Evolving Concepts in Treatment for Advanced Breast Cancer - Episode 2
Transcript:Joyce A. O’Shaughnessy, MD: The long-term safety looks good. We had the opportunity here to present the long-term 4-year safety data on MONALEESA-2, which is in the postmenopausal first-line setting with ribociclib and letrozole. As we’d expect, there were no surprises at all on safety with prolonged treatment. Only 0.9% of patients had any interruption in the ribociclib because of a slightly prolonged QTc [heart rate—corrected] interval, but no one stopped the ribociclib because of a prolonged QTc. The 1 sudden death early in the MONALEESA-2 was in a patient well outside the United States who had hypokalemia, was on methadone, and had a lot of comorbidities, etc. There was nothing further seen, so I feel very comfortable with the long-term safety. What about our patients with more aggressive disease, Erika, who we would be thinking about chemotherapy for?
Erika P. Hamilton, MD: There was a study from Dr Yeon Hee Park and colleagues out of Korea, and it was in about 200 premenopausal patients. They combined exemestane with palbociclib and a GnRH [gonadotropin-releasing hormone], and they compared it with capecitabine. It was essentially asking that question for those young patients, or even patients with visceral disease, that we’re very worried about—are we doing any harm by giving CDK4/6 as opposed to chemotherapy? It showed that the patients on endocrine therapy in combination with CDK4/6 inhibitors did even better, with a 6-month longer progression-free survival. I think this is really encouraging data. To go back to Sara’s point, I hope it encourages all oncologists to be using this first line and to really consider this the standard of care.
Joyce A. O’Shaughnessy, MD: Would that make sense? Even with the chemotherapy doublets—this was capecitabine alone, but even with doublets—median PFS [progression-free survival] might be in the 8- or 9-month range first-line. All the studies show that first line, the median PFS is 24 to 27 months, so it’s almost triple the PFS. It just makes sense. Also, the speed of response is fast.
Erika P. Hamilton, MD: Right.
Joyce A. O’Shaughnessy, MD: We know that within a couple of cycles, you’re down 30% on your tumor volume.
Erika P. Hamilton, MD: Right, and I think patients, in general, feel better on this than they do chemotherapy, so that’s an important issue of quality of life for patients as well.
Joyce A. O’Shaughnessy, MD: Yes. Now, how do you choose among the CDK4/6 inhibitors?
Erika P. Hamilton, MD: We’ve seen very similar hazard ratios with all 3 compounds across all the trials—hazard ratios in the 0.5 range. I think we all feel comfortable that the efficacy of these agents is almost exactly the same. A lot of times, we pick based on adverse-effect profiles. Palbociclib and ribociclib are more similar in their adverse-effect profile, with neutropenia being the most common adverse event. Abemaciclib has a little bit more GI [gastrointestinal] toxicity and about half the rate of neutropenia. Ribociclib also comes with some increased LFT [liver function test] and EKG [electrocardiogram] monitoring. We make a lot of these choices based on adverse-effect profile, probably.
Joyce A. O’Shaughnessy, MD: I will say that I actually choose abemaciclib, even first line for patients who I feel have the least possibility of being endocrine therapy sensitive. I know its subset analyses from the MONARCH 2 and MONARCH 3, but that’s the most in-depth analysis of the virulent breast cancers with short treatment-free intervals in PR [progesterone receptor]-negative, high-grade disease and liver metastasis. These are the least endocrine therapy sensitive.
It’s interesting that in the PALOMA-3, the survival was nice—a 10-month improvement in survival in those with endocrine therapy sensitivity. In endocrine therapy-resistant disease, there was no survival advantage. That was very rigidly defined. Endocrine therapy resistant was only 20% of the population, and they had to recur within 2 years of adjuvant endocrine therapy or not get 6 months of benefit in the first-line setting, so it was a very rigid 20%. Nonetheless, there wasn’t a survival advantage. Now, we don’t know for sure that it will be any different from abemaciclib, but the fact that it’s continuous without any breaks, and it’s a little broader spectrum of activity there, is very interesting. A little CDK9 in there—kind of interesting. That may bring down MYC and MIB for you, and that’s how it seems to work.
Anyway, it’s still early yet, but you get a little gut feeling over time, plus the fact that, just in terms of heavily pretreated patients in MONARCH 1 and also in the phase Ib, there was quite a bit of non-cross-resistance, late line.
Transcript Edited for Clarity