CDK4/6, PI3K Inhibition Among Top Advances Made in Metastatic Breast Cancer Treatment

Partner | Cancer Centers | <b>Georgetown Lombardi Comprehensive Cancer Center</b>

Julie M. Collins, MD, MPH, highlights key updates with targeted agents such as CDK4/6 and PI3K inhibitors in the treatment of patients with hormone receptor–positive breast cancer.

A great deal of progress has been made with regard to targeted therapy in hormone receptor–positive breast cancer, especially with CDK4/6 inhibitors and PI3K inhibitors in metastatic breast cancer, according to Julie M. Collins, MD, MPH, and emerging data on the former as adjuvant treatment has shown promise in those with high-risk, early-stage disease.

Results from the phase 3 SOLAR-1 trial showed that the PI3K inhibitor alpelisib (Piqray) in combination with fulvestrant (Faslodex) resulted in prolonged progression-free survival (PFS) in patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative advanced breast cancer who had received prior endocrine therapy. The median PFS with the alpelisib combination was 11.0 months versus 5.7 months with fulvestrant alone (HR, 0.65; 95% CI, 0.50-0.85; P <.001).1 The data led to the May 2019 FDA approval of alpelisib/fulvestrant for select patients with advanced or metastatic breast cancer.

Although data from the final overall survival (OS) analysis of SOLAR-1 presented during the 2020 ESMO Virtual Congress failed to cross the prespecified O’Brien-Fleming efficacy boundary (P ≤.0161) in postmenopausal patients, alpelisib/fulvestrant prolonged the median OS by 7.9 months versus fulvestrant alone (HR, 0.86; 95% CI, 0.64-1.15; P =.15) and suggested a survival benefit in several subgroups analyzed.2

The exploration of adjuvant CDK4/6 inhibitors such as palbociclib (Ibrance) and abemaciclib (Verzenio) in combination with endocrine therapy in the PALLAS and monarchE trials, respectively, has also been an important area of interest, according to Collins. The invasive disease-free survival (iDFS) rates observed with the palbociclib/endocrine therapy was 88.2% versus 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; log-rank P =.51);3 these rates were 92.2% versus 88.7% with abemaciclib/endocrine therapy and endocrine therapy alone, respectively (HR, 0.747; 95% CI, 0.598-0.932; P =.0096).4

“The data evaluating adjuvant CDK4/6 inhibitors in early-stage, high-risk breast cancer are both important and interesting. We haven’t seen an improvement over endocrine therapy in this population,” Collins emphasized. “The story continues to unfold and, as it does, we will keep our eyes peeled for more data. We should have more answers in the future for how this affects our patients and how we’ll incorporate what we learn into our treatment approaches.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Breast Cancer, Collins, an assistant professor at Georgetown University and a medical oncologist at MedStar Health, highlighted key updates with targeted agents such as CDK4/6 and PI3K inhibitors in the treatment of patients with hormone receptor–positive breast cancer.

OncLive®: Could you expand on the rationale for evaluating CDK4/6 inhibitors, as well as PI3K inhibitors, in HR-positive disease?

Collins: Tumor cell proliferation in many breast cancers is driven by hyperactivity of the cyclin D–CDK4/6 pathway. By blocking this pathway with CDK4/6 inhibitors, you can decrease tumor cell proliferation and prevent these cells from progressing from the G1 to S phase of the cell cycle, causing cell cycle arrest and what looks like cell senescence.

CCND1, which encodes cyclin D, is expressed in high levels in patients with estrogen receptor (ER)–positive breast cancer and CDK4/6 inhibitors have demonstrated strong synergy with antiestrogen therapies, which we use in ER-positive breast cancer. As such, it really makes sense to combine these therapies when we're treating patients with metastatic ER-positive breast cancer.

PI3K inhibitors are also important in the treatment of metastatic ER-positive disease. The PI3K/AKT/mTOR pathway plays an important role in mediating cell growth and survival in breast cancer.

PIK3CA mutations can occur in about 40% of ER-positive breast cancer cases. This mutation confers a poor prognosis; thus, it makes sense to check for this in our patients with metastatic ER-positive breast cancer to see whether we can utilize an agent such as alpelisib.

Speaking of alpelisib, could you highlight the SOLAR-1 trial? What was the significance of this research? 

The SOLAR-1 trial evaluated alpelisib plus fulvestrant versus fulvestrant alone in patients with metastatic hormone receptor–positive breast cancer. In the trial, patients did not need to have a PIK3CA mutation, but the results that we focused on, and for which the approval was based on, were those with this mutation.

The combination did receive regulatory approval from the FDA in 2019, based on a prolongation of progression-free survival to about 11 months versus about 5.5 months with fulvestrant alone. During the 2020 ESMO Virtual Congress, we saw that there was actually not a statistically significant improvement with the combination. However, importantly, we did still see a delay to time to chemotherapy, which is important for our patients in terms of staying out of the hospital, away from the infusion center, and being able to live their lives more freely. 

