Category 1 Recommendation of Ribociclib Plus an AI Represents Huge Advancement in Breast Cancer

The biggest update to the 2024 Breast Cancer NCCN guidelines was the addition of ribociclib (Kisqali) plus an aromatase inhibitor (AI) as a preferred regimen (category 1) for the treatment of patients with hormone receptor (HR)–positive, HER2-negative early breast cancer, according to Jairam Krishnamurthy, MD, FACP, who is a member of the NCCN guideline panel for breast cancer.¹

Krishnamurthy added that the FDA-approval of adjuvant ribociclib may also be applicable to a wider patient population than that of the abemaciclib (Verzenio) approval. Notably, ribociclib is the only category 1 preferred CDK4/6 inhibitor indicated in the NCCN guidelines for the first-line treatment of patients with HR-positive, HER2-negative metastatic breast cancer in combination with an AI.²

“The most recent NCCN guideline update for adjuvant ribociclib clarifies which indication that [agent] should be used [for], and also mentions abemaciclib and which indication that should be used [for],” Krishnamurthy said in an interview with OncLive^®. “It’s not a one-size-fits-all [approach]; as in all cases, the risk and benefit of any approach need to be weighed. We must keep in mind that the benefit should always outweigh the risk and keep the quality of life of patients in mind.”

The Most Notable 2024 NCCN Revisions in Breast Cancer:¹

• For patients with HR-positive/HER2-negative early breast cancer:
  • Ribociclib plus an AI has been added as a preferred regimen (category 1)
• For the systemic adjuvant treatment of HR-positive, HER2-negative disease in postmenopausal patients with pT1–3 and pN0 or pN+ tumors:

• A middle pathway option was added to all nodes to consider adjuvant abemaciclib or ribociclib for eligible patients
• Bottom pathway options were added for select patients who may be eligible for treatment with adjuvant abemaciclib or ribociclib and/or adjuvant olaparib (Lynparza) if they have a germline BRCA1/2 mutation

• For the systemic adjuvant treatment of HR-positive, HER2-negative disease in premenopausal patients with pT1–3 and pN0 tumors:
  • It was added to consider adjuvant ribociclib for eligible patients with tumors greater than 0.5 cm and pN0 disease
• For the systemic adjuvant treatment of HR-positive, HER2-negative disease in premenopausal patients with pT1–3 and pN+ tumors:
  • It was added as an option to all pathways in column 5 to consider adjuvant abemaciclib or ribociclib for eligible patients
• For adjuvant endocrine therapy with or without CDK4/6 inhibitor therapy:
  • The pathway was revised to include adjuvant abemaciclib or ribociclib in eligible patients
• For targeted therapies and associated biomarker testing for recurrent unresectable (local or regional) or stage IV (M1) disease:
  • Repotrectinib (Augtyro) was added in the NTRK fusion row (category 2A)
• For the locoregional treatment of cT1-3, cN0 or cN+, M0 disease:
  • The recommendation for breast-conserving surgery with surgical axillary staging (category 1) was modified to note this should be done with or without oncoplastic reconstruction
• For HER2-negative other recommended regimens:
  • Paclitaxel plus carboplatin (various schedules) was revised to note a category 2A recommendation
  • Docetaxel plus carboplatin was revised to omit the preoperative setting only recommendation and to add the category 2A recommendation
• For preoperative/adjuvant therapy regimens for HER2-positive disease:
  • A bullet was added for paclitaxel/carboplatin plus trastuzumab (Herceptin) and pertuzumab (Perjeta) as other recommended regimens
• For preoperative/adjuvant therapy regimens for HER2-positive disease:
  • The ado-trastuzumab emtansine (Kadcyla; T-DM1) regimen was added as a preferred regimen
  • Paclitaxel/carboplatin plus trastuzumab and pertuzumab was added for other recommended regimens
• NCCN noted “Section significantly revised” for: BINV-19; BINV-D; BINV-G; BINV-K; BINV-M; and PHYLL-1

In the interview, Krishnamurthy detailed what to take into consideration when implementing updated NCCN guidelines into practice, and the latest changes in the breast cancer field, particularly with ribociclib. Krishnamurthy is an associate professor in the Division of Oncology and Hematology and serves as the codirector of the Breast Cancer Program at the University of Nebraska Medical Center in Omaha.

OncLive: What 2024 NCCN updates have had an immediate influence on how you treat patients with breast cancer?

Krishnamurthy: The most recent updates [included] the addition of ribociclib to the guidelines [as] adjuvant endocrine therapy for those with HR-positive, HER2-negative disease based on data from the phase 3 NATALEE trial [NCT03701334].

