Continuing Osimertinib Treatment After Progression Prolongs Survival Benefit in NSCLC

Xiuning Le, MD, PhD

Xiuning Le, MD, PhD

Patients who continued receiving osimertinib (Tagrisso) after their non—small cell lung cancer (NSCLC) had progressed demonstrated a prolonged benefit beyond the initial progression event, according to a retrospective analysis of 118 patients from The University of Texas MD Anderson Cancer Center (MDACC) and the Moffitt Cancer Center and Research Institute (MCC).¹

A total of 76 patients progressed, with 47 continuing with osimertinib treatment. These patients exhibited a median second progression-free survival (PFS2) of 12.6 months. Continuation of osimertinib beyond progression was also associated with a longer overall survival (OS) compared with discontinuation (11.2 vs 6.1 months,P= .02).

Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), has demonstrated efficacy against both classical epidermal growth factor receptor (EGFR)-sensitizing mutations andEGFRresistance T790M mutations. Yet, despite its increasing role in NSCLC, data regarding resistance mechanisms to this agent are limited. In the study, Xiuning Le, MD, PhD, and colleagues said that gaining a comprehensive understanding of resistance mechanisms to osimertinib is needed if strategies to overcome resistance are to be successful.

Patients treated with osimertinib from January 2014 to October 2017 were selected from the GEMINI database from MDACC and the lung cancer databases of MCC. Information about patient demographics, previous lines of therapy, survival, and current status was collected until February 2018 (MDACC) and January 2018 (MCC), when the dataset was locked for the outcome analysis. The investigators reported that the median age was 63 years, 72% of the cohort were women, 68% were never smokers, and 95% received a previous EGFR TKI; specifically, 78% received erlotinib (Tarceva).

Time-to-treatment failure (TTF) on prior EGFR TKI was defined as time from initiation of first EGFR TKI until discontinuation of treatment due to progressive disease (PD) or toxicity. First PFS (PFS1) was defined as time from starting osimertinib until PD or death. For patients who continued treatment beyond progression, PFS2 was defined as time from starting osimertinib until second PD or death. OS1 was defined as time from starting osimertinib until death from any cause. OS from diagnosis (OS Dx) was defined as time from diagnosis of recurrent or metastaticEGFR-mutant NSCLC until death.

Median PFS1 was 8.4 months (95% CI, 6.7-10.7), and median OS1 was 25.2 months (95% CI, 17.5-29.2). After progressing on osimertinib, 62% continued with the treatment. The median PFS2 was 12.6 months (95% CI, 8.3-15.5) and 45% (21 patients) received palliative radiation for oligometastatic progressing lesions.

The investigators reported improved outcomes in the radiated population compared with nonradiated patients (PFS2, 15.5 vs 8.2 months; HR, 0.5; 95% CI, 0.3-31.0;P= .05). PD occurred in 62% (13/21) of radiated and 77% (20/26) of nonradiated patients. Among patients who received radiotherapy, the most commonly radiated sites were lung, mediastinal lymph nodes, bone, and brain. The investigators suggest that local consolidation therapies, such as radiotherapy, decrease the resistant subclone tumor burden, whereas continuation of osimertinib suppresses sensitive cells.

With a median follow-up of 39 months, OS Dx for the entire cohort was 71.9 months (95% CI, 51.4—92.1), a strikingly long survival compared with median OS of 19 to 28 months with first- or second-generation EGFR TKIs.

The investigators also analyzed genomic profiling data at the time of osimertinib progression. They found that cell-cycle gene alterations (CDK4/6orCCND/E1amplifications, orCDKN2Aloss) were associated with worse outcome, demonstrating the need for novel therapeutic options for these patients.

In the T790M-preserved group, previously defined osimertinib-resistantEGFRmutations were the most common resistance mechanisms. These mutations were exclusively observed in T790M-preserved cases, and the investigators report that this association was statistically significant (11/19 vs 0/21,P<.001). They observed that in most of the T790M-preserved cases, resistance is associated with continuedEGFRactivation through known resistance tertiary mutations (eg, C797S). In contrast, resistance in T790M-loss cases occurs through diverse and predominantlyEGFR-independent mechanisms.

In contrast to first-generation EGFR inhibitors, resistance mechanisms to osimertinib were found to be predominantlyEGFRindependent, includingMETamplification, PI3K pathway activation, and epithelial—mesenchymal transition.

The investigators said that continuing osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients. They suggested that further study will be needed, especially given the increasing role for osimertinib in the treatment ofEGFR-mutant advanced NSCLC.

Reference:

Le X, Puri S, Negrao MV, et al. Landscape of EGFR-dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC.Clin Cancer Res. 2018;24(24):6195-6203. doi: 10.1158/1078-0432.CCR-18-1542.