Thank you for the kind invitation to share the data on this study, namely ARCHER 1050, which is a direct head to head comparison of dacomitinib versus gefitinib as a first line treatment for patients with EGFR mutation. This is my disclosure.
A bit of background – dacomitinib is a second generation TKI, by that it implies two characteristics. First is irreversible bondage with the EGFR receptor; second is the pan-HER inhibition including HER1, HER2 and HER4. With this combination it implies more potent inhibition of the EGFR. In one single arm phase II study that [?? 0:40] and I had conducted, namely the ARCHER 1017, it had demonstrated a factor for patient with EGFR mutation we had a response rate of 75.6% and also a median progression free survival of over 18 months. Based on this data we’re quite confident to make the hypothesis that this may be more efficacious than gefitinib and this formulates the background for this randomised phase III study.
The study design is actually quite straightforward: patients have to be treatment naïve both to TKI and chemotherapy, good performance status and the patients actually do not have the CNS metastases. Why is this different from other studies? At the time when we designed the study we were not quite sure that dacomitinib had efficacy in the brain as well as for gefitinib that efficacy is actually marginal for CNS. So for that reason, for the fairness of patients, we decided to exclude patients with brain metastases. We randomised eligible patients one to one, dacomitinib at 45mg versus gefitinib at the standard dose of 250mg daily; two certification factors including the ethnicity, Asian versus non-Asian, as well as the mutation type, 19 versus 21. The primary endpoint is actually progression free survival and this is actually by an independent review body, blinded independent review. Secondary endpoints included progression free survival by the investigator that we will share with you.
The characteristics are actually quite balanced between the two arms in terms of age, gender, ethnicity also ECOG status and smoking status. Just to highlight the fact that we had predominantly Asian, as expected, approximately 75% of all enrolled patients were from Asia. Then approximately 65% of the patients were never smokers. This is quite classical of any first line study on EGFR TKI. This is the primary endpoint, it showed we have a very positive study. We reached the primary endpoint with the median progression free survival of 14.7 months versus 9.2 months. The hazard ratio is 0.59, this is very close to what we anticipated at 0.667 in the beginning, and the p-value is also highly significant at less than 0.001.
There are two features I would like to highlight to you about these Kaplan-Meier survival curves. First, they overlap in the first five or six months but then after they start to separate. Then the separation of the two curves continues, even at the arbitrary endpoint at 24 months it was 30.6% of patients are progression free versus only about 9.6% of the patients progression free. The difference at two years is almost 20%.
Now, the response rates are similar, which is about 75% on the dacomitinib and 73% on the gefitinib arm, however, you can see from this waterfall plot curve that the depth of the response is actually higher with the dacomitinib which implies it’s a more potent inhibition of the EGFR which is exactly what we have expected as well. Then the response rate, as stated, 75% versus 72%, then the median duration of response is about 14.8 months versus 8.3 months and then the p-value is also highly significant. Overall survival is immature, at this point it’s only 37% of the patients who have reached the survival event.
Toxicity wise, however, because of the more potent the EGFR inhibition, we are facing higher inhibition of the [?? 4:06]. As a result, diarrhoea, paronychia, dermatitis and stomatitis are more common. Grade 3 toxicity associated with dacomitinib was about 8.4%, 7.5% for the paronychia, 13.4% for the dermatitis and 3.5% for stomatitis. As compared to the gefitinib arm the incidence of grade 3 toxicity is actually relatively uncommon. On the other hand you may see that there is grade 3 hepatic toxicity related to gefitinib which is relatively uncommon on the dacomitinib arm.
As a result we do require dose modification. We have two dose modification levels, one is the first level is 30mg daily, the second level is 15mg daily. Then the gefitinib there’s only one dose level which is 250mg every other day. You can see that time to dose reduction is about the same but the duration of dose reduction is longer, 11.3 months with dacomitinib, 5.2 months with gefitinib. Approximately 66% of the dacomitinib arm required dose reduction: approximately 38% from the first dose level at 30mg daily and 28% in the second dose level of 15mg daily. On the other hand, gefitinib dose reduction was only required in approximately 8% of the patients.
Quality of life, they were able to inhibit the tumour growth so the lung cancer symptoms were reduced in both arms, a little bit more in the dacomitinib arm but basically they are significant, crossing the 10 point landmark. But on the GI toxicity as well as the mucositis, they seemed to be higher, meaning a worsening of the quality of life for the dacomitinib arm compared to the gefitinib arm. But overall the global quality of life is actually neutral in both the gefitinib and dacomitinib arms.
Allow me to summarise. I think this is the first randomised phase III study that compares second generation with a first generation TKI and was able to demonstrate an improvement in efficacy. The median progression free survival of 14.7 months is actually amongst the highest of all the randomised controlled studies on first line EGFR TKIs. Yes, we do have high toxicity due to the high inhibition associated with diarrhoea and skin rash but then on the gefitinib arm there seems to be more of the hepatic toxicity. Overall we do require dose reduction to accommodate the tolerability of the dacomitinib and this has been done relatively successfully. At the end of the day we have one additional choice. In my personal opinion dacomitinib should be one of the new so-called options to be considered as a first line treatment for patients with the EGFR mutation. Thank you very much for your attention.
