The 2020 San Antonio Breast Cancer Symposium has just come to an end. This has been a great conference despite the virtual format that we have been forced to have in 2020. Many important news have been presented; most of the data and most of my round-up will focus on the hormone receptor positive, HER2 negative subtypes with just a brief overview on the data in triple negative and the HER2 positive subtypes.
CDK 4/6 Inhibitor Trials
Starting with the adjuvant setting, we had a presentation of the update of three CDK 4/6 inhibitor trials. First, the monarchE study that updated the results previously published in the Journal of Clinical Oncology and presented at the ESMO 2020 conference with around five additional months of median follow-up for a total of 19 months of median follow-up. The study confirmed the benefit of adding abemaciclib for two years to adjuvant endocrine therapy. I remind that in this trial more than 5,600 patients with high-risk hormone receptor positive, HER2 negative breast cancer were enrolled, more than 60% of the patients had four or more than four positive nodes, and the other patients had between one to three positive nodes and other high-disease features, so this is the high-risk patient population. The invasive disease free survival at two years was improved by around 3% with the addition of abemaciclib to endocrine therapy. The same absolute benefit was observed in terms of distant relapse-free survival, 3% absolute difference, with a benefit that appeared to be consistent in all subgroups, with some interesting insights from a poster discussion session suggesting that a patient with luminal-B-like biology, so those patients with high Ki67, appears to derive the greatest benefit from the addition of abemaciclib in addition to adjuvant endocrine therapy, with around 5% absolute difference in invasive disease-free survival at two years.
On the other side we have two adjuvant palbociclib trials that have not suggested any improvement in survival outcomes with the addition of CDK4/6 inhibitor to adjuvant endocrine therapy. We had an exploratory analysis from the PALLAS trial, I remind this was a large trial with a very similar design as monarchE, more than 5,600 patients randomised to adding two years of a CDK4/6 inhibitor, in this case palbociclib, to adjuvant endocrine therapy. This trial was previously presented at ESMO suggesting no difference in survival outcomes. However, it was quite surprising to see a very high discontinuation rate. More than 40% of patients discontinued treatment and this was suggested as a potential explanation for the negative survival results observed in this trial as compared to monarchE.
At the San Antonio Breast Cancer Symposium we also have presented a kind of exploratory analysis to try to address this issue and to see if there were some signals of more activity and of a potential benefit of adding palbociclib to endocrine therapy in patients that actually received the treatment as planned before study inclusion. A per protocol analysis, or a landmark analysis adjusting for duration of exposure and actual exposure to treatment, did not suggest that palbociclib improved the outcomes of patients, so suggested that the high discontinuation rate is not probably a reason to explain the lack of improved survival outcomes in this setting.
With the same drug, palbociclib, we had the presentation of the Penelope-B trial, a very important study in the post-neoadjuvant setting. So it was a one-year adjuvant treatment with palbociclib with high-risk patients not responding well to neoadjuvant chemotherapy. This case was a very high-risk patient population and the trial is the first to report with a so long median follow-up, more than forty months of median follow-up. The trial did not show any significant difference between patients randomised to endocrine therapy alone or with the addition of palbociclib for one year. It’s interesting to note that in terms of invasive disease-free survival at two years, so the same survival outcomes as presented in monarchE or PALLAS, there was actually 4% absolute difference favouring palbociclib but this difference was not observed at four years where there was actually no survival difference between the two treatment options. This is something that strongly suggests the need to collect more long-term data also from the other adjuvant endocrine trials, and we are also waiting for the results of NATALEE with the use of ribociclib, in this case given for three years.
Early setting hormone receptor positive HER2 negative breast cancer
In the early setting for patients with hormone receptor positive HER2 negative disease there was another very important presentation, the RESPONDER trial, that wanted to look into the need to add adjuvant chemotherapy to patients with one to three positive nodes and hormone receptor positive HER2 negative disease, and a recurrence score with Oncotype DX of less than 25, so from zero to 25. More than 5,000 patients were randomised to receive or not chemotherapy in addition to endocrine therapy.
