Dear friends and colleagues, my name is Matteo Lambertini, I’m a medical oncologist and adjunct professor in medical oncology at the University of Genoa, San Martino Hospital in Genoa, Italy. Today it’s a great pleasure to discuss with you what are, from my perspective, the most important news in the breast cancer field that have just been presented at the ESMO 2020 conference. Despite this was a virtual event so we didn’t have the chance to meet in person, this was an exciting conference for the breast cancer track. We had the presentation of many important and practice changing clinical trials and I believe that the most important news are for patients with triple negative breast cancer in both the early as well the advanced setting and similarly for patients with hormone receptor positive, HER2 negative disease, again in both the advanced as well as in the early setting.

The ASCENT trial

I will start first with the triple negative breast cancer, starting with the advanced setting and with the presentation of what, from my perspective, has been the most important trial and the most awaited trial in the advanced setting which is the ASCENT trial. This is the registration trial for sacituzumab govitecan which is a new antibody-drug conjugate, anti-Trop-2 which is a marker highly expressed in breast cancer, particularly in triple negative disease. The chemotherapy agent linked to the antibody is SN-38 which is a derivative of irinotecan and more potent than irinotecan. This drug has already provided important data in terms of clinical activity with the phase I/phase II trial that was published in The New England Journal of Medicine a couple of years ago in a heavily pre-treated patient population.

The ASCENT trial was the phase III randomised trial in this specific population, so triple negative disease, heavily pre-treated patients that were randomised. More than 500 patients were randomised to receive sacituzumab govitecan or single agent chemotherapy of physician’s choice that could be eribulin, gemcitabine, vinorelbine or capecitabine. As already mentioned, this was a heavily pre-treated patient population, all the patients received a median number of four prior lines of therapy and we all know what this means in the triple negative disease setting. All the patients received prior taxane, 80% prior anthracycline, 65% prior carboplatin or capecitabine, around 30% prior immune checkpoint inhibitors and a bit less than 10% also single agent PARP inhibitor.

The trial was highly positive favouring sacituzumab govitecan as compared to standard chemotherapy. The performance of standard chemotherapy was quite poor as we expect in such a pre-treated patient population. The median progression free survival was 1.7 months in the chemotherapy arm as compared to 5.6 in the sacituzumab govitecan arm so around 4 months absolute difference in median progression free survival with a hazard ratio of less than 0.5 and similar hazard ratios in terms of overall survival and almost a doubling in the median overall survival from 6.7 to 12.1 with sacituzumab over chemotherapy alone. The drug was quite well tolerated with no major safety signal. The most important adverse events were haematological toxicities with around 60% grade 3/4 neutropenia that required the use of GCSF in a significant proportion of patients. Anaemia and diarrhoea were other side effects but there were no other major important side effects. One of the potential alarming side effects that we have observed with other types of agent like lung diseases, this was not observed with this drug.

So I believe that these are potentially practice-changing data and we hope to have soon available this drug for offering to our patients. There are already trials ongoing to try to move this drug a bit earlier on, so in less heavily pre-treated patients. I believe this can be really a very important molecule for the management of our patients.

IMpassion130 and IMpassion131

The other two randomised trials presented in the advanced setting for triple negative disease are first line treatment trials with the use of immune checkpoint inhibitors. The first is the final survival analysis of the IMpassion130 trial, the study that led to the approval of the combination of nab-paclitaxel plus atezolizumab as first line treatment of triple negative breast cancer patients with PD-L1 positive disease. The trial has been already published in The New England Journal of Medicine, updated in Lancet Oncology and now we have the presentation of the final survival analysis.
The trial confirmed that the benefit of adding immune therapy to chemotherapy was observed only in patients with PD-L1 positive disease with no difference and no benefit in patients with the PD-L1 negative tumours. The difference was around 7.5 months in terms of absolute difference in median overall survival with the addition of atezolizumab to chemotherapy. The three year overall survival was around 36% for the atezolizumab arm as compared to 22% for the chemotherapy alone arm.

In the same session, however, we had the presentation of another first line treatment trial, very similar design, just a bit less patients included. There were 900 in the Impression130, a bit more than 600 in the Impression131. In this trial the randomisation was chemotherapy with or without atezolizumab as in the other trial but the chemotherapy backbone was different. In this trial it was paclitaxel as compared to nab-paclitaxel in the 130 trial.

