AstraZeneca Canada announces that Health Canada has granted full approval (Notice of Compliance) for Tagrisso (osimertinib) for the treatment of patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

AstraZeneca today announced that the China Food and Drug Administration (CFDA) has granted marketing authorisation for Tagrisso (osimertinib) 40 mg and 80mg once-daily oral tablets for the treatment of adult patients with locally-advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Osimertinib (Tagrisso) is accepted for restricted use within NHS Scotland...for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC).

AstraZeneca today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Tagrisso (osimertinib, AZD9291) 80mg once-daily tablets for the treatment of patients with epidermal growth factor receptor (EGFR) T790M mutation-positive inoperable or recurrent non-small cell lung cancer (NSCLC) that is resistant to EGFR tyrosine kinase inhibitor (TKI) therapy.

Tagrisso is indicated for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small-cell lung cancer (NSCLC).

TAGRISSO is a kinase inhibitor indicated for...the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.

Osimertinib is recommended as an option for treating epidermal growth factor receptor (EGFR) T790M mutation-positive locally advanced or metastatic nonsmall-cell lung cancer (NSCLC) in adults...

The NCCN NSCLC Panel also recommends osimertinib (category 1) for patients with T790M who have symptomatic brain metastases after progression on erlotinib (with or without ramucirumab or bevacizumab), gefitinib, afatinib, or dacomitinib...

Osimertinib is the standard therapy for patients whose tumours are tested positive for T790M either in liquid biopsy or re-biopsy...

In 3014 patients, median OS: 22.8 months (21.6-23.8), median PFS: 11.1 months (11.0-12.0), median TTD: 13.5 months (12.6-13.9), and response rate: 57.3% (55.5-59.2). All end points reported with 95% Cis....Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC.

CONTRADICTING EVIDENCE: EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients.

FLAURA was a randomized (1:1), double-blind, international phase III study assessing the efficacy and safety of osimertinib (80 mg once daily) versus comparator first-generation EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily) in patients with previously untreated, EGFRm-positive (Ex19del or L858R) locally advanced or metastatic NSCLC...Among the five patients with de novo T790M detected, all patients treated with osimertinib achieved a PR.

CONTRADICTING EVIDENCE:...In pts with tissue T790M+ NSCLC and detectable baseline plasma EGFRm, continued presence of EGFRm at wks 3 and 6 was associated with less favorable outcomes with osimertinib.

In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib...The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001).

...Central confirmation of T790M+ mutation status...

Patients with a secondary T790M mutation receiving second-line osimertinib treatment had a median overall survival (OS) of 54.3 months, and the median OS was 31.9 months for non-T790M-mutated patients receiving second-line nonosimertinib treatments (HR = 0.36; CI: 0.21-0.62, P < 0.001).

We screened patients who were at least 21 years of age and had a histologic or cytologic diagnosis of advanced NSCLC harbouring a sensitizing EGFR mutation (Exon 19 deletion or Exon 21 L858R mutation) at the time of diagnosis….The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years....Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

Patients with T790M mutation who received osimertinib after progression had longer median OS (41 months vs. 23 months, p = 0.0001).

Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies.

Osimertinib showed an ORR of 57.3%(95%CI=52.6%, 61.9%); CR rate of 2.8%(95%CI=2.0%, 3.90%); PR rate of 55.3%(95%CI=49.9%, 60.6%); SD rate of 24.7%(95%CI=24.1%, 31.6%); PD rate of 9.1%(95%CI=6.0%, 13.6%). Osimertinib showed significant superiority over afatinib in terms overall survival and progression-free survival in T790M+ population; the OSHR was 0.60(95%CI=0.42, 0.86, P value=0.006); the PFSHR was 0.70(95%CI=0.53, 0.94, P value=0.016)....In general NSCLC population with T790M mutations, osimertinib was reasonably effective and safe. In terms of OSHR and PFHR, osimertinib was statistically superior over afatinib in NSCLC patients with T790 mutations.

Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs. 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs. 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs. 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients....This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity...

