reduction/interruption of AFA was performed in 15 (54%) pts. Median number of BEV administrations was 4 (range, 1-32). There were neither TRD nor ILD. Adverse events ≥grade 3: hypertension (29%); proteinuria (7%); diarrhea (7%); and rash (4%) were observed. One (4%) grade 4 duodenal perforation was reported. Conclusions: AFA+BEV after OSI resistance demonstrated moderate efficacy and favorable safety. A small portion of C797S pts exhibited the sensitivity. Higher potency was suggested in T790M/BRAF/KRAS/PIK3 mutation-negative and uncommon EGFR/HER2 mutation-positive pts. Selected population could obtain clinical benefit from AFA+BEV, based on rebiopsy results after OSI resistance. Clinical trial information: UMIN000030545.

Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations.

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]

All EGFR mutations are (not) created equal: focus on uncommon EGFR mutations.

Most common EGFR mutations in NSCLC include del19 and exon 21 L858R. Approximately 10% of patients have uncommon EGFR mutations (indels, missense mutations involving G719, L861 and S768 codons, and exon 20 insertions) that do not respond to TKIs. Of 490 EGFR mutated NSCLC samples, 60 cases harboring uncommon/compound EGFR mutations were reviewed retrospectively, and 44 were included for survival analysis. Sixty (12.2%) patients with a median age of 63 years (25-84years) had uncommon/compound EGFR mutations. Majority had no history of smoking (52; 86.7%). Most common major uncommon mutations (G719X in exon 18, L861Q in exon 21 and S768I in exon 20) were identified in 19 (31.7%) patients. 17 (28.3%) cases demonstrated exon 20 insertions. De novo T790M was observed in 7 (11.7%) cases and 9 cases exhibited compound/dual mutations. Among the 12 patients who received first-line EGFR TKI, 7 received afatinib. Median progression-free survival of patients following first-line afatinib was 8.13months, irrespective of mutation type exhibited. Overall response rate to first-line afatinib therapy was 57.1%. The current study highlighted that rare/dual EGFR mutations are heterogeneous with distinct clinical features in a large Indian cohort of EGFR mutated patients with NSCLC.

Afatinib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: An Updated Database of 1023 Cases Brief Report.

IntroductionPreviously, we developed a database of 693 patients with NSCLC and uncommon EGFR mutations treated with afatinib. Here, we provide an update of >1000 patients, with more data on specific mutations.MethodsPatients were identified from a prospective database developed by Boehringer Ingelheim and via literature review. Mutations were categorized as T790M-positive, exon 20 insertions, major uncommon (G719X, L861Q, S768I) and ‘others’. Patients with compound mutations (≥2 EGFR mutations) were analyzed separately. Key endpoints were time to treatment failure (TTF) and objective response rate (ORR).ResultsOf 1023 patients included, 587 patients were EGFR TKI-naïve and 425 were EGFR TKI-pretreated. The distribution of mutation categories was: major uncommon (41.4%); exon 20 insertions (22.3%); T790M (20.3%); and ‘others’ (15.9%); 38.6% had compound mutations. Overall, median TTF (TKI naïve/pretreated) was 10.7 and 4.5 months. ORR was 49.8% and 26.8%, respectively. In TKI-naïve patients, afatinib demonstrated activity against major uncommon mutations (median TTF: 12.6 months; ORR: 59.0%), ‘other’ mutations (median TTF: 10.7 months; ORR: 63.9%) including strong activity against E709X (11.4 months; 84.6%) and L747X (14.7 months; 80.0%), and compound mutations (11.5 months; 63.9%). Although sample sizes were small, notable activity was observed against specific exon 20 insertions at residues A763, M766, N771, and V769, and against osimertinib resistance mutations (G724S, L718X, C797S).ConclusionAfatinib should be considered as a first-line treatment option for NSCLC patients with major uncommon, compound, ‘other’ (including E709X and L747X) and some specific exon 20 insertion mutations. Moderate activity was seen against osimertinib resistance EGFR mutations.