The results actually were in the different direction as compared to the prior trial because there was no benefit of adding immune therapy, so atezolizumab, to single agent paclitaxel in this trial, no difference in progression free survival, no difference in overall survival. There was no difference also in the PD-L1 positive patient population. Actually in terms of overall survival there was a trend towards a worse overall survival for patients that received the immunotherapy in addition to paclitaxel with around 6 months absolute difference in median overall survival in the PD-L1 positive patient population favouring chemotherapy over chemotherapy plus immune therapy.

So putting these results in the context of the other available data, including the KEYNOTE-355 trial with pembrolizumab added to nab-paclitaxel, paclitaxel or gemcitabine/carboplatin, we have to pay more attention to the type of chemotherapy agent that we combine with immune therapy. We need more research effort in this field to try to better understand which is actually the best chemotherapy partner in this setting. But, based on this data, we can say that actually the chemotherapy partner actually matters for the efficacy and the activity of the immune therapy in this disease.

IMpassion031

Moving to the early setting, triple negative disease, still speaking about immune therapy we had a presentation and publication simultaneously in The Lancet of the important results of the IMpassion031 trial which randomised patients with triple negative disease to receive a neoadjuvant treatment with chemotherapy with or without atezolizumab. The chemotherapy backbone was the same in both treatment arms consisting of twelve weekly cycles of nab-paclitaxel followed by four cycles of dose dense doxorubicin and cyclophosphamide given every two weeks. The trial demonstrated a significant improvement in pathological complete responses with the addition of immune therapy to chemotherapy, around a 17% absolute difference from 41% to 58%. Importantly, the benefit of adding immune therapy to chemotherapy was observed irrespective of PD-L1 status.

Looking at these results and putting them into context with the NeoTRIP trial results with the use of atezolizumab in addition to nab-paclitaxel carboplatin without the anthracycline portion in the neoadjuvant setting as well as the KEYNOTE-522 trial with pembrolizumab in addition to paclitaxel, carboplatin and AC or EC in the neoadjuvant setting, I think that what we can say is that probably there is a difference in the meaning and the value of PD-L1 status between the early disease and the advanced disease. While PD-L1 positivity is a predictive marker of sensitivity to immune therapy, it appears to be an important predictive biomarker of sensitivity to immune therapy in the advanced setting, this is not the case in the early setting. In all these trials there were no major differences in the benefit of immune therapy added to chemotherapy according to PD-L1 status.

The other important message is that probably, as already seen for the advanced setting, the type of chemotherapy that we use together with immune therapy actually matters also in the neoadjuvant setting. The NeoTRIP study without the anthracycline cyclophosphamide portion of chemotherapy did not show any difference in pathologic complete response rate while the highest number of pathologic complete responses have been observed with the chemotherapy backbone of the KEYNOTE-522 trial, so carboplatin plus paclitaxel followed by the dose dense anthracycline cyclophosphamide portion of neoadjuvant chemotherapy.

SOLAR-1 and FLIPPER

Moving now to the hormone receptor positive, HER2 negative disease and starting again with the advanced setting, two important randomised trials presented at this ESMO 2020 conference. The first is the overall survival update from SOLAR-1 which is the study that led to the approval of alpelisib, an alpha-selective PI3K inhibitor, in combination with fulvestrant for the patients with hormone receptor positive, HER2 negative, PIK3CA mutated breast cancer.

In this trial almost 600 patients were randomised to receive fulvestrant alone or fulvestrant plus alpelisib and they were stratified based on the presence or absence of PIK3CA mutation. The first results of the trial in terms of progression free survival showed no benefit of alpelisib in the PIK3CA negative patient population while a significant benefit, an improvement from 5.7 to 11 months median progression free survival, in the PIK3CA mutated population. At this ESMO conference the overall survival data has been presented and the drug showed to prolong by around 7.9 months in terms of absolute number the median overall survival that was 31.4 in the control arm and 39.3 in the experimental arm. The results did not reach statistical significance, however, I believe that this is highly clinically relevant, suggesting that this is an active drug in the PIK3CA mutated population that we would like to use as a second line treatment option in endocrine resistant disease. However, this is a big challenge in Europe and in my country considering that the EMA approval of this agent is only after progression to endocrine therapy as single agent.

Other important information from this trial – that it allowed to delay the time to chemotherapy by around 8.4 months.
A second randomised trial, this was a second randomised trial but a phase II study, was presented for the endocrine sensitive population, so first line treatment in postmenopausal patients with hormone receptor positive, HER2 negative disease by the GEICAM group. It’s called the FLIPPER trial that included a bit less than 200 patients randomised to receive fulvestrant alone or fulvestrant plus palbociclib in the endocrine sensitive setting.

