Osimertinib Approved in China for EGFR T790M+ NSCLC

Sean Bohen, MD, PhD

The China Food and Drug Administration (CFDA) has approved osimertinib for the treatment of patients with locally-advanced or metastatic EGFR T790M-positive non—small cell lung cancer (NSCLC) with progression following treatment with an EGFR tyrosine kinase inhibitor (TKI).

Osimertinib was approved under the CFDA’s accelerated Priority Review Pathway. To receive the treatment, patients must have their EGFR T790M mutation status confirmed through a validated test.

“This is an important step forward for Tagrisso and a significant opportunity to bring a breakthrough medicine to patients with NSCLC in China, where EGFR mutation rates are some of the highest in the world,” Sean Bohen, MD, PhD, executive vice president, global medicines development, and chief medical officer at AstraZeneca, the manufacturer of osimertinib, said in a statement.

The FDA approved osimertinib in this setting in November 2015 based on data from 411 patients in 2 single-arm studies. In the first study, labeled AURA, the objective response rate (ORR) with osimertinib was 61% for those with EGFR T790M-mutant NSCL­­­C. In the second trial, known as AURA2, the ORR was 57%, according to the FDA.

In the phase II AURA2 trial, 210 patients at a median age of 64 years with locally advanced or metastatic NSCLC received oral osimertinib at 80 mg daily. All patients had tumors that tested positive for the T790M resistance mutation and all had progressed on an approved EGFR TKI. Patients had received a median of 1 prior therapy (range, 1-2).

In an updated analysis presented at the 2015 World Conference on Lung Cancer (WCLC),¹ the ORR with osimertinib was 71%, with 2 complete responses. The stable disease rate at ≥6 weeks was 21%, for a disease control rate of 92%. The median duration of response was 7.8 months (95% CI, 7.1-NR). The median progression-free survival (PFS) was 8.6 months (95% CI, 8.3-9.7).

In updated data from WCLC,² the ORR was 61% (95% CI, 54-68). The median duration of response was not reached at the time of the analysis and the median PFS was also not yet calculable. At this analysis, only a quarter of events had occurred.

In the data assessed by the FDA from both studies, 96% of responses were ongoing, with the duration of response ranging from 1.1 to 5.6 months. In an earlier dose escalation portion of the AURA study reported by the FDA, data for 63 patients were available for analysis. In this group, the ORR was 51% and the duration of response was 12.4 months.

In a combined analysis of the 411 patients in both trials, the most commonly reported all-grade adverse events (AEs) were diarrhea (42%), rash (41%), dry skin (31%), nail toxicity (25%), eye disorders (18%), nausea (17%), decreased appetite (16%), and constipation (15%). These events were primary grade 1/2, with a low rate of grade ≥3 AEs. The most common grade ≥3 AEs were pneumonia (2%) and pulmonary embolism (2%).

More recently, data from the phase III AURA3 trial showed that osimertinib reduced the risk of disease progression by 70% compared with a chemotherapy doublet in patients with EGFR T790M-mutant NSCLC who progressed after first-line targeted therapy, a benefit that was achieved with a dramatically lower rate of serious AEs. The positive findings were presented at the IASLC 17th World Conference on Lung Cancer and published simultaneously in The New England Journal of Medicine.^3,4

In the randomized AURA3 trial, patients who received osimertinib achieved a median PFS of 10.1 months (95% CI, 8.3-12.3) compared with 4.4 months (95% CI, 4.2-5.6) for participants treated with a platinum agent plus pemetrexed (HR, 0.30; P <.001).

Additionally, the median PFS duration for patients with CNS metastases was longer among those who received osimertinib than among participants treated with chemotherapy (8.5 months vs 4.2 months, respectively; HR, 0.32).

The objective response rate also was significantly higher with osimertinib; the ORR was 71% for the TKI versus 31% for chemotherapy (odds ratio, 5.39; 95% CI, 3.47-8.48; P <.001).

In the AURA3 study,1036 patients were screened from August 2014 through September 2015. After the selection process, 419 patients were randomized 2:1 to receive either osimertinib at 80 mg once daily, or a platinum—pemetrexed doublet consisting of pemetrexed (500 mg/m²) plus either cisplatin (75 mg/m²) or carboplatin (AUC5) every 3 weeks for up to 6 cycles. In all, 279 participants received osimertinib, and 140 patients received the platinum—pemetrexed regimen.

The study arms were well balanced, researchers noted. The median age was 62 years in the osimertinib group and 63 years in the chemotherapy cohort. Nearly all of the patients had metastatic disease; 33% of the osimertinib group and 36% of the chemotherapy arm had CNS metastases.

For prior EGFR-targeted therapy approximately 60% of the participants had received gefitinib (Iressa), 35% had been treated with erlotinib (Tarceva), and nearly 6% had taken afatinib (Gilotrif).

The primary endpoint of the study was PFS, as determined by investigator assessment according to RECIST v1.1. Secondary endpoints included response rate, duration, overall survival, and side-effect profiles.

In terms of AEs, toxicities of grade >3 severity were reported in 23% of the osimertinib group versus 47% of the chemotherapy arm. The most frequently reported grade >3 events in the chemotherapy arm were neutropenia (12%), anemia (12%), and thrombocytopenia (7%). The incidence of each of those toxicities in the osimertinib arm was 1% or less.

The most common adverse events of any grade, reported in >10% of participants, associated with osimertinib included diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%). For those treated with platinum—pemetrexed, the most common toxicities of any grade were nausea (49%), decreased appetite (36%), constipation (35%), and fatigue (28%).

References:

1. Mitsudomi T, Tsai C, Shepherd F, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA2 Phase II study. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1406.
2. Yang JC, Ahn M, Ramalingam SS, et al. AZD9291 in pre-treated T790M positive advanced NSCLC: AURA study Phase II extension cohort. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 943.
3. Papadimitrakopoulou V, Wu YL, Ahn M, et al. Randomized phase III study of osimertinib vs platinum-pemetrexed for EGFR T790M-positive advanced NSCLC (AURA3). Presented at: IASLC 17th World Conference on Lung Cancer; December 4-7, 2016; Vienna, Austria.
4. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum—pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674.

In the AURA trial, 201 patients at a median age of 62 years received osimertinib. Of patients enrolled, 30% were receiving osimertinib as second-line therapy while 70% were treated in the third-line setting. Ninety-eight percent of tumors tested positive for T790M.