ANTONIO LLOMBART INTERVIEW: HR+/HER2-
Today, we had the chance to sit down with Dr. Antonio Llombart, Breast Cancer Specialist and our “MedSIR Oncologist of the Month” to discuss the exciting landscape regarding HR+/HER- Breast Cancer.
MedSIR (MS): Thanks so much, Dr. Llombart, for being with us today. We have quite a bit to discuss thanks to the recent arrival of a few new agents for the treatment of metastatic breast cancer (MBC). If it’s OK with you, we will focus primarily on hormone-positive (HR+) disease.
Antonio Llombart (ALL): Sure! It’ll be my pleasure.
MS: Before we jump into these relevant advances, let’s get to know you a little bit better. What brought you to Oncology? When did you realize that you wanted to help this fight against cancer?
ALL: I must confess that I was born with this in my blood! Both my father and grandfather were excellent pathologists and their work in cancer research led them to found and run the Valencian Institute of Oncology. I view myself as the logical evolution of this process which is focused on the comprehensive care of cancer patients.
Also, I must not forget that during my training as a Medical Oncologist, many key people played a big role as mentors in developing my scientific vision such as Drs. Garcia-Conde, Lluch and Cervantes from the Clinical Hospital of Valencia; Drs. Spielmann and LeChevalier from the Gustave Roussy Institute in France and, more recently, Dr. Baselga from MSKCC.
MS: That’s a very interesting background! Thanks for sharing this personal side with us. Now, let’s jump right into the nitty-gritty. CDK inhibitors… tell us about their impact on HR+ MBC, also known as luminal disease. Are they as amazing as they sound?
ALL: It is true that all three CDK inhibitors (palbociclib, ribociclib, and abemaciclib) demonstrated ground-breaking results in their respective phase III trials in terms of their capacity to significantly delay the progression of breast cancer, not only as first-line therapy, but also in patients who had been previously treated with numerous lines of hormone therapy. So, yes, there’s no doubt that these agents will impact our treatment algorithms, however, I prefer to be very cautious. For example, we still are unclear about their impact on survival. Do these agents allow patients to live longer? My intuition is yes, but we don’t really have that answer yet. You must understand that no phase III trial tells the full story of a drug. We need to produce new results in specific patient populations and in specific treatment scenarios. Positive phase III trials allow for drug approvals, smaller posterior studies allow for the better understanding of drug behavior and fine-tuning its use. Additional biological studies in parallel will allow us to understand the molecular behavior of these specific tumors and the effect that these new compounds have on their genetic expression.
MS: Do CDK inhibitors mean the end of first-line single-agent hormone therapy? Do all luminal patients benefit?
ALL: These CDK inhibitors were generally explored in combination with hormone therapy and they demonstrated superiority versus single-agent hormone, BUT the populations explored did not represent the entire population of luminal patients. So, the short answer is clearly “no”. Additionally, single-agent fulvestrant demonstrated, in the recent phase III FALCON trial, significant benefit and very high absolute efficacy numbers, particularly among patients with more indolent (less aggressive) disease. Now, one should never compare numbers between two separate trials, but one cannot ignore that single-agent hormone therapy produces some nice results with less toxicity. My honest opinion is that CDK-inhibitor use will be very well adopted as the first option in the minds of most Breast Cancer Physicians, but we are far from knowing exactly when they are clearly the number one option over single-agent hormone therapy, considering cost and added toxicity.
Dr. Llombart speaking about his goal in oncology clinical trials: to improve the lives of his breast cancer patients.
MS: What do we still need to know about them? For example, what will the PARSIFAL and other trial results tell us? (for our readers: PARSIFAL is a MedSIR-sponsored large phase II front-line trial that randomized 464 patients to receive either palbociclib and fulvestrant or palbociclib and letrozole for HR+/HER2- MBC patients)
ALL: I am a clear proponent of CDK inhibitor use. My experience is very positive and I believe their target population will continuously grow and add to their registry phase III populations. But, we will only achieve this through extra trials that demonstrate their superiority over traditional options, such as single-agent hormone therapy or chemotherapy-based regimens.
The PARSIFAL trial is an excellent example of how a phase II study may change how we use these new agents, in this case palbociclib. The results, which should be ready by sometime next year, may allow us to juggle between different first-line endocrine partners, allowing us more therapeutic flexibility for our patients. But, we need to wait for the results. Also, we will be running quite a few molecular studies with biological samples from these patients. The results may help us to understand which patients benefit most from CDK inhibition and why patients end up progressing.
