Welcome to The Breast Cancer Sessions brought to you by the Video Journal of Oncology (VJOncology). This exclusive discussion features leading experts Erika Hamilton, Matteo Lambertini and Sibylle Loibl, who offer their perspectives on the most important announcements at the San Antonio Breast Cancer Symposium (SABCS) 2020 in the field of breast cancer.
The topics of discussion include their highlights from the meeting, CDK4/6 inhibitors in early breast cancer, the latest immunotherapy data, as well as the RxPONDER trial and what this could mean for premenopausal patients.
“One is the use of CDK4/6 inhibitor in the adjuvant setting. Now, we have clarified, a bit, their role and the evidence in this setting.”
– Matteo Lambertini
“I think early breast cancer and especially with hormone receptor-positive early breast cancer patients finally have had a focus this year.”
– Sibyll Loibl
CDK4/6 inhibitors in early breast cancer
“Well, if you ask me where we sit, I think we sit just in the middle. We don’t know where we sit. We still don’t know where we sit and I think we need more time. We need more time to have longer follow-up to see where the curves go…We need to wait until we have a median follow-up of at least four years to see if the initial hopeful data holds true.”
– Sybille Loibl
RxPONDER & premenopausal patients
“Based on this data, we cannot spare chemotherapy in premenopausal patients, recurrence score up to 25 with one to three positive nodes. However, we can speculate that some of the advantage seen with the use of chemotherapy in this setting could not be seen if we use ovarian function suppression. At least, the difference would have been smaller.”
– Matteo Lambertini
“I would also be careful just to interpret the data that only the premenopausal benefit from chemotherapy. Overall, this trial could not demonstrate that chemotherapy is not necessary for this patient population…The primary endpoint does not support it.”
– Sybille Loibl
“I think that the immunotherapy story in breast cancer is becoming a bit complicated right now, especially after San Antonio. I can admit that I’m a bit confused, especially on the best chemotherapy backbone to associate with the immune checkpoint inhibitors…In my clinic, if I would have all these options available, I would use the same treatment that was studied in the trial.”
– Matteo Lambertini
More highlights from SABCS 2020
“We still have the PAKT trial with capivasertib that so far has shown an overall survival benefit, so I’m really encouraged and curious to see what we see in some of these AKT trials in the future, not only in triple-negative, where I think the biology’s a little bit different, but we’ve also seen some pretty encouraging results from hormone receptor-positive breast cancer.”
– Erika Hamilton
Erika Hamilton: Welcome to the breast cancer sessions with VJ Oncology. I'm Dr. Erika Hamilton and I'm joined by Matteo Lambertini and Sibylle Loibl.
Briefly, I'm Erika Hamilton. I direct the breast cancer research program at Sarah Cannon Research Institute in Nashville, Tennessee. Matteo, would you like to introduce yourself?
Matteo Lambertini: Hello. My name is Matteo Lambertini. I'm a medical oncologist from the University of Genova, Genova in the Northwest of Italy.
Erika Hamilton: Great. Thanks so much for joining us. And Sybille, would you like to introduce yourself as well?
Sybille Loibl: My name is Sybille Loibl. I'm a gynecologist/oncologist from Frankfurt, Germany and I'm the head of the German Breast Group.
Erika Hamilton: Great, thank you so much. First, let's just start off with, what did we find the most exciting out of San Antonio this year? It's been an interesting 2020 with things being virtual, but it's been nice to see that our progress really hasn't stopped.
Matteo, I may start with you. What did you think was the single most exciting thing coming out of San Antonio?
Matteo Lambertini: I think the most important news are in the field of early breast cancer, luminal-like breast cancer, so hormone receptor-positive, HER2-negative disease, with two most important topics. One is the use of CDK4/6 inhibitor in the adjuvant setting. Now, we have clarified, a bit, their role and the evidence in this setting. The other one is the possibility to use Oncotype DX to spare chemotherapy, also in some patients with a node-positive disease. I think these are the two most important news from San Antonio 2020 from my side, from my perspective.
