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Welcome to the Breast Cancer Sessions with the Video Journal of Oncology (VJOncology.com).

Following an exciting day at the ESMO 2022 meeting in Paris, France, leading breast cancer experts get together to share their highlights. Join Elisa Agostinetto and Evandro de Azambuja as they dissect key updates in breast cancer.

 

Welcome to the Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology).

Following an exciting day at the ESMO 2022 meeting, leading breast cancer experts get together to share their highlights. Join Elisa Agostinetto and Evandro de Azambuja as they dissect key updates in breast cancer. In hormone receptor-positive HER2-negative breast cancer, overall survival results from the TROPiCS-02 study (NCT03901339) evaluating sacituzumab govetican, and MONARCH-3 (NCT02246621) investigating the addition of abemaciclib are discussed. In addition, findings from the DATA trial (NCT00301457), which evaluated whether extended adjuvant endocrine therapy was associated with significant benefit are discussed. In triple-negative breast cancer, the findings from SYNERGY (NCT03616886) and BELLINI (NCT03815890) trials are also considered, which aim to improve understanding of the role of immunotherapy in breast cancer.

Transcript

Elisa Agostinetto:
Hello, my name is Elisa Agostinetto. I’m a medical oncologist and research fellow at Institut Jules Bordet in Brussels, Belgium. And I’m here with Dr. Evandro de Azambuja from the Institut Jules Bordet to discuss some of the most interesting results that have been presented so far at ESMO 2022 in the field of breast cancer. First of all, let me say, I don’t know if Evandro agrees, but so far it has been a very exciting congress with so many interesting data presented in the field of breast cancer, both in early and the metastatic setting. So there are two main topics that I would like to discuss with you and in particular the findings presented in two breast cancer subtypes. In hormone receptor-positive, HER2 negative breast cancer and in triple negative breast cancer. So starting from HR-positive, HER2 negative breast cancer, we saw for instance the results and proferred paper session on Friday of the TROPiCS-02 trial that were among the most awaited results of ESMO 2022.

Elisa Agostinetto:
So just to give a bit of context, TROPiCS-02 was a randomized Phase III trial testing sacituzumab govitecan over treatment of a physician’s choice in patients with hormone receptor-positive, HER2-negative metastatic breast cancer who were pretreated in the metastatic setting. Meaning that the patients should have received between two and four prior lines of chemotherapy in the metastatic setting. The preliminary analysis of TROPiCS-02 had already been presented at ASCO 2022 where we saw the results of a progression-free survival and in particular that sacituzumab govitecan was associated with a significant improvement in PFS, although the magnitude of the benefit was quite limited because it was around 1.5 months.

Elisa Agostinetto:
But what we observed at ESMO 2022 was the presentation of the overall survival data. Indeed, at the time of ASCO 2022, the overall survival data were still immature and what we saw at the ESMO 2022 was the presentation of the overall survival data that confirmed that sacituzumab govitecan was associated with a statistically significant improvement in OS with an improvement of 3.2 months, and a hazard rato of 0.79. And I would like to ask your thoughts about these study results. What are your thoughts about these improvements in overall survival?

Evandro de Azambuja:
Thank you very much Elisa for the kind introduction in the discussion for this paper. Indeed, sacituzumab govitecan is an antibody-drug conjugate that has been approved for triple-negative, that has improved the progression for survival and overall survival in the triple negative. And as you mentioned, that ASCO 2022 presented data on the progression-free survival, the primary end point of TROPiCS-02 and indeed it was positive. We question ourselves 1.5 month, is that clinically useful? And now they present the data in the overall survival during this ESMO 2022 and indeed the overall survival significantly improved in this patient population which is a patient population that is heavily pretreated, median lines of chemotherapy were three. And these patient despite being resistant to endocrine therapy, despite them being multiple treatments, they had an improvement in overall survival. This is very meaningful for our patients.

