ASCO 2020: Breast cancer roundup

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Published: 11 Jun 2020
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Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy

Dr Matteo Lambertini provides the main developments in breast cancer research that were presented at the ASCO 2020 virtual meeting.

He outlines the most important abstracts surrounding breast cancer in this order:

- ECOG 2108
- HER2CLIMB
- PHOEBE
- PARSIFAL
- MONLEESA-3
- BYLieve
- KEYNOTE-355
- Bicalutamide in combination with palbociclib
- TBCRC 048
- KAITLIN
- TRAIN-2
- PHERGain
- MINDACT
- ALTERNATE
- SYSUCC-001
 

Dear colleagues, it’s a great pleasure to discuss with you what are, from my perspective, the most important breast cancer abstracts presented at ASCO 2020. It has been a special conference, considering that due to all the COVID-19 related issues that we know unfortunately very well, this conference has moved to an online only event, a virtual conference only. But, despite that, I think that in the breast cancer track it has been a great event with many important data presented in both the advanced as well as early setting.

I will start reviewing the most important abstract in the advanced setting and before going to the different breast cancer subtypes I will start with the ECOG 2108 trial which is a study that assessed the role of local treatment in patients with de novo stage 4 breast cancer and this was presented in the plenary session of ASCO 2020. In this trial, asking a very highly relevant clinical question, 390 patients with de novo stage 4 breast cancer were registered before starting first line treatment. Those patients without disease progression between 4-8 months following the start of first line treatment were randomised to receive or not local therapy. Around 250 patients were randomised, the majority, more than 60%, having hormone receptor positive disease, a third of them HER2 positive disease and less than 10% triple negative breast cancer. The study did not show any difference in survival outcomes between patients who received or did not receive local treatment, no difference in progression free survival, no difference in overall survival. Interestingly, at the subgroup analysis of progression free survival according to tumour subtype there was no difference in the HER2 positive and hormone receptor positive cohort while in the triple negative subset, even though this was a small cohort, there was a trend towards worse outcomes for patients who received local therapy as compared to those who did not receive any local treatment. The use of local therapy reduced the risk of local progression but with no difference in quality of life between the two treatment arms.

So this trial is telling us that local therapy in patients with de novo stage 4 breast cancer should not always be proposed to patients. However, as also discussed by the discussant, there is still the role for this option for sure for patients with local symptoms or local progression. It probably has a role also for patients with de novo oligometastatic disease, however, in this specific setting probably with more data, more evidence from trials, is needed before considering the standard option, also in this specific subgroup of patients.

Moving to the HER2 positive data, two important trials have been presented. HER2CLIMB reported more data in the specific cohort of patients with CNS disease. A further trial presented data on the role of pirotinib, so both trials presented data on the two tyrosine kinase inhibitors, in HER2CLIMB tucatinib. This was a phase III randomised trial in patients that progressed after receiving pertuzumab trastuzumab and TDM1, so a kind of third line treatment according to our current standard. Patients were randomised to receive trastuzumab plus capecitabine with or without tucatinib. The primary endpoint of the trial was presented at San Antonio last year and published in The New England Journal of Medicine and this led to the FDA approval of tucatinib in this setting. At ASCO 2020 we had the presentation and the simultaneous publication in The Journal of Clinical Oncology of the data for the specific cohort of patients with CNS disease, so with brain metastasis. Bear in mind that in this trial almost half of the population included had CNS disease at the time of randomisation, so around 300 patients. Tucatinib shows high activity also in patients with brain metastasis, significantly improving progression free survival, overall survival, response rate, also in the CNS, almost doubling the number of responses in the CNS from 20% to more than 40%. Importantly, it also delayed and reduced the risk of progression in the brain, so this so-called CNS-PFS, a more than 60% reduced risk of progressing in the brain with 40% of patients still free from progression in the brain at twelve months after randomisation in the tucatinib arm, as compared to 0% in the placebo arm, showing high activity of this agent especially, above all, for patients with CNS disease.

