Medicine Matters oncology

During the annual ESMO meeting 2020, we presented the overall survival analysis of the SOLAR-1 trial. SOLAR-1 is a randomized trial testing the efficacy of alpelisib in patients with hormone-receptor-positive, HER2-negative, PIK3CA-mutant metastatic breast cancer pretreated with endocrine therapy.

We previously reported that alpelisib improves PFS by five to six months with a hazard ratio of 0.65, the median PFS moving from 5 months to 11 months in patients with hormone-receptor-positive, HER2-negative, PIK3CA-mutant metastatic breast cancer. There was no effect on patients without PIK3CA mutation.

Now we reported the overall survival data. What are the key message? First, the median OS is increased by 7.9 months. Nevertheless, this increase is a numerical increase, but is not statistically significant, the p-value being 0.15. The hazard ratio was 0.85.

We then looked at some subgroups. First, we look at the group of patient with liver and/or lung metastases. That was a stratification factor. In this group of patients, there was a large numerical increase in the median overall survival of around 14 months.

We also observed an increased OS in the group of patients where the PIK3CA mutation could be detected by ctDNA. All these results converge to a hypothesis that will be that patients with a more aggressive disease and presenting PIK3CA mutation will be the ones deriving more benefit from this drug [INAUDIBLE] targeted therapy, creating an oncogene addiction.

So the next step on the development of PI3-kinase inhibitor, first, have an optimal scientific exploitation of SOLAR-1. First thing, to derive a predictor of benefit of alpelisib, what are the molecular and genomic determinants of the benefit? Second, thanks to some analysis after treatment, understand what are the mechanisms of resistance. So these two data can be derived from SOLAR-1 and will drive further development.

What are the next steps for alpelisib? First, we have the BYLieve study that is confirming the efficacy post-CDK4/6. Second, can we move the drug earlier in the disease like in first-line sitting in patients who are refractory-- who are predicted to be refractory to endocrine therapy? Third, combined with drugs that could reverse resistance, that are the three short-term perspectives for alpelisib.

Then, looking broader at the field, what are the other things coming? First, can we have new generation of PI3-kinase that would be even more specific of the mutation? Second, which combination is going to synergize with PI3-kinase inhibitor? And, again, this will come from the analysis of mechanisms of resistance and predictors. And the question three, again, that is broader is how can we better manage and predict toxicity.