Epidermal Growth Factor Receptor Exon Research Articles

Detection of EGFR mutations in liquid biopsy samples using allele-specific quantitative PCR: A comparative real-world evaluation of two popular diagnostic systems

PurposeThe detection of epidermal growth factor receptor (EGFR) mutations in plasma cell-free DNA (cfDNA) is an auxiliary tool for the molecular diagnosis of non-small cell lung cancer (NSCLC), especially when an adequate tumor tissue specimen cannot be obtained. We compared the diagnostic accuracy of two commonly used in vitro diagnostic-certified allele-specific quantitative PCR assays for detecting plasma cfDNA EGFR mutations. MethodsWe analyzed EGFR mutations in plasma cfDNA from 90 NSCLC patients (stages I–IV) before treatment (n ​= ​60) and after clinical progression on EGFR tyrosine kinase inhibitors (n ​= ​30) using the cobas EGFR mutation test v2 (Roche Molecular Systems, Inc.) and therascreen EGFR Plasma RGQ PCR kit (Qiagen GmbH). ResultsThere was higher concordance between plasma cfDNA and matched tumor tissue EGFR mutations with cobas (66.67%) compared with therascreen (55.93%). The concordance rate increased to 90.00% with cobas (Cohen's kappa coefficient, κ ​= ​0.80; p ​< ​0.0001) and 73.33% with therascreen (κ ​= ​0.49; p ​= ​0.0009) in advanced NSCLC patients. In treatment-naïve patients, cobas was superior to therascreen (sensitivity: 82.35% vs. 52.94%; specificity: 100% vs. 100%). In patients with clinical progression on EGFR tyrosine kinase inhibitors, EGFR exon 20 p.T790M was detected in 30% and 23% of cfDNA samples by cobas and therascreen, respectively. ConclusionsCobas was superior to therascreen for detection of plasma EGFR mutations in advanced NSCLC. Plasma cfDNA EGFR mutation analysis is complex; therefore, the diagnostic accuracy of commercially available assays should be validated.

TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib

Tumor protein p53 (TP53) is a tumor suppressor gene and TP53 mutations are associated with poor prognosis in non-small cell lung cancer. However, the in-depth classification of TP53 and its relationship with treatment response and prognosis in epidermal growth factor receptor (EGFR)-mutant tumors treated with EGFR tyrosine kinase inhibitors are unclear. Circulating tumor DNA was prospectively collected at baseline in advanced treatment-naïve EGFR-mutant lung adenocarcinoma patients treated with gefitinib in an open-label, single-arm, prospective, multicenter, phase 2 clinical trial (BENEFIT trial) and analyzed using next-generation sequencing. Survival was estimated using the Kaplan–Meier method. Of the 180 enrolled patients, 115 (63.9%) harbored TP53 mutations. The median progression-free survival (PFS) and overall survival (OS) of patients with TP53-wild type tumors were significantly longer than those of patients with TP53-mutant tumors. Mutations in exons 5–8 accounted for 80.9% of TP53 mutations. Mutations in TP53 exons 6 and 7 were significantly associated with inferior PFS and OS compared to wild-type TP53. TP53 mutation also influenced the prognosis of patients with different EGFR mutations. Patients with TP53 and EGFR exon 19 mutations had significantly longer PFS and OS than patients with TP53 and EGFR L858R mutations, and both groups had worse survival than patients with only EGFR mutations. Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. Moreover, TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types.

PRS15 A Cost-Utility Analysis of Dacomitinib As First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer with EGFR Exon 21 L858R Substitution Mutation in China

Dacomitinib is a human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The study was conducted to evaluate the cost-effectiveness of Dacomitinib versus other TKI comparators (gefitinib, erlotinib, icotinib, afatinib and osimertinib) for locally advanced or metastatic non-small cell lung cancer with EGFR exon 21 L858R substitution mutation from the social perspective in China. A three-state partitioned survival model was developed with a 15-year horizon. Hazard ratios (HR) of overall survival and progression-free survival were obtained from the phase III trial ARCHER 1050 and a network meta-analysis. Direct cost as well as indirect cost were considered. Drug prices were obtained from national reimbursement drug list and listed drug list. In addition, gefitinib used centralized procurement price; the prices of dacomitinib and icotinib were reduced based on Patient Assistance Programs (PAP). Utilities were obtained from ARCHER 1050 which used EQ-5D-5L and quality-adjusted life year (QALY) was measured. The discount rate was 5%. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. For dacomitinib comparing to gefitinib, erlotinib, icotinib and afatinib, the ICURs were 208,853, 187,209, 78,863 and 100,455 RMB per QALY respectively. ICURs of gefitinib and erlotinib were higher and which of icotinib and afatinib were lower than the 106,819 RMB WTP threshold (1.5 times of 2019 Chinese GDP per capita). Osimertinib was dominated by dacomitinib. The incremental cost per life year (LY) were 117,452, 138,262, 17,504 and 57,329 RMB respectively. Under the 106,819 RMB WTP threshold, dacomitinib was not cost-effective compared to gefitinib and erlotinib and; was cost-effective compared to icotinib and afatinib; and was cost-saving compared to osimertinib.

