In this real-life study, as a primary endpoint; Osimertinib demonstrated a quite impressive TTD with a median of 21.6 months, in pretreated advanced EGFR-mutant NSCLC patients. Secondary endpoints were also consistent with 82.2% of ORR, and estimated-median OS of 32.1 months, with a favorable safety profile.
AURA3 was an international, phase 3 study that randomized 419 patients with T790M-mutant advanced NSCLC to second-line Osimertinib or chemotherapy arms (6). The study reported a median of 10.1 months PFS with Osimertinib treatment. Demographic and clinical features of the patient population were similar in terms of age (62 and 57), sex (female, 62% and 59%), rate of CNS involvement (33% and 30%), and EGFR mutation subtypes (exon 19 del, 68% and 68%) in AURA3 and our study, respectively (6). However, in the Osimertinib arm of the AURA3 study, 65% of the patients were Asian, 83% of the patients had adenocarcinoma histology (in our study it was 98%), 96% had only one-line of previous treatment (in our study it was 59%) (6). Moreover, our study group had received more previous treatment lines before Osimertinib.
In this context, the survival outcomes of other real-life studies varied between median 9.4 and 14.5 months of PFS, in the second-line treatment of advanced NSCLC with T790M mutation (9–14). The Spanish Lung Cancer Group reported a median of 9.4 months PFS in 155 patients, and this was a very close to the PFS reported in the pivotal phase 3 trial (6, 10). Other studies from different regions and ethnicities like China, Japan, France, and Poland demonstrated slightly better real-life outcomes than the AURA3 trial with approximately median 11–14 months of PFS (9, 11–14). In general, outcomes of real-life experiences with the different classes of drugs just like cytotoxic chemotherapy, barely exceed the success of pivotal studies. Because patients often have more comorbidities and worse performance status than patient population strictly selected in phase 3 studies. However, targeted agents typically could demonstrate similar or better results in several studies. Clinicians’ increasing experience in the management of treatment side effects and sustainable clinical benefit observed in some patient groups might contribute to these results.
Median 21.6 months of TTD in our study was a quite different outcome than the PFS results of phase 3 AURA3 or other real-life studies. Of course, these two different end-points did not refer to the same situation, and they could not be compared directly in any clinical scenario. Indeed, our aim mostly emphasizes the distinct features of the TTD and PFS as study end-points. Unlike other studies, TTD did not identify the disease progression as “an event” according to RECIST criteria, and includes patient subgroups in which clinicians decided to continue the treatment post-progression.
Importance of TTD was demonstrated in a recent study that analyzed 18 different randomized studies with 8947 NSCLC patients (15). Five of these 18 studies included 1151 patients who received targeted TKI therapy for EGFR-mutant NSCLC. Median TTD exceeded median PFS by 2 months (13.4 versus 11.4 months) in this subgroup. Also, the rate of “late TTD” (identified as TTD – PFS ≥ 3 months) was 12.4% in EGFR-mutant patients and this rate was higher than chemotherapy and immunotherapy studies (15). Another study from Spain which included 91 patients who received post-progression treatment after second or third-line Osimertinib therapy for T790M mutation-positive disease, reported a median of 6.4 months post-progression PFS with Osimertinib treatment in 50 (54%) patients (16). Both post-progression PFS and OS were significantly longer in the post-progression Osimertinib arm compared with other treatments in this study (16).
The other determinant that might improve the TTD could be inclusion of local ablative therapies (LAT) to patient care. As one of the weaknesses of our study, our database did not include the percentages of patients who received LAT. However, it is a routine part of daily clinical practice especially for patients whose disease showed oligoprogression and/or isolated CNS progression (17). A recent study by Zeng et al., included 108 patients (n = 83 for the second-line Osimertinib) who had oligo-residual disease (≤ 5 metastatic lesions) and treated with Osimertinib, demonstrated a PFS advantage in patients (n = 14) who had received LAT compared with others (NR vs 12.8 months, p = 0.01) (18). In this small patient subgroup (n = 8 for first-line Osimertinib, and n = 6 second-line Osimertinib) in which administered LAT to their Osimertinib treatment, 3-year PFS rate was reported as 54.5% (18).