Rationale and design of a phase II trial of dacomitinib in advanced non-small cell lung cancer patients with uncommon epidermal growth factor receptor mutations: a prospective and single arm study (DANCE study)

BackgroundDacomitinib is a second-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). ARCHER-1050 showed that this agent can improve progression-free survival and overall survival in advanced non-small cell lung cancer patients with sensitive EGFR mutation compared to gefitinib. However, it is unclear whether dacomitinib is effective in patients with sensitizing uncommon EGFR mutations in exon 18–21. The aim of this study is to investigate the safety and efficacy of dacomitinib in these patients.MethodsThis is a single arm, prospective, open label and phase II trial. Sample size will be calculated by a minimax two-stage design method based on the following parameters: α = 0.075, 1-β = 0.9, P0 = 0.20, P1 = 0.45 and a dropout rate of 10%. A total of 30 eligible patients will be included. Patients will receive continuous oral therapy with dacomitinib (45 mg/day) until disease progression, withdrawal of consent, or unacceptable toxicity, whichever occurs first. The primary endpoint is objective response rate (ORR) per RECIST version 1.1, as assessed by investigators’ review. The second endpoint is disease control rate (DCR), PFS, OS, and safety.DiscussionWe conduct a single arm, phase II study to investigate the safety and efficacy of dacomitinib in advanced NSCLC patients with sensitizing uncommon EGFR mutations. The results of the DANCE study will provide new data regarding efficacy and safety of these patients.Trial registrationNCT04504071

Tyrosine Kinase Inhibitor Activity in Patients with NSCLC Harboring Uncommon EGFR Mutations: A Retrospective International Cohort Study (UpSwinG).

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard of care for patients with EGFR mutation-positive non–small-cell lung cancer (NSCLC) with common mutations (Del19 or L858R); however, 7%-23% of NSCLC tumors harbor uncommon EGFR mutations. These mutations are highly heterogeneous, and developments in detection techniques are helping to identify mutations with little or no clinical data.Patients and MethodsIn this retrospective, global, multi-center study (NCT04179890), existing health records were identified for consecutive EGFR TKI-naïve patients with uncommon EGFR mutations (T790M, ex20ins, major uncommon [G719X, L861Q, or S768I], or “other” mutations; compound mutations) treated with erlotinib, gefitinib, afatinib, or osimertinib in first or second line. Endpoints included time-to-treatment failure (TTF), objective response rate (ORR), and overall survival (OS).ResultsOverall, 246 patients (median age: 69.5 years; Asian: 84%) were included from 9 countries. Most patients (92%) received an EGFR TKI as first-line therapy; 54%, 43% and 3% received afatinib, first-generation TKIs, and osimertinib, respectively. Median TTF and OS with EGFR TKIs were 9.9 and 24.4 months; ORR was 43%. In patients treated with first-line chemotherapy (n = 20), median TTF and ORR were 6.6 months and 41%. Outcomes were most favorable in patients with major uncommon or compound mutations. Overall, TTF was 11.3 months with afatinib and 8.8 months with first-generation EGFR TKIs across mutation categories. In most mutation categories, median OS was >2 years.ConclusionIn a real-world setting, EGFR TKIs were the preferred treatment option in patients with uncommon EGFR mutations; strongest outcomes were seen in patients with major uncommon and compound mutations.

Uncommon EGFR mutations: state-of-the-art and case reports

Uncommon EGFR mutations: state-of-the-art and case reports

Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis.

BackgroundInformation on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst non-small-cell lung cancer (NSCLC) is lacking.ObjectiveThe objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature.Materials and methodsSearches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom) were performed. Articles were reviewed against pre-specified criteria and their quality was appraised using a published checklist. Prevalence estimates were synthesised by random-effects meta-analyses.ResultsEighty unique studies of moderate-to-high quality were included in the PLR. The meta-analysed prevalence for EGFR mutations was 12.5% (95% confidence interval [CI]: 11.0, 14.1) in any stage NSCLC and 14.8% (12.8, 17.1) in advanced/metastatic NSCLC. The prevalence of exon 20 insertions was 0.7% (0.4, 1.1) in any stage NSCLC and 6.1% (4.0, 9.4) in any stage EGFR-positive NSCLC. Mutation status was primarily measured using direct sequencing or a combination of methods. One study reporting exon 20 insertions in advanced/metastatic disease was identified, which reported a prevalence of 0.5% in overall NSCLC and 4.0% in EGFR-positive NSCLC.ConclusionsEGFR exon 20 insertion mutations are rare in NSCLC. There is a high unmet need in patients with exon 20 insertions, including effective therapies. Prospective cohort studies are needed to better clinically characterise these patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11523-022-00868-z.

