T790M Mutation-positive Non-small Cell Lung Cancer Research Articles

Befotertinib for patients with pretreated EGFR T790M mutated locally advanced or metastatic NSCLC: Final overall survival results from a phase 2 trial

BackgroundIn the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. MethodsEligible patients received oral befotertinib of 50 mg (cohort A) or 75–100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. ResultsA total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1–48.3) in cohort A and 36.7 months (35.9–37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1–27.2) in cohort A and 31.5 months (26.8–35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9–26.3) and 26.4 months (95 % CI: 23.0–29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6–29.1) and 35.5 months (95 % CI: 29.3–NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. ConclusionBefotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

EP08.02-064 ASTRIS China: A Real-world Study of Osimertinib in Patients with EGFR T790M Positive Non-small-cell Lung Cancer (NSCLC)

ASTRIS is the largest global wide study of osimertinib in a real-world setting in patients with EGFR T790M mutation-positive advanced NSCLC. Here we present the final analysis of Chinese subset of the ASTRIS study.

Effectiveness and safety of Osimertinib on non-small cell lung cancer therapy

Lung cancer is a disease causing millions of deaths around the globe without adequate means of medical treatment. As one subtype of lung cancer, non-small cell lung cancer (NSCLC) involves mutations in epidermal growth factor receptor (EGFR) and is commonly treated with EGFR tyrosine kinase inhibitors (TKI). Yet, cancer cells adapt and resist rapidly to TKIs and constant updates are required. Osimertinib (AZD9291) is the latest generation of EGFR-TKI designed to inhibit EGFR mutation and T790M, a second-site genetic mutation responsible for EGFR-TKI resistance. Nearly two-thirds of NSCLC patients who are EGFR mutation-positive and experience resistance after being treated with an EGFR-TKI develop the T790M mutation, for which there have been limited treatment options. Osimertinib arises as a potent drug against metastatic EGFR T790M mutation-positive NSCLC. Osimertinib has undergone an elevated FDA approval process to the market. This review summarizes clinical trials of different phases to illustrate the effectiveness of Osimertinib against NSCLC, as well as variable mutations in Osimertinib resistant patients. Further studies are required to address Osimertinib’s toxicity as well as treatments against resistance to Osimertinib.

Aumolertinib: A Review in Non-Small Cell Lung Cancer.

Aumolertinib (formerly almonertinib; Ameile®) is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) that is selective for mutant EGFR over wild-type EGFR. It has been developed for the treatment of advanced EGFR mutation-positive non-small cell lung cancer (NSCLC). In the phase3 AENEAS trial conducted in Chinese patients, aumolertinib as first-line treatment significantly prolonged progression-free survival (PFS) and duration of response (DoR) compared with gefitinib in patients with advanced EGFR mutation-positive NSCLC; overall survival (OS) data from this study are immature. In the phase1/2 APOLLO trial, aumolertinib showed good clinical activity (based on objective response rate, PFS, DoR and OS) in Chinese patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who had progressed on or after prior EGFR-TKI therapy. Aumolertinib has a generally manageable tolerability profile; adverse events associated with wild-type EGFR inhibition (e.g. rash and diarrhoea) were less frequent with aumolertinib than gefitinib in AENEAS. Thus, aumolertinib is a promising new option for both first-line and second-line treatment in patients with advanced EGFR mutation-positive NSCLC.

