Table 2.

Benefit–risk analysis for osimertinib in the treatment of patients with metastatic NSCLC who have progressed on or after EGFR TKI therapy and who have developed a T790M resistance mutation

DiseasePatients with EGFR mutation–positive metastatic NSCLC who have progressed on or after EGFR TKI therapy and who have developed a T790M resistance mutation.
Unmet needMetastatic EGFR T790M mutation–positive NSCLC that has progressed on or after EGFR TKI therapy is often treated with cytotoxic chemotherapy, which is generally associated with marginal clinical benefit and significant toxicity.
Clinical benefitOsimertinib was associated with an ORR as assessed by a BICR of 57% (95% CI, 50–64; AURA extension) and 61% (95% CI, 54–68; AURA2). The activity of osimertinib was generally consistent across clinically relevant subgroups. Tumor responses were durable, with a median DOR that had not been reached at the time of the primary analysis.
RiskThe primary safety evaluation was based on 411 patients. The most common AEs (≥25%) were diarrhea, rash, dry skin, and nail toxicity. Grade 3–4 AEs were reported in 28% of patients. Dose reductions occurred in 4.4% of patients, and 5.6% of patients discontinued therapy due to AEs.
UncertaintiesAlthough ORR is considered an endpoint that can reasonably predict clinical benefit in metastatic NSCLC, no correlation with overall survival or how a patient feels or functions has yet been established. Therefore, traditional approval for osimertinib requires confirmation of clinical benefit. Additional data are needed to assess the safety and efficacy of osimertinib: in patients with hepatic impairment; in patients with CNS metastasis; in combination with CYP3A4 inhibitors, inducers, substrates, as well as BCRP substrates; and in patients with germline and de novo EGFR T790M–mutated NSCLC.
ConclusionsOsimertinib meets the criteria for accelerated approval under the provisions of subpart H of 21 C.F.R. 314 (16). Osimertinib has a favorable benefit–risk profile for the treatment of patients with EGFR mutation–positive metastatic NSCLC who have progressed on or after EGFR TKI therapy and who have developed a T790M resistance mutation. Osimertinib is associated with a large magnitude of durable responses in a population of patients for whom available treatment options generally offer marginal clinical benefit. The risks associated with osimertinib are acceptable in the context of the disease being treated.