Main reasons of choosing TTD as our primary end-point were also the weaknesses of our study. TTD was more suitable for a retrospective study that did not perform a central assessment of treatment response and included many centers around the country which may have different clinical approaches and LAT practices. But at the same time, it might reflect directly the sustainable and real-life beneficial effects of treatment to allow the post-progression continuation and other interventions to the treatment process. Clinicians’ choice to hold on to the drug throughout median 21.6 months was quite understandable in this very special patient subgroup who did not have too many treatment options after Osimertinib treatment, rather than chemotherapy which has highly suspicious efficacy in third or later-lines.
TTD was significantly longer in favor of women, patients with Exon 19 deletion, and patients without brain metastasis compared to men, Exon 21 L858R mutation, and patients with brain metastasis, respectively. There was greater risk reduction observed in female gender and patients with Exon 19 del mutation, with both first-line and second-line Osimertinib treatment, in pivotal phase 3 studies (6, 19). Also, our results were compatible with a recent meta-analysis by Lee et al. that demonstrated 50% greater benefit in Exon 19 del mutation than Exon 21 L858R mutation (p < 0.01), and 27% greater benefit in women than men (p = 0.02) with first or second-generation EGFR-TKIs compared with chemotherapy (20). Real-life studies from Poland and France also reported significant PFS advantage in patients with Exon 19 del mutation (11, 12).
Brain metastasis is a worse prognostic factor for NSCLC and drug penetrance to CNS remains a problem even for highly effective therapies like Osimertinib (21). TTD in patients with brain metastasis is significantly shorter than patients without brain metastasis, however, median 11.4 months of TTD was similar to the AURA3 trial’s 8.5 months of PFS (6). In our study, patients with asymptomatic brain metastasis might be under-represent in our brain metastatic subgroup because of the lack of periodic brain MRI screening in daily clinical practice.
In the pivotal phase 3 trial, 71% of the patients achieved ORR and 93% DCR with Osimertinib (6). In our study, ORR was higher (82%) and DCR was similar with 95%. Studies from Europe already reported lower rates with approximately 40–50% of ORR (10, 12). No data was indicating that the Turkish population might be more “sensitive” to this treatment than Western population. Our study did not perform a central assessment for radiological review, and patient-selection bias always has to be taken into consideration as a possible determinant of a retrospective study.
After median 13 months follow-up, estimated median OS was 32.1 months (median 27.7 months for second-line and 32.1 months for ≥ 3-lines of treatment). Median OS of the Osimertinib arm in AURA3 trial was 26.8 months (7). Real-life results showed a median OS of 20 months in the western population and 24 months in the Asian population (11, 14). In a phase 2 study, 3-year OS rate was 54% in Japanese patients (22). In another study, median OS from the failure of first-line EGFR-TKI was reported as 42.6 months in patients who had T790M mutation with a history of Osimertinib use (23). Relatively short follow-up period, risk of patient-selection bias, and also possible differences in the sequential therapies might have affected our OS results.
Safety profile was favorable with only 5.5% of temporary drug interruption. Most common side effects were similar with recent data. Rates of any adverse events and grade 3–4 adverse events were lower than the AURA3 study (6). Clinicians’ tendency to underestimate the side effects –especially grade 1 and 2- which will not influence treatment strategy, might be a possible reason in daily clinical practice. For example, grade 1–2 pneumonitis was seen in 9 of 279 patients in AURA3 however it was none in our study. Probably, asymptomatic grade 1 events might be underestimated and the symptoms of grade 2 events might be explained with other clinical entities. But grade ≥ 3 pneumonitis was seen in one patient in both studies (6).
In conclusion, Osimertinib is a highly effective therapy in second-line treatment of NSCLC patients with T790M mutation, with a favorable safety profile.