...the median OS of patients with acquired T790M mutation who were treated with osimertinib for the second line after first-generation EGFR TKI was significantly longer than those without acquired T790M compared with gefitinib (36.5 months vs 20.8 months; HR 0.685, 95% CI 0.53-0.90, p=0.007) and erlotinib (36.5 months vs 19.1 months; HR 0.529, 95%CI 0.41-0.97, p=0.037).

This study confirmed that the greater efficacy of later-line osimertinib for NSCLC with T790M mutation than without T790M mutation.

393 (69.4%) patients were treated with second-line osimertinib as monotherapy, including 282 patients harbored EGFR T790M positive mutation, of whom the ORR of was 57.4% (162/282), DCR was 95.7% (270/282), and the median PFS reached 14.5 months....This real-world analysis further confirmed the therapeutic effectiveness and safety of osimertinib as second-line treatment in NSCLC patients with EGFR T790M mutations with consistent benefit across different subgroups...

A total of 5 studies with 273 second-line and 282 later-lines osimertinib users met the criteria and were included. The median OS and PFS in second-line users were range from 20.7 to 27.7 months and 9.4 to 15.5 months, respectively. Among later-lines users, the median OS and PFS were range from 18.0 to 32.1 months and 9.7 to 12 months, respectively. There was only one study reported hazard ratio of PFS between group (HR: 0.71, 95% CI: 0.36-1.4) for pooled analysis. There was no significantly clinical difference between second-line and later-lines osimertinib users. It means that osimertinib, a salvage drug for T790M-positive advanced NSCLC patients, had demonstrated efficacy even when administered as later-lines treatment.

Eligible patients (≥18 years) had advanced, metastasis NSCLC...EGFR T790M mutation-positive confirmed by local validated molecular test. All patients received osimertinib 80 mg, orally once daily….The mPFS in T790M-positive patients confirmed by tissue (n=783) and plasma (n=567) was 13.1 months (95%CI 12.5-13.8) and 10.0 months (95%CI 9.5-11.0), respectively....These data support osimertinib as a standard second-line treatment in patients with EGFR T790M-positive NSCLC after first-line EGFR-TKI therapy in real world.

CONTRADICTING EVIDENCE: In EGFR T790M- positive NSCLC, the PFS and overall survival (OS) of the patients with PE were significantly shorter than those of the patients without PE (median PFS 16.8 vs. 8.3 months, p = 0.003; median OS 44.9 vs. 14.2 months, p = 0.007). In the multivariate analysis, the presence of PE was independently associated with shorter PFS and OS in EGFR T790M-positive NSCLC patients, but not EGFR T790M-negative patients....These data suggest the efficacy of osimertinib may differ between EGFR T790M-positive and negative NSCLC patients with PE.

Through the last follow-up in May 2021, afatinib and osimertinib demonstrated better progression-free survival (PFS, p < 0.01) and overall survival (OS, p < 0.01) than gefitinib and erlotinib….A total of 44 patients with T790M mutation retained for this study had a mean age of 71 years, and 32 (72.7%) patients were women. All but one patient presented metastatic NSCLC (stage IV)....The ORR and DCR were 31.8% and 52.3%, respectively. Afatinib (ORR 50.0%, DCR 83.3%) and osimertinib (ORR 60.0%, DCR 80.0%) had numerically higher ORR and DCR than gefitinib (ORR 19.0%, DCR 38%) and erlotinib (ORR 16.7%, DCR, 16.7%).

NSCLC patients, with de novo T790M, who registered at our institute between 01/03/2015 and 31/12/2019, were considered for retrospective analysis...The median PFS and OS for the entire cohort were 10.4 (95% CI = 7.6–19.7) months and 24.9 (95% CI = 15.7–NA) months, respectively. The median PFS for patients on osimertinib was 19.8 (95% CI = 11.6–28.0) months versus 8.8 (95% CI = 6.6–10.9) months for those on other systemic therapy.

