AstraZeneca’s Tagrisso (osimertinib) has been approved in Japan for the adjuvant treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after surgery.

Osimertinib is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in adults.

Osimertinib is a preferred first-line EGFR TKI option for patients with EGFR positive metastatic NSCLC…

First-line osimertinib is now considered one of the options for patients with a tumour with sensitising EGFR mutations.

AstraZeneca’s supplemental New Drug Application (sNDA) for Tagrisso (osimertinib) in combination with chemotherapy has been accepted and granted Priority Review in the US for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC).

Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC.

Safety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0-38) versus 25.1 (0-39) months….No new safety signals were reported and HRQoL was maintained over 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB-IIIA EGFRm NSCLC.

Positive high-level results from the FLAURA2 Phase III trial showed AstraZeneca’s Tagrisso (osimertinib) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to Tagrisso alone for patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC)....FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of 586 patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5))...

Positive high-level results from the ADAURA Phase III trial showed AstraZeneca’s Tagrisso (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), a key secondary endpoint, compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent.

With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

Osimertinib resulted in significantly superior survival after resistance to front-line TKIs (P < 0.0035); the median OS reached 28.0 months (95% CI, 23.0-32.9), and the T790M status showed no difference in clinical effectiveness (P = 0.386)….In conclusion, EGFR TKIs have a significant effect on patients with EGFR-mutant BM, and the application of osimertinib further improves survival outcomes regardless of T790M status.

Resected EGFR-mutant NSCLC patients treated with osimertinib experienced improved DFS and a lower risk of brain recurrence than those treated with gefitinib or erlotinib.

For patients harboring EGFR positive mutations, osimertinib appears to significantly increase progression-free survival, compared to 1st generation EGFR-TKI (HR 0.46, 95 %CI 0.38-0.55), 2nd generation EGFR-TKI (HR: 0.59, 95 %CI 0.34-0.99), conventional chemotherapy (HR 0.30, 95 %CI 0.14-0.66), radiotherapy (HR 0.20, 95 %CI 0.14-0.29), and radiotherapy plus 1st generation TKI (HR 0.21, 95 %CI 0.14-0.32).

First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC.

Osimertinib showed the most favorable DFS, with significant superiority versus erlotinib (HR 0.4, 95% CI 0.24-0.66), gefitinib (0.42, 0.26-0.67), chemotherapy (0.23, 0.15-0.33) and placebo (0.17, 0.12- 0.24), but with no significant improvement versus CT +TKI (0.86, 0.42-1.74)....EGFR-TKIs monotherapy provided more survival improvement for patients with exon 19 deletion than with L858R mutation (HR, 0.31 [0.13, 0.75] for exon 19 deletion, and 0.48 [0.35, 0.65] for L858R mutation, respectively).

There was a clinically meaningful improvement in CNS DFS with osimertinib: 82% reduction in risk of CNS disease recurrence or death. Results support that osimertinib reduces risk of CNS recurrence in the resected EGFRm NSCLC setting.

AstraZeneca’s Tagrisso (osimertinib) has received acceptance for its supplemental New Drug Application (sNDA) and has also been granted Priority Review in the US for the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent.

In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years….In patients with stage IB to IIIA EGFR mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo.

AstraZeneca’s Tagrisso (osimertinib) has been granted Breakthrough Therapy Designation (BTD) in the US for the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent....The FDA granted the BTD based on data from the Phase III ADAURA trial, which were also recently presented during the plenary session of the American Society of Clinical Oncology ASCO20 Virtual Scientific Program.

...Phase III ADAURA trial showed AstraZeneca’s Tagrisso (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent.

AstraZeneca today announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) for Tagrisso (osimertinib) for the 1st-line treatment of patients with metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).

...Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC)...

Patients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included…. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%.

We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment....The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001).

In the China cohort, osi + CT demonstrated a clinically meaningful improvement in PFS over osi-mono with a manageable safety/tolerability profile consistent with the global study population, supporting osi + platinum-pem as a new 1L tx option for pts in China with advanced EGFRm NSCLC. Table: 562P.