An evaluation of aumolertinib for the treatment of EGFR T790M mutation-positive non-small cell lung cancer

ABSTRACT Introduction Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can significantly improve patient prognosis when used on patients with EGFR-mutant non-small cell lung cancer (NSCLC), but those patients often develop acquired resistance after 9–14 months of treatment. These resistance mechanisms are complex and diverse, with the EGFR T790M mutation being the most common. Aumolertinib is a new third-generation EGFR-TKI that is highly selective for EGFR-sensitizing mutations and EGFR T790M resistance mutation. Areas covered This review summarizes the mechanism of action, efficacy, and safety of aumolertinib for EGFR T790M mutation-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects. Expert opinion Aumolertinib has shown good efficacy and safety for advanced EGFR T790M mutation-positive NSCLC patients who have progressed after EGFR-TKI treatment. It is expected to become a new treatment option, and to aid the establishment of new treatment standards. A phase III clinical study is currently underway to evaluate the suitability of aumolertinib as a first-line treatment. At present, more drug combinations and different applicable populations are being further explored. Future challenges include exploring mechanisms of aumolertinib resistance and determining its efficacy in European and American populations.

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

BackgroundOsimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.MethodsEnrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.ResultsThirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.ConclusionOsimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Progression pattern and post-progression treatment of furmonertinib (AST2818) in EGFR T790M mutation positive NSCLC patients: A post-hoc analysis from a multicenter, single-arm study.

e21071 Background: Furmonertinib (AST2818) is a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which can irreversibly inhibit both EGFR sensitizing and T790M resistant mutations. However, like other EGFR-TKIs, progression is still unavoidable when treated with furmonertinib. Methods: In a multi-center, single-arm phase IIb study (NCT03452592), non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation received furmonertinib 80mg/d treatment until disease progression, death or treatment cessations for other reasons. This is a post-hoc analysis of the progression pattern and post-progression treatment. Results: A total of 220 patients were enrolled in this study. At baseline, 105 (48%) patients had central nervous system (CNS) metastases, 84 (38%) were EGFR L858R mutated and 9 (4%) were ECOG performance status 2. At data cut-off (December 31, 2020), 179 out of 220 (81%) patients had progressed assessed by investigators (patients who died before assessed as progression were excluded). The most frequent progression site was lung (n = 106，48%), followed by CNS (n = 33, 15%), lymph node (n = 22, 10%), liver (n = 20, 9%) and bone (n = 16, 7%). CNS progression rate were 3%, 8%, 13% and 15% at 3, 6, 12 and 18 months, respectively. After progression, 52% (93/179) patients continued furmonertinib monotherapy based on the judgement of continuous benefit by investigators which was permitted in the protocol. The median post-progression treatment time of furmonertinib was 3.02 months (range 0.03-18.27). Overall, 48% (86/179) patients discontinued furmonertinib and later-line treatments were decided by investigators. The post-progression survival (PPS) was 17.3 months in the furmonertinib-continued group and 12.4 months in the furmonertinib-not-continued group (HR 0.57 [95%CI 0.40-0.80], p = 0.0048). Conclusions: Although about half patients had CNS metastases at baseline, CNS progression rate was relatively low in this study. Post-progression continuous treatment of furmonertinib monotherapy might still bring survival benefit to certain NSCLC patients with EGFR T790M mutation which need further exploration. Clinical trial information: NCT03452592.

Wighteone exhibits an antitumor effect against EGFR L858R/T790M mutation non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) harboring activating EGFR mutations were initially treated by first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), unfortunately, the efficacy of these drugs is limited, mostly frequent due to T790M mutation. Although osimertinib has been approved to treat patients with T790M-positive NSCLC, the majority of patients will develop C797S mutation and suffer diseases again. Therefore, more novel therapeutic strategies for T790M mutation-positive NSCLC are urgently required. We hypothesized that wighteone, a natural compound isolated from plant derivatives, has antitumor effects against NSCLC with T790M mutation. In this study, we created a Ba/F3 cell line harboring EGFR L858R/T790M mutation (Ba/F3 EGFR L858R/T790M cell line), and then used this cell line and a human NSCLC cell line with EGFR L858R/T790M mutation (NCI-H1975) to investigate the effects and mechanism of wighteone. The results showed that wighteone inhibited cell proliferation, suppressed EGFR signaling pathway, caused cell cycle redistribution and induced cell apoptosis. Our studies suggest that wighteone may provide a novel potential therapeutic strategy for NSCLC patients with T790M mutation.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small-cell lung cancer (NSCLC): A phase II clinical trial.