Successful treatment of EGFR T790M-mutant non-small cell lung cancer with almonertinib after osimertinib-induced interstitial lung disease: a case report and literature review

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have revolutionized the standard treatment for EGFR T790M-positive non-small cell lung cancer (NSCLC). Osimertinib is one of the third-generation EGFR-TKIs and is currently the most advanced in clinical development. Interstitial lung disease (ILD) is a potentially fatal side effect of osimertinib use. Successful rechallenge with the second-generation TKI afatinib following osimertinib-induced ILD has been reported. However, few reports have discussed the safety and efficacy of third-generation TKI rechallenge in this patient population. In this paper, a case of lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was initially diagnosed with early lung cancer, for which surgical treatment was performed. The postoperative diagnosis indicated stage IB (pT2N0M0) right lung adenocarcinoma. Genetic testing (amplification-refractory mutation system) revealed EGFR exon 19 deletion. More than 2 years after surgery, multiple metastases occurred in both lungs, so gefitinib (250 mg per day) was administered. However, 6 months after the start of gefitinib treatment, the tumor progressed. Lung tumor biopsy was performed for genetic testing (NGS) and an EGFR T790M mutation was observed. Subsequently, second-line treatment with osimertinib (80 mg per day) was given for 3 months. The evaluated response suggested a partial response (PR) with the occurrence of grade 3 ILD. Pemetrexed plus bevacizumab chemotherapy was subsequently administered, resulting in stable disease. However, following a severe drug reaction after six courses, the patient’s chemotherapy was discontinued. Another third-generation TKI, almonertinib (110 mg per day), was rechallenged based on no ILD having been reported in a phase I/II study of this drug. After 4 months of almonertinib administration and 6 months without ILD recurrence, partial remission was attained. This is the first report of successful treatment with almonertinib after osimertinib-induced ILD. The results suggested that almonertinib had a significant effect in patients with EGFR T790M mutation, with fewer side effects and better survival benefits for patients with advanced lung cancer.

Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS).

8524 Background: Neoadjuvant treatment has demonstrated efficacy in several types of cancer and is increasingly used for the treatment of early-stage cancers with the potential of cancer downstaging to enhance complete surgical resection and to improve clinical outcomes. Recent evidences have demonstrated that the neoadjuvant use of first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may provide clinically meaningful improvement in EGFRm non-small cell lung cancer (NSCLC) patients, however, limited data were reported on osimertinib, the third-generation EGFR-TKI, in the neoadjuvant setting. Here we present an interim analysis of osimertinib as neoadjuvant treatment for resectable EGFRm NSCLC. Methods: NEOS is a prospective, multi-center, single-arm study to evaluate the efficacy and safety of osimertinib as neoadjuvant treatment in resectable EGFRm (19del/L858R) lung adenocarcinoma. Eligible patients were treated with osimertinib 80 mg orally per day for six weeks followed by surgery. Assessment of response to neoadjuvant therapy was performed according to RECIST 1.1. The primary endpoint was response rate. Secondary endpoints included safety, R0 surgical resection rate, quality of life, major pathologic response (MPR) rate, pathological complete response (pCR) rate, and N2 downstaging rate. Results: As of Dec. 17, 2020, 18 eligible patients (median age 61 [range 46-73], 27.8% male, 22.2% ECOG PS 1) have been enrolled. Patients with clinical stages IIa, IIb, and IIIa (8th AJCC) accounted for 16.7%, 22.2% and 61.1%, respectively. Half (9/18) of the patients had EGFR exon 21 L858R mutations and the other half (9/18) had EGFR exon 19del mutations. Amongst all 15 patients who completed efficacy assessment after neoadjuvant osimertinib, the response rate (RR) was 73.3% (11/15) and the disease control rate (DCR) was 100% (15/15). R0 surgical resection was performed in 93.3% (14/15) patients. Pathological downstaging occurred in 53.3% (8/15) patients. 42.9% (3/7) of the patients with confirmed N2 lymph nodes experienced downstaging to N0 disease after receiving neoadjuvant osimertinib. One patient was identified with a pCR. Adverse events (AEs) were reported in 66.7% (12/18) of patients, with the most common AE being rash (8/18, 44.4%), oral ulceration (8/18, 44.4%), and diarrhea (5/18, 27.8%). No grade 3-5 AEs or serious AEs were reported. Conclusions: Interim analysis from this study indicated neoadjuvant osimertinib as an effective and feasible treatment in patients with resectable stage II-IIIB EGFRm NSCLC. The trial is ongoing and the final results will be provided in the future. Clinical trial information: ChiCTR1800016948.

Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.

Interim results of a phase II single arm trial combining afatinib with cetuximab in patients with EGFRex20ins positive NSCLC.

9112 Background: Epidermal growth factor receptor exon 20 insertions (EGFRex20ins) are identified in 4-10% of all EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). Treatment options are limited. A case series showed that dual EGFR blockade with afatinib and cetuximab can induce tumor responses with manageable toxicity. We report on the first seventeen EGFRex20ins patients treated with afatinib in combination with cetuximab. Methods: In this Simon’s two stage, single-arm, phase II trial, patients with advanced NSCLC harboring an EGFRex20ins mutation were treated with afatinib 40 mg once daily, in combination with cetuximab 500 mg/m2, every two weeks, in five institutions in the Netherlands. Supportive medication consisted of minocycline, loperamide and skin creams. No previous line of treatment was required and asymptomatic brain metastases were allowed. The primary endpoint was disease control rate (DCR) after 18 weeks of treatment. Secondary endpoints included safety, response rate (RR), duration of response (DOR) and progression-free survival (PFS). Patients were treated until progression or unacceptable toxicity. A Simon’s two stage optimal design was used in order to minimize the number of patients being treated in the event that the regimen proves to be inactive. The estimated sample size of the first stage was 17 patients. At least four successes were required to enter stage 2 of the trial (alpha = 0.10; power = 0.90). Results: Eighteen patients were enrolled between Jan 2019 and Aug 2020; one patient did not meet the eligibility criteria due to absence of measurable disease. Median age was 66.0 years, 65% female, 53% never smoker. 47% of patients were treated as first-line therapy. Median prior lines of treatment was 1 (range 0-6). 53% received prior platinum-based chemotherapy. The primary endpoint was met as disease control was achieved by 10 patients (59%) after 18 weeks of treatment. Median PFS was 5.5 months. Best responses were partial (n = 8, RR 47%), stable (n = 7) or progressive disease (n = 2). Four patients were still on treatment at the cut-off date (Feb 2021). Most common treatment-related adverse events (TRAEs) were diarrhea (71%), rash (65%), paronychia (59%) and dry skin (53%). Grade III TRAEs were reported in 59% of all patients. Grade III TRAEs ≥ 10% included rash (n = 3; 18%) and diarrhea (n = 3; 18%). No grade IV toxicity was observed. One patient died due to respiratory failure after infusion of study medication, probably related to disease progression, possibly treatment related. 82% of patients required a dose reduction. Rate of treatment discontinuation due to AEs was 12% (n = 2). Conclusions: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 59% at 18 weeks and a 47% RR, with manageable toxicity. Clinical trial information: NCT03727724.

Phase 1b/2 study of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated non-small cell lung cancer who received prior therapy: Final overall survival and safety.