In the other trial, the PHOEBE trial, another TKI has been assessed, pirotinib. Pirotinib is different from tucatinib which is a highly selective anti-HER2 TKI. Pirotinib is a pan-HER TKI targeting HER1, HER2 and HER4. Last year at ASCO we had a presentation of the phase III randomised trial of capecitabine plus pirotinib versus capecitabine. This year we had a presentation of the PHOEBE trial, so a similar design but the capecitabine plus pirotinib arm was compared to the standard of care, capecitabine plus lapatinib. The trial was conducted in China in patients that did not receive prior pertuzumab nor prior TDM1, so it’s not really the patient population that we would treat with capecitabine plus lapatinib in my country, for example. However, the trial showed very important data favouring the use of pirotinib over lapatinib with almost a doubling in the median progression free survival from around 7 months with lapatinib to more than 12 months with pirotinib and an important trend favouring pirotinib also in terms of overall survival. So based on this data this drug has been approved in China.

Moving to the hormone receptor positive population, again in the advanced setting, I would like to mention two trials that I think have really clarified what is our sequencing of treatment in the advanced setting. The first trial, the PARSIFAL study from the Spanish group, a first line trial in the endocrine sensitive population randomising patients, pre- and postmenopausal women with endocrine sensitive disease, to first line palbociclib plus AI, letrozole, and in the other arm palbociclib plus fulvestrant. So it was a head to head comparison between fulvestrant and an AI together with a CDK4/6 inhibitor in the endocrine sensitive population.

The trial has a strong rationale because we have data suggesting that fulvestrant is superior to an AI as single agent in the endocrine sensitive population. Also we have very interesting results from the MONALEESA-3 trial in the endocrine sensitive cohort with the use of fulvestrant plus ribociclib suggesting very long progression free survival with this combination. However, this trial did not show any difference between the two treatment arms in terms of progression free survival, nor in overall survival. Importantly, there was very promising progression free survival data also with the combination of AI plus palbociclib with a 33 month median progression free survival. So more than 2½ years of median progression free survival with a CDK4/6 inhibitor plus an AI in the endocrine sensitive population, so confirming, once again, the clear effect of this combination in the advanced setting.

In the second trial, the BYLieve study, that was a three arm phase II trial, open label, three cohort, non-randomised trial. In this study the authors tested the role of alpelisib in different specific patient populations and we had a presentation of the first cohort of patients - those patients progressing after CDK4/6 inhibitor and an aromatase inhibitor – testing the role of fulvestrant plus alpelisib if PI3K mutated. This is actually what we could consider nowadays the most proper sequencing of treatment for patients progressing after AI plus CDK4/6 inhibitor - what is the activity of alpelisib plus fulvestrant. We had data also from the SOLAR-1 trial in this specific subgroup of patients, however, it was only a small subgroup of patients in the trial. In this study more than 100 patients progressing on CDK4/6 inhibitors and an AI received fulvestrant and alpelisib in this cohort and the study showed important activity of this drug in this specific setting with more than 50% of patients still free from disease progression at six months and an important median progression free survival of around 7 months in this specific cohort suggesting the clinical activity of this drug also in patients progressing after AI plus CDK4/6 inhibitor.

In the triple negative cohort the most important data derived from the KEYNOTE-355 trial, a much awaited phase III trial, first line treatment, triple negative disease, randomised to receive chemotherapy or chemotherapy plus immune therapy – pembrolizumab in this study. The chemotherapy backbone in the two trials could be abraxane single agent, paclitaxel single agent or the combination of carboplatin plus gemcitabine. The trial showed important efficacy of the combination, the addition of immune therapy to chemotherapy, only in the PD-L1 positive cohort and specifically in the so-called CPS ≥10 cohort with a trend favouring the use of immunotherapy also in the cohort of patients with CPS>1, so with any type of PD-L1 positivity. However, as mentioned, the trial met its primary endpoint and statistical significance only in the CPS ≥10 cohort. In this specific cohort very similar data as those shown with atezolizumab plus abraxane in the PD-L1 positive population in IMpassion130. In this specific regard the progression free survival improved by around 4 months with a hazard ratio of 0.65. So I think that as soon as pembrolizumab will be approved for this specific cohort of patients we will have now two different immunotherapy options to be considered and to decide in the first line treatment for patients with triple negative breast cancer and PD-L1 positivity.

