PALMIRA Trial Results: Palbociclib Rechallenge Falls Short in Advanced Breast Cancer

Antonio Llombart Cussac, MD, PhD, Hospital Arnau de Vilanova, Spain, discusses key findings from the PALMIRA trial, which evaluated rechallenge with palbociclib in patients with advanced HR+/HER2- breast cancer. He explains why maintaining the same CDK4/6 inhibitor did not offer meaningful clinical benefit and how these results contrast with prior studies such as MAINTAIN and postMONARCH. The interview also explores biomarker-driven strategies, optimal sequencing of therapies, and future directions for improving outcomes in the second-line setting.

Transcript:

What were your expectations going into the trial regarding potential PFS gains from palbociclib rechallenge, and how did the actual results align with those expectations?

Dr. Llombart-Cussac: Well, obviously at the time that we designed the study, we had a long discussion with the one of the funders, with Pfizer, about what could be and what should be the size of the study in order to provide sufficient evidence that a palbo rechallenge could play a major role.

Indeed, at that time we didn’t know exactly how these drugs work, but we have the exciting database on the first line and second line setting with the different CDK4/6 inhibitor and this amazing benefits in terms of PFS. So the question was if the CDK4 inhibitor could work in a similar way than we observed that anti-HER2 therapies works in the HER2 metastatic disease, in which re-challenge has become a standard of care.

The design of the study was very specific and very different in one concept to the other study that had been run about re challenging with CDK4/6 inhibitors, because here we specifically look at for maintaining the same CDK4/6 inhibitor. That was the the major difference with the old study and the other ones.

And it’s true that we expected to have the initial, the design of the study was, was designed in order to observe a benefit that could be in the rates of a hazard ratio 4.7, So not as significant as for the first line CDK4/6, but sufficient enough to provide a clinical benefit and not just a statistically significant one.

Obviously, the final results are very clear, although we observe a very small signal, nothing really relevant in terms of clinical benefit. So clearly showing that re-challenging the same CDK4/6 inhibitor at least related to palbociclib has no clinical interest.

The difference in progression-free survival did not reach statistical significance, but the clinical benefit rate was numerically higher with rechallenge. How should clinicians interpret these findings in practice, especially for select patient subgroups?

Dr. Llombart-Cussac: It’s sure that there are some patients that achieve a benefit. But finally, when you analyze even the patients in the palbo-maintaining therapy, the number of patients that achieved a significant prolongations in her second line was very limited. Although it was slightly better and superior, when you analyze the number of patients that are achieved, I would say it 6 or 12 months of PFS on the second line was very limited. Particularly we analyze the 12 months.

But it is true that, I mean one of the surprising findings is that in this study we accepted patients coming from letrozole but also from fulvestrant in the first line not being resistant to the prior to the other chance of endocrine therapy. That was because we designed another study that was the PARSIFAL and half of the patient on PARSIFAL could also be included in this study.

So in order to not lose some opportunities, and there is an interesting signal in the patient that switches from letrozole to fulvestrant with—sorry, from fulvestrant to letrozole. So there we observe some interesting signs.

But I think that that although that could merit another study, it’s quite difficult to design now and to try to answer which are the patient that truly could benefit from maintaining palbociclib. And I think that honestly with a great number of the opportunities that that we have right now in this second-line setting, analyzing mutations like ESR1, PI3 kinase, and others as well as other treatments. I think that obviously maintaining palbociclib for me doesn’t seem something reasonable in any scenario because we have probably better options for all patients in this setting.

Given the contrasting outcomes between PALMIRA and studies like MAINTAIN and postMONARCH, what are your thoughts on whether differences in CDK4/6 inhibitors or patient selection might explain the divergence in results?

Dr. Llombart-Cussac: Obviously the feeling that clinicians have is that palbociclib is less potent than Ribo [ribociclib] and Abema [abemaciclib]. At least that was that was how it looks from the data, the final data related to survival. My thought is that if you want to rechallenge with a CDK4/6 inhibitor, you should change the CDK4/6 inhibitor. What doesn’t make sense is to maintain the same.

I mean MAINTAIN as well as postMONARCH, the vast majority of patients came from a different CDK4/6 inhibitor: in MAINTAIN about 86% of patients have been pretreated with palbociclib. Very few came from Ribo to Ribo, and that’s the same postMONARCH. Very few patients have received prior abemaciclib.

So I think that there are some arguments to continue on a CDK4/6 inhibitor, but the reasonable thing is to change the CDK4/6 inhibitor. That would be my message. It is true that we don’t have clear data about Ribo after Ribo or Abema after Abema. But what makes sense is that if you want to do something, change the CDK4/6 inhibitor.

What role do you think biomarkers such as ESR1 or PIK3CA mutations might play in refining patient selection for CDK4/6 inhibitor rechallenge strategies moving forward?

Dr. Llombart-Cussac: I think that is essential. I mean, I cannot imagine how in the future we’ll be able to decide just by clinical arguments the second line setting. Because the benefit that we are observing with the new PI3 kinase inhibitors as well as with the ESR1 inhibitors, I think this is amazing. Patients that will not be tested for at least these two mutations—I don’t talk about other one like ATK or PTEN or even in the future mTOR.

But I think that it becomes crucial when you have to make the decision about a second line among patients that you consider that continues to have an endocrine opportunity to check for the best one. Because those patients that will progress very quickly to a second line endocrine therapy, if not selected by your biomarkers will be certainly driven directly to chemotherapy.

So it’s important to target very well, which is the second line treatment, because that opens the chances also not just for this second line, but also perhaps opportunities for a third line of endocrine therapy before being moved to chemo. So I think that I cannot imagine right now in my clinic, even in countries like mine where we have some limitations to have access to some of the drugs that are in the market in other countries to take the decision without any biomarker.

Because it is true that the clinical benefit to the CDK4/6 inhibitors is a very strong prognostic factor and probably also predictive for more endocrine sensitivity. But the one that really targets the optimal endocrine treatment, it should be driven by biomarkers.

Looking ahead, how should this trial inform the design of future studies on second-line therapy in HR+/HER2- ABC, and are there specific combinations or novel agents you believe warrant investigation in this setting?

Dr. Llombart-Cussac: My feeling is the second line will have very good new opportunities in the very, very next future with the new drugs. Both ESR1 inhibitors as well as by the P3 kinase pathway. But again, it’s true that even the most sensitive patients have limited benefits from these treatments, OK. So the median PFS in this population second line, perhaps we will be able to improve up to one year. We are now in the 7, 8, 9 months.

So I think that in the future the major efforts will be related to how we can increase the sensitivity in the first line. And I think the inavolisib study, in INAVO120, has shown very nicely that we have room in the first line setting to continue to improve the benefits of CDK4/6 inhibitors. There are new CDK4/6 inhibitors, very attractive, that seems much more potent than other CDK4/6 inhibitors. But I think that in the future triplets will become a very standard approach for patients with mutations with PI3 kinase pathway.

And I think that that will be the way particularly to identify the patients with less sensitivity criteria, the ones that have endocrine chances, but at the same time you are not so sure that they will have a very long journey on endocrine therapy. Those are the ones for which we will have to focus on the first line trying to implement and to improve the benefit exhausting everything, but all in the first line. I think that that’s where we will see the major gains.