Data from patients with advanced NSCLC...were retrospectively collected. Following re-biopsy, these patients were evaluated for the presence of the T790M mutation via next-generation sequencing (NGS), amplification refractory mutation system or Roche Cobas z480 (Cobas) analyses of tissue samples...the median PFS-2 of 32 patients receiving osimertinib was 9.1 months (95% CI: 8.012-10.118), the median PFS-2 of the 13 patients who switched to chemotherapy was 6.8 months (95% CI: 3.484-10.116), and the median PFS-2 of the 19 patients who received continuous TKI treatment was 2.9 months (95% CI: 2.740-3.060). Of these three groups, the PFS-2 of patients receiving osimertinib was significantly longer compared with that of patients who underwent chemotherapy or sustained first-generation TKI treatment (P<0.001).

Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer than the remaining 8 patients without Osimertinib treatment (p = 0.08). Osimertinib was associated with promising efficacy in patients with de novo T790M mutation...

Osimertinib was found to be effective in T790M-positive but not T790M-negative NSCLC. The median overall survival (OS) was 61.8 months for patients with T790M mutation undergoing later-line osimertinib compared with 30.1 months for patients without T790M mutation undergoing chemotherapy only. Osimertinib independently prolonged OS after afatinib progression....This study confirmed the efficacy of sequential afatinib and osimertinib treatment. T790M mutation detection and osimertinib availability are important for prolonging survival in patients with NSCLC harboring EGFR mutations.

73 patients were tested for the T790M mutation; 30/73 (41%) patients were found to be positive for T790M….All 30 T790M patients were treated with osimertinib as their second-line treatment….A significant survival benefit was observed in patients treated with osimertinib in second-line treatment compared to those who did not receive osimertinib when landmark survival analysis was used (Figure 2b).

In this multicentre, single-arm, open-label, phase IIa study, patients with locally advanced or metastatic NSCLC harbouring centrally confirmedEGFR Thr790Met mutation received 80 mg osimertinib daily….The ORR was 77.3% (17/22 [95% confidence interval {CI} 54.6 to 89.3]). The DCR was 86.4% (19/22, [95% CI 65.1 to 97.1]). The median PFS was 23.1 months (95% CI 14.1 to NE). The median OS was 28·4 months (95% CI 25.6 to NE).

...the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months….Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC.

Enrolled 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….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.

CONTRADICTING EVIDENCE: A low frequency of the EGFR T790M allele in plasma tended to predict an inferior efficacy of osimertinib and shorter PFS.

This is a multi-center, international, academic-initiated retrospective study of mNSCLC with ucEGFRmut treated with osimertinib prior to any other EGFRi….Median DOR was 17.4 months (95% CI 9.1-NA). RR for G719X was 43.8%, 33.3% for T790M, and 71.4% for L861Q....Median PFS was 9.1 months (95% CI 8.1–19.2). Median OS was 18.4 months (95% CI 13.5-NR)....Osimertinib showed activity in ucEGFRmut with 85% disease control rate and encouraging PFS and DOR. This report comprises, to the best of our knowledge, the largest dataset of osimertinib as the first EGFRi for ucEGFRmut.

...combined Osi/Bev versus Osi in pts with NSCLC with EGFR-mt (exon 19 del or L858R) and T790M-mt at progression on prior EGFR TKI...the median PFS was 15.4m (95% CI 9.2-18.0) and 12.3m (6.2-17.2) (PFS events: 64 & 65) in the Osi/Bev and Osi arm respectively (HR 0.96; 0.68- 1.37; p=0.83). Median OS was 24.0m (17.8-32.1) in Osi/Bev and 24.3m (16.9-37.0) in Osi arm (deaths: 46 & 43) (HR 1.03; 0.67-1.56; p=0.91). ORR was 55% in both arms.

The intracranial progression free survival was 39.7 versus 3.5 months for T790M + and T790M- patients, respectively (p < 0.001). The overall intracranial disease control rate (iDCR) was 81%, and for T790M + and T790M- patients the DCR was 89% versus 55%, respectively....CNS efficacy of osimertinib in patients with the T790M resistance mutation, while other treatment options should be considered for EGFR-TKI relapsed T790M-negative patients with brain metastases.