MS: Exciting! We’ll keep our eyes open for these results…
Whenever a new drug family impacts treatment, a new market opens up, which is the “post-new drug” scenario. What is next after CDK inhibitors? Any interesting information regarding PI3K inhibitors? What about traditional chemotherapy and hormone therapy? Do they have a role in the post-CDK scenario? How about following up a CDK inhibitor with another CDK inhibitor like we see with Herceptin in HER2-positive disease? And, lastly, any role for immunotherapy in luminal disease?
ALL: This is the exciting part! The correct answer is that we have no idea. At this point it’s all speculation. Only clinical trial results, along with molecular studies, will tell us. Knowing in what molecular/genetic state CDK inhibitors leave the tumor could help us quite a bit in understanding what to do afterwards. We are currently running an interesting trial called BioPER which is a small 30-patient study that looks to test palbociclib in patients who had previously benefitted from palbociclib treatment. This is a study focusing on molecular mechanisms of late sensitivity and resistance to CDK4/6, but, being a small study, will not provide much evidence whether or not to continue CDK inhibition after prior CDK progression. However, the great news is that next year we will launch the PERSEPHONE study that will address this question: patients on long progression to a palbociclib regimen will be randomized to a second endocrine therapy treatment in combination with either palbociclib or placebo.
As for PI3K inhibition, it is too early to say, but there definitely seems to be a scientific rationale for their use in PI3K-mutated patients.
I also think that patients will continue to be treated with traditional chemotherapy, but more and more as a last option after exhausting endocrine agents and novel targeted agents. It is true, however, that it appears that eribulin, which is considered a traditional chemotherapeutic agent, may convert hormone resistant tumors into a hormone-sensitive state which, if demonstrated clinically, would allow physicians to re-administer endocrine therapy in these patients. This would be amazing.
On the subject of eribulin, we will soon begin the KELLY trial, which will look at eribulin in combination with pembrolizumab in pretreated luminal disease patients. (Immunotherapy agents have shown promise in triple-negative breast cancer.) This is a single-arm trial but we hope the addition of immunotherapy to chemotherapy demonstrates a real role for these new agents. It would be a great addition to our treatment armamentarium.
Lastly, and quite recently, olaparib, which is a PARP inhibitor, demonstrated significant improvement in efficacy in the HER2-negative population with BRCA1/2 mutations. The problem here is that this population is infrequent in HR+ disease and this agent is highly associated with triple-negative breast cancer. But, PARP inhibitors may absolutely also play a role in luminal disease and are worth looking at more deeply in this specific disease setting.
MS: What about everolimus? Does it still have a role to play here?
ALL: mTOR inhibitors should continue to play a role but the context for everolimus use has definitely changed. It was approved following failure to single-agent hormone therapy. However, the tolerability profile is much worse than CDK4/6 inhibitors and it may remain as a reasonable option beyond progression to CDK4/6 inhibitors, however, in this context its efficacy may not be the same when following CDK-inhibition. Let’s wait and see.
MS: Wow, that sure is a dense field. It must be hard to keep up with all the new data! If I may, let’s leave metastatic disease and touch on early disease for HR+ patients. It seems like we’ve made great strides and more and more breast cancer patients are being cured. What’s left for us to improve in terms of neoadjuvant and adjuvant treatment? Can these new CDK inhibitors impact early disease treatment?
ALL: We are just now beginning to get a glimpse of the potential of these inhibitors for the treatment of early disease. However, my feeling is that the field is using a bit too much of a classical approach. Neoadjuvant and adjuvant studies aren’t taking advantage of the molecular platforms available that will be of standard use in the near future. Additionally, various studies in the neoadjuvant setting are comparing CDK4/6 inhibitors to chemotherapy with the goal of decreasing tumor burden in terms of pCR or RSB 0-1. In my opinion, the primary objective of these studies should be therapeutic downstaging (less need for chemotherapy) rather than tumor downstaging. Hopefully, we can soon begin to launch trials with this new approach.
MS: Lastly, what message of hope would you give to the many breast cancer patients and their families? Will we one day convert Breast Cancer into a chronic disease? What are the near-future goals that you would like to see reached?
ALL: Average survival of an insulin-dependent diabetic or a patient with renal insufficiency is now in the same range as patients with hormone-sensitive advanced breast cancer, and even those with HER2-positive disease. Today, the chronification of breast cancer is real! Our goal for the next ten years should be more ambitious. Molecular tumor characterization and the development of therapies against new cellular targets stemming from this research should allow us to reach 5-year survival rates of nearly 90% very quickly.
MS: Let’s keep our fingers crossed! Thank you so much, Dr. Llombart, for your time. It was really wonderful to learn so much. Next time let’s discuss HER2-positive disease. Exciting things are also happening there.
ALL: That would be great! Thank you very much!