Osi + platinum-pem was well tolerated and clinical benefit continued with 3 further years’ exposure. Data support long-term tolerability of 1L osi + platinum-pem for EGFRm advanced NSCLC. Table: 568P.

The result is consistent with FLAURA study for patients with EGFR-activating mutation. Osimeritinib showed clinical activity in patients with EGFR uncommon mutations as first-line treatment.

Eligible pts (≥18 y [Japan: ≥20] with EGFRm advanced NSCLC...In FLAURA2, pts with CNS mets in the osi-CTx arm had a clinically meaningful reduction in the risk of CNS progression, with high CNS ORR (and high CR) and durable responses, with a manageable and tolerable safety profile.

We retrospectively analyzed patients who received first-line osimertinib at 13 Swiss centers….Median progression-free survival (PFS) was 19.2 (95 % CI, 14.3–23.5) and 8.7 (95 % CI, 2.8–15.6) months for patients with common and uncommon EGFR mutations.

Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations.

We conducted a single institution retrospective chart review of patients initially diagnosed with EGFR-mutated NSCLC between January 2021 and December 2022….All patients received front-line osimertinib….The median progression-free survival was 10.6 months (1.4 - 25 months)....Our study shows that osimertinib is continued beyond progression in clinical practice.

Thirty-seven patients were enrolled. Among 36 patients who were evaluable for response, ORR was 50% (95% CI, 33% to 67%). Median follow-up time from the date of first dose to data cutoff was 61.0 (range, 49.7 to 68.8) months. Median PFS was 8.0 (95% CI, 6.8 to 9.2) months, and median OS was 27.0 (95% CI, 18.5 to 35.5) months. Median DoR was 13.5 (range, 1.0 to 43.0) months...Osimertinib continued to show favorable activity with manageable toxicity after long-term follow-up in patients with NSCLC harboring uncommon EGFR mutations.

Osimertinib continuation in conjunction with metronomic oral vinorelbine may enable overcoming TKI resistance and prolong the survival of patients with EGFR-mutant advanced NSCLC beyond limited progression on osimertinib treatment.

...we enrolled 242 EGFR-mutant stage IIIB-IV NSCLC patients who progressed on first- or second-generation EGFR-TKI treatments…second-line osimertinib was associated with longer OS compared to chemotherapy and other EGFR-TKI treatment (p =0.001). In the multivariate analysis, only second-line osimertinib was an independent predictor of PFS (p =0.023).

Osimertinib in mNSCLC pts harboring uC-EGFRm other than exon 20 insertions showed clinical activity with manageable toxicities.

There were 254 patients with advanced EGFR mutated NSCLCs...The median CNS progression free survival was 14.00 (9.51,18.48) months. The median CNS progression free survival between no Osimertinib treatment and Osimertinib treatment was 13 (10.38,15.61) months and 21 (17.49,24.5) months, respectively. The median survival was 30.03 (19.6,40.45) months...Treatment with EGFR TKIs improved CNS progression free survival better than historical data.3rd generation EGFR TKIs Osimertinib in later line prolong clinical benefit of CNS Progression free survival and overall survival better than 1st generation EGFR TKIs alone.

NSCLC patients with confirmed EGFR mutation were retrospectively reviewed from a single institutional database from 1/2010-12/2022. We identified patients who received osi after interval therapy….Two patients achieved partial response (PR) (13%), and 6 patients had stable disease (SD) as the best response (38%). Median duration of initial osi was 13.9 months (range 1.9-26.4), and median duration of osi rechallenge was 3.6 months (range 1.0-10.3). Patients who had PR/SD were on osi for 7.5 months (range 2.7-10.3)....Osi rechallenge is a potential option for advanced EGFR NSCLC patients to obtain disease control at later lines of therapy.

Descriptive observational, and retrospective study of patients with advanced NSCLC and EGFR + treated TKI-EGFR in the period 2015-2022….ORR: 77.4% partial response, 9.7% complete response and 12.9% disease progression….Osimertinib presents an adequate safety profile for patients with G1, G2 toxicities, generally easy to manage in clinical practice.

