ESMO 2022 has been a great conference, including for breast cancer. Maybe we did not have huge news in the breast cancer field but still some important news to be discussed in both the early and advanced setting. I will focus on trial updates. We always require long-term follow-up data from the trials and here, indeed, we had some important updates from phase III trials in both the early and advanced setting.
Starting from the advanced setting, I will start with the MONARCH 3 trial, which is probably the oral presentation we were expecting the most from this conference because we have already available in our clinical practice abemaciclib and we have also available the other CDK4/6 inhibitors palbociclib and ribociclib in this setting. At the ESMO 2022 conference we had the overall survival update from this trial. Just briefly to remind that this was a phase III trial in patients with hormone receptor positive/HER2 negative breast cancer with endocrine sensitive disease that were randomised to receive endocrine therapy alone with aromatase inhibitors with or without abemaciclib. We know that all the trials met their primary endpoint of progression free survival and earlier this year the New England publication for the MONALEESA-2 trial with ribociclib in the same setting meeting the overall survival again in a significant way. We had the presentation at ASCO of PALOMA-2 data that despite showing a PFS benefit did not show an overall survival benefit.
MONARCH 3: Interim overall survival results of abemaciclib plus a nonsteroidal aromatase inhibitor in patients with HR+, HER2- advanced breast cancer
In the MONARCH 3 trial, this was an interim analysis, so it’s not the final analysis, at a median follow-up of beyond five years. The trial showed a median overall survival of 67 months for patients treated with abemaciclib plus endocrine therapy, as compared to around 55 months in patients receiving endocrine therapy alone. So it’s around a one year gain in median overall survival with a p-value of 0.03 which is not statistically significant according to the trial design. To me, from a clinical perspective, I would say that this is very relevant information to be shared with my patients in clinical practice, this one year overall survival gain, from a clinical perspective but, of course, I’m looking forward to the final overall survival results when we can really make also statistical consideration of this study. So we should consider still these results as not the final ones from this trial.
One important information coming out from this trial is also the updated curve for progression free survival. We know that the trial met its primary endpoint, it was presented and published several years ago, but here the authors have updated also the PFS data at a median follow-up of 5.8 years. What they show is a doubling in the progression free survival but, most importantly, we are seeing what happens five years after diagnosis of metastatic disease where we see that we have 9% of the patients in the endocrine therapy alone arm that are progression free at the time of the five-year cut-off as compared to more than 25% in the abemaciclib arm. Meaning that we can also counsel our patients, saying that with this treatment option at the five-year cut-off we actually have one quarter, so one out of four patients, around 25% of the patients that are still free from progression which is, of course, highly relevant information to be discussed.
Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HRD/HER2- metastatic breast cancer
In the hormone receptor positive/HER2 negative field we had another important overall survival update from an antibody-drug conjugate, sacituzumab govitecan. It’s the TROPiCS trial in which patients with hormone receptor positive/HER2 negative pre-treated disease, pre-treated already with endocrine therapy and with several chemotherapy lines, were randomised to sacituzumab govitecan single agent as compared to chemotherapy single agent of physician’s choice. At the ASCO conference a few months ago we had the presentation of the progression free survival data – the trial met its primary endpoint showing an increase in PFS. At this ESMO conference we had the overall survival update from the trial and the trial, again, met also the overall survival endpoint in the sense that median overall survival moved from 11 months to around 14 months with this option, hazard ratio of 0.79 that was statistically significant. Before, of course, we could discuss about the clinical value of this data but still, despite being only three months, it’s still an important overall survival gain that we can see with these new treatment options.
The authors of the TROPiCS trial have also looked into the performance of this agent according to the HER2 status because we know that in the same patient population with HER2 low disease, meaning 1+, 2+ FISH negative, we have also another potential antibody drug conjugate that we can use, trastuzumab deruxtecan, that has shown incredible results in this setting. The mechanism of action of the antibody is completely different between the two treatment options so there is not really a strong rationale to test the performance of sacituzumab govitecan, which is an anti-TROP2 agent, in the HER2 zero or HER2 low disease. But still the order of the TROPiCS trial presented the performance of these agents in the different HER2 categories, showing that actually the performance gain in survival outcomes observed with this option, as compared with chemotherapy, is actually the same for patients with HER2 zero or 1+ or 2+ FISH negative disease.
Dose-dense adjuvant chemotherapy in early-stage breast cancer patients: End-of-study results from a randomised, phase III trial of the Gruppo Italiano Mammella (GIM)
Moving now to the early setting, also in this setting I wanted to highlight the trials that reported long-term outcomes which is something we always advocate, especially for patients with hormone receptor positive disease; to have a clear understanding of the efficacy of the treatment we need very long-term outcomes. We had two trials, the GIM2 study and the DATA trial, that presented a median follow-up beyond ten years.
I will start with the GIM2, the Italian trial that investigated actually two questions in terms of best adjuvant chemotherapy in patients with node-positive breast cancer, hormone receptor negative and hormone receptor positive disease. This was a four-arm, 2x2 factorial designed trial in which patients received four cycles of anthracycline-based chemotherapy that was EC or FEC and then four cycles of paclitaxel, 175mg/m2. Two randomisations, the first one was to receive 5FU, yes or no, together with EC in the first four cycles. The second randomisation was to receive these eight cycles of chemotherapy every three weeks, standard interval, or every two weeks dose dense.
The trial is a positive study in terms of disease free survival, it was also already published in The Lancet a few years ago and now at this ESMO we had the 15-year follow-up data from this trial in which the authors have shown a clear advantage for the dose-dense chemotherapy regimen as compared to the standard interval chemotherapy also at this long-term follow-up for both disease free survival and overall survival. It’s around 9% absolute gain in 15-year PFS for dose-dense chemo and around a 7% OS gain at 15 years with dose-dense chemotherapy. This benefit of dose-dense chemotherapy was observed in both patients with hormone receptor negative and hormone receptor positive disease, so including among those with luminal-like tumours.
For the second randomisation, the 5FU question, apparently there is no difference between the two comparisons receiving 5FU yes or no. So the main take-home message from this trial is that we can omit 5FU from the adjuvant or neoadjuvant chemotherapy setting and for patients with high risk disease, node positive disease, that are candidates to receive chemotherapy, including those patients with hormone receptor positive disease, dose-dense chemotherapy should be considered as the preferred treatment option.
Extended adjuvant aromatase inhibition after sequential endocrine therapy: Final results of the phase III DATA trial
The final abstract that I wanted to highlight is the DATA trial investigating in the long-term follow-up the efficacy of extended adjuvant endocrine therapy. This is a trial in which patients with hormone receptor positive disease that received 2-3 years of tamoxifen treatment were randomised to receive three additional years of anastrozole or six years, so extended duration. The trial was updated at this ESMO with DFS data beyond ten years showing a 3% absolute gain for the extended treatment arm. The result was not statistically significant, it was close to be but it was not statistically significant, however, if we put it into the context of the other available evidence, including the recently published GIM4 trial with a similar design, I think the main message is that in patients that received tamoxifen in the first two or three years of adjuvant endocrine therapy it is of benefit to use at least five years of AI. So it’s worth extending treatment up to seven or eight years max. Of course, the decision to extend the treatment depends on several factors, including the risk of recurrence, but these long-term data are providing further information on the potential relevance of this treatment option for some patients with hormone receptor positive disease.
So, again, ESMO 2022 – important news in breast cancer, particularly long-term follow-up for trials and now we are already looking forward to the next event, the San Antonio Breast Cancer Conference.