CDK4/6 inhibitors target the cyclin-dependent kinases (CDKs) 4 and 6, which control cell-cycle transition from G1 to S phase and are largely regulated through association with D-family cyclins.¹ These agents work synergistically with ET by inhibiting cyclin D–CDK4/6 activation, which occurs downstream of estrogen signaling.^2-4 The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are approved by the FDA for HR-positive/HER2-negative advanced or metastatic breast cancer and have been investigated in HR-positive EBC.^5-7

Despite all 3 drugs having efficacy in the metastatic setting, the same activity has not been seen consistently in HR-positive EBC. The PALLAS and PENELOPE-B trials were negative for adjuvant palbociclib, whereas monarchE demonstrated positive results with abemaciclib in the EBC disease setting.¹ Possible explanations for the different findings include that monarchE enrolled higher risk patients, that abemaciclib has continuous dosing rather than on-off schedules with palbociclib, and/or that abemaciclib inhibits CDK4 more strongly than CDK6. I should note that the study populations with lower risk HR-positive disease do merit follow-up, because approximately one half of relapses occur after approximately 5 years.⁸

Key ongoing trials in the setting of HR-positive/HER2-negative EBC include NATALEE, which is evaluating ribociclib plus adjuvant ET (NCT03701334). This trial includes lower-risk patients but was modified to enroll additional patients with node-positive disease based on the monarchE results. ADAPTlate is evaluating delayed initiation of abemaciclib in Years 2-6 plus adjuvant ET in patients with high-risk EBC (NCT04565054). We will discuss these trials in more detail.

The phase III monarchE trial compared adjuvant abemaciclib plus ET vs ET alone in high-risk patients with HR-positive/HER2-negative EBC where risk was defined as nodal positivity.9,10 Patients either had ≥4 positive lymph nodes or 1 3 positive lymph nodes in addition to another high risk feature (eg, Ki-67 expression ≥20%). Of importance, patients had to be randomized within a specific treatment window of ≤16 months after surgery.

The results showed benefit from adding abemaciclib to adjuvant ET, with an absolute improvement of 3% in the 2 year rate for invasive disease free survival (iDFS). This was sustained and improved at 3 years, with an absolute improvement of 5.4% in the 3-year iDFS rate. The daily dosing with abemaciclib demonstrated less effect on blood counts than other CDK4/6 inhibitors, but abemaciclib is associated with more gastrointestinal toxicity. These positive data led to the FDA approval of abemaciclib in combination with adjuvant ET (tamoxifen or an aromatase inhibitor) for adults with HR-positive/HER2-negative, node-positive EBC at high risk of recurrence with a Ki-67 score ≥20%.⁷

This early evidence of benefit certainly requires longer follow-up, but the data are impressive given that this was an extremely high–risk patient population. If you look at the iDFS curve shown here, the curves have separated over time without oscillating or crossing over. So, I think the data are real and that this regimen is an exciting new option for patients who are HR positive, who have not had many therapeutic options with iDFS benefit.

The ongoing phase III NATALEE trial has completed accrual and randomized 5101 patients with both lymph node–positive and lymph node–negative HR-positive/HER2-negative EBC to receive either adjuvant ribociclib plus ET and goserelin or ET alone (NCT03701334).¹¹ The ribociclib dose at 400 mg/day in this study is lower than the standard FDA-approved dose at 600 mg/day used in metastatic breast cancer.⁶ The lower dose is intended to decrease the risk of toxicity. However, the NATALEE trial retains the standard monitoring schedule for toxicities.

It is important to remember that ET alone does not require as much monitoring as CDK4/6 inhibitors, which require monitoring of liver function, bone marrow suppression—particularly leukopenia—and neutropenia. I saw firsthand the fatigue of patients in this trial, who were ready to be done with therapy and go back to their normal daily lives. The monitoring tests may take only 5 minutes in the clinic, but visiting the clinic requires time off from work, driving, etc. This cumulative time commitment is something we must consider moving forward with these new therapies in patients with EBC.

The primary endpoint of NATALEE is iDFS, and key secondary endpoints include relapse-free survival, distant disease-free survival (DFS), OS, and safety.

ADAPTlate is a multicenter phase III trial evaluating CDK4/6 inhibitors in 1250 patients at 2-6 years after primary diagnosis (NCT04565054).¹² All patients are pre- or postmenopausal women with high-risk HR-positive/HER2-negative EBC and could not have previously received a CDK4/6 inhibitor. It is important to note that these patients are outside of the treatment window required for monarchE, in which patients had to be enrolled ≤16 months after surgery.

Patients ≥2-6 years after their initial diagnosis of breast cancer are being randomized to receive either abemaciclib in Years 0-2 followed by ET in Years 2-8 or standard ET alone from Year 0 for 5-8 years. The primary endpoint is iDFS, and secondary endpoints include distant DFS, OS, patient quality of life, and the occurrence of central nervous system metastases.

