NEW STANDARD OF CARE FOR EGFR+ NSCLC

For patients with advanced non–small cell lung cancer (NSCLC) and an activating mutation in the epidermal growth factor receptor (EGFR) gene, the management of acquired resistance now offers the potential for further EGFR-directed treatment before turning, most commonly, to conventional chemotherapy. The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib has been demonstrated to have significant activity in patients with EGFR mutation-positive acquired resistance, overwhelmingly more in the 50% to 60% who develop a T790M mutation as a mechanism of resistance.^[1] The US Food and Drug Administration (FDA) has approved osimertinib for T790M mutation–positive acquired resistance based on this early phase 1/2 work.^[2] Despite the availability of osimertinib and its demonstrated efficacy, testing for this marker remained limited. This is in part because osimertinib had not been compared with an active therapy in a phase 3 trial.

The AURA-3 trial randomly assigned 419 patients with EGFR T790M-positive advanced NSCLC and acquired resistance after a prior EGFR TKI in a 2:1 fashion to either the third-generation EGFR TKI osimertinib at 80 mg by mouth daily or standard cisplatin or carboplatin with pemetrexed.^[3] The trial demonstrated a highly significant efficacy advantage for osimertinib over chemotherapy in terms of objective response rate (ORR, 71% vs 31%; odds ratio, 5.39; P < .001) and progression-free survival (PFS, median 10.1 vs 4.4 months; hazard ratio [HR], 0.30; P < .0001). Among the 144 patients, median PFS also strongly favored osimertinib (8.5 vs 4.2 months; HR, 0.32). Toxicity also favored osimertinib, as the rate of grade 3 toxicities was twice as high with chemotherapy as with osimertinib (47% vs 23%, respectively). The most common adverse effects (any grade) with osimertinib were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%), while those with chemotherapy were nausea (49%), diminished appetite (36%), constipation (35%), and anemia (30%).

In AURA-3, the comparator to osimertinib was the clear best alternative widely used outside of a trial, with platinum doublet therapy frequently selected in the absence of further mutation-directed therapy^[4] and a platinum-pemetrexed combination commonly favored as a potential optimal choice in patients with lung adenocarcinomas. Osimertinib demonstrated a highly significant benefit in efficacy that was accompanied by an overall more favorable toxicity profile, thus adding an option not otherwise available and simply deferring platinum doublet chemotherapy until subsequent progression.

Osimertinib has now emerged as the standard of care for EGFR T790M mutation–positive NSCLC after progression on a prior EGFR TKI, making it mandatory to look for T790M once acquired resistance has developed. Of note, there is an FDA-approved plasma-based companion diagnostic, providing a noninvasive approach as an initial "first pass" when looking for T790M. However, because plasma testing is still evolving and has a sensitivity in the 60%-80% range,^[5] a negative plasma test may represent a false negative and should ideally be followed by a tissue biopsy before concluding that a patient is T790M negative, especially given the very favorable efficacy and tolerability of osimertinib and with availability limited only to those positive for this marker.

With the AURA-3 phase 3 trial convincingly demonstrating the greater efficacy and tolerability of osimertinib over conventional chemotherapy for T790M mutation–positive NSCLC, it emerges as the clear standard of care in this setting. Unless it demonstrates superiority over first-line gefitinib or erlotinib in the completed but not-yet-reported FLAURA trial,^[6] its use remains restricted to those patients who are tested and found to have a T790M mutation. Whether by plasma, urine, tissue, or a combination of these platforms, it is now imperative to test for this marker in EGFR mutation–positive patients with acquired resistance to provide them with an opportunity to benefit from osimertinib.