Evandro de Azambuja:
So we can improve 3.5 months overall survival. They have presented data in other trials for quality of life. Quality of life is maintained, efficacy is very good. Safety, we know already from the sacituzumab govitecan, the safety profile. We didn’t see major adverse events in this trial compared to previous ones. So I think this is very good news for our patients. Most of the guidelines will need to be updated now to include sacituzumab govitecan based on this presentation to ESMO 2022, improvement in overall survival by 3.5 months in heavily pretreated patient population.

Elisa Agostinetto:
Yes, I totally agree with you and one point that you mentioned that I really want to underline is that these patients were heavily pretreated. So this is a subset of patients for whom we do have limited therapeutic options in our clinical practices. So a population that represents a highly unmet clinical need and I think that it’s promising and encouraging to see that sacituzumab govitecan has already been changing the treatment landscape for triple-negative breast cancer and is showing also this promising results in other breast cancer subtypes, namely for patients with hormone receptor positive, HER2 negative breast cancer. Another study that was presented at ESMO 2022, again for patients with hormone receptor positive, HER2 negative metastatic breast cancer, but in this case not for heavily pretreated patients but in first line, was the MONARCH 3 trial. So again, just to give a bit of context, MONARCH 3 was a randomized phase three trial testing the addition of abemaciclib to an aromatase inhibitors for patients with hormone receptor positive, HER2 negative metastatic breast cancer in first line.

Elisa Agostinetto:
Again, also for MONARCH 3, we had already seen the results in progression-free survival published in the JCO in 2017 that showed a significant improvement in PFS with the addition of abemaciclib. So what we saw at ESMO 2022 was the presentation of the interim of survival results of MONARCH 3. And in this presentation what we saw is that abemaciclib was associated with a numerical longer overall survival over the placebo, but these results did not meet the threshold of statistical significance as per statistical study design. Again, I want to underline that this was not the final overall survival analysis. This was the interim analysis too. So probably the final analysis will occur in 2023 when the number of events both in the intention-to-treat population and in the subgroup of patients with visceral metastasis will be reached. But again Evandro, I would like to ask your opinion on this data and if what we can expect maybe from these final overall survival in 2023, if we can guess something?

Evandro de Azambuja:
Yeah, this is a very good question Elisa. Just put in the context, today we have three CDK4/6 inhibitors that are approved, palbociclib, ribociclib, abemaciclib. And the MONARCH 3, they are looking for the overall survival interim analysis. All these three trials showed consistent and similar magnitude, the medium progress-free survival is improved when you give CDK4/6 inhibitors to our patients in combination with endocrine therapy, first-line therapy in this case. So here what we saw, we see the median progress-free survival that’s positive. The overall surviving interim analysis is not statistically positive yet but you see a clear separation of the curve that is over 12 months overall survival benefit are added.

Evandro de Azambuja:
So what you have to wait is until 2023 to see the final results, unfortunately more less for patients, but we have to follow those patients. But I’m quite confident that you’re going to see positive results in overall survival because now the separations that could have existed, we already have a 12 months benefit for abemaciclib combined with endocrine therapy compared to endocrine therapy alone. So my guess is that we are going to see a positive result next year. Just need to wait a little bit longer.

Elisa Agostinetto:
I totally agree with you and I think it’s what everybody is hoping right now. And now just to stay always in the topic of patients with hormone-receptor positive, HER2-negative breast cancer, but moving to the early setting, I would like to ask your opinion on another interesting trial that was presented at ESMO 2022 and I’m talking about the results of the DATA trial. So the DATA trial was a study that tested in patients with hormone receptor-positive breast cancer in the early setting receiving 2-3 years of adjuvant tamoxifen and without any signs of disease progression were randomized to receive either three years of aromatase inhibitors with anastrozole or six years of aromatase inhibitors with anastrozole. So a study that is testing whether the extended adjuvant endocrine therapies associated with a significant benefit for our patients.