e21704 Background: Osimertinib has been shown to be effective against epidermal growth factor receptor ( EGFR) T790M-positive non-small cell lung cancer (NSCLC), but so far all clinical trials have targeted performance status (PS) 0 to 1 cases. The efficacy and safety of osimertinib in EGFR T790M-positive NSCLC patients with poor PS remain elusive. Methods: We conducted an open-label, multi-center, single-arm phase II study to evaluate the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2 to 4. Patients received 80 mg of osimertinib once daily. The primary endpoint was progression-free survival (PFS). The planned sample size was 18 patients to achieve power of at least 80% with one-sided alpha of 0.05 and expected and threshold PFS as 8.2 months and 3.0 months. Results: Eighteen patients (4 men and 14 women) were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55–85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and were previously treated with first- or second-generation EGFR- tyrosine kinase inhibitors, and 10 patients (56%) had central nervous system (CNS) metastasis. The overall median PFS was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate (ORR) was 53%, the median time to first response was 1.5 months, the median duration of response was 6.7 months, and the median overall survival (OS) was 12.7 months. Moreover, improved PS scores were observed in 13 patients (72%) including six with PS 2, six with PS 3, and one with PS 4. Osimertinib also showed an ORR of 60% in the patients with CNS metastasis, and the median PFS and OS were 6.5 months and 22.0 months, respectively. Although anemia, rash, and anorexia were frequently reported, the incidence of grade 3 adverse events was low, and no grade 4 or 5 events were observed. Interstitial lung disease (ILD) was observed in three patients (two with grade 2, one with grade 1). All three patients discontinued osimertinib treatment and recovered from ILD. Conclusions: Osimertinib therapy could be a promising treatment option for patients with EGFR T790M mutation-positive advanced NSCLC who have poor PS. Clinical trial information: UMIN000027655.

Efficacy and safety of alflutinib (AST2818) in patients with T790M mutation-positive NSCLC: A phase IIb multicenter single-arm study.

9602 Background: Alflutinib (AST2818) is a third generation EGFR-TKI. This phase IIb, multicenter, single arm study (ALSC003, NCT03452592) aimed to assess the efficacyand safety of Alflutinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic EGFR T790M mutated NSCLC who progressed after first/second-generation EGFR-TKIs therapy or primary EGFR T790M mutation positive received 80 mg Alflutinib orally once daily. Tumor tissue samples underwent central laboratory testing for EGFR T790M mutation. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Efficacy was assessed by independent radiological review committee per RECIST 1.1. Safety was assessed by NCI CTCAE version 4.03. Results: From Jun 4, 2018 to Dec 8, 2018, 220 patients were enrolled with a median age of 61.0 (range 29 to 80) years. According to the AJCC version 8 staging system, 212 (96.4%) cases were in stage IV, and 8 (3.6%) cases in stage III. All patients had EGFR T790M mutation. By April 12, 2019, the ORR was 73.6% (95% CI 67.3–79.3). The DCR estimated at 6 and 12 weeks were 87.3% (95%CI 82.1-91.4) and 82.3% (95%CI 76.6-87.1), respectively. The median PFS was 7.6 months (95% CI 7.0–NA). Median OS and DoR have not been reached. 209 (95.0%) patients had at least one adverse events (AEs), which were mostly grade 1 or 2 and well tolerable. The most common AEs were increased aspartate aminotransferase (33 [15.0%]), upper respiratory tract infection (33 [15.0%]), and cough (33 [15.0%]). Grade 3 to 5 AEs occurred in 42 (19.1%) patients. The most common one was elevated γ-glutamyltransferase (n = 4). There were 3 deaths patients, 2 of which possibly not be related to the study drug, and 1 could not be determined. No interstitial pneumonia was reported. Conclusions: Alflutinib has promising efficacy and acceptable safety profile for the treatment of EGFR T790M mutated NSCLC patients. Clinical trial information: NCT 03452592 .