9048 Background: Primary findings from the phase 1b/2 study (NCT01610336) demonstrated clinical activity of combination therapy with capmatinib, a potent and selective MET inhibitor, and gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in heavily pre-treated patients with EGFR-mutated and MET dysregulated non-small cell lung cancer (NSCLC). The objective response rate (ORR) was 27% in patients across phase 1b/2 of the study. At the recommended phase 2 dose (R2PD) of capmatinib 400 mg twice-daily (bid) and gefitinib 250 mg once-daily (qd), the ORR was 47% in patients with high MET-amplified tumors ( MET gene copy number ≥6). Here, we report the updated data on the efficacy and safety from the NCT01610336 study. Methods: Patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutation with a recorded clinical benefit on prior single-agent EGFR-TKI before progression and confirmed dysregulated MET pathway after progression on EGFR TKIs were included. Patients in phase 1b received capmatinib 100 to 800-mg capsules qd or 200 to 600-mg capsules or tablets bid, plus gefitinib 250 mg qd. Patients in phase 2 received the R2PD dose. Data on the overall survival (OS) and cumulative safety endpoints are reported in this final analysis. Results: Overall, 161 patients received the combination treatment in this study; phase 1b (n = 61) and phase 2 (n = 100). The median age of patients was 60.0 years, mostly Asian (67.1%) with an Eastern Cooperative Oncology Group performance status of 0/1: 18.0%/78.3%. At data cut-off on May 27, 2020, all patients had discontinued the study; 82 out of the 100 patients in phase 2 had died and 18 were censored (mostly lost to follow-up [n = 15]). One patient was still on treatment with a partial response and rolled over to another study. The median (range) follow-up time for OS was 12.2 (0.9-70.2) months. The median OS was 13.9 months (95% confidence interval, 11.6-15.7 months). The median (range) duration of exposure for capmatinib plus gefitinib was 16 weeks (0.4-209.7 weeks) during phase 1b and 18.5 weeks (0.4-268.0 weeks) during phase 2. Majority of the patients (98.8%) experienced ≥1 adverse event (AE); 87% of the patients had treatment-related AEs. Most common treatment-related AEs (reported in ≥20%) were nausea (28.0%), peripheral edema (23%), rash (21.7%), and decreased appetite (21.1%). Grade 3 or 4 treatment-related AEs occurred in 51 patients (31.7%) across both phases, of which, the most frequent (reported in ≥5%) were increased amylase and increased lipase (6.2% each) and peripheral edema (5%). Conclusions: Capmatinib 400 mg bid in combination with gefitinib 250 mg qd was well-tolerated and showed encouraging clinical activity in patients with EGFR-mutant and MET-dysregulated NSCLC. Clinical trial information: NCT01610336.

Initial low dose of dacomitinib for first-line treatment of patients with EGFR exon 21 mutated non-small cell lung cancer.

e21083 Background: Dacomitinib showed superior efficacy for patients with epidermal growth factor receptor (EGFR) sensitive mutations as compared to that of gefitinib, especially for those harboring exon 21 L858R mutation. However, the grade 3-4 treatment related adverse events were more common in patients receiving 45mg of dacomitinib as initial treatment. Hence, we did this study to explore efficacy and safety of low dose dacomitinib for first-line treatment of patients with EGFR exon 21 mutated non-small cell lung cancer (NSCLC). Methods: We retrospectively analyzed data of patients with EGFR exon 21 mutated advanced NSCLC treated with 15 mg dacomitinib as initial therapy between August 2019 and December 2020 at Affiliated Dongguan Hospital, Southern Medical University, China. EGFR mutation was identified using the scorpion amplification refractory mutation system method (ARMS) or next-generation sequencing technology (NGS). A total of 9 NSCLC patients with exon 21 mutation were included. All of these patients received dacomitinib (15 mg, once a day) until disease progression or unacceptable toxicity. Response was assessed according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Toxicities were recorded and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. The last follow-up date is February 10, 2021. The primary end point was objective responsive rate (ORR). The secondary end points were disease control rate (DCR), median progression-free survival (PFS) and treatment related toxicity. Results: Among the 9 patients with EGFR exon 21 mutated NSCLC in this study, 8 patients harboring L858R mutation while one patients harboring L861Q mutation. The median age of treatment patients was 70 years (range, 39-87 years). There were 3 patients with brain brain metastases (33.3%) and had never received whole-brain radiation therapy (WBRT), surgery, radiosurgery or systemic treatment.They all received low dose of dacomitinib as initial treatment. The ORR was 77.8% and DCR was 100%. The median PFS data was not mature. None of these patients had a progression disease until the last follow-up date. Treatment related adverse events were generally mild. The most frequent toxicity was rash (44.4%), the remaining adverse events included rash, pruritus, diarrhea, abnormal hepatic function, anaemia and elevated creatinine, all of which occurred only once during the treatment period. None of the patients experienced grade 3 or higher toxicities. Conclusions: Our study showed that dacomitinib (15 mg, once a day) may be also effective for patients harboring EGFR exon 21 mutated NSCLC, with significantly reduced toxicities as compared to that of standard dose. Prospective or real-world studies are needed to further illuminate the effect of low dose of dacomitinib on EGFR exon 21 mutated patients.