Elisa Agostinetto:
Again, also for the DATA trial, we had already seen the preliminary results that were published in The Lancet Oncology that showed at the time that there was no significant difference in terms of disease-free survival between patients receiving three years of anastrozole compared to patients receiving six years of anastrozole. But on the contrary, that patients receiving six years of anastrozole had a higher incidence of adverse events. And I’m talking about myalgia, arthralgia, osteopenia, and osteoporosis. So what we observed at ESMO 2022 was the presentation of the final results and the final results confirmed that overall there was no significant difference between the patients receiving three years of anastrozole and patients receiving six years of anastrozole, both in terms of disease-free survival nor in terms of overall survival.

Elisa Agostinetto:
Interestingly, we see at the subgroup analysis there seems to be a benefit for patients who have both estrogen receptor-positive and progesterone receptor-positive and in patients with node-positive disease. So I think that it’s really quite interesting to hear your opinion on these results also because you gave a very brilliant and nice presentation on the extended adjuvant endocrine therapy at the educational session. So I would really be interested to hear your opinion on these results.

Evandro de Azambuja:
Thank you Elisa. Indeed, the DATA trial is a long follow-up, 10 years now, it did not show that giving 8 to 9 years of aromatase inhibitors on top of the tamoxifen total duration, versus 6 to 7 years, improved disease-free survival, nor overall survival. Indeed, as you mentioned, there are sub groups of exploratory analysis, ER positive, PR positive, they seem to derive the most benefit and also the node positive disease. Again what you can conclude from this trial we see more treatments stop due to side effects. We see more osteoporosis on those trials. But if you take all those trials with extended endocrine therapy, there is a clear indication for extended endocrine therapy for most of our patients, particularly intermediate and high-risk patients, you go to 7-8 years and part of that should be aromatase inhibitors. Patients with low risk or very low risk, you can give five years tamoxifen or five years aromatase inhibitors.

Evandro de Azambuja:
One thing for me, and that’s why I discussed in my lecture, is patients with a very high risk of disease, four positive lymph nodes or more, tumors five centimeters or more. Those patients are underrepresented in those trials. So maybe those are the patients that you derive benefit from 10 years, but you cannot forget that today you also have different strategies to decrease the relapse in the first five years. One strategy is using abemaciclib for two years, another strategy LH-RH aromatase inhibitors or tamoxifen. In patients who have germline mutations BRCA1/2 estrogen receptor, they can also use olaparib for one year and bisphosphonate or denosumab in the adjuvant setting. So all the strategies try to reduce the risk of relapse and I think it’s important for most of patients we have to discuss with them the extended endocrine therapy. But today the indication is 7-8 years maximum. A few cases I would discuss up to 10 years, depends on a very high risk.

Elisa Agostinetto:
I totally agree with you. And now I would like you to discuss another topic, that is triple-negative breast cancer. Because also for this breast cancer subtype we saw some interesting data and I would like to mention in particular two studies that I find personally very interesting. One of these is the SYNERGY trial that was a randomized Phase II study testing the combination of oleclumab, a monoclonal antibody, anti-CD73 in combination with the immune checkpoint inhibitor durvalumab plus chemotherapy for patients with the triple negative breast cancer in first line. So patients were randomized to receive either oleclumab plus durvalumab plus chemotherapy or durvalumab plus chemotherapy. In this study the primary endpoint was the clinical benefit rate at 24 weeks and unfortunately this is a negative study because the addition of oleclumab didn’t improve the clinical benefit rate at the 24 weeks.

Elisa Agostinetto:
But still I think it is a very interesting study and there are some very interesting aspects that I would like also to discuss with you. For instance, the fact that in both arms there were some exceptional long lasting responses. And the fact that for instance, I would be very interested to see also the results of the translational analysis of this trial to see for instance if there is any difference at a translational level between these patients with exceptional long lasting response and those patients who didn’t respond to the treatment for instance. I don’t know, what are your thoughts about this trial?