Erika Hamilton: Yeah, absolutely, Matteo. I think a lot of people would agree with you on that. It was definitely a big year for early ER-positive disease. Sybille, anything else to add to that? Were those your big takeaways, anything else that stood out to you?
Sybille Loibl: I think in general, what is presented on Wednesday morning in the general session, are supposed to be the most important highlights. I think early breast cancer and especially with hormone receptor-positive early breast cancer patients finally have had a focus this year and also with the IBIS II data, which we were presented in other smaller studies, we could see that there is a focus on these special breast cancer patients this year. The CDK4/6 inhibitor trials have long been awaited and some have already been shown at ESMO last year, in 2020, and have shown some expected and some unexpected results. And now, a third trial joined and it partially, but really not confirmed what has been presented in the first two trials with a very, very, very short follow-up for the hormone receptor-positive HER2-negative breast cancer population.
Erika Hamilton: Yeah, absolutely. You've kind of hit the big topics here. Certainly, we initially saw negative data from PALLAS, which I think was disappointing. And then, we ended up seeing positive data for monarchE. And then, at San Antonio, we saw PENELOPE-B. Do you want to tell us a little bit about PENELOPE-B and where do you think we sit now with these three trials? How do you think things are going to end up?
Sybille Loibl: Well, if you ask me where we sit, I think we sit just in the middle. We don't know where we sit. We still don't know where we sit and I think we need more time. We need more time to have longer follow-up to see where the curves go, looking at the PENELOPE-B curves, we still, I have to fear, but I don't hope to see that, but we don't know that yet that the monarchE data might also first convene. And then, we have no positive results because when you look at the PENELOPE-B curves early, they separate nicely and then they come together again and currently, we don't know.
Overall, I wouldn't say the trials are negative or positive. All trials leads to some increase of knowledge. I would say the trials just haven't met the primary endpoint, which is rather disappointing, mainly for the patients, because we have lost the enthusiasm and we cannot give the drug to those patients.
Fortunately, monarchE has positive data, has confirmed primary endpoint, which was important to see this year after the interim analysis presented at ESMO. But the final IDFS analysis only came four months after the interim analysis and so we don't have so many more events and it's still median follow-up of less than two years. Personally, I think it's too short. We need to wait until we have a median follow-up of at least four years to see if the initial hopeful data holds true. The trial for this effect of is rather overpowered. That's why we see such a significant effect. PENELOPE-B might be a little underpowered to show any effect. I think the question of the role of the CDK4/6 inhibitors in early hormone receptor positive, HER-2 negative breast cancer has not yet been answered and we need to wait.
We cannot give the patients right away abemaciclib, maybe some of our very high-risk patients where we assume they already have metastasized, they might benefit, but otherwise, I might be too conservative here, but I would be very cautious here to give false promises to our patients. So in summary, the PENELOPE-B trial is a special trial because it was the first trial started. That's why we only used one year of the CDK4/6 inhibitors, but for the next generation, we used two year and then NATALEE, the last trial, which is still recruiting uses three years of the CDK4/6 inhibitor, but what we have seen also is that the compliance is very difficult to keep up. That's why, maybe, that was one of the reasons in PALLAS, with over 40% of the patients did not complete the treatment and stopped early, whereas in the monarchE, it was only 16% of the patients. I think this is a much better rate of patients completing the treatment.
And then, the second is that the population selected was a very high-risk population. Those patients that have not responded to neoadjuvant chemotherapy so they are already at high risk deemed to need chemotherapy, but they had not responded optimally and had a large tumor at the beginning, had still a lot of tumor residual disease and had a higher grading of ER-negative. They could be ER-negative and progesterone receptor-positive and still qualify for participation. This is the so-called CPS-EG score, which we used to select the high-risk population. It's a very high-risk population with a three year IDFS of 77%. It's probably the highest risk population treated with the CDK4/6 inhibitor in early breast cancer.