Mechanisms of resistance to osimertinib.

The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. The most common mechanism of acquired resistance to first- and second-generation EGFR TKIs is represented by the secondary T790M mutation. Osimertinib, a third-generation TKI designed to target both EGFR sensitizing mutations and T790M, was first approved for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. The FLAURA study demonstrated that first-line treatment of EGFR mutant patients with osimertinib significantly improved progression free survival (PFS) over first-generation EGFR-TKIs, thus leading to its approval also in this setting. Moreover, osimertinib has shown significant central nervous system (CNS) activity and a favorable safety profile. The current review focuses on the clinical development of osimertinib, the mechanisms of acquired resistance identified in patients receiving osimertinib and the strategies currently under evaluation to overcome resistance.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor: A retrospective multicenter study of its real-world efficacy and safety in advanced/recurrent non-small cell lung carcinoma.

BackgroundOsimertinib is recommended for T790M mutation‐positive advanced non‐small cell lung cancer (NSCLC) resistant to first‐ and second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real‐world use of osimertinib; however, reports involving third/later‐line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M‐positive NSCLC patients.MethodsThis retrospective, observational, multicenter study included T790M‐positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan‐Meier method was used to analyze progression‐free survival (PFS) and overall survival (OS). PFS‐associated clinical characteristics were evaluated using the Cox proportional hazards model.ResultsThe objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second‐line and third−/later‐line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any‐grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis.ConclusionsOsimertinib demonstrated efficacy even when administered as third−/later‐line treatment to NSCLC patients. Osimertinib‐related pneumonitis was observed more frequently than previously reported.Key pointsSignificant findings of the studyOsimertinib shows efficacy even as later‐line treatment in T790M mutation‐positive NSCLC patients previously treated with EGFR‐TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies.What this study addsOsimertinib was approved for previously EGFR‐TKI‐treated EGFR T790M‐positive NSCLC. With the increasing frequency of its use as first‐line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR‐TKI‐treated NSCLC.

ASTRIS, a large real-world study to evaluate the efficacy of osimertinib in epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer patients: Clinical characteristics and genotyping methods in a Spanish cohort

PurposeOsimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. MethodsASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. ResultsThe Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. ConclusionsASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices.

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown. We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2-4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017. Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39-89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36-70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3-13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred. Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis.

Osimertinib is the only Food and Drug Administration‐approved third‐generation epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI). A meta‐analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment‐naïve patients with EGFR‐TKI‐sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6‐month PFS 83% (95% CI 80–87%), and 12‐month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier‐generation EGFR‐TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6‐month PFS 63% (95% CI 58–69%), and 12‐month PFS 32% (95% CI 17–47%). EGFR‐TKI‐naïve patients with EGFR‐positive mutations tend to have longer median PFS than EGFR‐TKI‐pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation‐positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation‐positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.

Non–Small Cell Lung Cancer with Resistance to EGFR-TKI Therapy: CT Characteristics of T790M Mutation–positive Cancer