ADAPTlate is focusing on a real unmet need by assessing high-risk patients who do not meet the treatment window of ≤16 months after surgery for adjuvant abemaciclib. It would be fantastic to treat this high-risk patient population, because I sometimes have patients come in who have seen the monarchE data but do not qualify because with the current FDA approval guidelines and healthcare insurance coverages, they missed the monarchE-defined treatment window ≤16 months after surgery. ADAPTlate will determine whether patients can still benefit from delayed CDK4/6 inhibitors in combination with ET and could potentially lead to a new standard of care for patients who missed the 16-month postsurgery window. It also would benefit patients who received radiation therapy and do not immediately want another therapy requiring upfront frequent monitoring when they thought they were done with medical visits and treatment. Being able to give patients a treatment break for 6-12 months may increase their motivation and adherence for later therapies that require close monitoring and visits to the office for several years.

This meta‑analysis compared ET with chemotherapy and found that rates of radiographic response, clinical response, and breast conservation favor ET over chemotherapy, but pathologic compete response (pCR) favors chemotherapy.¹³ CDK4/6 inhibitors are not greatly effective in achieving tumor shrinkage, meaning that overall responses, breast-conservation rates, and tumor shrinkage rates are not the best markers of efficacy for these agents. When we look at those parameters, chemotherapy often was the neoadjuvant treatment of choice to increase eligibility for breast conservation.

We are still figuring out which patients are the most likely to benefit from neoadjuvant ET. CDK4/6 in combination with ET may offer advantages over chemotherapy, as well. Regardless, because the biology of HR-positive disease depends on estrogen signaling, it would be ideal if we could avoid chemotherapy.

Shown here is a snapshot of ongoing trials exploring CDK4/6 inhibitors in patients with HR-positive/HER2-negative EBC (NCT04565054, NCT04293393, NCT03701334, NCT04584853).^11,12,14 CARABELA, eMonarchHER, and POETIC-A are all assessing abemaciclib. CARABELA is in the neoadjuvant setting and is evaluating abemaciclib in combination with letrozole with or without a luteinizing hormone–releasing hormone (LHRH) agonist. Both eMonarchHER and POETIC-A are evaluating abemaciclib in combination with ET in the adjuvant setting. We will go over some of these trials in more depth.

The randomized phase II CARABELA trial enrolled 200 women with intermediate-/high-risk HR-positive/HER2-negative EBC (NCT04293393). Risk factors include elevated Ki-67 expression, grade 3 histology, and PR loss. Patients are randomized to receive letrozole plus abemaciclib with or without LHRH vs doxorubicin plus cyclophosphamide followed by paclitaxel and docetaxel. The patients undergo surgery after ≤12 months of therapy with letrozole plus abemaciclib with or without LHRH or ≤8 months of chemotherapy.

The primary endpoint is residual cancer burden, and secondary endpoints include invasive event-free survival (EFS), Ki-67 expression changes, radiographic response, the rate of breast conservation surgery, and safety. It will be interesting to determine which regimen is better in a head‑to‑head fashion, and this trial will hopefully help us decide which patients should receive ET plus a CDK4/6 inhibitor or chemotherapy.

The phase II ImmunoADAPT has enrolled 40 patients with stage II-III HR-positive breast cancer who have not received ET in the past 10 years and have never received a CDK4/6 inhibitor or immune checkpoint inhibitor (NCT03573648). Following a biopsy, patients are randomized to receive a 28‑day lead‑in with ET alone or ET plus palbociclib based on the hypothesis that the CDK4/6 inhibitor will improve response to subsequent immunotherapy. After the lead-in and a second biopsy, patients receive 3 cycles of avelumab plus ET or ET plus palbociclib plus avelumab before undergoing surgery. The primary endpoint is clinical response rate, and secondary endpoints are safety and tolerability.

This trial will help determine if CDK4/6 inhibitors in combination with ET make tumors more immune responsive, like we observed in the setting of triple‑negative breast cancer. Trials in the population with HR-positive disease have struggled to show a validated benefit with immunotherapy in either the metastatic or neoadjuvant setting because of tumor heterogeneity.

neoMONARCH is a multicenter, randomized phase II trial of 224 postmenopausal women with stage I-IIIB HR-positive/HER2-negative breast cancer who have not received previous systemic treatment.¹⁵ Patients are randomized to receive a 2-week lead-in with abemaciclib plus anastrozole (n = 74), abemaciclib alone (n = 75), or anastrozole alone (n = 74). Following the lead-in, patients receive 14 weeks of abemaciclib in combination with anastrozole. A baseline biopsy precedes treatment, another biopsy follows the 2‑week lead‑in, and a final biopsy occurs after the final 14 weeks of treatment. The primary endpoint is the percent change in Ki-67 expression from baseline to 2 weeks of treatment, and secondary endpoints are pCR, objective response, and radiologic response.

One advantage of CDK4/6 inhibitors is reduced cell proliferation—which may be an important marker of efficacy to help us determine which patients are likely to benefit from neoadjuvant CDK4/6 inhibitors. If cell proliferation does not decrease with CDK4/6 inhibition, this strategy may need to be abandoned in favor of other strategies.

