Leveraging CDK4/6 Inhibitors in Earlier Settings to Boost Outcomes in HR+ Breast Cancer

Examining the best way to utilize CDK4/6 inhibitors in both the neoadjuvant and adjuvant settings for patients with breast cancer is necessary to improve care, said Angela DeMichele, MD, MSCE, in a presentation during the 19th Annual International Congress of the Future of Breast Cancer^® East meeting.¹

“In the neoadjuvant setting, I’m going to focus on what these studies tell us about the mechanism of action of CDK4/6 inhibitors. I'm going to talk a little bit about what the best end point would be and how could we use these agents in the neoadjuvant setting to improve care,” said DeMichele. “Then, I will focus on the adjuvant setting, where we have very early data. We’re living in a time of press releases; that’s where we get most of our first reads on scientific outcomes, and so we'll just touch on where we are at in that area.”

In her presentation, DeMichele, a professor of medicine and epidemiology at the University of Pennsylvania; the Jill and Alan Miller Endowed Professorship in Breast Cancer Excellence; and the co-leader of the Breast Cancer Research Program in the Abramson Cancer Center, highlighted key updates with CDK4/6 inhibitors and shed light on where research is headed.

Neoadjuvant Setting

DeMichele kicked off her talk by examining how the use of endocrine therapy plus CDK4/6 inhibitors in the neoadjuvant setting could potentially improve patient care. This approach could help identify primary endocrine resistance; it could potentially replace chemotherapy with equivalent outcomes and less toxicity; it could improve neoadjuvant chemotherapy in patients with the highest risk; and it might enable the selection of the best adjuvant combination treatment.

“However, in order to do this we need to know which population of tumors and patients are appropriate for this approach and we need to have really robust surrogate outcomes to tell us whether patients have achieved the best outcome for a long-term recurrence end point,” stressed DeMichele. “These are areas where we are still struggling to understand how to use these agents.”

With regard to considering the best end point, a lot of attention has been turned to the Preoperative Endocrine Prognostic Index (PEPI) score, which was developed to identify patients who are at a low risk for recurrence after neoadjuvant endocrine therapy. With endocrine therapy, DeMichele said that it is unlikely that a pathologic complete response (pCR) will be observed; as such, other end points are needed to understand how the tumor responded to treatment.

The modified PEPI (mPEPI) score 0 (without ER) at surgery is defined as a primary tumor of up to 5 cm (pT1-2), negative nodes (pN0), and a Ki-67 of <2.7%. Results from early studies, such as P024 and IMPACT, indicated that patients who achieved a PEPI 0 score with neoadjuvant endocrine therapy alone were found to have a significantly lower risk of recurrence, according to DeMichele.²

In the phase 3 ALTERNATE trial (NCT01953588), investigators set out to prospectively validate the mPEPI score as a surrogate end point for relapse-free survival (RFS) in patients with early, estrogen receptor (ER)–positive, HER2-negative breast cancer who were treated only with neoadjuvant endocrine therapy.

Specifically, the goal was to identify which patients could avoid treatment with chemotherapy and identify the optimal endocrine therapy options for neoadjuvant treatment, said DeMichele. A secondary end point of this research was to understand whether an early change in Ki-67 could adequately triage patients to chemotherapy. The primary end point was based on mPEPI, which notably, does not include the estrogen receptor component of PEPI. Additionally, a composite end point was used, an endocrine-sensitive disease rate (ESDR), which was the sum of partial complete response plus mPEPI following 6 months of neoadjuvant endocrine treatment.

In the trial, investigators compared anastrozole, fulvestrant, or the combination as the initial therapy for postmenopausal patients with clinical stage II or III, ER-positive, HER2-negative disease. Results from the surgical time point were presented during the 2020 ASCO Virtual Scientific Program and results showed that almost all patients with Ki-67 of ≤10% at baseline remained at Ki-67 of ≤10% at week 4 of the study.³ However, about two-thirds of those with a Ki-67 of ≥10% at baseline were able to be covered to a lower Ki-67 of ≤10% at week 4. Moreover, the ESDR was 18.6% in those who received anastrozole (n = 434), 22.7% in those given fulvestrant alone (n = 431), and 20.5% in those given the combination (n = 434).

“We saw that 20% of the patients would have the desirable end point at surgery that we would hope would predict for very good long-term outcomes,” said DeMichele. “However, longer-term follow-up is needed to determine whether this surrogate endpoint will correlate with recurrence outcomes.”