CHRYSALIS-2: A phase 1/1b study of lazertinib as monotherapy and in combination with amivantamab in patients with EGFR-mutant NSCLC.

TPS9132 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved clinical outcomes for patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC); however, patients will inevitably progress due to acquired resistance mutations. Lazertinib is a potent, brain-penetrant, 3rd-generation EGFR TKI with efficacy against activating EGFR and resistance T790M mutations. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating EGFR and MET mutations. Synergistic inhibition of the EGFR by targeting the receptor’s extracellular domain with amivantamab and the kinase domain with lazertinib, may lead to more potent inhibition of the EGFR pathway and potentially delay resistance. In the ongoing CHRYSALIS phase 1 study (NCT02609776), preliminary antitumor activity has been demonstrated with the combination of lazertinib and amivantamab in patients with treatment-naïve and osimertinib-relapsed EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). Methods: CHRYSALIS-2 is an ongoing phase 1/1b open-label study of lazertinib as monotherapy and in combination with amivantamab in patients with advanced EGFRm NSCLC (NCT04077463; https://clinicaltrials.gov/ct2/show/NCT04077463 ). Phase 1 of the study has confirmed the safety and tolerability of lazertinib monotherapy in Japanese patients. The objective of phase 1b is to characterize the preliminary efficacy of lazertinib in combination with amivantamab in subpopulations of patients with EGFRm NSCLC (Phase 1b Expansion Cohorts) at the recommended combination dose of 1050 mg (1400 mg, ≥80 kg) IV amivantamab dosed weekly in cycle 1 (28-day cycle), every other week thereafter, and 240 mg oral lazertinib QD. Global enrollment in Phase 1b Expansion Cohorts is currently ongoing. Expansion Cohort A is enrolling patients who have progressed on 1st or 2nd-line osimertinib followed by platinum chemotherapy; Expansion Cohort B is enrolling patients with EGFR exon 20 insertion (Exon20ins) mutation who have progressed on prior therapy; and Expansion Cohort C is enrolling patients with uncommon non-Exon20ins EGFR mutations (i.e., S768I, L861Q, G719X) who are treatment-naïve or received 1st or 2nd-generation EGFR TKI as last therapy. The primary endpoints of the study are frequency of dose-limiting toxicity for phase 1 and 1b combination cohorts, and overall response rate for phase 1b expansion cohorts. Key secondary endpoints include safety (adverse events), pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, and overall survival. Safety assessments will include monitoring AEs, clinical laboratory tests, ophthalmologic examination, ECG, and ECHO/MUGA. Blood samples will be collected to access PK. Tumor response will be assessed every 6 weeks by the investigator using RECIST, v1.1. Clinical trial information: NCT04077463.

Amivantamab compared with real-world therapies in patients with NSCLC with EGFR Exon 20 insertion mutations who have progressed after platinum doublet chemotherapy.