Nine of the 17 patients with de novo T790M mutation received Osimertinib, whose overall survival tended to be longer...Osimertinib is associated with promising efficacy in patients with de novo T790M mutation…

The objective response rate was 54.2%, the median progression-free survival was 12.0 months, and the overall survival was 23.0 months for the NSCLC patients treated with osimertinib. Three different technologies to assess T790M mutation (including ARMS, ddPCR, and NGS) could accurately predict the efficacy of osimertinib.

CONTRADICTING EVIDENCE:...the size of the EGFR T790M-positive clone impacts response to osimertinib….genomic analysis revealed that T790M subclonality is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients….results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients...

Consecutive patients with T790M-positive NSCLC...underwent either oral 80 daily OSI or oral 40 daily AFA every 3 weeks for up to 6 cycles...After a median follow-up of 24 months (range, 3 to 28), a significant improvement in OS was detected (hazard ratio [HR] 0.59, 95% confidence interval [CI], 0.39–0.91; p = 0.0160; median, 13.7 months [95% CI, 11.1–14.8] for OSI vs 9.6 months [95% CI, 8.4–10.2] for AFA)....

Median overall survival was 20.7 months (95% CI: 18.9–28.4) for T790M+ and 10.6 months (95% CI: 8.6–23.6) for T790M- patients, respectively....After progression, most T790M+ patients continued osimertinib, whereas most T790M- patients received a different treatment line....Better outcomes were shown in patients receiving osimertinib.

Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas® ), were treated with osimertinib….Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%.

Uncommon mutation categories were: major uncommon (G719X, L861Q, S768I; 73%); compound (35%); ex20ins (12%); T790M (7%); other (9%). Most pts (n = 226; 92%) were treated in 1st-line with an EGFR TKI; 132 (54%), 70 (28%), 35 (14%) and 7 (3%) received afatinib, gefitinib, erlotinib and osimertinib....Overall median OS was 24.4 mos....ORR was 42% overall (major: 50%; compound: 49%; other: 44%; T790M: 20%; ex20ins: 17%); afatinib: 44% (DoR: 12.0 mos); 1st-gen TKIs: 44% (DoR: 11.0 mos)....Response was highest in pts with major uncommon, and/or compound mutations.

This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer...

T790M was detected in 40 (80%) of 50, resulting in a 79% osimertinib introduction rate, as one patient refused osimertinib….Median overall survival (OS) in osimertinib introduced group was 92.5 (95% CI: 62.9-not reached), while in non osimertinib median OS was 39.0 months (95% CI: 22.2-not reached) (p = 0.04).

Osimertinib demonstrated a superior therapeutic benefit with high efficacy and low toxicity for T790M-positive advanced NSCLC patients...

...single-centre phase I study enrolled adult patients (aged 52–77 years) with EGFRm advanced NSCLC with CNSm...with confirmed EGFR T790M...MRI showed marked reduction in CNSm mass and volume following 3–4 weeks’ treatment with daily osimertinib 80 mg...

…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.

The median progression free survival (PFS) was 10.5 months (95% CI: 8.95, 11.41), and 26.5% of patients survived without PD at 18 months...The median overall survival (OS) was 19.0 months after receiving the first dose of osimertinib and 40.9% survived at 24 months...clinical benefits of osimertinib were demonstrated in EGFR T790M positive NSCLC patients...

...we confirmed that osimertinib is effective even beyond second-line for advanced EGFRm+ NSCLC for T790M+ patients.

CONTRADICTING EVIDENCE: We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment….Multivariate analyses showed that a higher T790M allele frequency was associated with a trend towards a shorter PFS (adjusted HR 1.19, 95% CI 0.99-1.42, P = 0.05) and a significantly shorter OS (adjusted HR 1.25, 95% CI 1.02-1.53, P = 0.03) of the patients.