How did the approval of alpelisib change how you approach biopsies for patients with metastatic hormone receptor–positive disease?

We now have a tendency to get a biopsy for molecular testing earlier, which makes a lot of sense in these patients, as we wouldn't want to miss the opportunity to potentially treat them with alpelisib and fulvestrant.

The PALLAS and monarchE trials utilized adjuvant CDK4/6 inhibitors in high-risk, early-stage disease. How did these data compare?

Both the PALLAS and monarchE trials looked at 2 years duration of a CDK4/6 inhibitor in patients with high-risk, early-stage breast cancer. The PALLAS trial utilized palbociclib, while the monarchE trial utilized abemaciclib.

 

There were some differences in terms of eligibility between the trials, with the monarchE trial including more stringent and high-risk patients. In monarchE, patients had to have at least 4 axillary lymph nodes positive for breast cancer, or 1-3 positive axillary lymph nodes and at least 1 other high-risk feature, which included a grade 3 tumor that was 3 cm or greater or a Ki-67 that was greater than or equal to 20%. In comparison, the PALLAS trial enrolled patients with either stage II or III disease. In both trials, pre- and post-menopausal women were eligible. If [a patient was] pre-menopausal, they had to be on ovarian function suppression so that they were functionally post-menopausal.

Recently, we heard that PALLAS was halted for futility, while monarchE was just presented during the 2020 ESMO Virtual Congress and showed positive data. Both of these trials had a primary end point of iDFS. In the PALLAS trial, we saw that the iDFS curves overlapped entirely, while in monarchE, we saw some separation of the curves with about a 3.5% absolute difference in iDFS with the addition of abemaciclib to endocrine therapy. In monarchE, we saw that the risk of invasive disease was reduced by 25% and the risk of distant metastasis was reduced by 28%. 

Although these trials were seemingly similar, one trial was positive while the other was negative. Could you speak to some of the reasons to potentially explain why?

In terms of eligibility, there was a difference with regard to the patients who were accrued to these studies. The monarchE trial was weighted toward higher-risk patients with a higher-risk of recurrence. In PALLAS, 37% of patients had N2 or N3 disease, whereas 59% of the patients in monarchE had N2 and N3 disease. All patients in monarchE who had N1 disease had additional high-risk factors, which made them eligible.

There also may be a difference in therapy. Although these are both CDK4/6 inhibitors, we understand that not all of these agents act exactly the same. We know that abemaciclib is given continuously while palbociclib is an intermittent therapy; this could potentially cause a difference [in outcome]. They are the same drug class, but they might have slightly different effects.

We should also note that, in PALLAS, there was a 42% early discontinuation rate due to a more stringent protocol, whereas the rate of early discontinuation in monarchE was only 16%. As common sense would have it, if a patient is not able to take a medication, then the they will not be able to benefit from that medication.  

The last thing that I want to touch on, which is very important, is that these are very early analyses and I don't believe the story is over yet. PALLAS still plans to do at least 10 years of long-term follow-up. With regard to monarchE, the median follow-up was only about 15.5 months and only about 12 patients had completed the 2 years of therapy when the data were presented. 

What was the clinical significance of these findings?

This is the first improvement with endocrine therapy that we've seen in the adjuvant setting in quite some time, so it’s very exciting. We all just need to continue to follow these data and see where it leads us in the long-term. As breast oncologists, one thing that we're always concerned about for our patients is late relapse, especially with our [patients who have] hormone receptor–positive disease. That is part of a story that we do not have any information on yet, in terms of how adjuvant CDK4/6 inhibitors may influence late relapses in this patient population.

What are some areas of investigation with regard to CDK4/6 inhibitors?

It is not yet understood whether we should be sequencing CDK4/6 inhibitor therapies; this is an important question that is currently being evaluated in ongoing trials. We're also investigating whether there may be a benefit to continuing CDK4/6 inhibitors after progression, similar to how we do in HER2-directed therapies in HER2-positive metastatic breast cancer. These are questions that will be answered over the next several years and, depending on the results of these trials, we may be able to keep patients off chemotherapy even longer.

 

References

  1. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904
  2. André F, Ciruelos EM, Juric D, et al. Overall survival (os) results from SOLAR-1, a phase III study of alpelisib (ALP) + fulvestrant (FUL) for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020. LBA18.
  3. Mayer EL, Gnant MI, DeMichele A, et al. PALLAS: a randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone or HR+/HER2- early breast cancer. Ann Oncol. 2020;31(suppl 4):LBA12. doi:10.1016/j.annonc.2020.08.2240
  4. Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib in high risk early breast cancer. Ann Oncol. 2020;31(suppl 4):LBA5_PR. doi:10.1016/j.annonc.2020.08.2238