9052 Background: Amivantamab is an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune cell-directing activity. Amivantamab has demonstrated efficacy and safety in patients (pts) with EGFR exon 20 insertion (Exon20ins) in the ongoing CHRYSALIS phase 1 study in advanced non-small cell lung cancer (aNSCLC). Because CHRYSALIS is a non-randomized, single arm study, external controls (EC) can add valuable context in interpreting amivantamab’s efficacy and appreciating the unmet needs given real-world therapies. A protocol-driven treatment comparison was conducted of amivantamab vs real-world therapies in pts with Exon20ins aNSCLC who progressed after platinum chemotherapy. Methods: Custom curated, real-world data abstracting clinically relevant measures that are not typically available from off-the-shelf datasets were obtained from 3 US-based companies: Flatiron, COTA, and ConcertAI. Datasets were de-duplicated via a tokenization procedure, analyzed separately and as a single pooled database. Key eligibility for the EC included: Exon20ins aNSCLC, prior platinum chemotherapy, ≥1 line after platinum therapy, and ECOG PS 0 or 1. Propensity score weighting (average treatment effects on the treated) was used to adjust for differences in age, brain metastases, ECOG PS, and number of prior lines of therapy (LOT). Results: The amivantamab-treated population (N = 81) included post-platinum pts with EGFR Exon20ins aNSCLC treated at the recommended phase 2 dose (Sabari WCLC 2020 Abs #3031). After de-duplication of the custom real-world datasets, 126 unique pts formed the EC. Most frequent treatments after platinum doublet chemotherapy in the EC group were checkpoint inhibitors (CPI; 25%), single-agent, non-platinum chemotherapies (25%), and EGFR tyrosine-kinase inhibitors (TKIs; 16%). Baseline demographics were generally similar between amivantamab and the EC pts; notable differences included a higher percentage of Asian pts (56% vs 9%) and more prior LOT (median 2 vs 1) among the amivantamab compared to the EC pts. Median overall survival (OS) among amivantamab pts was 22.8 months and EC pts was 13.1 months (HR = 0.53 [95% CI, 0.33, 0.86]). Similarly, amivantamab pts had longer progression-free survival (8.3 vs 2.9 months; HR = 0.46 [95% CI, 0.33, 0.63]) and time to next treatment (14.8 vs 4.8 months; HR = 0.42 [95% CI, 0.29, 0.6]) compared to the EC pts. Confirmed overall response rate was 40% among amivantamab pts and 10% for the EC pts (odds ratio = 4.44 [95% CI 2.42, 8.14]). Conclusions: Amivantamab demonstrated a 10-month higher OS than real-world therapies in the post-platinum setting. The poor performance of the EC, frequently treated with CPI, single chemotherapies, and EGFR TKI, highlights the ineffectiveness of these agents and the urgent need to find more alteration-specific treatments in aNSCLC.

Efficacy of various types of chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 in-frame insertions.

e21155 Background: Approximately 4% of epidermal growth factor receptor (EGFR)−mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs), as they result in steric hindrance of the drug-binding pocket. Studies have shown that chemotherapy is superior to currently approved EGFR TKIs as a first-line or second-line treatment for EGFR exon 20 in-frame insertions. Nevertheless, the difference in the efficacy of different chemotherapy regimens in patients with EGFR exon 20 in-frame insertions remains unclear. Methods: Data from advanced NSCLC patients harboring EGFR exon 20 in-frame insertions from an independent cohort (Jenn-Yu Wu, 2019) was used to analyze the objective response rates (ORRs), disease control rates (DCRs), progression-free survival (PFS), and overall survival (OS) of different chemotherapy regimens. Results: Thirty-five advanced NSCLC patients harboring EGFR exon 20 in-frame insertions treated with chemotherapy were used to analyze, of which 7 received gemcitabine plus cisplatin (GC), 22 received pemetrexed plus cisplatin (PC), and 6 received taxol plus cisplatin (TC). ORRs were 31.82% for the patients received PC, 14.29% for GC, and 16.67% for TC. DCRs were 72.73% for the patients received PC, 42.86% for GC, and 16.67% for TC. Median PFS was numerically longer in patients who received PC chemotherapy (6.10 m; 95 % CI: 3.46–8.75) than GC (4.20 m; 95 %CI: 2.40–6.00; P = 0.14) or TC (3.40 m; 95 %CI: 1.96–4.84; P = 0.06). Median OS was significantly longer in patients who received PC chemotherapy (22.20 m; 95 % CI: 8.87–35.53) than GC (9.00 m; 95 %CI: 7.46–10.54; P = 0.04), and numerically longer than patients who received TC (8.10 m; 95 %CI: 0.00–22.62; P = 0.19). Conclusions: These results suggest that pemetrexed plus cisplatin may be the preferred chemotherapy for patients harboring EGFR exon 20 in-frame insertions, but further validation is needed in large clinical studies.

Erlotinib and Onalespib Lactate Focused on EGFR Exon 20 Insertion Non-Small Cell Lung Cancer (NSCLC): A California Cancer Consortium Phase I/II Trial (NCI 9878)

BackgroundOnalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non–small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC. Patients and MethodsStandard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. ResultsEleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m2 intravenously on days 1, 8, and 15 every 28 days. ConclusionOverlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).