Adding a CDK4/6 Inhibitor to the Mix

In the neoadjuvant, single-arm phase 2 NeoPalAna trial (NCT01723774), patients with pre-/post-menopausal stage II/III ER-positive, HER2-negative breast cancer received 4 weeks of anastrozole, followed by 4 cycles of anastrozole plus palbociclib (Ibrance). The trial stratified by PIK3CA mutational status. The primary objective of the trial was to determine whether the addition of the CDK4/6 inhibitor to anastrozole would lead to a higher rate of complete cell cycle arrest (CCCA), defined as a Ki-67 of <2.7%, compared with anastrozole alone.

Results showed that CCCA was only about 28% following treatment with anastrozole alone and that increased to 87% following 2 weeks of treatment with the combination.⁴ “That meant that 84% of patients who were resistant to anastrozole alone could become sensitive with the addition of a CDK4/6 inhibitor,” said DeMichele.

Additionally, prior to this study, it was thought that there might be a differential response between luminal A and luminal B tumors with palbociclib. Results showed that at day 15, both subtypes reported a significant drop in Ki-67 and a higher CCCA. Patients with luminal A tumors went from 40% to 100%, and those with luminal B tumors went from 9% to 75%. “Both subtypes responded to the CDK4/6 inhibitor,” stressed DeMichele.

In the randomized, multicenter phase 2 FELINE trial (NCT02712723), investigators evaluated letrozole plus ribociclib (Kisqali) compared with letrozole plus placebo in postmenopausal patients with ER-positive, HER2-negative anatomical stage II/III disease and a primary tumor of >2 cm. Patients were randomized 1:1:1 to either placebo plus letrozole, intermittent ribociclib plus letrozole, or continuous ribociclib plus letrozole. Patients continued treatment until the day before surgery. Importantly, patients with a Ki-67 of >10% on day 14 were removed from the trial.

The primary objective of the trial was to understand whether the addition of ribociclib to endocrine therapy would lead to more patients with a PEPI of 0 at the time of surgery. “Really, the goal of which is to obviate the need for adjuvant chemotherapy,” noted DeMichele. The primary end point of the trial was PEPI score of 0 at surgery, which was established with 80 patients in groups B plus C and 40 patients in group A needed to show an increase in PEPI 0 by 20%.

Results showed that the addition of ribociclib to letrozole as neoadjuvant therapy did not result in the number of patients with a PEPI score of 0.⁵ The addition of the CDK4/6 inhibitor to endocrine therapy did result in a near doubling in the proportion of patients who achieved CCCA at day 14, but that did not persist all the way to surgery, according to DeMichele. Early suppression of Ki-67 from the combination achieved at day 14, was not upheld at the time of surgery. Additionally, the continuous dose of ribociclib in the neoadjuvant setting was found to have similar efficacy to what was seen with the intermittent dose, although difference existed with regard to toxicity.

Neoadjuvant Endocrine Therapy Plus CDK4/6 Inhibitors Versus Chemotherapy

The next question to consider is whether the combination of neoadjuvant endocrine therapy and CDK4/6 inhibitors could replace chemotherapy in patients to improve outcomes and decrease treatment-associated toxicities.

“We need to think about the surrogate that might be important here,” said DeMichele.

For chemotherapy, pCR and residual cancer burden (RCB) have proven to be prognostic in patients with HER2-positive or triple-negative disease, according to DeMichele. However, not many patients with ER-positive, HER2-negative disease are able to achieve pCR/RCB on endocrine treatment.

PEPI is an end point that is under consideration, but it has not been utilized in chemotherapy studies. As such, there are concerns with using this end point in the space, said DeMichele. Additionally, PEPI is strongly dependent on Ki-67, which is known to drop when CDK4/6 inhibitors are administered.

Another end point under exploration is risk of recurrence (ROR) score, which uses the Prosigna assay to incorporate subtype switch from luminal B to luminal A as an alternative end point that might be more sensitive to differences and more predictive of ultimate outcome.⁶ “Essentially, what you get back when you submit tumor for an ROR score, is a ROR that is categorized as either low-, intermediate-, or high-risk and you’re told the subtype of the tumor that you submitted, and that is ultimately turned into a percentage probability of distant recurrence,” explained DeMichele.

In the randomized, parallel, phase 2 NeoPAL study (NCT02400567), investigators examined neoadjuvant letrozole plus palbociclib versus chemotherapy in patients with stage II/III, ER-positive, HER2-negative disease; notably, the trial included both patients with Luminal A and Luminal B disease. Treatment with palbociclib was continued until 24 hours prior to surgery. The primary end point of the trial was RCB 0-1 and the secondary end point was PEPI 0.

Results showed that the median ROR score for patients with high-risk Luminal B disease was 70 with letrozole/palbociclib versus 73 with chemotherapy alone.⁷ As expected, the combination was also found to be less toxic, with only 2 serious adverse effects reported in those who received it versus 14 of those who were given chemotherapy. However, the trial’s primary objective of RCB 0-1 in ≥20% of patients was not met. Notably, a greater drop in Ki-67 was noted with the combination and thus, a higher PEPI 0 was observed. PEPI 0 was 17.6% in the combination arm versus 8% in the chemotherapy arm. Additional follow-up are needed, said DeMichele.

