Jhaveri Compares Safety and Duration of Adjuvant CDK4/6 Inhibitors in HR+ Breast Cancer

Komal Jhaveri, MD, FACP

Section Head, Endocrine Therapy Research Program

Clinical Director, Early Drug Development Service

Memorial Sloan Kettering Cancer Center

New York, NY

CASE SUMMARY

• A 52-year-old woman presented with a mass in the left breast on routine mammogram.
• Mammogram/ultrasound shows a 1.9-cm mass.
• Core biopsy shows grade 3 invasive ductal carcinoma (IDC), estrogen receptor 80%, progesterone receptor 25%, HER2 < 1 by immunohistochemistry; 21-gene recurrence score of 25; Ki-67, 25%
• Sentinel lymph node biopsy negative for IDC
• PET-CT staging negative for distant metastasis
• Germline testing negative for pathogenic variants
• She underwent left mastectomy
• Tumor was 2.1 cm, grade 3 IDC
• Anatomic stage: T2pN0M0/IIA

What was the safety profile of ribociclib (Kisqali) in the phase 3 NATALEE trial (NCT03701334)?

JHAVERI: Neutropenia is the most common toxicity. All-grade neutropenia [occurred in] 62% [of patients] and grade 3 neutropenia in 42% [Table¹]. This is at the 400-mg dose, which is lower than the dose in metastatic disease, where you see slightly higher rates of both. You do see other toxicities, like arthralgia [or] nausea, but the most important ones I…want to highlight are neutropenia and aspartate aminotransferase [AST] and alanine aminotransferase [ALT] increase, which is something that can happen that you want to watch out for in clinic as well. There was 19% with ALT increase of all grades and 6% grade 3 ALT increase, and 16% AST increase, all-grade, and grade 3 was 4%.

Adverse event [AE]–related discon-tinuations [were needed] in 19% and the median time to discontinuation was 4 months. So if somebody’s having toxicity, maybe you stop the medication, and that happened early on. Luckily, we’re checking the blood values very frequently anyway, so you are going to identify those patients soon enough. You are going to hold doses, you are going to dose reduce, or you might discontinue if it just doesn’t get better or keeps getting worse. But that was happening early on in the [trial], so whoever discontinued, discontinued early on.

How are the pharmacokinetics and efficacy of adjuvant ribociclib affected by dose reduction?

We did not necessarily know that until they did the analysis that they presented at the European Society for Medical Oncology Annual Congress [ESMO], where they at least showed that if you dose reduce, you are not losing efficacy, which is nice and in line with the metastatic setting, and which is also in line with what we have done with the monarchE trial [NCT03155997] and abemaciclib [Verzenio]: you start at 150 mg, you go to 100 mg, you can go to 50 mg, and the efficacy was maintained.

With ribociclib, we now have NATALEE data as well. You start at 400 mg, you can go down to 200 mg, and efficacy is maintained [From the Data²]. But you can’t dose reduce lower. There is 1 dose reduction for NATALEE, unlike in the metastatic setting, where you are allowed 2 dose reductions because you start at 600 mg.³ With monarchE you can also dose reduce, and efficacy is maintained.⁴ At least there’s some reassurance there.

In the updated analysis presented at ESMO, rates of discontinuation were 20%; they remained stable.⁵ The most common reason for discontinuation was liver-related toxicities. Approximately 9% of these patients had grade 3 or higher liver-related AEs. With this lower dose, grade 3 QT prolongation was very low, just 1%, which was nice. There was no grade 3 interstitial lung disease [ILD] and a very small proportion, 1.6% of patients, with ILD/pneumonitis that was reported out. Febrile neutropenia was very low at 0.3%....

When they looked at tamoxifen and ribociclib put together, the QTc prolongation rate was high, and if you have psychological issues and you have other psychiatric medications, or you’re taking a lot of nausea medications and have QTc-prolonging drugs, that’s going to complicate that even more. So I think it’s good for safety that we [do not combine them in this setting].

Do liver-related AEs get resolved over time?

They did for some patients, and they had to discontinue because of the way the trial was written. If you didn’t have a recovery by 28 days, you couldn’t start [the next cycle], so you ad to come off [treatment]. Some patients came off because of that; I’ve seen sometimes it can take longer. I’ve seen that with abemaciclib as well. It doesn’t just come back within 1 week or 2 weeks. Sometimes can take up to 4 to 6 weeks for [AST/ALT] to come down, and eventually it will. But it can take slightly longer in some patients. We don’t know why. For most patients, it was happening [early], so you’ll be able to identify that. Keep an eye on that and hold it. Dose reduce it or discontinue. Without dose reduction, I never got any liver function tests [LFTs] to come down.

How do you choose between adjuvant ribociclib and abemaciclib in patients eligible for either?