A Case Report of Primary Resistance to EGFR TKI in Lung Adenocarcinoma Due to Coexisting MET Exon 14 Skipping Mutation with Excellent Response to Combination of Gefitinib and Capmatinib

AbstractTreatment of nonsmall cell lung cancer (NSCLC) carrying an epidermal growth factor receptor (EGFR) mutation depends on EGFR tyrosine kinase inhibitors (TKIs). However, all patients treated with EGFR TKI eventually develop progressive disease. Approximately, 20% of patients do not respond to EGFR TKIs, which is defined as primary resistance. The prognosis of these patients is similar to NSCLC with nondriver mutations. We report a case of a patient with EGFR exon 21 mutation who rapidly progressed in 15 days on Gefitinib. Next-generation sequencing (NGS) showed a MET exon 14 skip mutation coexisting with EGFR exon 21 mutation, causing primary resistance to EGFR TKI. Based on NGS reports, a treatment combining Gefitinib and Capmatinib, a MET inhibitor, induced a rapid response in the patient, which was sustained at the end of 8 months. This clearly emphasizes the need for comprehensive genomic profiling using NGS over single gene testing.

1P Real-world frequency of non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations by site of insertion

1P Real-world frequency of non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations by site of insertion

Detection of EGFR mutation of pulmonary adenocarcinoma in sputum using droplet digital PCR

BackgroundIt is still unclear whether epidermal growth factor receptor (EGFR) mutation of primary lung adenocarcinoma can be detected on sputum samples. This study aimed to examine EGFR mutations of primary lung adenocarcinoma in sputum samples using droplet digital polymerase chain reaction (ddPCR) and compare it with an EGFR mutation in surgically resected lung cancer.MethodsSputum was prospectively collected from the patients before complete resection of the primary lung cancer at Kanagawa Cancer Center from September 2014 to May 2016. ddPCR was performed to detect EGFR exon 21 L858R point mutation (Ex21) and EGFR exon 19 deletion mutation (Ex19) in sputum samples from patients with lung adenocarcinoma. The concordance of EGFR mutation status in sputum samples and tumors in surgically resected specimen was evaluated for each positive and negative cytology group.ResultsOne hundred and eighteen patients with primary lung adenocarcinoma provided sputum samples. Sputum cytology was positive in 13 patients (11.0%). ddPCR detected two cases of Ex21 and two cases of Ex19 in sputum cytology positive cases. Compared to surgically resected specimens, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 80.0%, 100%, and 100%, respectively, in sputum cytology positive cases. In contrast, the sensitivity, specificity, and positive predictive value of EGFR mutation (Ex19 and Ex21) detection were 3.1%, 100%, and 100%, respectively, in sputum cytology negative cases.ConclusionsEGFR mutations in primary lung adenocarcinoma can be detected with high sensitivity in sputum samples if sputum cytology is positive.

Relationship between epidermal growth factor receptor mutations and CT features in patients with lung adenocarcinoma

The purpose of this study was to investigate the relationship between epidermal growth factor receptor (EGFR) mutation status and computed tomography (CT) features in patients with lung adenocarcinoma. A total of 483 patients with lung adenocarcinoma diagnosed between January 2015 and April 2020 were included in this study. All patients underwent a preoperative chest CT, and a total of 31 detailed CT features were quantified. The mutation status of EGFR exon 18-21 was detected by a polymerase chain reaction (PCR)-based amplified refractory mutation system. Student's t and Fisher's exact or chi-square tests were used to compare continuous and categorical variables, respectively. Least absolute shrinkage and selection operator (LASSO) regularisation was used to determine the optimal combination of CT features and clinical characteristics to predict the EGFR mutation status. The model was tested using a validation set consisting of 120 patients. EGFR mutations were found in 249 (51.6%) of 483 patients with lung adenocarcinoma. Univariate analysis showed that 14 CT features and two clinical characteristics correlated significantly with the EGFR mutation status. Smoking history, long-axis diameter, bubble-like lucency, pleural retraction, thickened bronchovascular bundles, and peripheral emphysema were independent predictors of the EGFR mutation status, according to LASSO regularisation. In the training and verification cohorts, the areas under the curve of the prediction model were 0.766 and 0.745, respectively. CT features of patients with lung adenocarcinoma can help predict the EGFR mutation status.

Activity of tarloxotinib-E in cells with EGFR exon-20 insertion mutations and mechanisms of acquired resistance.