Evandro de Azambuja:
Yeah, this trial interesting because indeed you test the addition of oleclumab to immune checkpoint inhibitors, durvalumab and chemotherapy. Today the standard of care for first-line metastatic breast cancer, triple-negative that have a PD-1/PD-L1 positive, they should receive immunotherapy with chemotherapy. So they are receiving the standard of care today, which is durvalumab, but interesting, it did not increase. But for me the thing is, we included all patient population. They were not selected for PD-1/PD-L1 positive in the beginning. So maybe this played a role but indeed it would be very interesting to see translational research for the trials to understand who are the patients that may benefit from this strategy and those who have a very long lasting progression-free survival. And this you see in other trials with immunotherapy, some patients they respond extremely well and they are years without any progression.

Elisa Agostinetto:
Yes, I believe that really immmunotherapy is a bit revolution in the treatment of several cancer types, including breast cancer. And always talking about immunotherapy in triple-negative breast cancer, we saw also the results of another very interesting trial. This time in the early setting and I’m talking about the BELLINI trial, the BELLINI trial was a study testing nivolumab and the combination of nivolumab plus ipilimumab for patients with early triple-negative breast cancer and tumor infiltrating lymphocytes. So the study design was quite interesting because it really aimed to test whether four weeks of immunotherapy with nivolumab plus ipilimumab could induce an immune response in the primary tumor before surgery, so in the neoadjuvant setting.

Elisa Agostinetto:
And personally I find that this study design very interesting because we know that traditionally breast cancer is considered as a cold tumor type that does not derive great benefit from immunotherapy. But I think that the triple-negative breast cancer compared to the other breast cancer subtype is actually the ideal candidate to test immunotherapeutic strategies because it has a relatively higher rate of tumor infiltrating lymphocytes compared to other breast cancer subtypes. A relatively higher tumor mutational burden, a relatively higher expression of PDL1, for the instance. So I really like the idea of trying to identify among all breast cancer those tumors who are more likely to benefit from immunotherapy. What’s your opinion about this?

Evandro de Azambuja:
Yeah, this is a very interesting trial and I think I have to congratulate our Dutch colleagues, they have a very novel trial design. Testing four weeks of immunotherapy and then they give chemotherapy, surgery. They saw that some patients, they really can see the response to the immuno response. You can see increase in CD8. Some patients, this was not a large trial, three patients, they refused to go further on chemotherapy, they were operated and some patients they had pathologic complete response only with two doses of immunotherapy. This is very interesting. What they looked at was the correlation between the CD8 and the imaging MRIs on those patients. So we still could see some imaging was a little bit blurry, but when you operate the patients they had a pathological complete response and all had an increase in CD8.

Evandro de Azambuja:
So it highlights also the way you are assessing response of patients receiving immunotherapy. Today, you have to look different, people have to be trained to look for MRI in a different way. It is not the way you give chemotherapy. The response is not the same in imaging. So they really need to change a little bit the way you analyze. But indeed, a very interesting, provocative trial. I think it should be validated large patient population because today you give immunotherapy for patients with triple-negative, it would require neoadjuvant chemotherapy, so we are combining this. It would be interesting to be able to select those patients who are extremely respondent, you just give a little bit immunotherapy, chemotherapy and you operate on the patient. So we could save a lot of toxicity for patients. We could save a lot of money for healthcare system.

Elisa Agostinetto:
I totally agree with you Evandro. If you don’t have any additional remarks I can say to conclude as I mentioned at the beginning of our discussion, that it has been a very interesting Congress so far with very interesting data that can really help us to advance in the care of patients with breast cancer. So thank you all for listening to us and thank you Evandro for this nice discussion.

Evandro de Azambuja:
Thank you. Thank you very much. It’s very nice to be back in person in this conference, ESMO 2022.

Disclosures

Recording date: 12-September-2022; Feature publication date: 07-October-2022.

Elisa Agostinetto

Dr Agostinetto reports no relevant disclosures.

Evandro de Azambuja

Dr de Azambuja reports no relevant disclosures.