A total of 150 patients with EGFR-mutated NSCLC treated in first line with 1st, 2nd or 3rd gen TKI were included in this analysis….Progression-free survival under first-line TKI treatment was superior in patients receiving osimertinib as compared to 1st/2nd gen TKIs (median not reached vs 12.2 months, P = 0.038)...

This investigation was a nonrandomized, open-label, single-arm, phase II prospective, proof-of-concept study. Eligible patients were treatment-naïve, nonoperable, stage III EGFR-mutant NSCLC patients….Neoadjuvant osimertinib therapy is feasible in stage III patients, followed by definitive radiation and/or surgery, with an ORR of 95.2% and an excellent safety profile.

...osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164))….Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM...

In an ongoing, multicountry prospective study, data for pts with EGFRm NSCLC receiving 1L osimertinib were extracted from the CRISP registry (AIO-TRK-0315) in Germany....This study demonstrates the rw effectiveness of 1L osimertinib in pts with advanced EGFRm NSCLC, supported by the interim PFS, TTNTD and TTD.

...a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy...Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA).

This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer….Thirty-eight patients were included in the analysis. The 1-year PFS rate was 59.4% (95% confidence interval [CI], 46.1%-72.7%)...osimertinib was tolerable for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer.

The aim of the study was to assess osimertinib for patients with RT-naïve CNS metastasis of EGFR mutations positive NSCLC….Systemic ORR (n=26) by RECIST, median PFS and OS were 64.0% (95%CI 45.2–82.8%), 11.5 months (6.9–NE), and 23.7 months (16.0-NE), respectively.

Eligible patients were treatment-naïve, non-operable, stage III EGFR-mut NSCLC. Received 80 mg oral osimertinib daily for 12 weeks before definitive RT and/or surgery….The ORR was 93.75%, (16 PR & 1 PD).

In this updated analysis, in pts with stage IIꟷIIIA disease DFS HR was 0.23 (95% CI 0.18, 0.30; 242/470 events; 51% maturity); 3-yr DFS rate was 84% with osimertinib vs 34% with PBO. In the overall population (stage IBꟷIIIA) DFS HR was 0.27 (95% CI 0.21, 0.34; 305/682 events); 3-yr DFS rate was 85% with osimertinib vs 44% with PBO. In the osimertinib arm, fewer pts experienced local/regional and distant recurrence vs PBO....With 2 yrs further follow-up, a continued DFS benefit was sustained with osimertinib vs PBO, consistent with the primary analysis. These mature data reinforce adjuvant osimertinib as standard of care for pts with EGFRm stage IB–‍IIIA NSCLC after complete tumour resection and adjuvant CT, when indicated.

CONTRADICTING EVIDENCE: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care....Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08; p = 0.02).

This updated analysis confirms the effectiveness of osimertinib as first-line treatment in EGFR-mutant aNSCLC patients although mOS has just been reached.

To investigate the efficacy and safety of adjuvant EGFR tyrosine kinase inhibitors for resected EGFR-mutated non-small-cell lung cancer....Adjuvant chemotherapy followed with osimertinib significantly prolonged disease-free survival compared with chemotherapy (hazard ratio [HR]: 0.2; 95% CI: 0.14-0.29), chemotherapy followed with erlotinib (HR: 0.33; 95% CI: 0.18-0.6), chemotherapy followed with gefitinib (HR: 0.36; 95% CI: 0.16-0.82), gefitinib (HR: 0.26; 95% CI: 0.17-0.41) and icotinib (HR: 0.56; 95% CI: 0.3-0.98)....Chemotherapy followed with osimertinib brings about the best disease-free survival.

This is a multi-center, retrospective study of ucEGFRm mNSCLC treated with osimertinib as first EGFRi....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)….Osimertinib demonstrated activity in ucEGFRm with 91% disease control rate and encouraging PFS and DOR.

The CRR/DCR were 3.0%/97.0% (95% CI; 0.0-7.2%/92.8%-100.0%), respectively….OSI combined with platinum-based chemotherapy for previously untreated EGFRm advanced NSCLC showed the excellent efficacy with tolerable toxicity.

