The SOLAR-1 study is a phase III randomised trial that evaluated the efficacy of alpelisib, an α-selective PI3 kinase inhibitor, in patients with hormone receptor positive HER2 negative P3CA mutated metastatic breast cancer.
What were your methods?
In SOLAR-1 we included patients who were previously treated with endocrine therapy and presented with metastatic breast cancer. We had two different cohorts: the first cohort of patients that was the population of the primary endpoint were patients with P3CA mutated breast cancer. The other cohort was a cohort of patients without P3CA mutation where the mutation is defined as a mutation on exome 7, 9 and 20. The trial randomised fulvestrant plus placebo versus fulvestrant plus alpelisib given at 300mg/day. The primary objective was to show a benefit on progression free survival assessed by the investigators.
What were the results?
We previously reported in 2018 at the ESMO annual meeting that alpelisib improved progression free survival from 5 months to 11 months with a hazard ratio of 0.65 meaning that the trial met its primary objective. Then we reported that quality of life was not affected by alpelisib, so there was no detrimental effect on quality of life that was reported during conference. Now we just reported during the ESMO annual meeting 2020 results on overall survival. Overall survival was a secondary objective. The results showed that there is a numerical difference on median overall survival of 7.9 months between fulvestrant plus placebo and fulvestrant plus alpelisib in the group of patients with P3CA mutation.
This numerical difference was not statistically significant with a p-value of 0.15. The hazard ratio was 0.86. Interestingly, some subgroups of patients derived more benefit. For example, patients with liver and/or lung metastasis, that was a stratification factor, presented a numerical difference between the control and experimental arms of 14 months, that is higher than the overall population, suggesting that in this group of patients with aggressive disease alpelisib could have maybe a bigger impact on overall survival. We could also observe that in the group of patients with P3CA mutation detected by ctDNA the difference in median OS was 9 months.
Finally, the last result is the fact that alpelisib delayed the start of cytotoxic chemotherapy by 9 months, 8-9 months, meaning that patients who received alpelisib started chemotherapy 8-9 months after, again in patients with P3CA mutated breast cancer.
What are you concluding from these findings?
Our conclusions are that alpelisib improves progression free survival and this is clinically meaningful. There is no detrimental effect on quality of life, that reinforces the benefit that is observed on PFS. The numerical difference we see in overall survival supports the observation we previously made on the primary endpoint and supports the concept that alpelisib has a positive impact on patients with metastatic breast cancer, meaning that the difference we observed on PFS that is 5-6 months now translates in to a 7.9 month difference on median overall survival. So we translate the benefit on PFS onto OS. The lack of statistical significance is very likely due to the small sample size and the fact that the trial was not designed to address this endpoint.
What do you think will be the clinical implications of this study?
This data on overall survival reinforces the benefit-risk ratio and is one more additional piece in the puzzle to implement this drug to the group of patients with P3CA mutations. Also it raises the hypothesis that alpelisib has a really very strong impact on patients with more aggressive disease.