Purpose To evaluate the clinical and CT characteristics of T790M mutation-positive non-small cell lung cancer (NSCLC) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy failure. Materials and Methods A retrospective study of 304 patients with NSCLC who underwent rebiopsy after first-line EGFR-TKI therapy was conducted. Rebiopsy methods included CT- or fluoroscopy-guided lung biopsies (n = 105), endobronchial US- or bronchofibroscopy-guided biopsies (n = 66), pleural fluid analysis (n = 47), other solid organ biopsies (n = 43), US-guided axillary or supraclavicular lymph node biopsies (n = 31), and cerebrospinal fluid analysis (n = 12). CT findings at the initial diagnosis and rebiopsy were analyzed. Progression-free survival, the duration from the start of TKI therapy to rebiopsy, and survival were calculated. Results At rebiopsy, 144 (47.4%) patients were T790M mutation positive. The percentages of T790M mutation-positive NSCLCs were similar in 106 patients with rebiopsy of the lungs (53 [50%] of 106) and in 77 patients with rebiopsy of the primary lung lesions (36 [47%] of 77). T790M mutation positivity was associated with peripheral tumors (odds ratio [OR], 2.6; P = .01), pleural tag (OR, 5.0; P < .001), and air bronchogram (OR, 4.0; P = .006) at CT after TKI failure. The duration from the start of TKI therapy to rebiopsy was longer in T790M mutation-positive than in T790M mutation-negative patients (20.5 vs 13.6 months; P < .001). Cumulative survival from the time of rebiopsy to the last follow-up was significantly longer in patients with T790M mutation-positive lung cancers (P = .014). However, median survival time after rebiopsy was not statistically different between patients with and those without T790M mutation. Conclusion Peripheral tumor location with vascular convergence, the presence of a pleural tag, and air bronchogram of lung lesions at CT at the time of rebiopsy were significantly associated with T790M mutation in patients with non-small cell lung cancer after first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy failure. © RSNA, 2018 Online supplemental material is available for this article.

Osimertinib for Previously Treated Patients With Advanced EGFR T790M Mutation-Positive NSCLC: Tolerability and Diagnostic Methods From an Expanded Access Program.

IntroductionThe osimertinib (AZD9291) US Expanded Access Program (EAP) provided compassionate access to osimertinib prior to US Food and Drug Administration (FDA) approval for patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) following progression on tyrosine kinase inhibitors (TKIs) targeting EGFR. Here, we report the patient demographics, safety and tolerability, and diagnostic methods used for T790M testing in the EAP.MethodsAdult patients with EGFR T790M-positive NSCLC following progression on prior EGFR-TKI therapy (irrespective of line of therapy) were enrolled in the EAP and treated with 80 mg osimertinib once daily until dose reduction, discontinuation, or completion of the EAP following FDA approval (November 2015). Various testing methods were allowed for the required T790M testing.ResultsIn total, 248 patients from 25 centers throughout the USA were enrolled in the EAP. The starting dose of 80 mg osimertinib once daily was maintained for 96% (n = 238) of patients over the duration of the EAP (median duration of exposure 84 days). Most patients (overall 83% [n = 205/238]; patients aged ≥ 75 years 83% [n = 48/58]) completed the EAP and transitioned to commercially available osimertinib following FDA approval. Serious adverse events considered to be treatment related by investigators were reported in five patients (2%), all aged ≥ 65 years, and were dyspnea, deep vein thrombosis, femur fracture, alanine aminotransferase increase, and pneumonitis, respectively. A variety of biospecimen types were collected: solid tumor tissue (73%), blood (20%), cytology (6%), and urine (2%). PCR-based methods were most commonly used for determining EGFR mutation status (47%) followed by next-generation sequencing (33%).ConclusionIn a real-world setting, osimertinib was well tolerated, and most patients, including patients aged ≥ 75 years, transitioned to commercially available osimertinib following FDA approval. The EAP suggests there has been an uptake of minimally invasive T790M testing methods at some centers.FundingAstraZeneca (Wilmington, DE, USA).

Abstract A162: Continuous treatment with rociletinib in EGFR transgenic mice results in acquired resistance to both rociletinib and osimertinib and intra-“patient” tumor heterogeneity

