Breast cancer roundup from ASCO 2021

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Published: 18 Jun 2021
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Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy

Dr Matteo Lambertini provides ecancer with a roundup of the most important breast cancer research from ASCO 2021.

Dr Lambertini provides detailed information on the following trials:

- OlympiaA
- ECOG-ACRIN EA1131
- GeparNuevo
- ADAPT HER2+/HR-
- PALOMA-3
- MONALEESA-3
- DAWNA-1
- SYSUCC-002

Dear colleagues and friends, it is a great pleasure to share with you some of my main take home messages from the ASCO 2021 conference. It has been a difficult year, we all know all the difficulties that we had to face over the past year and, despite that this is the second conference taking place online only, it’s really nice to see that cancer research has progressed despite all these difficult times. Many important news have become available to improve the care of our patients. In the breast cancer track at the ASCO 2021 conference we have heard many important news in this regard.

I have decided to select only two main take home messages from each of the different settings – adjuvant, neoadjuvant and metastatic – starting, for obvious reasons, from the adjuvant setting. The obvious reasons are that we all know that the OlympiA trial has been presented in the plenary session of the conference and simultaneously published in The New England Journal of Medicine. This is a much awaited trial because we had the positive press release a few months ago. In this study BRCA carriers that completed adjuvant or neoadjuvant chemotherapy and had a high risk of disease recurrence in HER2 negative disease were randomised to receive one additional year of treatment with a PARP inhibitor or placebo. More than 1,800 patients were included, most of these patients had BRCA1 pathogenic variance, more than 70% of them; 80% of them had triple negative disease; half of them received adjuvant chemotherapy the other half neoadjuvant chemotherapy; most of the cases, almost 94% of the cases, anthracycline taxane based chemotherapy with a platinum agent that was used in around a quarter, 25%, of the patients.

Both the adjuvant and neoadjuvant setting could be enrolled in the study with specific inclusion criteria for the triple negative setting or for the hormone receptor positive, HER2 negative setting in the two different scenarios. For the neoadjuvant setting patients with triple negative breast cancer could be enrolled if no pCR; for the luminal population a much higher risk than no pCR itself had to be satisfied to be enrolled with a CPS+EG score of more than 3, equal or more than 3. For the adjuvant setting, again a high risk patient population, for the luminal part four or more than four positive nodes; for the triple negative part a tumour larger than 2cm and/or node positive disease.

The trial reported the results at an interim analysis at 2.5 years median follow-up showing a significant and clinically meaningful improvement in invasive disease free survival at three years with a gain of 8.8 absolute different at three years, a hazard ratio of 0.58. Very similar findings in terms of distant relapse free survival – 7.1% absolute difference at three years, 0.57 hazard ratio. In terms of overall survival, so far no significant difference between the two treatment arms with the curves starting to separate and around 4% absolute gain for the olaparib arm but that was not statistically significant.

In terms of side effects we observed the known side effects of PARP inhibitors – fatigue, nausea and mostly haematological toxicity. The grade 3/4 events that have been experienced were mostly haematological toxicities in terms of anaemia, for example. But these side effects apparently did not worsen the quality of life of patients with the preliminary data from the patient reported outcome analysis showing no difference between the two treatment arms. Apparently there is also no difference between the placebo and the olaparib arm in terms of myelodysplastic syndromes or acute myeloid leukaemias that are some side effects potentially related to the use of PARP inhibitors for a long period of time.

These results are, for sure, practice changing and very important and the first change in our clinical practice from these results is that probably we need to test all patients with HER2 negative disease, early breast cancer, high risk of recurrence according to the criteria of the OlympiA trial for BRCA. So we are moving towards a kind of universal BRCA testing and this is something that will change a lot the way we approach the care of patients in the early setting. However, it’s very important to highlight also that we need long-term follow-up. 2.5 years is an interim analysis, we need long-term follow up data to see potential differences also in survival to interpret better the subgroup analysis, also the potential benefit for the hormone receptor positive cohort, for patients that were previously exposed to platinum-based chemotherapy. Importantly, the long-term follow-up is particularly relevant to collect the data on second primary malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia.

The second important study presented for the adjuvant setting that was presented and simultaneously published in The Journal of Clinical Oncology is the ECOG-ACRIN EA1131 trial, a study for triple negative breast cancer patients that received neoadjuvant treatment and for whom pCR was not achieved. The trial was first a three-arm study – observation, capecitabine versus platinum-based chemotherapy, single agent cisplatin or carboplatin for four cycles. Then after the publication of the CREATE-X trial results the observation arm has been closed and so the trial became a direct comparison between capecitabine versus platinum-based chemotherapy as post-neoadjuvant treatment, so in patients without pCR following surgery. So a high risk patient population, slightly more than 300 patients included because the trial stopped the accrual when at one of the interim analyses no difference was observed between the two treatment arms and the trial was unlikely to show any difference.

Importantly, this trial was designed first as a non-inferiority study of platinum versus capecitabine and then if the non-inferiority was met a superiority hypothesis would have been tested. Based on this data three-year outcomes were very similar between the two treatment arms with no difference between capecitabine and platinum-based chemotherapy. The non-inferiority was not met and it’s interesting and also worrisome to see the outcomes of these patients with less than a 50% rate of invasive disease free survival at three years. So a setting for whom we really need additional options to improve the care of these patients. Other trials also investigating the use of platinum-based chemotherapy in the adjuvant setting are currently ongoing.

