One hundred and fifty-five patients who started osimertinib treatment between August 2016 and December 2018 were analyzed. Table 1 shows the main demographic data. One hundred and fifty-five were T790M positive: 70% (109/155) had EGFR deletion in exon 19, 25% (39/155) exon 21, and 5% (7/155) other previous mutation status. Four patients (2.6%) received osimertinib as first line, 83 (53.5%) as second line, 31 (20.0%) as third line and 37 (23.9%) as the fourth of further lines.
Palliative radiotherapy use was also registered. Of the 155 patients included, 73 (47.1%) received radiotherapy treatment during follow up, of whom 60 (38.7%) started radiotherapy before beginning osimertinib treatment, and 13 (8.4%) started radiotherapy after beginning osimertinib treatment.
Regarding chemotherapy, 152 of the 155 patients included (98.1%) received chemotherapy during follow up.
According to RECIST v 1.1, best response to osimertinib was distributed thus: 2 (1.3%) p with complete response, 63 (40.6%) with partial response, 48 (31%) with stable disease, 18 (11.6%) with progression and 21 (15%) without registered response. Of the 131 patients with registered response to osimertinib treatment, estimated objective response (PR or CR reached) was 42%. Regarding comparison of response rates between treatment lines when osimertinib was administered, no statistically significant differences were observed among the 75 patients who received osimertinib in first or second line with registered response (of the 35 that responded, 46.7%) and the 56 patients who received osimertinib in third or fourth line with registered response (of the 30 that responded, 53.6%) (p-value = 0.482). Table 2 shows the drugs administered as first, second and third lines prior to osimertinib.
Adverse events (AEs)
Table 3 shows a summary of AEs on osimertinib classified according to the CTCAEv5.0. One hundred and fifty-five patients received treatment and were included in the study. Of these, 76 (49.0%) did not show AEs; 29 (18.7%) showed AEs with a maximum grade of 1; 32 (20.6%) showed AEs with a maximum grade of 2; 14 (9%) showed AEs with a maximum grade of 3; 2 (1.3%) with a maximum grade of 4; and 2 (1.3%) with a maximum grade of 5.
Osimertinib dose was adjusted in 26 patients (16%) and was due to toxicity in 18 of these (11.6%). Treatment was discontinued in 4 patients (2.6% of the total treated) due to toxicity.
Follow up and overall survival
Patients were monitored from the beginning of osimertinib treatment until time of death, loss to follow up or study closure while they were still alive. Median follow up for all patients was 11.7 months (range 0.4-32.0 months), while the median for those patients that were alive was 14.9 months (range 1.8-32.0 months).
Of the 155 patients included, 80 (51.6%) died during follow up. Median estimated overall survival for these patients was 17.3 months (95% CI, 13.4-21.3 months). Figure 1.
Overall survival can be compared depending on the line of treatment patients received. Of the 87 patients who received osimertinib as first (4 patients) or second line (83 patients), 46 died during follow up (52.9%). Of the 68 patients that received osimertinib as third (31 patients), forth (22 patients), fifth (11 patients), sixth (2 patients) or seventh line (2 patients), 34 died during follow up (50.0%). No statistically significant differences are observed between the overall survival curves of these two groups of patients (osimertinib as <2nd line versus >3rd line, p-value = 0.392).
Of the 155 patients included, 89 (57.4%) progressed during follow up, 16 (10.3%) died before progression and 50 (32.3%) were still alive without progression at the trial’s closure. Figure 2 shows the estimated PFS curve for this type of patients, with a median PFS of 9.4 months (95% CI, 7.3-11.6 months).
PFS can be compared by treatment line. Of the 87 patients that received osimertinib as first or second line, 61 progressed or died during follow up (70.1%). Of the 68 patients who received osimertinib as third or further line, 44 progressed or died during follow up (64.7%). No statistically significant differences were observed between the PFS curves of both groups of patients (p-value = 0.113).
Follow up of patients with CNS metastases at osimertinib treatment initiation
Presence of CNS metastases was registered at the beginning of osimertinib treatment in 45 patients (29.9%).
Significant differences were observed according to the absence or presence of brain metastases prior osimertinib initiation [10.3 months (95% CI, 7.8-12.8 months) and 7.2 months (95% CI, 3.9-10.6 months), respectively (HR = 1.546 with 95% CI, 1.030-2.321); p-value=0.034].
No significant differences were observed when comparing OS according to presence or absence of CNS metastases at the initiation of osimertinib treatment (p-value = 0.365). Median OS was 18.3 months (95% CI, 14.9-21.7 months) and 13.8 months (95% CI, 11.0-16.6 months) for those patients without and with brain involvement prior to osimertinib initiation, respectively.
Follow up of patients that received osimertinib as last treatment
Overall survival for the 134 patients that received osimertinib as last treatment (no posterior treatment registered) was compared with that of the 21 patients that did receive subsequent chemotherapy and no significant differences were observed (p-value = 0.411).
Of the 134 patients, whose last treatment was osimertinib, the end date was not registered for 52 of them, so they continued on treatment at the date of treatment data collection closure (31/12/2018).
Follow up ofT790M+ “de novo” patients
Overall survival and PFS of the 10 (8.3%) “T790M+ de novo” patients were analyzed.
The small number of these subgroup of patients does not lend itself to precise estimates, making it difficult to detect potential differences. Median estimated overall survival for these patients was 14.8 months (95% CI, 3.1-26.5 months), while estimated median PFS was 8.6 months (95% CI, 0.0-18.1 months).
Of the 6 patients included in this group that had received previous treatment, 3 (50%) died during follow up. Estimated median overall survival for these patients was 15.6 months, while estimated median PFS was 9.4 months.
Health service resources
Data on use of health service resources during treatment with osimertinib (from first dose to last) was collected. It was assumed that all 155 patients had finished treatment with osimertinib, so none were censored.
The use of health service resources is described according to previous characteristics before osimertinib treatment. Table 4 shows the main number of resources used according to different characteristics. A comparison between the values observed using the Mann-Whitney U test is also shown. The results show that stage T3-T4 patients consumed more resources, with a significant difference in R13 (other imaging tests). Similarly, non-smokers and those who had more previous chemotherapy lines also required more resources.