Abstract Activating mutations in EGFR are key drivers in a subset of non-small cell lung cancer (NSCLC) patients, as well as effective predictors of response to first-generation reversible EGFR tyrosine kinase inhibitor (TKI) therapy. However, resistance develops in many patients due to acquisition of a T790M mutation in EGFR. Rociletinib and osimertinib target the T790M mutation, and have been evaluated in previously treated EGFR mutant lung cancer patients. Osimertinib recently received FDA approval for treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy. However, there is limited information on the mechanisms of resistance to these drugs, as well as limited in vivo models for acquired resistance to examine signaling pathways and/or possible treatments to abrogate resistance. We treated an EGFR-L858R-T790M transgenic lung adenocarcinoma mouse model daily with rociletinib to examine sensitivity and acquired resistance. Rociletinib exhibited potent antitumor activity as a single agent, resulting in complete tumor regression and suppression of phospho-EGFR. Despite the success of treatment, after long-term dosing (4-5 months) tumors acquired resistance to the drug, as evidenced by tumor regrowth on MRI. DNA from multiple tumor samples representing four individual drug-resistant mice was sequenced, and several novel mutations in EGFR were observed that may account for the resistant outgrowth of tumors in these mice. These included an insertion and a deletion mutation as well as missense mutations. Interestingly, in some cases different mutations arose in individual tumor nodules within the same mouse, suggesting that each tumor is an individual resistant clone. All mutations were located in the kinase domain of EGFR. For example, a de novo G796C mutation was one of the potential mechanisms of resistance to rociletinib found in two isolated nodules from one mouse lung. A mutation at the same amino acid has been found in a lung cancer patient after treatment with osimertinib; moreover, this mutation was found in a cell line mutagenesis screen to study the resistance to different EGFR TKIs. We generated Ba/F3 cell lines carrying each de novo identified EGFR mutation (along with the activating L858R and T790M mutations) and compared the potency of EGFR TKIs to cell lines carrying only the activating mutations. The cells that expressed putative acquired resistance mutations proved to be resistant to both rociletinib and osimertinib in vitro, suggesting that these mutations indeed mediated acquired resistance in vivo. Tumor nodules from drug-resistant transgenic mice were transplanted into recipient mice and expanded for further evaluation. Mice with transplanted resistant tumors did not respond to rociletinib or osimertinib treatment. Pathway analysis showed that phospho-EGFR was no longer suppressed in drug-resistant tumors carrying a deletion mutation, confirming that novel mutations result in drug resistance. We discovered that resistance to third-generation EGFR inhibitors may occur through novel mutations in EGFR. Heterogeneity of mutations in different nodules within the same lung is akin to intra-patient heterogeneity and highlights the utility of mouse models for examining acquired resistance to drugs. Citation Format: Rajaa El Meskini, Anthony Iacovelli, Alan Kulaga, Michelle Gumprecht, Myla Spencer, Lilia Ileva, Andrew Simmons, Zoë Weaver Ohler. Continuous treatment with rociletinib in EGFR transgenic mice results in acquired resistance to both rociletinib and osimertinib and intra-“patient” tumor heterogeneity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A162.

Investigation of the metabolic stability of olmutinib by validated LC-MS/MS: quantification in human plasma.

Olmutinib (OTB, Olita™) is an orally available third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). It was developed by Boehringer Ingelheim and Hanmi Pharmaceutical Co. Ltd for the cure of non-small cell lung cancer (NSCLC). In May 2016, OTB was approved in South Korea for the treatment of patients suffering from metastatic or locally advanced EGFR T790M mutation-positive NSCLC. A LC-MS/MS methodology was validated for OTB quantification in human plasma. An extended application for this validated LC-MS/MS is OTB metabolic stability evaluation. Chromatographic separation of OTB and ponatinib (PNT, IS) was attained using a reversed phase with isocratic elution. The linearity of the developed LC-MS/MS method ranged from 5.00 to 500.00 ng mL−1 with r2 ≥ 0.9999 in human plasma. LOD and LOQ were 1.12 and 3.39 ng mL−1, respectively. The intra-day and inter-day precision and accuracy were 1.17 to 2.75% and 97.86 to 101.48%, respectively. The intrinsic clearance (CLint) was 2.71 mL min−1 kg−1 and the in vitro half-life (t1/2) was 48.80 min. A review of the literature revealed that there are no previous articles about the quantification of OTB in human plasma using LC-MS/MS or its metabolic stability assessment.