Erika Hamilton: Yeah, I completely agree. I agree about the follow-up. Matteo, there has been a lot of talk about picking the high-risk population for these three trials. PALLAS and monarchE tried to pick high-risk patients based on nodal status and then monarchE had some additional criteria, but PENELOPE-B, really based on a non-pCR chemotherapy where, as you know, pCRs for ER-positive, we traditionally think are a little bit less important than, say, triple negative or HER2. What are your thoughts on the patient populations here or differential activity of CDK4/6? Anything to add here, Matteo?
Matteo Lambertini: I completely agree that that this is just the beginning of the story for the CDK4/6 inhibitor in the early setting but I think that as compared to ESMO 2020, after San Antonio, we have some more insights on the topic. If I go back to ESMO 2020, my two main explanations for the different findings of PALLAS and monarchE, were what we have just mentioned, so different patient population, different definition of high-risks population and also discontinuation of age, which was much higher in PALLAS as compared to monarchE. However, in San Antonio, where the presentation or in the post discussion session of the PALLAS data in which the author has performed a per-protocol analysis and also landmark analysis adjusting for exposure to palbociclib and they could not observe any difference.
And in the PENELOPE-B, the discontinuation rate actually was not that high as compared to PALLAS and actually was even lower than monarchE, so probably, discontinuation was not the main reason for the negative results of PALLAS and the same for the high-risk patient population. Because it's true that PALLAS included more patients with one to three positive nodes as compared to monarchE, but actually, PENELOPE-B is the one with the highest patient population and still could not see any difference.
So, yeah, one of the potential explanations is that abemaciclib and palbociclib are different CDK4/6 inhibitors. This is not supported in the advanced setting, but this is one of the potential explanations that we have to consider for these results, but I think the most important point Sybille has mentioned is the followup, which is really too short for PALLAS and monarchE to derive strong conclusions on the role of these two molecules in the early setting. MonarchE, I think the results are really important. The 3% absolute difference in IDFS, which is mundane in [inaudible: ‘distant’] relapses. What it is actually doing, abemaciclib, is reducing these recurrences, which is what we want to see in the early setting but I think it's very important, especially in such a high-risk patient population, to continue to following these patients and to see what's going on after a few years, hoping not to see the curves coming together as seen in PENELOPE-B after four years.
Erika Hamilton: Yeah, I absolutely agree with you and we're probably remiss if we don't mention that the ribociclib is still currently enrolling and they went back and enrolled some higher-risk patients with more positive nodes, so we eagerly await what we see for that third adjuvant CDK4/6 trial as well.
Matteo, your other big highlight and takeaway from San Antonio is the RxPONDER data, so kind of the mirror of TAILORx for patients that had node positive. Do you want to tell us a little bit about that?
Matteo Lambertini: Yeah, I think this is a very important study. It is a kind of second step of the TAILORx in which the authors wanted to address the role of adjuvant chemotherapy added to endocrine therapy for patients with one to three positive nodes, hormone receptor-positive, HER2-negative breast cancer and patients with recurrence score from zero to 25 were randomized to receive or not chemotherapy in addition to endocrine therapy.
Overall, the trial is negative because actually, in the overall population, it showed that chemotherapy adds benefit on the top of endocrine therapy, but what we waited was the subgroup analysis according to menopausal status, so breaking down the patient population in the premenopausal and postmenopausal patient population. What we see is that in the postmenopausal patient population, there is actually no benefit of adding chemotherapy on the top of endocrine therapy: same results, no signals that chemotherapy can add something in these patients irrespective of recurrence score and number of positive nodes. So same results in one, two or three positive nodes and according to recurrence score.
On the contrary, for premenopausal patients, there is apparently a larger benefit with the addition of chemotherapy in the order of 4% to 5% absolute defence in IDFS at five years. However, as we have also seen in TAILORx, it's a bit complicated to interpret the results in the premenopausal patient population, especially in the U.S., where OFS was not that common to be given before 2016, when the guidelines were updated on this topic. Also, in RxPONDER, the majority of premenopausal patients did not receive ovarian functions operation, so received sub-optimal endocrine treatment, as compared to what we would give now in 2021.