The trial showed a significant improvement in progression free survival with the addition of palbociclib to fulvestrant with a one-year progression free survival that went from 71.9% to 83.5% and this was the primary endpoint. The median progression free survival was increased by around 10 months from 22 to almost 32 months with a hazard ratio of around 0.5.

Despite being a small study, this adds more information on the potential role of the combination of fulvestrant plus a CDK4/6 inhibitor in the endocrine sensitive population together with the PARSIFAL and the MONALEESA-3 trial. I believe that this is a treatment option we have and that we should use in the clinic but probably not to all patients with endocrine sensitive disease. It calls for thinking about what could be the next treatment line.

PALLAS and monarchE

In the hormone receptor positive, HER2 negative disease the most important news during ESMO 2020 were presented in the early breast cancer track with one presentation in the Presidential session and the other in the oral session. These are the two adjuvant trials of CDK4/6 inhibitors - the first, the PALLAS, with the use of palbociclib and the second one, the monarchE with the use of abemaciclib. The trial design of these two trials was very similar in terms of randomisation to endocrine therapy alone, that could be tamoxifen, AI, with or without LHRH analogue in the case of premenopausal status and the randomisation was endocrine therapy alone with or without two years of CDK4/6 inhibitor, that was palbociclib in PALLAS and abemaciclib in monarchE. The sample size was also quite similar – more than 5,600 patients included in both trials.

The main differences were in terms of patient characteristics with those included in monarchE being at higher risk as compared to those in PALLAS.

Starting with PALLAS, the majority of patients, around 60% of patients, had the so-called high clinical risk meaning that more than four or four positive nodes or patients with less than four positive nodes with large tumour or grade 3 tumours. But still there were around a bit more than 10% of patients with node negative disease and almost 50% of patients with 1-3 positive nodes. Around 80% of the patients had received prior chemotherapy, so still 20% did not. In the majority of the cases, almost 70% of cases, the endocrine therapy partner was an aromatase inhibitor.

The study was negative so at this analysis there was no difference in survival outcomes between patients who received endocrine therapy alone or endocrine therapy together with palbociclib with a three year invasive disease free survival of around 88% in both treatment arms and a distant relapse free survival of around 90% in both treatment arms, no difference between the two treatment options.

Different results in the monarchE trial, that was actually a positive trial and made it to the Presidential session. It was simultaneously published in The Journal of Clinical Oncology. The main difference in terms of patients included in this trial were that the patients were at higher risk of disease recurrence. In this case patients had to have four or more than four positive nodes and for patients with 1-3 positive nodes they had to have at least one other bad disease feature, in terms of large tumour, T3/T4, high Ki67 or grade 3 tumour. Actually the majority, more than 60%, had N2/N3 disease. Similarly, the majority received prior chemotherapy – 95% of the patients. Similarly to the PALLAS trial the most used endocrine agent was an aromatase inhibitor, that was in around 60% of the patients.

In terms of results, the addition of abemaciclib significantly increased both the invasive disease free survival as well as the distant relapse free survival. In terms of invasive disease free survival there was a hazard ratio of 0.75, so 25% reduction in developing an invasive event. Around 3.5 absolute difference in two-year invasive disease free survival from 88.7 to 92.2. A similar benefit was observed in terms of distant relapse free survival which is highly relevant in this patient population, high risk patient population, with a hazard ratio close to 0.72. Again, around a 3% difference from 90.3% of two-year distant relapse free survival in the endocrine therapy alone arm, to 93.6% in the CDK4/6 inhibitor arm. In this case the most important side effect was diarrhoea in 80% of the patients but in most of the cases of G1/G2 grade.

I think that there will be a lot of discussion in the coming months and years on why the two trials show different results but two possible explanations are that first we have a different patient population – it was a much higher risk for the monarchE as compared to the PALLAS trial. The other important difference is the discontinuation rate with more than 40% of the patients in PALLAS discontinued the CDK4/6 inhibitor before the two years of treatment while the discontinuation rate was less than 10% as compared to PALLAS in the monarchE trial.

Irrespective of the results that we have, so one negative, one positive trial so far, I think therefore both of these trials are highly relevant and highly important to collect long-term follow-up data because these are patients with high risk hormone receptor positive breast cancer that have a significant risk of recurrence also beyond five years. So long-term follow-up is highly important in this field.