Mafalda Oliveira, MD, PhD, on Primary Results of SOLTI VALENTINE

This is a trial testing HER3-DXd, an anti-HER3 antibody drug conjugate, either alone or in combination with Letrozole, and standard multi-agent chemotherapy in high-risk HR-positive, HER2-negative early breast cancer. This trial was based on the prior results of the SOLTI TOT-HER3 trial, where we observed that one dose of HER3-DXd induced an increase in the CelTIL score. That is a score that looks at the high infiltration of immune cells and decreased tumor cellularity in patients with HR-positive, HER2-negative early breast cancer. Also, we observed a very nice correlation with this biological outcome and response. So, in SOLTI VALENTINE, the objective of the trial was to look at the PCR rate of HER3-DXd, either alone or in combination with letrozole. And we also included a control arm from standard multi-agent chemotherapy in order to include the right patient population in the trial. Patients had six cycles of HER3-DXd, or a combination with letrozole, and then underwent surgery. And tumor was collected at baseline, cycle two, day one, and also at surgery. 122 patients were included in the trial. The randomization was 2:2:1. So, around 100 patients, more or less, were included in HER3-DXd arms and 20 more patients were included in the control arm. What we observed in SOLTI VALENTINE is that HER3-DXd, either alone or in combination, has led to comparable PCR rates and overall response rates as multi-agent chemotherapy based in anthracyclines and taxanes. This is an interesting result also because although the pathological complete response rates were low, we observed a significant decrease in grade 3 or higher adverse events in the HER3-DXd arms. There were also less treatment discontinuations, less dose reductions and dose interruptions in patients treated with HER3-DXd. Mainly the side effects observed with this drug were GI, as expected. But in the multi-agent chemotherapy arm, there was a high proportion of grade 3 hematological adverse events that were not present with HER3-DXd. And there were no ILD cases observed. This is also an important point. And respect to the biological activity of HER3-DXd in this population, we observed a very nice reduction in Ki-67 from baseline to cycle two, day one, and also at the time point of surgery, especially in the HER3-DXd plus Letrozole arm, and also reduction or a change in the biological profile of these high-risk tumors from more proliferative at baseline to less proliferative luminal A and normal-like subtype at the time of surgery. And we also mirrored the results of TOT-HER3 in the sense that in the HER3-DXd arms, there was also an increase in CelTIL that correlated very well with response rates. So, as a summary, I would say that for SOLTI VALENTINE, HER3-DXd has led to a comparable PCR rates and overall response rates as multi-agent chemotherapy with significantly less side effects. And we believe these results support the future development of this drug in high-risk early HR-positive, HER-II-negative breast cancer.