Afatinib followed by osimertinib in EGFR+ T790M NSCLC extends chemo-free time
Sequential treatment with afatinib followed by osimertinib enables prolonged chemotherapy-free treatment while sustaining clinical benefit in patients with EGFR-mutation positive (EGFR+) non-small–cell lung cancer (NSCLC) who acquire T790M mutation, according to the real-world retrospective GioTag study presented at ESMO Asia 2018.
“Regardless of which first-line TKI* is chosen, acquired resistance is inevitable. Emergence of the T790M mutation is the main molecular resistance mechanism to gefitinib, erlotinib, and afatinib, and is found in about 50–70 percent of tumours at the time of acquired resistance,” explained Dr Ross Soo of the National University Hospital, Singapore. “Treatment with sequential EGFR TKIs, with osimertinib reserved as a second-line option, may therefore maximize time on targeted drugs.”
The multinational observational study analysed data retrospectively collected from 204 patients (median 60 years, 53.9 percent female) with EGFR+ (of which 73.5 percent were Del19 and 26 percent were L858R mutations) NSCLC who acquired T790M after afatinib therapy. About one quarter of the patients (24.5 percent) were Asians. [ESMO Asia 2018, abstract LBA7]
The primary endpoint of time on treatment (ToT), defined as duration from afatinib initiation to osimertinib discontinuation, was an overall median of 27.6 months (90 percent confidence interval [CI], 25.9–31.3). When the treatment was analysed individually, the patients received afatinib for a median of 11.9 months (90 percent CI, 10.9–12.2) and osimertinib for a median of 14.3 months (90 percent CI, 12.8–15.9). The main reason for osimertinib discontinuation was progressive disease (n=98), followed by deaths (n=4) and adverse events (n=2).
Landmark analysis showed that the OS rate was 79 percent at 2 years and 69 percent at 2.5 years. The 2-year OS rate was particularly higher, at 83.9 percent in the patient subgroup with ECOG PS 0/1.
Calling these an “encouraging results”, Soo said “Sequential afatinib and osimertinib provided sustained clinical benefit in real-world clinical practice.”
In general, clinical benefit in terms of ToT was consistent across subgroups. Patients with poor prognosis, including those with stable brain metastases (median, 19.4 months) and ECOG performance status (PS) ≥2 (median, 22.2 months) also appeared to benefit.
Specifically, median ToT was longer in the patient subgroup with Del19 EGFR vs those with L858R mutation (median, 30.3 vs 19.1 months). In particular, ToT was further prolonged in Del19 patients who also had ECOG PS 0/1 (median, 36.4 months, 90 percent CI, 29.2–46.7).
Noting that approximately 75 percent of the patients were Del19-positive, Soo said this likely reflects the higher frequency of T790M acquired resistance in Del19-positive vs L858R-positive tumours.
Asian patients also derived a greater benefit than non-Asians (median ToT, 46.7 vs 27.6 months).
“With a median ToT of 27.6 months in real-world setting, notably prolonged in Asian patients and those with Del19-positive disease, sequential therapy appears feasible and potentially effective,” said Soo.
“While prospective studies are needed to fully determine the optimum treatment strategy, this sequential approach might offer sustained clinical benefit, while avoiding chemotherapy,” he added.