Based on this data, we cannot spare chemotherapy in premenopausal patients, recurrence score up to 25 with one to three positive nodes. However, we can speculate that some of the advantage seen with the use of chemotherapy in this setting could not be seen if we use ovarian function suppression. At least, the difference would have been smaller. Of course, it's just speculation. I have no data to support what I'm just saying, but it's a similar speculation that we have done with TAILORx.
Erika Hamilton: Yeah, absolutely. I think it was very reassuring for all of us to see that those positive nodes were postmenopausal, another group of patients that we can spare chemotherapy. Certainly, we're trying to give everybody we can the best outcome, but we're also trying to not over treat patients. Sybille, any comments on the premenopausal population?
I think there's a good, healthy debate going on whether some of that benefit truly was chemotherapy. And then, there are some people that feel like most of it was probably a variance depression. Are there any premenopausal patients, whether that's lower lymph nodes or any other characteristics where you would discuss with them ovarian suppression with endocrine therapy instead of chemotherapy in this population?
Sybille Loibl: Honestly, I would not withhold chemotherapy from these very young patients. I know that ovarian function suppression is a very good treatment, but we have absolutely no data comparing optimal ovarian function suppression with optimal chemotherapy.
All data show that a GnRH analog for two years without tamoxifen is as good as chemotherapy and the chemotherapy was CMF. CMF is a very good chemotherapy to shut down the ovaries, but it's inferior in terms, even in compared to an optimal anthracycline regimen so I would be careful to say from these data, only because I think around 12% only had an ovarian function suppression, we can't spare chemotherapy.
I would also be careful just to interpret the data that only the premenopausal benefit from chemotherapy. Overall, this trial could not demonstrate that chemotherapy is not necessary for this patient population. These are the overall results and this is the primary endpoint and we have to focus on the primary endpoint. The primary endpoint does not support it. Now, we want to explain, where does this come from? It probably comes from, mainly, the premenopausal patients and the interaction test was positive, but we don't know how exactly this was measured, premenopausal activity, and how were the patients after chemotherapy? How many had regained ovarian function suppression? How many started later with a generic analog within the first two years? All those we don't know and that's why I would be more careful.
I know a lot of people say, "Well, this is just the effect of the ovarian function suppression which we see here." I am a bit more hesitant to support that and I'm also not supporting the postmenopausal patients with one to three lymph nodes do not need any chemotherapy at all. We need to be a bit more careful with this ungated de-escalation. We have made tremendous benefit and effect in the last 20 years with increasing the treatment and with optimizing the treatment, not only as a systemic treatment, but also radiotherapy, surgery, endocrine therapy, targeted agents.
And now, we just say we can forget about that, we just give them a endocrine therapy, optimal endocrine therapy and maybe we should give them just anti-HER2 therapy with a little bit of chemotherapy and we get the same results. I would be very careful here too, because some of those recommendations we give are not proven. Some of those recommendations are not proven in a randomized phase three trial, properly powered, as a non-inferiority trial. This trial really had a different approach and overall, the trial could not confirm that chemotherapy can be spared for everybody.
Erika Hamilton: Yeah, I agree. I feel very similar with the premenopausal. I think we all hope that that was the benefit, but I just don't think we have the data to reliably tell somebody that. Let's switch over to metastatic disease for a little bit. Matteo, we saw the results of KEYNOTE-355. We've certainly seen a lot of results, both in the early stage setting and in the metastatic setting with immunotherapy for triple negative breast cancer. Where do you stand with that? What are your thoughts coming out of San Antonio?
Matteo Lambertini: I think that the immunotherapy story in breast cancer is becoming a bit complicated right now, especially after San Antonio. I can admit that I'm a bit confused, especially on the best chemotherapy backbone to associate with the immune checkpoint inhibitors, because now we have three trials, first-line treatment, triple-negative breast cancer, two with atezolizumab, one showing positive results with atezo plus Abraxane but a similar trial with atezo plus paclitaxel not show any benefit of the addition of atezo.