Eligible patients had confirmed EGFR-T790M–positive NSCLC....Median PFSo was 8.4 months [95% confidence interval (CI), 5.8–10.9]. Overall ORR was 39.4%....Patients with undetectable plasma EGFR mutations at week 6 had improved PFSo compared with those with detectable mutations (not reached vs. 4.5 months; 95% CI, 0.0–1.1; P < 0.05)....Osimertinib had potent activity against EGFR-T790M–positive NSCLC with CNS metastases.

...cohort 1, LM patients were treated with osimertinib with CSF and plasma genotyping performed before the first dosing of osimertinib (baseline, n=45);...Median iPFS was significantly longer in patients with T790M-positive CSF genotyping (15.6 months) than T790M-negative CSF (7.0 months; P=0.04).

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. A total of 12 of the 15 patients had undetectable plasma T790M and decreased activating mutation allelic frequency (AF) at week 4. None of the 12 patients had disease progression within 16 weeks.

This is an observational study at 3 Italian Centers enrolling EGFR mutant aNSCLC pts progressing after 1-2 gen TKI...89 pts with PD to first line TKI were included, 52 were T790M positive (P), 37 negative (N). All P received osimertinib, 22 out of 37 (59%) N received second line treatment (p < 0.001)...mPFS2 was 11.6 months (m; 95%CI 8.2-14.9) in P, 5.9 m (95%CI 4.8-7.0) in N (p < 0.001), hazard ratio (HR) 0.32 (95%CI 0.19-0.57, p < 0.001).

The study compromised 23 advanced EGFR T790M-mutated NSCLC patients...high T790M abundance (The mPFS were 9.00±1.48 and 25.00±0.00months for ctDNA T790M <4.2% and ≥4.2%, HR=0.17, 95%CI: 0.02-1.38, log-rank P=0.049) and prior icotinib (mPFS for patients who took gefinitb, erlotinib and icotinib were 14.00±7.33, 8.00±2.96 and 23.00±0.00months, HR=0.77, 95%CI: 0.43-1.39, log-rank P=0.014) were associated with improved osimertinib-related PFS.

...T790M-mutated NSCLC patients may have a better response, and longer PFS when treated with osimertinib therapy after previous chemotherapy compared to after previous TKI treatment.

In T790M-mutated pts, Osimertinib provided a median OS of 10 months [6-10] and a DCR of 100%.

Patients (n = 203) had T790M-positive disease following first-line afatinib and started osimertinib treatment...Median time on treatment with afatinib and osimertinib was 27.7 months (90% CI: 26.7–29.9). Median OS was 37.6 months (90% CI: 35.5–41.3)…

Patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer treated with second-line or later oral osimertinib....The objective response rate was 69.9%; disease control rate was 86.7%; and median progression-free survival (PFS) was 12.3 months. At 6 and 12 months, PFS rates were 77.4% (95% confidence interval [CI], 75.9-78.9) and 53.2% (95% CI, 51.3-55.1) and overall survival rates were 88.3% (95% CI, 87.2-89.4) and 75.4% (95% CI, 73.8-77.0), respectively.

In EGFR mutant population, acquired T790M was identified by ctDNA assay in 54% (34/63) of patients, all without concurrent tissue genotyping and received matched therapy (osimertinib) solely according to liquid biopsy results. The response rate at 3 months in the whole population was 62%. The response rate at 3 months in the whole population was 62%.

This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old...The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached)....results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment.

The median PFS of patients harboring EGFR exon 19 deletions/T790M (19del/T790M) and those harboring EGFR 21 L858R/T790M were 13.27 and 9.77 months (p = 0.001), respectively….The EGFR T790M mutation is likely to coexist with 19del and indicate longer PFS and OS1 than EGFR 21 L858R/T790M.

Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC...

The overall median PFS was 7.0 months (90% confidence interval: 5.5-8.9 months)...Osimertinib therapy could be a promising treatment option for patients with EGFR T790M mutation-positive advanced NSCLC who have poor PS.