Moving to the neoadjuvant setting the two studies that I have selected are first the GeparNuevo trial. The survival outcomes from this study, a phase II trial from the German group, in which patients with triple negative disease received a neoadjuvant treatment with a taxane base, an anthracycline, cyclophosphamide-based chemotherapy with the addition of durvalumab versus placebo. The patients, slightly less than 200 patients, received first weeks of durvalumab or placebo then this treatment in addition to nab-paclitaxel for twelve weeks and then in addition to four cycles of epirubicin cyclophosphamide given in a dose dense fashion, so every fourteen days before surgery. The primary endpoint of the trial was pCR and the study did not meet its primary endpoint because there was only a numerically higher but not statistically significant increase in the pCR rate between the two treatment arms and these data were published in 2019 in Annals of Oncology.

At ASCO 2021 the authors presented the survival outcomes at more than 40 months median follow-up and the three year outcomes show a significant improvement favouring the durvalumab arm in all the analysed outcomes – invasive disease free survival, distant disease free survival as well as overall survival. This benefit was observed independently of PD-L1 status and this is important and different from what we see in the advanced setting. And apparently, and this is interesting to see, the patients with pCR in the durvalumab arm did much better than patients with pCR in the placebo arm, so in the no immunotherapy arm.

We are now waiting for the KEYNOTE-522 survival trial results with the survival outcomes that will be presented soon at one of the upcoming conferences. For this trial we already have a positive press release suggesting that the addition of pembrolizumab to neoadjuvant chemotherapy increases significantly survival outcomes of these patients but to what extent we need to see the upcoming results.

The other trial that I have selected is the survival outcomes from the ADAPT HER2+/HR- setting. In this study this was a phase II randomised trial in which patients with HER2 positive, hormone receptor negative disease were randomised to receive a neoadjuvant treatment for twelve weeks of dual anti-HER2 blockade alone, pertuzumab trastuzumab, or dual anti-HER2 blockade, pertuzumab trastuzumab, plus paclitaxel. The trial reported in 2017 in Annals of Oncology the pCR rate showing that more than 90% of patients in the taxane group achieved a pCR and almost one-third, more than 30% of patients in the no chemotherapy arm achieved a pCR. Most of the patients achieving a pCR in the Taxol arm did not receive further chemotherapy following surgery while the majority, around 70%, of patients in the dual anti-HER2 blockade alone arm received adjuvant chemotherapy following surgery. So with this caveat in mind that we really do not know to what extent the adjuvant chemotherapy has played a role in this regard, but the authors reported five year outcome results with very good outcomes, particularly in the Taxol arm with a distant disease free survival and overall survival of 98% in the Taxol trastuzumab pertuzumab arm, suggesting that the ongoing trials investigating the de-escalation of chemotherapy using the neoadjuvant setting and pCR as a way to select those patients to de-escalate their treatment could be a very reasonable approach. We are waiting for the phase III trial results.

In the advanced setting the first topic to be discussed is a CDK4/6 inhibitor for which we had three oral presentations, updated overall survival data from the PALOMA-3 trial, the study investigating fulvestrant with or without palbociclib in the endocrine resistant population and the overall survival data of MONALEESA-3 of fulvestrant with or without ribociclib in an endocrine sensitive and endocrine resistant population. In both trials the addition of a CDK4/6 inhibitor improved overall survival and it was interesting to note that the more endocrine sensitive the disease the larger the expected benefit of the addition of a CDK4/6 inhibitor. So we are really looking forward at one of the upcoming conferences to the presentation of the first line setting in the trials, focussing on the endocrine sensitive, on the purely endocrine sensitive population, receiving AI plus CDK4/6 inhibitor like the MONALEESA-2 and the MONARCH 3 data.

However, we did not only have MONALEESA-2 and PALOMA-3 updates but we also had a presentation of the first data of the DAWNA-1 trial with the use of a new CDK4/6 inhibitor, so a fourth CDK4/6 inhibitor, dalpiciclib. This trial was conducted in the endocrine resistant population and randomised patients to receive fulvestrant with or without dalpiciclib. The study reported only results in terms of PFS, no OS results, but the PFS results were consistent to those that we observed in prior trials with a doubling in the median PFS from 7.2 to 15.7 months and the result was statistically significant in favour of the addition of the CDK4/6 inhibitor. The toxicity profile was very similar to what we expect with the CDK4/6 inhibitors however, probably this agent showed a higher haematological toxicity with more grade 3/4 neutropenia events as compared to what we are experiencing with the other three available CDK4/6 inhibitors. But more data, more mature data, are needed from this trial to make some indirect comparison with the other trials in the same setting.

The second topic for the advanced setting is actually the SYSUCC-002 trial. A very important study in the first line setting of patients with triple positive disease – HER2 positive, hormone receptor positive – receiving first line treatment. The trial randomised patients to receive chemotherapy plus trastuzumab or endocrine therapy plus trastuzumab with the idea of a non-inferiority design that wanted to show that avoiding chemotherapy for patients with triple positive disease was not detrimental as compared to chemotherapy. The trial included almost 400 patients and indeed was able to demonstrate the non-inferiority of the endocrine therapy arm as compared to the chemotherapy arm with a hazard ratio that was less than 1.0 in the direction of favouring the endocrine therapy arm.

These are very interesting and important results, however we have to keep in mind that the chosen treatment, especially the chosen anti-HER2 treatment, was trastuzumab alone while we all know that the current first line treatment in this setting is the combination of trastuzumab and pertuzumab with taxane-based chemotherapy, so dual anti-HER2 blockade. The authors did not present absolute rates, however, by looking at the Kaplan-Meier curves indeed what we observe with these two treatment options seems to be much lower in terms of median PFS and OS as compared to what we see with the current standard of care. However, these are interesting data and more research is needed in the field of triple positive disease and to try to avoid chemotherapy for some patients.

So ASCO, as mentioned, has been a great conference for breast cancer with many important news, some of them that we really hope to have to apply very soon in the clinic.