Overall there was an apparent benefit for chemotherapy of less than 2% absolute difference in invasive disease-free survival at five years, however when the result was broken down according to menopausal status there was a clear lack of difference, so a lack of improvement, with the addition of chemotherapy in post-menopausal women, same survival outcomes, no benefit with the addition of chemotherapy. On the contrary, in pre-menopausal patients, there was apparently a large benefit, around 5% absolute improvement in IDFS with the addition of chemotherapy to endocrine therapy.
However in this setting we have to consider that only a few patients, less than 20%, received ovarian function suppression, which we know can be important for high-risk patients. This result was observed irrespective of number of positive nodes, so one, two or three, as well as irrespective of the actual recurrence score, so same result from zero to 25. The main message is that in post-menopausal women with one to three positive nodes, hormone receptor positive, HER2 negative disease, recurrence score 25 or less, we can safely forego adjuvant chemotherapy in this setting.
Advanced setting hormone receptor positive HER2 negative breast cancer
In the advanced setting for patients with hormone receptor positive HER2 negative disease, some interesting data from the three MONALEESA trials biomarker analysis presented by Aleix Prat, suggesting that performing the PAM50 in the tumour sample of the majority of patients enrolled in these three MONALEESA trials. This analysis confirmed the prognostic value of the different PAM50-defined breast cancer subtypes. This analysis also confirmed that not all hormone receptor positive, HER2 negative diseases are luminal tumours when analysed on a transcriptomic level, but there was some tumours with a basal-like or a HER2-enriched biology. Despite the prognostic value of these different subtypes with the better survival for the luminal-A and then luminal-B HER2-enriched and worse for the basal-like subtypes, this analysis suggested that the benefit of the addition of ribociclib to endocrine therapy was observed in all PAM50-defined subtypes but the basal-like even though there were only few numbers on this and the sample size was too small in this specific subgroup. However, very interestingly, this analysis suggested that the highest and largest benefit was observed for the HER2-enriched subtype.
In the poster spotlight session, there was also presentation of updated overall survival data from the MONALEESA-7 trial, so the trial that investigated the addition of ribociclib to an aromatase inhibitor or tamoxifen in pre-menopausal breast cancer patients with ovarian function suppression. In the last New England publication the median follow-up was not reached in the CDK4/6 inhibitor arm. In this updated analysis the median overall survival was reached with an increase of ten months median overall survival with the addition of ribociclib to endocrine therapy to around 58 months median overall survival. Importantly, there was also a phase III presentation by the ECOG group on the use of entinostat in addition to endocrine therapy. The trial unfortunately was negative and did not suggest a benefit with the use of this agent.
There was a chemotherapy trial in this patient population with the use of a combination of capecitabine and an oral taxane called tesetaxel, as compared to capecitabine alone as first or second line chemotherapy in patients with hormone receptor positive HER2 negative disease. The trial was positive, suggesting a benefit with this dual chemotherapy combination with a benefit of around three months absolute improvement in progression-free survival, suggesting the possibility to have this new oral treatment option for our patients in this setting.
Triple negative breast cancer
For the other disease subtypes, there was less news presented. In the triple negative subtypes important data in the early setting are the patient-reported outcomes, data from the IMpassion031 trial suggesting no, the trial that showed that the addition of atezolizumab to neoadjuvant chemotherapy increases the PCR rates and that was published in the Lancet during the ESMO 2020 conference. At the San Antonio Breast Cancer Symposium the authors presented data suggesting that the addition of atezolizumab does not worsen the quality of life of our patients.
In the advanced setting, some important biomarker data from the ASCENT trial, so the study that shows great benefit and a significant improvement in survival outcomes, PFS and OS, with sacituzumab govitecan, the antibody drug conjugate, as compared to single-agent chemotherapy in heavily pre-treated triple-negative breast cancer patients. The trial was presented at ESMO and now at San Antonio the authors have presented the biomarker data suggesting that the benefit of this treatment was observed irrespective of the BRCA status, also in BRCA mutated breast cancer patients there was the same benefit with the use of this agent as well as irrespective of the expression of TROP2. I remind that sacituzumab is an anti-TROP2 antibody drug conjugate. In both patients with the TROP2 positive or TROP2 negative disease there was a benefit with sacituzumab as compared to the standard arm.
