ASCO 2022, finally in person again, has been a great conference in the breast cancer field and I
would really like to mention a few important topics for advanced breast cancer, specifically ADCs and
CDK4/6 inhibitors. We had some important news to better address these two topics. I will start with
the most exciting one which is the ADC and particularly the plenary session that we had on Sunday
here at ASCO with the use of trastuzumab deruxtecan, so an ADC targeting HER2. But in this specific
trial, called DESTINY-Breast04 this drug has been investigated in patients with so-called HER2-low
breast cancer, meaning the HER2 negative disease but HER2 1+, 2+, FISH negative. Mostly patients
with hormone receptor positive disease, almost 500 patients with this subtype, and around 60 patients
with triple negative breast cancer.
This was a trial in which patients received at least one chemotherapy line for advanced breast cancer,
so it was a pre-treated population, not particularly heavily pre-treated. This trial randomised patients
to receive this ADC as compared to standard chemotherapy, single agent chemotherapy that could be
capecitabine, gemcitabine, eribulin or nab-paclitaxel/paclitaxel. The results are extraordinary – there
was a big standing ovation of the presentation of these results – they were published simultaneously
in The New England Journal of Medicine. So what the study demonstrated was a doubling in
progression free survival from five months median PFS with chemotherapy alone to ten months, a
hazard ratio of 0.51, something that is not very common to see in oncology in general, not only in
breast cancer. Then also a significant benefit in overall survival – around 6.5 months median OS
difference between chemotherapy alone, 17.5 months median OS, to almost 24 months median OS
with the use of the ADC. So these are really practice-changing data. We really hope to have these
drugs as soon as possible available for our patients with HER2-low disease.
This is a drug that is already available in clinical practice for patients with HER2 positive disease; we
have several studies that have shown major benefit with the use of this agent in the HER2 positive
field. At this ASCO we had some updated information on the safety profile of this drug which is
different as compared to T-DM1, so the ADC that we have been using for now a quite long time in
breast cancer. So we had the safety data in the long-term follow-up from the DESTINY-03 trial which
is the randomised trial in the HER2 positive setting which placed this drug as our current standard
second line option in patients with HER2 positive disease progressing on the CLEOPATRA regimen,
so taxane, trastuzumab, pertuzumab. These safety data are particularly relevant because this drug
needs some more attention in terms of managing the medication as compared to T-DM1. Specifically,
the most important side effects are nausea – almost three-quarters of patients, so three out of four
patients, develop nausea, around 10% grade 3, a bit less than 10% grade 3. This requires antiemetic
prophylaxis so we need to consider this agent as a moderate to high emetogenic drug. The second
important safety information in the long term was the lung toxicity because there are reports in the
clinical trials of potential, also fatal, events in terms of lung toxicity. Around 10% of the patients
developed this toxicity that could be G3, so quite important for the patient in a few patients. So this
requires closer monitoring of these drugs. So when we look at the CT scan that patients are doing to
reassess the disease we need to talk to the radiologist to really check also the lung, irrespective of the
cancer assessment, also in terms of this pneumonia, pneumonitis, that can develop during the drug
just to be sure that we recognise early the grade 1 toxicity which is the asymptomatic toxicity. What
we have seen in this long-term analysis is that this toxicity appears usually in the first six months of
use of the drug. So we need to pay particular attention in the first months of treatment.
In the ADC world we had another two important oral abstract presentations. We start with probably
the most important of the two which is the TROPiCS-02 trial. This is a phase III trial that randomised
patients with hormone receptor positive, HER2 negative disease, so a similar population as the
DESTINY-04 but it’s not only the HER2-low, it’s the real HER2 negatives, also HER2 0, that were
randomised to receive chemotherapy of physician’s choice, single agent chemotherapy, as compared
to another ADC, sacituzumab govitecan, that is already available for triple negative breast cancer
There are a few differences of this trial as compared to the DESTINY-04. First, the chemotherapy
agents that could be used – capecitabine, gemcitabine, eribulin and vinorelbine, not a taxane – and
then this was a more heavily pre-treated patient population. So the median lines of chemotherapy that
patients received in the advanced setting was three as compared to one in DESTINY-04. So this is
important also to interpret the results.