BackgroundApproximately 10% of non‐small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in‐frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR‐tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia‐activated prodrug that releases a potent, irreversible pan‐ERBB TKI (tarloxotinib‐E) under solid tumor hypoxia.MethodsWe examined the efficacy of tarloxotinib‐E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib‐E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib‐E by establishing cells with resistance to tarloxotinib‐E via chronic drug exposure after N‐ethyl‐N‐nitrosourea mutagenesis treatment.ResultsAmong all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib‐E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib‐E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR‐TKIs. As acquired resistance mechanisms to tarloxotinib‐E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation.ConclusionsThese findings indicate that tarloxotinib‐E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib‐E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.

Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: A systematic literature review.

ObjectivesThe burden of epidermal growth factor receptor (EGFR) exon 20 insertion mutation (Exon 20ins) in non-small cell lung cancer is not well understood. A systematic review was conducted to identify evidence on mutation frequency, prognostic impact, clinical, patient-reported, and economic outcomes associated with Exon 20ins.Materials and methodsSearches were conducted in Embase and Medline and supplemented with recent conference proceedings. Included studies were not limited by intervention, geography, or publication year.ResultsSeventy-eight unique studies were included; 53 reporting mutation frequency, 13 prognostic impact, 36 clinical outcomes, and one humanistic burden. No economic burden data were identified. The frequency of Exon 20ins mutation ranged from 0.1% to 4% of all NSCLC cases and 1% to 12% of all EGFR mutations. Data on the prognostic impact of Exon 20ins were heterogeneous but highlighted poorer outcomes in patients with Exon 20ins mutation compared with patients with other EGFR mutations and EGFR wildtype across a wide range of therapies and treatment lines. Comparative evidence on the clinical efficacy and safety of currently available therapies were limited, as were sample sizes of studies reporting on real-world effectiveness. Nine single-arm trials and 27 observational studies reported clinical outcomes for patients with Exon 20ins. Trends towards better survival and response were observed for chemotherapy compared with TKIs as first-line treatments. For subsequent treatment lines, novel targeted therapies provided encouraging preliminary responses while results for chemotherapy were less favorable. Limited safety data were reported. One conference abstract described the symptom burden for Exon 20ins patients with fatigue and pain being most common.ConclusionFindings of the systematic review show a high unmet need for safe and efficacious treatments for patients with Exon 20ins as well and need for further evidence generation to better understand the patient-level and economic impact for these patients.

Structural Basis for the Functional Changes by EGFR Exon 20 Insertion Mutations.

Simple SummaryNon-small cell lung cancer (NSCLC) is the most common type of lung cancer that claims the lives of many worldwide. Activating mutations occurring on the epidermal growth factor receptor (EGFR) protein have been associated with the pathogenesis of NSCLC, among which exon 20 insertion mutations play a significant role. The objective of this study is to examine the dynamic structural changes occurring on the EGFR protein as a result of two common EGFR exon 20 insertion mutations, V769insASV and D770insNPG. The study further aims to uncover the mechanisms by which the insertion mutations increase kinase activity. Our results suggest that the insertion mutations stabilize structural elements key to maintaining the active EGFR conformation. Furthermore, the insertions disrupt an interaction essential in stabilizing the inactive conformation, which could drive the kinase from an inactive to an active EGFR state.Activating somatic mutations of the epidermal growth factor receptor (EGFR) are frequently implicated in non-small cell lung cancer (NSCLC). While L858R and exon 19 deletion mutations are most prevalent, exon 20 insertions are often observed in NSCLC. Here, we investigated the structural implications of two common EGFR exon 20 insertions in NSCLC, V769insASV and D770insNPG. The active and inactive conformations of wild-type, D770insNPG and V769insASV EGFRs were probed with molecular dynamics simulations to identify local and global alterations that the mutations exert on the EGFR kinase domain, highlighting mechanisms for increased enzymatic activity. In the active conformation, the mutations increase interactions that stabilize the αC helix that is essential for EGFR activity. Moreover, the key Lys745–Glu762 salt bridge was more conserved in the insertion mutations. The mutants also preserved the state of the structurally critical aspartate–phenylalanine–glycine (DFG)-motif and regulatory spine (R-spine), which were altered in wild-type EGFR. The insertions altered the structure near the ATP-binding pocket, e.g., the P-loop, which may be a factor for the clinically observed tyrosine kinase inhibitor (TKI) insensitivity by the insertion mutants. The inactive state simulations also showed that the insertions disrupt the Ala767–Arg776 interaction that is key for maintaining the “αC-out” inactive conformation, which could consequently fuel the transition from the inactive towards the active EGFR state.