There was also a presentation of more data from the KEYNOTE-355 trial, the study that showed that the addition of pembrolizumab to chemotherapy as firs -line treatment is beneficial for patients with PD-L1 positive, triple negative breast cancer. It was very interesting to see which type of chemotherapy performed the best in this trial because three regimens could be used: the taxane paclitaxel alone, nab paclitaxel, or a combination of gemcitabine and carboplatin, and based on the IMpassion130 and IMpassion131 data and the different results with atezolizumab combined with paclitaxel or nab paclitaxel it was very interesting to see any signal in this direction also in KEYNOTE-355. However, the trial did not show that there was a different expected benefit with the addition of pembrolizumab with these three different types of chemotherapy regimen and could not show a worse performance of pembrolizumab if added to paclitaxel, so could not confirm the data with IMpassion130 and IMpassion131. Of course this was an underpowered exploratory analysis, however there was no signal in this analysis of a different performance of the three different chemotherapy regimens.
There was also a presentation of ipatasertib trial, so an AKT inhibitor added to paclitaxel as first-line treatment in triple-negative breast cancer patients with a PI3K, AKT or PTEN alteration. However the trial was negative and did not show any improvement with the addition of this AKT inhibitor to single-agent paclitaxel in this setting.
HER2 positive breast cancer
Finally, for the HER2 positive patient population we had data in the early setting from the DAPHNe trial, a study that tried to address the feasibility of a kind of strong regimen, meaning weekly paclitaxel/trastuzumab and the addition of pertuzumab in the neoadjuvant setting. This regimen is associated with around 57% pathological complete responses, so quite good PCR rates. This opens the doors to the possibility to de-escalate the chemotherapy burden, so remove the anthracycline portion to responding patients in the future. However, this trial did not present survival data and was underpowered to support this statement, but there are ongoing trials that are trying to assess if this regimen and if patients achieving PCR with this regimen can be spared the toxicity of anthracycline or further chemotherapy in the adjuvant setting.
There were also updated data from the ExteNET trial, the study that led to the approval of neratinib and extended anti-HER2 treatment in patients with HER2 positive disease. At this San Antonio the authors have presented updated survival data suggesting a potential overall survival improvement for the very high-risk patient population and also lower number of patients developing CNS, so brain metastases, in the neratinib arm as compared to patients not receiving neratinib.
In the advanced setting there were again some updates of previously published or presented trials. First the PERTAIN study, the trial that investigated dual anti-HER2 blockade trastuzumab and pertuzumab as compared to trastuzumab in patients with triple positive disease as first-line treatment or as maintenance treatment after induction chemotherapy. This trial was previously published in the Journal of Clinical Oncology and the updated analysis confirmed the same findings: benefit for dual anti-HER2 blockade in progression-free survival, only a trend in overall survival, it was not statistically significant and the better outcomes, PFS and OS, for patients that received first induction chemotherapy and then maintenance endocrine therapy.
Then we had data also from the HER2CLIMB trial with the addition of tucatinib to trastuzumab and capecitabine, showing and confirming the benefit of this triple combination. The benefit appeared to be larger in the hormone receptor negative patient population as compared to the hormone receptor positive population. The benefit with adding tucatinib to this regimen was observed irrespective of hormone receptor status, but there were some signals that there was an even higher expected benefit for the hormone receptor negative population.
Also we had some updated data from the DESTINY-Breast01 trial with trastuzumab deruxtecan in patients progressing on T-DM1 and this update confirms the important results of this trial in terms of progression-free survival as well as in terms of responses with this regimen.
This has been a great San Antonio with many important news, and we really hope that we can see and meet in person next year at San Antonio 2021.