Clinical outcomes of advanced non-small cell lung cancer patients harboring distinct subtypes of EGFR mutations and receiving first-line tyrosine kinase inhibitors: brain metastasis and de novo T790M matters

BackgroundThe clinical features, survival outcomes and patterns of treatment failure of advanced non-small cell lung cancer (NSCLC) patients harboring distinct subtypes of EGFR mutations and receiving first-line EGFR tyrosine kinases inhibitor (TKIs) are not fully understood.MethodsConsecutive metastatic EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs from October 2010 to March 2020 were enrolled and classified into two main groups based on the EGFR mutation subtypes: common mutation (L858R or exon 19 deletion), uncommon mutation (other EGFR mutations).ResultsOf the 1081 patients included, 74 (6.8%) harbored uncommon mutations. The baseline characteristics were generally balanced between the two groups, except that bone metastasis developed less frequently in patients with uncommon mutations (p = 0.02). No significant difference of survival outcomes was found between the two groups, except that among patients with baseline brain metastasis, the intracranial time to progression was significantly shorter in patients with uncommon mutations. Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). The patterns of treatment failure were generally consistent between the two groups, except which patients with uncommon mutations had a higher risk developing progressive disease in the brain.ConclusionFirst-line EGFR-TKIs seemed to be less effective in controlling and preventing brain metastasis in patients with uncommon EGFR mutations and Osimertinib was associated with promising efficacy in patients with de novo T790M mutation, which warranted further validation.

Various Subtypes of EGFR Mutations in Patients With NSCLC Define Genetic, Immunologic Diversity and Possess Different Prognostic Biomarkers.

Based on data analysis of 9649 Chinese primary NSCLC patients, we calculated the exact proportion of EGFR subtypes in NSCLC and evaluated the TMB level, PD-L1 expression level and tumor immune microenvironment among different EGFR mutation subtypes. Postoperative follow-up data for 98 patients were collected and analyzed. The results showed that several uncommon EGFR mutation subtypes have a higher proportion of TMB-high or strong positive PD-L1 expression than the total EGFR mutation group. In addition, different subtypes have different characteristics related to the immune microenvironment, such as G719 mutations being associated with more CD8+ T cell infiltration into tumors; except for EGFR 19del, CD8+ T cell infiltration into tumors of other EGFR mutation subtypes were similar to that of wildtype EGFR. Moreover, follow-up results revealed that components of the immune microenvironment have prognostic value for NSCLC patients, with different prognostic biomarkers for NSCLC patients with and without EGFR mutations. These results suggest that patients with different EGFR mutations need to be treated differently. The prognosis of NSCLC patients may be assessed through components of tumor immune microenvironment, and ICIs treatment may be considered for those with some uncommon EGFR mutation subtypes.

Co-occurrence CDK4/6 amplification serves as biomarkers of de novo EGFR TKI resistance in sensitizing EGFR mutation non-small cell lung cancer

Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) remains an issue of concern. We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 years). Uncommon EGFR mutation subtypes were significantly variable enriched in de novo resistance. The remaining sensitizing EGFR mutation subtypes (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6 × 10–4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36–73%] compared to IRs/LTRs [range 4–22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4/6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80–7.31, p-value < 0.001]. The presence of CDK4/6 amplification in pretreatment specimen serves as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.

Budget Impact Analysis of afatinib for first-line treatment of Non-Small Cell Lung Cancer (NSCLC) patients with uncommon EGFR mutations

Background: The current clinical practice for patients affected by Non-Small Cell Lung Cancer (NSCLC) with uncommon mutation is based on afatinib and osimertinib, second and third generation of Tyrosine Kinase Inhibitor (TKI) respectively. For uncommon EGFR mutations, it is still unclear which EGFR TKI is most effective, since there are few dedicated prospective studies and Next Generation Sequencing (NGS) techniques trace an increasingly large and sometimes little-known population of EGFR mutations. Objective: To determine the economic impact associated to afatinib and osimertinib, a Budget Impact model considering a 3-year time horizon with two scenarios was developed: a first scenario, called AS IS, based on treatment with afatinib and osimertinib according to a distribution of market shares as emerged from clinical practice; a second suitable scenario, called TO BE, based on reviewed literature data, assuming for each year a 10%, 15% and 20% increase in afatinib use, respectively. Methods: Budget Impact analysis was conducted using a dynamic cohort model, in which the annual number of patients with NSCLC and uncommon mutations was equally distributed over 12 months. Progression-free survival (PFS) data for afatinib and osimertinib were extrapolated up to 36 months from published Kaplan Meier curves, and then the number of patients was estimated for each treatment. Results: The increase of 10% in afatinib use allowed a saving of drug acquisition costs for the Italian NHS, over the 3-year time horizon, of –€ 622,432. The univariate sensitivity analysis shows the market share of osimertinib to be the parameter significantly affecting the results achieved in the base case. Conclusions: The potential increase in the use of afatinib in patients with NSCLC and uncommon mutations leads to lower drug acquisition costs, lower Budget Impact and a saving of money for the Italian NHS.