Patients with resectable NSCLC with epidermal growth factor receptor (EGFR) mutation who received osimertinib as neoadjuvant therapy followed by surgery at our center were included….The objective response rate (ORR) was 69.2% (9/13), and the complete resection rate was 100%.....Neoadjuvant osimertinib therapy seemed to be safe and feasible for resectable EGFR-mutated NSCLC.

…EGFRm+ pts treated with osi…Median post bone mets OS was 30.8 months (95% CI 21.9-39.7). Median post SRE OS was 31.1 months (95% CI 15.8-46.5).

Records of 84 lung adenocarcinoma patients with an EGFR sensitive mutation who received first-generation EGFR-TKI as first-line therapy and sequenced by osimertinib after progression were retrospectively reviewed in this study….Among 60 patients who had at least one measurable lesion, 35.0% of patients (21/60) had PR to osimertinib, and 63.3% patients (38/60) had SD during osimertinib treatment. The ORR was 35.0%, and the DCR was 98.3%.

Before enrollment termination, 23 and 11 patients received treatment across Parts A and B, respectively. The most common AEs across Parts A and B were: diarrhea (50%), nausea (41%) and decreased appetite (35%). Twelve patients (35%) reported ILD-related AEs (lung disorder/ILD/pneumonitis). In Part A, ORR was 43% (95% CI: 23ꟷ66); median DOR was 20.4 months. In Part B, ORR was 82% (48ꟷ98), median DOR was 7.1 months and median PFS was 9.0 months (3.5ꟷ12.3).

Uncommon EGFR mutations were identified in 18% (n=26) of 144 consecutive patients initiated on first line osimertinib for stage III/IV EGFR-mutated NSCLC...Among all 26 patients, partial response was observed in 85% (n=22) including all tumors with compound mutations, and only one patient experienced disease progression as best response (Table). One-year PFS was 46%. Median PFS and median OS were 11 months (95% CI 9-16) and 35 months...Overall, osimertinib exhibited favorable efficacy in patients whose tumors possessed uncommon EGFR mutations...

The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials....A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib.

Patients with resected stage IBꟷIIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years….A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS HR = 0.16, 95% CI: 0.10ꟷ0.26) and without adjuvant chemotherapy (HR = 0.23, 95% CI: 0.13ꟷ0.40), regardless of disease stage.

Here we conducted a retrospective study involving untreated EGFR-mutant NSCLC patients with BMs receiving first-line osimertinib or first-generation EGFR-TKIs....osimertinib was found to prolong OS (37.7 months vs. 22.2 months, p=0.027)....In summary, compared with first-generation EGFR-TKIs, osimertinib is associated with improved OS in untreated EGFR-mutant NSCLC with BMs.

The model predicted improved OS with osimertinib vs PBO in the adjuvant setting (Table)…Stage IB–IIIA EGFRm NSCLC...Median life-years OS (95% CI)...Osimertinib...11.42 (9.09, 14.66). Based on this model, adjuvant osimertinib is predicted to increase life expectancy vs PBO for stg IB–IIIA EGFRm NSCLC, with a substantial proportion of time spent disease free and a 17.4% absolute improvement in OS at 10 yrs.

Among 9 patients who have completed 12 weeks of osimertinib therapy, ORR was 100%, (2 CR, 7 PR, 0 SD or PD)…Osimertinib induction in stage III EGFRm NSCLC is feasible and led to tumor shrinkage in 92% of the cases, resulting in a significant reduction of the radiation field and enabling preservation of the lung tissue radiation-induced toxicity.

We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib...Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%.

This phase 2, open-label pilot study, which enrolled NSCLC stage IIIA/B patients harboring an EGFR-mutation. Osimertinib (80 mg) was given daily for 12 weeks as induction treatment before definitive radiotherapy and/or surgery….Osimertinib therapy is feasible in stage III EGFR-mutant NSCLC with an ORR of 90%.

A total of 44 patients with EGFR variant–positive NSCLC receiving EGFR-TKI therapy were included...25 (66%) presented PFS of more than 12 months (age at treatment start: 74 (9) years; 76% females; 16 on erlotinib, 4 on afatinib, 4 on osimertinib, 1 on gefitinib).