Now, we have the pembrolizumab data and in San Antonio, they presented the subgroup analysis according to type of chemotherapy and in this trial, it could be paclitaxel, nab-paclitaxel or carboplatin gemcitabine. Apparently, there is no difference or actually, the piece that the paclitaxel is lightly better than the other two. Actually, there is no difference between the three, but paclitaxel is not the worse as we would have expected based on the atezolizumab data and a similar consideration in the early setting.
Again, we have positive pembrolizumab trial with carbo taxol followed by an anthracycline/cyclophosphamide-based chemo, positive trial with nab-paclitaxel atezo followed by anthracycline/cyclophosphamide, a negative trial, even though still a short follow-up, the NeoTRIP, with carbo nab-paclitaxel without anthracyclin cyclophosphamide. At San Antonio, they presented an NCI trial with carboplatin taxol, so not nab-paclitaxel, plus atezo without anthracycline/cyclophosphamide in the early setting, showing increased pCR rate.
Now, I can say that I'm a bit confused on which is the best chemotherapy backbone. In my clinic, if I would have all these options available, I would use the same treatment that was studied in the trial. If I have to choose first line, if I have to use atezolizumab first-line, I would use nab-paclitaxel. If I would use pembrolizumab, I would use any of the three chemotherapy regimen, and the same, I would apply in the resected. This would be my take after San Antonio, of this data.
Erika Hamilton: Yeah, I thought the same, Matteo. I thought it was very interesting in that smaller trial with the immunotherapy presented at San Antonio. It was only 60 patients, but the control arm really under performed there. The control arm pCR rate was only about 18%. I think, certainly, when we're talking about small numbers of patients, sometimes, we see a little bit of swing just based on the patients that are included.
There's been a lot of talk about testing, that the testing for atezolizumab doesn't necessarily overlap with the testing for PD-L1 positivity with pembrolizumab. Sybille, what do you make out of all of this and what are you currently doing in your clinic?
Sybille Loibl: Well, currently we follow a similar principle as Matteo just suggested. If you have done the test showing PD-L1 positivity, which goes with atezolizumab, then we would give them nab-paclitaxel. The majority of patients already had paclitaxel in early breast cancer, so we would like to switch anyway in the metastatic setting, either to taxane or to another completely other chemotherapy. Nab-paclitaxel goes with atezo and if for any other reason that I don't want to give nab, I want to give another chemotherapy, I have done another test, the patient comes already, got another test done, I would go for pembro with one of the other chemotherapy regiments tested.
This is, I think, an easy solution for the metastatic setting. We don't know where we end up in the early setting. The NeoTRIP trial, which did not show an increased pCR rate, we have to keep in mind that this trial, this is the secondary outcome and the primary endpoint is EFS, which we haven't seen. And the problem with pCR is, if you enroll too high-risk patient, a lot of tumor load, involved node, the risk, the likelihood to get a pCR is lower than with smaller tumors. In the very small tumors, they treat with chemotherapy regardless of the treatment you add, and in the high-risk population, it also might not achieve the optimal pCR because the tumors are less likely to achieve a pCR anyway.
We really need to see what we found interesting in the NeoTRIP trials, that they found a correlation between one positivity and pCR rate. Only the IC2/3 PD-L1 positive, they had a higher pCR rate than the placebo arm or chemotherapy alone arm. There is the IC1 or the IC0 PD-L1, there was no difference. This is the only trial suggesting maybe there is an effect, whereas the other two trials didn't see a correlation or predictive value of the PD-L1 test, regardless what test you use with the effect of the checkpoint inhibitor.
Erika Hamilton: Yeah, I think that's totally right.
Sybille Loibl: More questions than answers.
Erika Hamilton: Yeah, right. That's all right. Sometimes, that's what we get. With the time we have remaining, why don't we wrap up with each one of us saying one other titbit from San Antonio that we were excited to see? Or, alternatively, something we're excited to see in the future that's coming. Maybe I'll start with this.