In the triple negative cohort there are two other phase II single arms trials that I would like to mention. The first presented as a poster discussion with a combination of bicalutamide and palbociclib in patients with ER negative, HER2 negative and androgen receptor positive disease with a very nice and interesting clinical benefit rate with this combination – more than 36% at six months clinical benefit rate – opening the door for a potential phase III trial in this setting.

Then the second important single arm phase II study that actually does not apply only to triple negative patients but it’s of particular importance for the triple negative population is the TBCRC 048 trial in which around 50 patients received olaparib single agent. Patients with germline mutation other than BRCA or somatic mutations, including potentially BRCA somatic mutations in the absence of germline BRCA mutation. Among all the patients included, those that derived the highest benefit from the use of olaparib single agent were two groups of patients – those with germline PALB2 mutation, a more than 80% objective response rate in this specific cohort of patients. The second group of patients, those with somatic BRCA mutation without germline BRCA mutation, with around 50% clinical benefit objective response rate. So this trial is actually opening the door to the potential use of PARP inhibitors also beyond germline BRCA mutated patients.

Moving now to the early setting, again going into the main three different tumour subtypes, I will start with the HER2 positive subtype. Here we had the presentation of three main studies, all of them testing a kind of de-escalated approach. I will start with the KAITLIN trial which is the largest in terms of number of patients included. This was a phase III trial including more than 1,800 patients with HER2 positive disease, node positive or node negative but tumour larger than 2cm and hormone receptor negative that received first surgery. So this is a type of population that we currently treat mostly with neoadjuvant treatment, however in this study patients were randomised after receiving surgery to receive anthracycline based chemotherapy, 3-4 cycles of anthracycline based chemotherapy, and then in one treatment arm patients received standard taxane plus pertuzumab plus trastuzumab and in the other arm the taxane was not given and instead of giving taxane the combination of TDM1 plus pertuzumab was given. The trial, however, was negative, it did not show any difference in invasive disease free survival between the two treatment arms. The most important finding is a very good outcome observed in both arms with an invasive disease free survival despite being a kind of high risk patient population of more than 93% in both treatment arms.

The other two trials, the TRAIN-2 study and the PHERGain, again studied two different kinds of potential de-escalating approaches. The first trial, the TRAIN-2, is a Dutch study that already reported the primary result, the pathologic complete response, in Lancet Oncology a couple of years ago. This was a study in which the authors treated patients with HER2 positive disease in the neoadjuvant setting, randomising them to receive or not anthracycline together with dual anti-HER2 blockade trastuzumab and pertuzumab. So in one arm patients received chemotherapy followed by taxane carboplatin, all the treatment given with dual anti-HER2 blockade. In the other arm patients did not receive the anthracycline portion of the chemotherapy but received more cycles, actually a total of nine cycles, of the combination of taxane, carboplatin, again with dual anti-HER2 blockade. In Lancet Oncology a couple of years ago the authors presented the lack of difference in pathologic complete response between the two treatment arms. At ASCO this year the authors reported survival outcome at three years showing, again, no difference between the two treatment arms, suggesting that in some patients we may potentially de-escalate chemotherapy and spare the use of anthracyclines with still very good survival data at three years with an event free survival again exceeding 93% in both treatment arms and very good overall survival data with more than 98% overall survival in both treatment arms at three years.