A multi-country prospective cohort study is in progress, analyzing patients with locally advanced or metastatic EGFRm NSCLC treated with 1L osimertinib monotherapy...Median rwTTNTD was 17.9 months (95% CI: 16.2 – 23.6 months) and median rwTTD was 17.2 months (95% CI: 13.8 – 19.8 months).

After neoadjuvant therapy of osimertinib, 2 cases reached clinial complete response, 9 reached partial response, 2 reached stable disease, with 84.6% objective response rate (ORR) and 100% disease control rate (DCR)….This retrospective study indicated that neoadjuvant therapy with osimertinib in EGFR mutant resectable IA-IIIB NSCLC patients was well-tolerated and could induce well pathological responses.

Adult patients with EGFR-mutated non-small cell lung cancer (NSCLC)...Fifty-two (30.2%) patients received osimertinib and 120 (69.8%) patients received another EGFR TKI. The PFS rates at 6, 12, and 18 months were 86.3%, 79.5%, 69.8% in the osimertinib group...Osimertinib demonstrated greater 12 and 18 month PFS compared to other EGFR TKIs.

Osimertinib 80 mg once daily shows good efficacy in pretreated EGFRm NSCLC patients with LM regardless of their T790M status.

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)….Interim analysis from this study indicated neoadjuvant osimertinib as an effective and feasible treatment in patients with resectable stage II-IIIB EGFRm NSCLC.

A total of 193 NSCLCBM patients with an EGFR mutation were identified....The median OS (mOS) in patients who received first and third-generation EGFR TKIs was 59.8 months and 65.9 months respectively (p-value (p) = 0.06). The median PFS (mPFS) between the first and third-generation EGFR TKI cohorts was 44.3 months and 66.9 months respectively (p= 0.048, hazard ratio (HR) = 0.50 (95% confidence interval (CI) = 0.25, 0.99)....We determined that there was a significant mPFS benefit in osimertinib compared to erlotinib or gefitinib...in patients with NSCLCBM.

...osimertinib only group had significantly improved OS compared with chemotherapy or palliative care only groups (37.5 versus 17.5 and 15.3 months, respectively; P = .017)....Multivariate analysis showed that continuous gefitinib after Response Evaluation Criteria in Solid Tumor‐defined PD (hazards ratio [HR] 0.273, 95% CI: 0.132‐0.564, P < .001), osimertinib treatment (HR 0.244, 95% CI: 0.122‐0.487, P < .001), and better performance status (HR 0.360, 95% CI: 0.163‐0.796, P = .012) were significantly and independently correlated with better survival.

...998 patients claimed that osimertinib showed efficacy superior to the standard EGFR TKIs used in the first-line treatment of advanced EGFR mutation-positive NSCLC.

…advanced EGFR mutated NSCLC patients...The longer PFS of prior first-generation EGFR-TKI might also result in the longer PFS of osimertinib. Moreover, active-EGFR MAF, T790M MAF and T790M/active-EGFR MAF ratio might be potential markers of outcome in patients treated with osimertinib.

There were 813 patients enrolled, with 562, 106, and 32 received first-line gefitinib, erlotinib, and osimertinib, respectively, while 113 received second-line osimertinib. At a median follow-up of 18.1 months, the median OS was 45.5 months.

This is a subcohort analysis from a larger nonrandomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 mg to 160 mg in EGFR-mutated advanced non-small-cell lung cancer (NSCLC) patients with intracranial progression in either first- (arm A) or second-line setting (arm B for T790M+ and C for T790M-)....Eleven patients, 5 in arm A, 4 in arm B, and 2 in arm C were reported in this study....The mPFS of osimertinib before dose escalation was 11.4 ± 8.9 (6.6-30.7) months for arm A, 8.7 ± 1.8 (6.3-11.2) for arm B, and 14.5 ± 7.8 (6.7-22.3) for arm C....Median iPFS was 4.3 ± 7.4 (0.7-25.5) months; 3.8 ± 6.4 (1.8-18.9), 5.6 ± 9.7 (0.7-25.5), and 7.0 ± 2.7 (4.3-9.6) for arms A/B/C, respectively.