I think you have options. You are going to use them based on the data that you see, based on the safety profile that you see, and based on the baseline comorbidities that the patient would have. And the good news is you…have the option to switch, [such as] if they did not tolerate one but they tolerate the other drug well. For somebody who had bad neutropenia…with ribociclib despite the dose reduction or had an LFT issue, you can give them abemaciclib. Or if somebody is struggling with diarrhea when you start with abemaciclib, you can switch them over to ribociclib.

Ribociclib has a 3-year duration. Abemaciclib has a 2-year duration. One has to keep that in mind. The dose in the metastatic setting is different for ribociclib than the dose in the adjuvant setting. There is a 400-mg dose for ribociclib in the early stage vs 600 mg in the metastatic setting.³ Liver toxicity is [over] 30% [in the metastatic setting]; it’s still there [in the adjuvant setting] but less. [Abemaciclib] gives you diarrhea, but it’s 2 years. [Ribociclib] gives you more neutropenia, maybe LFT [elevation], and it’s for 3 years, but doesn’t give you the diarrhea. Those are the kinds of discussions you will have with your patients, and some people might have choices there. The good news is we have something to offer for everybody, but those are the kind of things that you think about.

What percentage of patients had dose reduction of abemaciclib in monarchE?

It was [43%] with dose reduction and 18% discontinued with mature data.⁴ But by the time we presented the 5-year data, 100% had come off abemaciclib. [A total of] 80% had more than 3 years of follow-up available to them, so it was a mature data set. Diarrhea was the most common reason in terms of discontinuation rates.⁶ When we broke it down in older patients, those patients who discontinued happened in the first 6 months and they never dose reduced, so there is an opportunity for us to educate our patients, [let them] tell us about it, dose modify it, and that way we can continue the therapy rather than just discontinuing.

Does the efficacy seen with dose reduction affect your starting dose?

Everybody’s pharmacokinetics are different, so we don’t want to take away the benefit from somebody who would have otherwise tolerated it well. It’s OK to dose reduce rather than starting them [lower] and just assuming that everybody should get a lower dose. The FDA is working on Project Optimus for this reason. Now they’re mandating [investigators] to study 2 doses and making sure that you could consider a lower dose and don’t have to go with the maximum tolerated dose. But we don’t know that because this is how we studied them. In the metastatic setting, I’m not starting everybody at 400 mg because NATALEE did it at 400 mg. I’m still doing 600 mg because not every patient requires a dose reduction.

Older patients are my only patients where I would make that exception…. You could define older differently for different people, but we’ve seen that the severity and higher grade of toxicities in an older patient population is much higher, and that’s where they struggle the most, and that’s where adherence is the worst. So there, I don’t mind starting at a lower dose. I would still play with it and see if I wanted to give them a higher dose if they’re tolerating it and had no issues, but I would be more cautious there. For my younger patients, I always start at the recommended dose and dose reduce if I have to.

How was the dose and duration of ribociclib in NATALEE determined?

There were some ideas about how we should do it for longer and maybe we should do it at a lower dose. They looked at the lower dose from AMALEE [NCT03822468] in the metastatic setting, where they compared 400 mg to 600 mg, and although it did not meet the efficacy end point, the toxicity end point was met.⁷ That’s why they chose 400 mg, so that was some good logic there. The 3 years was more of an arbitrary discussion that maybe if we gave it for longer, it would have a better benefit. Why did the PALLAS trial [NCT02513394] do 2 years, but PENELOPE-B [NCT01864746] did 1 year [of palbociclib (Ibrance)]? We sometimes make these arbitrary decisions.

Could you describe the safety profile of abemaciclib in monarchE in more detail?

Diarrhea is the most common; 84% of patients had some kind of diarrhea.8 Grade 3 diarrhea was about 10%. We did see some fatigue and arthralgia. Neutropenia is low with abemaciclib compared with what we’ve seen with palbociclib and ribociclib. We do see slightly higher rates of venous thromboembolism, and more so for patients who are given tamoxifen, because monarchE does allow tamoxifen, and those patients have a higher risk of developing blood clots because of the tamoxifen risk and the abemaciclib risk. Although you can give [tamoxifen], make sure you keep an eye on that.

Discontinuation rates were 19% for abemaciclib.⁶ ILD was slightly higher here, 3.3% was reported in the monarchE trial, so we can’t forget about pneumonitis with CDK4/6 inhibitors and have to bear that in mind as well.

Could you summarize the practical considerations for the 2 drugs?

For abemaciclib, you have 3 kinds of tablet strengths: 50 mg, 100 mg, and 150 mg.⁹ We don’t use the 200-mg tablet. We have 200-mg tablets for ribociclib. We start at 150 mg twice daily for abemaciclib, for ribociclib, we start at 400 mg in two 200-mg tablets.3 It has the pack with letrozole, which is nice. There are 2 dose reductions with monarchE and 1 dose reduction with NATALEE.

_REFERENCES

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