The results are positive in the sense that the trial met its primary endpoint, showing a significant PFS,
progression free survival, benefit for patients receiving the ADC versus chemotherapy. But in terms of
how clinically meaningful was this result, probably a bit less positive than the p-value itself or the
primary objective itself, in the sense that the ADC demonstrated a 1.5 month improvement in median
PFS which is something that, of course, if we indirectly compare to the DESTINY-04 data is, of
course, much less relevant in terms of potential advantage.
The other trial that was presented in this setting was a phase I/II trial with another ADC, patritumab
deruxtecan, in patients with hormone receptor positive, HER2 negative disease, triple negative breast
cancer and a few patients also with HER2 positive disease. Very preliminary data but an interesting
objective response rate between 20-30% in triple negative and hormone receptor positive disease,
more than 40% in the HER2 positive set.
So we have many ADCs coming now to the clinic, the main question we have right now is how to
sequence these drugs, do we need more than just one agent as we have for chemotherapy in terms
of sequencing? So having more of these agents will be relevant to improve the care of our patients in
terms also of maybe toxicity profile which, in some cases, is different as compared to chemotherapy.
Moving to the other topic, which is CDK4/6 inhibitor in patients with advanced hormone receptor
positive, HER2 negative disease. This is now our standard of care in the endocrine sensitive,
endocrine resistant disease. But here at ASCO we had two important presentations to mention. One
is the PALOMA-2 overall survival data. PALOMA-2 is a trial in the endocrine sensitive setting that
randomised patients to receive aromatase inhibitor with or without palbociclib, first line endocrine
sensitive disease. These data are particularly relevant because it is a few years that we are
discussing if these three CDK4/6 inhibitors are the same or there are differences. There are some
pharmacological differences but in terms of progression free survival the results are very similar in the
endocrine sensitive endocrine resistant settings with all three agents.
But now we start to have overall survival data, we have positive OS data from ribociclib in this setting.
We start to have some positive data also with abemaciclib so the palbociclib data were much awaited,
also to decide which agent to be used and to be discussed with our patients. Unfortunately, these
data were negative, meaning that there were no overall survival benefits with the addition of
palbociclib on top of endocrine therapy. So this is a bit complicated to interpret because the PFS data
gains of this trial were exactly the same as compared to what we have seen with MONALEESA-2 or
MONARCH 3, so the other two trials with ribociclib and abemaciclib in the same setting. This is
something that is very important to be discussed with our patients at the time we prescribe a CDK4/6
inhibitor in addition to endocrine therapy. So it’s not only a matter of a different toxicity profile, a
different way we administer the three agents but also in terms of different efficacy results that we are
seeing with these agents.
In the same topic, the final abstract that I wanted to discuss is the MAINTAIN trial which is a small
phase II trial but with a very important and critically clinically relevant question which is what to do
beyond CDK4/6 inhibitors, so in patients that progress on endocrine therapy plus a CDK4/6 inhibitor.
The question that the trial wanted to answer is if it’s relevant to use a CDK4/6 inhibitor in patients
progressing on a CDK4/6 inhibitor, so using these agents beyond progression as we do for anti-HER2
therapy. So this was a randomised trial in patients progressing on endocrine therapy and a CDK4/6
inhibitor, randomising patients to switch endocrine therapy single agent or switch endocrine therapy
and continue a CDK4/6 inhibitor and in this case it was ribociclib.
The trial was positive, it met its primary endpoint – 2.5 month gain in median progression free survival
– with an interesting 0.57 hazard ratio which is quite interesting, quite nice results to see. Of course,
it’s a small trial, we have to await other studies ongoing in the same setting and with a similar design
that will provide more evidence in this regard. But this trial clearly shows that these patients, so
patients progressing on CDK4/6 inhibitor and endocrine therapy, have quite an aggressive disease.
So the median PFS of patients receiving endocrine therapy alone, progressing on first line CDK4/6
inhibitor, was quite poor, it was around 2.5 months median PFS, less than three months meaning that
this is a population where we really need to do something more than just endocrine therapy. These
are additional data to support that maybe adding targeted agents to endocrine therapy can be helpful
in these specific patients.
So overall going back from ASCO 2022, we have important news to share with our patients already
on Monday morning for clinical practice. But also some drugs like trastuzumab deruxtecan that we
hope to have very soon to improve the care of patients also with hormone receptor positive, HER2-
low, so HER2 negative but HER2-low, disease which is something extraordinary that we really hope
to have available very soon.