The phase 2 CORALLEEN trial (NCT03248427) is another notable trial that set out to examine neoadjuvant letrozole in combination with ribociclib versus multiagent chemotherapy in patients with postmenopausal HR-positive, HER2-negative, stage I-IIIA breast cancer with a tumor size of ≥2 cm; this trial only enrolled patients who were Luminal B. The primary end point of the trial was ROR score.

“At the time of surgery, the proportion of patients who became ROR low were similar in the chemotherapy arm at 46.1% and the ribociclib/letrozole arm at 46.9%,” said DeMichele.⁸ “So almost 50% of the patients converted to a low ROR which would be presumed to afford these patients a good long-term outcome.”

Results also showed intrinsic subtype conversion from Luminal B to Luminal A, added DeMichele. Furthermore, the combination had a lower RCB 0-1 rate, at 6.1%, versus 11.8% with chemotherapy.

Early Data With Adjuvant CDK4/6 Inhibitors

Currently, 4 key adjuvant phase 3 trials are ongoing: NATALEE (NCT03701334), PALLAS (NCT02513394), monarchE (NCT03155997), and PENELOPE-B (NCT01864746).

In May 2020, the independent data monitoring committee for the PALLAS trial, which is comparing palbociclib plus adjuvant endocrine therapy with adjuvant endocrine therapy alone in patients with hormone receptor–positive, HER2-negative, early-stage breast cancer, announced that the trial is unlikely to demonstrate a statistically significant improvement in the primary end point of invasive disease-free survival (iDFS) at a pre-planned interim analysis.⁹

In June 2020, a press release on the monarchE trial, with is examining abemaciclib (Verzenio) in combination with adjuvant endocrine therapy versus adjuvant endocrine therapy alone in patients with HR-positive, HER2-negative early breast cancer, showed that the combination led to a significant reduction in the risk of breast cancer recurrence or death, meeting the primary end point of iDFS.¹⁰

Notably, based on the activity reported in the study, abemaciclib is now the only CDK4/6 inhibitor to achieve a statistically significant reduction in the risk of recurrence in this patient population.

“Completely different results were seen between the 2 trials. The question, of course, is why? One difference is the risk groups that were enrolled on the trials. For PALLAS, 1,000 of the 5,800 patients had stage IIA disease; no patients with stage IIA disease were enrolled on monarchE. In fact, monarchE had a much higher-risk population,” said DeMichele. “That could be important, given that this is very early follow up. A higher-risk population at an early 2-year follow-up may be skewed in having more recurrences. As such, it’s important to be careful when interpreting early results. What we learn in the first 2 years is important, but it might not be the whole story.”

Full data from these trials are expected to be reported at the 2020 ESMO Congress.

References

1. DeMichele A. Neo/adjuvant CDK4/6 inhibitors. Presented at: 19th Annual International Congress of the Future of Breast Cancer® East meeting; July 17-18, 2020. Accessed July 17, 2020.
2. Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor–positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100(19):1380-1388. doi:10.1093/jnci/djn309
3. Ma CX, Suman VJ, Leitch M, et al. ALTERNATE: neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106. J Clin Oncol. 2020;38(suppl 15):504. doi:10.1200/JCO.2020.38.15)suppl.504
4. Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017;23(15):4055-4065. doi:10.1158/1078-0432.CCR-16-3206
5. Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). J Clin Oncol. 2020;38(suppl 15):505. doi:10.1200/JCO.2020.38.15_suppl.505
6. Wallden B, Storhoff J, Nielson T, et al. Development and verification of the PAM50-based Prosigna breast cancer gene signature assay. BMC Med Genomics. 2015;8:54. doi:10.1186/s12920-015-0129-6
7. Cottu P, D’Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018;29(12):2334-2340. doi:10.1093/annonc/mdy448
8. Gavilá J, Saura C, Pascual T, et al. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: an open-label, multicenter, two-arm, randomized study. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019. Session GS2. https://bit.ly/30lHFmd.
9. Verzenio (abemaciclib) significantly reduced the risk of cancer returning in people with high risk hr+, her2- early breast cancer. News release. Eli Lilly and Company. June 16, 2020. Accessed July 17, 2020. https://bit.ly/3fv2fq8.
10. Pfizer provides update on phase 3 PHALLAS trial of Ibrance (palbociclib) plus endocrine therapy in HR+, HER2-, early breast cancer. News release. Pfizer. May 29, 2020. Accessed July 17, 2020. https://bit.ly/2BegYrc.