The third study, the PHERGain, this is a very, very interesting study. It’s a very complex design, I will try to briefly mention what is the portion of the trial that has been presented at ASCO. In this study patients with HER2 positive disease were randomised to receive taxane based chemotherapy with TCHP, so docetaxel, carboplatin and dual anti-HER2 blockade, the trastuzumab plus pertuzumab for six cycles and a PET scan at baseline and after two cycles. In the other arm patients received only dual anti-HER2 blockade for the first two cycles, so before receiving the second PET scan, so pertuzumab plus trastuzumab. Then after the first two cycles patients not responding to the first two cycles received TCHP chemotherapy for six cycles and those patients who responded continued to receive dual anti-HER2 blockade without chemotherapy until surgery. Those patients at surgery that achieved pCR despite not receiving chemo were spared chemotherapy also in this post-surgical part. At this ASCO the authors presented the results of the first part of the trial showing that around 80% of patients receiving pertuzumab plus trastuzumab for the first two cycles actually responded according to PET scan after two cycles. Among these patients up to 40% achieved a pathologic complete response without receiving any type of chemo. So this is a very important study, of course we need to wait the survival data to better assess the possibility to de-escalate chemotherapy in these patients. But his study provides very important and promising data to potentially find a niche and a specific patient population for whom we can spare chemotherapy in the HER2 positive setting.

Moving to the hormone receptor positive subtype, the luminal subtype, the most important data is the updated analysis from the MINDACT trial, the study assessing the role of MammaPrint, of genomic tests to potentially de-escalate chemotherapy use in this specific cohort of patients with hormone receptor positive disease. The trial already reported results at five years, which was the primary endpoint of the study for patients with clinically high risk but genomic low risk, the primary endpoint of the study was to find a distant metastasis free survival of more than 92% in this cohort of patients that did not receive chemotherapy. With more mature data at almost nine years of median follow-up the trial still confirmed to be positive in the sense that the five year distant metastasis free survival was more than 92%, so the lower boundary of the confidence interval was more than 92%. MammaPrint confirmed to have an important prognostic role in this specific patient population. However, at the longer follow-up there are some interesting data in terms of potential chemotherapy benefit in the discordant group, so patients that received or not chemotherapy with discordant clinical or genomic risk. So, with longer follow-up the difference in the potential benefit of chemotherapy appears to be larger with around 2.5% absolute benefit of chemotherapy in the overall patient population. But, interestingly, the results appear to be mostly present in the premenopausal patient population with almost 5% absolute difference in outcomes at eight years in this specific setting suggesting that considering that most of these patients receive tamoxifen as adjuvant endocrine therapy the authors suggest that the potential benefit of chemotherapy they could not exclude that this could be somehow also related to the benefit of ovarian function suppression obtained with the use of chemotherapy instead of the real benefit of chemotherapy. However, I think that this data should be discussed with caution with our patients and the potential benefit of chemotherapy in this setting should be disclosed, specifically in patients younger than 50 years. In patients older than 50 years apparently there was no major difference with or without the use of chemotherapy.
In the hormone sensitive population there were another two neoadjuvant trials to be presented, two neoadjuvant studies, both of them unfortunately negative studies. In one study, the ALTERNATE study, the authors tested AI, anastrozole versus fulvestrant versus a combination of the two. In the other trial letrozole with or without two different schedules of ribociclib but in all these studies there was no difference as compared to AI alone treatment in terms of response to this treatment assessed with the PEPI score, so with a PEPI 0 score at the time of surgery.

Finally, moving to the triple negative subtype, only one trial that I wanted to mention is the Chinese study assessing the role of metronomic capecitabine as adjuvant treatment in triple negative breast cancer patients receiving standard adjuvant or neoadjuvant chemotherapy. In the trail more than 400 patients were randomised to receive a year of capecitabine with a metronomic schedule as compared to observation. The study was significantly in favour of the use of capecitabine with a significant improvement in disease free survival at five years, almost 10% absolute improvement, and a non-significant but interesting trend favouring the use of capecitabine also in terms of overall survival. So this trial further supports the use of capecitabine in high risk patients with triple negative disease after receiving standard neoadjuvant chemotherapy.