We also saw the results of IPATunity130 and this was ipatasertib, the AKT inhibitor in first-line, triple-negative. And if you recall, we've seen some pretty encouraging phase two data with the AKT inhibitors, but unfortunately, this trial was negative. It did take patients with alterations in the PI3 AKT pathway, but unfortunately, it was negative.
We still have the PAKT trial with capivasertib that so far has shown an overall survival benefit, so I'm really encouraged and curious to see what we see in some of these AKT trials in the future, not only in triple-negative, where I think the biology's a little bit different, but we've also seen some pretty encouraging results from hormone receptor-positive breast cancer. That may be my looking to the future statement. Matteo, what are you excited to see or thinking about these days?
Matteo Lambertini: I have a conflict of interest on this study, but I will mention also our presentation, the general session three, because I think it's a very important message for many, many women. It's a large meta-analysis on the safety of pregnancy after breast cancer, safety from both fetal side and maternal side.
Here, we clearly show, putting together many studies that were done in the last years that after adequate treatment and follow-up, having a pregnancy following breast cancer is not detrimental for the prognosis of the patient. It's safe for the patient. There is no increased risk of major malformation for the baby. There is an increase of some pregnancy complications like caesarian section, is more for gestational age for which I think we should follow these pregnancies more closely during gestation, but the main message is that we need to keep in mind that there's life after cancer.
Also, when we discuss treatment or medication with patients, we also have to think about the long-term follow-up and also the possibility to go back to a normal life, including the possibility to have a family for many young women. I think it's an important message.
Erika Hamilton: Yeah, Matteo, I agree. I think that's important for a lot of our patients. Sybille, what about you?
Sybille Loibl: Well, there were many other interesting studies and we all waited very long for the entinostat trial, which was also not meeting its primary endpoint. We had another phase two trial showing a huge difference and the phase three trial not confirming the result and I think this underlines that we need to be very careful what conclusions we draw from or drew from our phase two trials - we can easily be misled.
I think a randomized phase three trial remains the standard, the goal to confirm the effectiveness of a new drug. We have been there with the IPATunity study. Unfortunately, the AKT inhibitor did not improve PFS for these patients, but I think we need to wait additional analysis. It's an interesting drug which might not have yet found its place in the triple-negative breast cancer scenario, as you said, and similar with the entinostat trial. I think we need to understand why we have a positive phase two trial. Is it just the selection bias of the patients we enroll here or do we really have different characteristics or different tumor characteristics which might point to a positive result compared to a result which is rather disappointing?
I think a lot of people hoped to improve the treatment in the metastatic breast cancer setting further, but so far, we could not see it. We also saw a lot of additional analysis from large trials. The KEYNOTE study, as already mentioned, we saw sub-group analysis, quality of life analysis from IMpassion 031, I assume it was, and I think we should look at all those data as well to get a more comprehensive picture of what the role of the checkpoint inhibitor is in breast cancer.
Erika Hamilton: Yeah, absolutely. Thanks, Matteo and Sybille, for joining me and discussing this. On behalf of VJ Oncology, we'd also like to thank our viewers for discussing our thoughts post-San Antonio.
Dr. Hamilton reports consulting fees paid to institution only (no personal fees) from: Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond and NanoString
Dr. Hamilton reports research/clinical trial support paid to institution only (no personal fees) from: Seattle Genetics, Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, Macrogenics, Abbvie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1Therapeutics, Karyopharm Therapeutics and Torque Therapeutics.
Dr Loibl reports grants and other from Amgen, grants and other from Abbvie, grants and other from Roche, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, other from SeaGen, grants from Imunomedics, other from Prime/Medscape, other from Eirgenix, grants, personal fees, and other from DSI, other from BMS, other from Merck, other from Puma, and personal fees from Chugai; in addition, Dr Loibl has a patent for EP14153692.0 pending.
Dr. Lambertini reports the following conflicts of interest: Advisory role for: Roche, AstraZeneca, Lilly and Novartis Speaker honoraria from: Roche, Takeda, Sandoz, Pfizer, Lilly and Novartis
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