A total of 15 eligible patients received osimertinib. Before starting treatment, EGFR-activating mutations were detected in the ctDNA of all patients, and EGFR T790M was detected in 93% of the cases. Osimertinib treatment was associated with an objective response rate of 53% and a median progression-free survival of 7.3 months. 

To assess time-to-treatment failure (TTF) in US patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC)...In 129 patients at US centers, median TTF was 28.4 months (90% CI: 27.0-34.1). Median overall survival was 47.6 months (90% CI: 35.5-51.5)...Sequential afatinib-osimertinib in this US-treated population was associated with long median TTF and represents an effective, evidence-based treatment option for US patients with EGFR mutation-positive NSCLC not presenting with active brain metastases or de novo T790M.

15 of 17 EGFR-mutant patients received EGFR-TKI therapy with gefitinib (n = 13) or osimertinib (n = 2). The OS tended to be longer in the TKI group than in the CT or BSC group (16.9 months vs. 7.2 months or 9.8 months, p = 0.059). Among the 34 super-elderly NSCLC patients with a PS score of 3-4, 7 with EGFR-mutant received gefitinib therapy and the remaining 27 received BSC alone. The OS tended to be longer in the TKI group than in the BSC group (4.6 months vs. 2.3 months, p = 0.060).

T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No significant difference in mOS was demonstrated according to T790M mutational status (10.1 months [95% CI 4.31-15.82] vs. 9.0 [6.81-11.21], P= 0.936)....Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.

...first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice...

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer...Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases...Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib...~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively.

Osimertinib showed highly active and durable in NSCLC patients harboring uncommon EGFR mutation with manageable safety profile, consistent with previous reports.

Patients with histologically confirmed metastatic or recurrent NSCLC harboring EGFR mutations...Median duration of response was 11.2 months (95% CI, 7.7 to 14.7 months)....Osimertinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring uncommon EGFR mutations.

We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy….After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.

In this study, OSI induced higher CD47 expression, an important anti-phagocytic immune checkpoint, via the NF-κB pathway in EGFR-mutant NSCLC HCC827 and NCI-H1975 cells...The combination treatment of OSI and the anti-CD47 antibody exhibited dramatically increasing phagocytosis in HCC827 and NCI-H1975 cells...combining the anti-CD47 antibody significantly augmented the anticancer effect of OSI in HCC827 xenograft mice model.

We found that the anti-proliferative effect of the combined treatment was significantly greater than that with either alone for both PC-9 and H1975 cells (Figure 1A)....Osimertinib+pemetrexed caused increased apoptotic activity as documented by increased proportions of annexin V-positive cells (Figure 1C). These results indicate that combining osimertinib with pemetrexed increases apoptosis and thus leads to enhanced anti-proliferative activity of NSCLC cells with EGFR mutations.

Osimertinib+pemetrexed treatment delayed the emergence of resistance relative to monotherapy in vitro and in vivo....We found that the anti-proliferative effect of the combined treatment was significantly greater than that with either alone for both PC-9 and H1975 cells....Osimertinib+pemetrexed caused increased apoptotic activity as documented by increased proportions of annexin V-positive cells (Figure 1C). These results indicate that combining osimertinib with pemetrexed increases apoptosis and thus leads to enhanced anti-proliferative activity of NSCLC cells with EGFR mutations...combining osimertinib with pemetrexed significantly hinders the emergence of osimertinib resistance relative to monotherapy in these EGFR-mutant NSCLC cells.

...EGFR mutations, including C797S/G (22.1% vs. 0.5%), L718Q/V (6.2% vs. 0.3%), L792F/H (4.4% vs. 0.3%), were significantly more enriched in the osimertinib cohort. Our computational model has also successfully predicted their sensitivities to osimertinib: WT (-35.19 kcal/mol) > L792F (-34.10 kcal/mol) > L718Q (-30.33kcal/mol) > C797S (-28.02 kcal/mol), which are consistent with our previous in vitro validations....in silico structural model was proved to be powerful and robust in the prediction of osimertinib sensitivity of EGFR mutants.