In the phase I AURA trial patients
In the phase I AURA trial, patients with EGFR activating mutations and centrally confirmed tumor and/or plasma genotyping (BEAMing) T790M result were enrolled. Among 216 patients with both plasma and tissue genotyping results, the concordance rate was 82% for Timolol Maleate in 19 deletions, 86% for L858R and 70% for T790M. Outcomes were similar for 179 patients T790M+ in tumor (62% ORR and 9.7 months PFS) and for 167 patients T790M+ in plasma (63% ORR, 9.7 months), but unexpectedly differed for T790M- in plasma (46% ORR, 8.2 months PFS) and T790M- in tumor (26% ORR, 3.4 months PFS). These data suggest that patients with a T790M negative results in plasma genotyping may be divided in two subgroups with different outcome: T790M undetected (38% ORR, 4.4 months PFS) and T790M uninformative (64% ORR, 15.2 months PFS) (Oxnard et al., 2016). These data suggest that plasma and tissue genotyping can have complementary roles and that liquid biopsy should be offered early to identify T790M+ candidates for Osimertinib therapy, reserving traditional tissue biopsy to T790M- cases in plasma.
The favorable toxicity profile of 3rd generation EGFR TKIs pave the way to combinatory schedules with other agents in order to provide a more comprehensive anti-tumor activity and/or to prevent the emergence of resistant clones. Several clinical trials are ongoing evaluating different combinations in EGFR-mutated NSCLCs in various setting [Table 5].
Recently, safety concerns raised from the ongoing multi-arm phase Ib study TATTON evaluating different combinations and schedules of Osimertinib with other investigational agents, since 38% of patients treated with Osimertinib plus the anti-PDL1 inhibitor Durvalumab developed an interstitial lung disease (ILD) at an unexpectedly higher frequency compared with both single agents (2.9% and 2.0%, respectively) (Ahn et al., 2016) (Table 6).
Conclusions Preclinical and clinical data with mutant-selective EGFR TKIs are promising and are changing the therapeutic landscape of EGFR-mutated NSCLCs (Fig. 1). The rapid FDA approval of Osimertinib (only 2.8 months after first patient treated) and the fast development of Rociletinib and Olmutinib are profoundly influencing the therapeutic algorithm of EGFR mutant NSCLCs, with a new and effective option after acquired resistance to 1st and 2nd generation EGFR TKIs. Ongoing trials will produce the definitive evidences of the best in class EGFR TKI and the optimal therapeutic sequence of these agents.
Conflicts of interest
Grant support This work was supported by the Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO), A.S.S.O. (Associazione Siciliana Sostegno Oncologico)Onlus and Borsa Dottorati FSE XXXII Ciclo Unime.