Other alterations, such as EGFR T790 M, are responsive to osimertinib, while the EGFR C797S alteration seen in osimertinib resistance demonstrates preclinical sensitivity to combined brigatinib and cetuximab.

Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS.

40 participants were recruited in the T790M cohort….Median PFS was 7.1 months (95%CI,3.4 – 13.6 months) and ORR assessed by RECIST was 40.5% (95%CI, 24.7 – 57.9%)....This first study assessed the efficacy of osimertinib for patients with radiotherapy-naïve CNS metastasis of EGFR T790M mutation-positive NSCLC.

The persistence of T790M was associated with longer PFS (HR, 0.40; 95% CI, 0.19-0.84; P=0.01) and TTD (HR, 0.54; 95% CI, 0.39-0.76; P=0.0004). Furthermore, overall analysis the survival outcomes including PFS and TTD subgroups also showed preferable clinical benefits for patients with the T790M persistence (HR, 0.57; 95%CI, 0.45-0.73; P<0.00001).

Overall ORR was 48 % (95 % CI, 41 %–55 %), 60 % (51 %–69 %) for T790M-positive patients and 28 % (15 %–41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001....This study confirms the efficacy of osimertinib for T790M-positive patients.

Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months)....In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.

For patients (N = 145) with T790M (+) metastatic NSCLC treated by Osimertinib as 2nd line therapy, the ORR was 75.1%, the mPFS was 276 days. Subgroup analysis showed that for those with both T790M (+) and CNS metastasis (N = 146), the mPFS was 280 days and CNS ORR was 67.2%.

AZD9291 was associated with a higher objective response rate and longer progression-free survival in patients with T790M-mediated drug resistance than in those with non–T790M-mediated resistance….the current median progression-free survival in patients with detectable EGFR T790M (9.6 months) is encouraging.

...epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers...The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation...

We treated 9 EGFR-mutant patients with rociletinib and subsequent osimertinib...Osimertinib was administered at 80 or 160 mg daily; no dose reductions were necessary...Among 6 patients who transitioned directly from rociletinib to osimertinib (patients 1-6), retrospective longitudinal response measurements show that despite acquired resistance to rociletinib, all derived clinical benefit from osimertinib with either prolonged SD or PR.

This is a multi-center, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC osimertinib-treated as first EGFR inhibitor....The largest subgroups were G719X (30%), L861Q (20%) and de novo T790M (15%)….For de novo T790M ORR was 44%, mPFS 12.7m, mDOR 46.2m….Osimertinib demonstrated activity in ucEGFRmut with high rate of disease control systemically and intracranially.

The significant partial tumor response achieved by subject 1 with AZD9291 was observed only in the T790M-positive lung metastases whereas the bone scapula metastasis (Del19 and T790M wild-type) was stable....In subject 2, we also observed a sustained partial response in T790M-positive lung disease with loss of T790M at acquired resistance to AZD9291....AZD9291 can efficiently suppress the growth of T790M- positive cells…

…we reported the presence of the less common de-novo EGFR T790M mutation in a stage IV NSCLC patient. The patient received osimertinib as first-line treatment and achieved durable progression-free survival (PFS) for 24 months.

We herein report a case of squamous cell transformation combined with the epidermal growth factor receptor (EGFR) mutation T790M...The patient received treatment with the third-generation EGFR-TKI osimertinib, achieving a good clinical response.

We identified germline EGFR T790M mutation in the patient’s lung adenosquamous carcinoma. He was treated with osimertinib and achieved complete response for more than 30 months...

Second-generation EGFR-TKI dacomitinib-resistant cells with T790M-exhibited higher sensitivity to osimertinib than first-generation EGFR-TKI gefitinib-resistant cells with T790M via inhibition of AKT and ERK signaling and promotion of apoptosis….Our results demonstrate that the progression of tumor heterogeneity via both genetic and non-genetic mechanisms might affect osimertinib sensitivity in tumors with acquired resistance harboring EGFR-T790M mutation.