Guidelines haven’t been updated [to a heavy extent in 2024], but inavolisib [Itovebi] was approved [recently], so it is also likely to show up on the guidelines. I don’t know if it is happening or not, or when it will happen, but one would expect that to be on the guidelines since the FDA has approved it. I don’t believe there were any other major updates that happened this year other than the [addition of] adjuvant ribociclib.

How has the addition of adjuvant ribociclib to the therapeutic landscape impacted practice?

The FDA approval and the NCCN guidelines mention of ribociclib happened very recently. We haven’t had as much opportunity to offer adjuvant ribociclib yet, but going forward, it’s going to be applicable for a larger population compared with who we were offering abemaciclib to. In the [trial leading to abemaciclib’s approval], the phase 3 monarchE trial [NCT03155997], the definition of high-risk was a little more [strict] in terms of abemaciclib being applicable only for the highest of the high-risk [population]. [In NATALEE], there were quite a few lymph node-negative patients [included], everybody didn’t necessarily need to be lymph node-positive, and patients didn’t necessarily need to have a lot of positive lymph nodes. It’s a wider population that adjuvant ribociclib will be applicable for.

What is key to note for community oncologists who are adapting to the recent guideline changes?

It is important to know that ribociclib was not given at the standard dose that we use in the metastatic setting, which is usually 600 mg. [Instead] it was only [given at] 400 mg [in a] 3 weeks on and 1 week off schedule. In addition, patients are given this drug for 3 years as opposed to abemaciclib which is given for 2 years. That’s a major difference.

Convincing patients to take 2 years of abemaciclib is quite hard because these drugs have adverse effects [AEs], and we have to remember that these patients have already undergone surgery, chemotherapy, radiation, and are also committed to [receiving] at least 5 years of endocrine therapy in most cases. We were asking them to do 2 years of abemaciclib as well, and now if we have to talk to them about 3 [years of] ribociclib on top of all of that, that’s going to be the major challenge in terms of convincing and counseling patients and managing their AEs.

What is important to note about the tumor agnostic approval of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and how it has impacted NCCN guidelines in general?

For any HER2-positive cancer, T-DXd could be applicable, which provides another line of treatment for many other cancers where there are not as many treatment options. In breast cancer, we are using it for patients with HER2-positive metastatic disease in the second-line and beyond [settings], and the responses that we’ve seen have been very similar to what the clinical trial data showed. We are also using the drug in the HER2-low space. This clearly shows that T-DXd use has only been increasing over the years, and it is likely to increase further with this agnostic indication.

Have you faced any challenges integrating updates to the guidelines into your practice?

[There are] not really challenges [with integration], but I feel that a lot of times insurance companies lag behind in terms of what’s already in the guidelines, or even for that matter, what literature is published. This is a little disappointing and frustrating at the same time because that delays the availability of drugs to patients. Some work needs to be done on that part.

How do you communicate guideline changes to your patients who are receiving treatment?

If there is a guideline change that is applicable to them, I usually call them or whenever they see me next in clinic—which is typically fairly soon—I discuss it with them [noting that] we probably should make these changes now to treatment because this is applicable. [I ask]: Would you be interested in something like this? We discuss the data in detail as to what it means and how it’s applicable to that particular patient, and what the potential AEs of the approach are.

Are there any changes you anticipate coming in 2025 following guideline updates that you’d like to highlight?

I would expect inavolisib to make it to the guidelines at some point. Literature presented at the San Antonio Breast Cancer Symposium could change a lot of things, but I don’t know what is likely to happen. There are many current studies which [data] are highly anticipated for such as the phase 3 DESTINY-Breast05 study [NCT04622319] for adjuvant T-DXd [vs T-DM1]. There is an ongoing study where T-DXd plus tucatinib [Tukysa] is being used for metastatic disease that is also eagerly awaited. There are neoadjuvant T-DXd studies ongoing, which are eagerly awaited in terms of seeing pathologic complete remission rates. If those studies become positive, they would make it to the guidelines.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2024. Accessed November 21, 2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. Novartis ribociclib (Kisqali®) recognized as Category 1 preferred breast cancer adjuvant treatment by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). News release. Novartis. October 24, 2024. Accessed November 21, 2024. https://www.novartis.com/news/media-releases/novartis-ribociclib-kisqali-recognized-category-1-preferred-breast-cancer-adjuvant-treatment-nccn-clinical-practice-guidelines-oncology-nccn-guidelines#:~:text=Ribociclib%20(Kisqali)%20is%20the%20only%20CDK4/6i%20recommended,high%20genomic%20risk/Ki%2D67%20%E2%89%A520%%20or%20Grade%2031.