NSABP FB‑13 is a single-arm phase II trial of 24 premenopausal women with HR-positive/HER2-negative breast cancer who had no previous ET but were candidates for neoadjuvant ET (NCT03628066). Additional enrollment criteria were tumors of ≥2 cm and a 21-gene recurrence score <26. The 2 cohorts are based on recurrence score. Following an initial biopsy, patients receive letrozole plus palbociclib and goserelin for 6 weeks. Following another biopsy, patients receive either 6 more cycles of therapy (if Ki-67 ≤10%) or chemotherapy or surgery (if Ki-67 >10%). A final biopsy is done at the time of completion of study therapy or definitive surgery.

The primary endpoint of the trial is complete cell cycle arrest, and secondary endpoints include overall response rate (ORR) and pCR. This trial, like the others, is trying to determine who can be spared chemotherapy and instead receive neoadjuvant ET with a CDK4/6 inhibitor.

Another ongoing trial has enrolled 200 women with HR-positive/HER2-negative breast cancer with tumors >15 mm and Ki-67 expression ≥14% (NCT03969121). Patients could not have received previous radiotherapy or systemic therapies. Patients are randomized to receive ET for 16 weeks plus palbociclib on Days 1-21 of 28-day cycles for 4 months vs ET for 16 weeks plus placebo. Following treatment, patients undergo surgery.

The coprimary endpoints are preoperative endocrine prognostic index at 4 months and recurrence risk score. Secondary endpoints include a decrease in Ki-67 expression at 4 months, pCR, the rate of breast-conserving surgery, and adverse events.

The development of resistance to ET is linked to the development of ESR1 mutations.¹⁶ These mutations are very rare in primary tumors but increase in frequency with progression and the number of treatment lines. So, how can we offset this resistance?

SERDs are a new class of drugs that may have greater activity in aromatase inhibitor–resistant cancers with ESR1 mutations.^17,18 Fulvestrant is currently the only SERD with FDA approval, but this agent has poor bioavailability, so its efficacy is limited.¹⁹ Oral SERDs may have better bioavailability and efficacy; these agents are currently in clinical trials in the setting of advanced breast cancer.²⁰

This table shows oral SERDs currently under clinical investigation either alone or in combination with PI3K inhibitors and CDK4/6 inhibitors.^20-28 Most of the patients enrolled on these trials have received several prior lines of therapy including CDK4/6 inhibitors and fulvestrant. Patients with ESR1 mutations also are enrolled.

These agents would be potentially advantageous to patients because they are administered orally rather than as an injection like fulvestrant. However, it is unclear if there will be enough of an efficacy and tolerability benefit for their approval.

ADCs represent another promising therapeutic strategy based on the data for trastuzumab emtansine in the setting of HER2-positive metastatic breast cancer. As I previously alluded to, HER2 expression can be low, and HER2-directed ADCs still can have efficacy in HER2-low disease through the bystander killing effect. Bystander killing occurs when the toxic payload is released from the antibody either intracellularly—in which case it can cross the cell membrane—or extracellularly.²⁹ The payload can then kill surrounding cells that do not express HER2. Because 45% to 55% of patients with breast cancer have HER2-low disease, ADCs could benefit a substantial number of patients if they are found to be effective in clinical trials.

T-DXd consists of a HER2-targeting antibody conjugated to the topoisomerase inhibitor deruxtecan.^30,31 T-DXd is currently approved in the setting of advanced HER2-positive breast cancer for patients who have received prior anti-HER2-based therapy either in the metastatic setting or in the (neo)adjuvant setting and have developed disease recurrence ≤6 months after completing therapy.³²

The DESTINY-Breast04 trial found that T-DXd improved PFS in patients with HR-positive breast cancer and low HER2 expression. HER2 low was defined as 1+ by IHC or 2+ with negative in situ hybridization.³³

T-DXd also is being examined in earlier-stage breast cancer. The randomized, open-label phase II TALENT trial is comparing neoadjuvant therapy with T-DXd alone vs T-DXd plus anastrozole and a gonadotropin-releasing hormone agonist in men and premenopausal women (N = 58) with HR-positive/HER2‑low stage I-II breast cancer.³⁴ HER2 low is defined as having an IHC score of 1+ or 2+ and being negative by fluorescence in situ hybridization. T-DXd is given every 3 weeks for 6 cycles, whereas anastrozole is given daily for each cycle. If either arm has ≥2 patients who achieve pCR, that arm will advance to the next stage and enroll 15 additional patients.

The primary endpoint is pCR at definitive surgery, and secondary endpoints are clinical objective response, biomarker analyses, and safety. We hope the trial will show some benefit that could be practice changing for patients with HER2-low EBC not currently eligible for HER2‑directed therapy. Given that these therapies are showing a signal of efficacy, the data from the TALENT trial will be quite interesting.

Another ADC under investigation is sacituzumab govitecan, which is currently approved for metastatic triple-negative breast cancer.³⁵ The antibody targets TROP2, an antigen expressed in numerous malignancies, including triple-negative breast cancer. The payload, an irinotecan metabolite, is not typically used for breast cancer.

Sacituzumab govitecan is being assessed in 1200 patients with HER2-negative EBC at high risk of recurrence in the phase III SASCIA trial (NCT04595565). To be eligible, patients had to have received standard neoadjuvant chemotherapy and still have residual disease despite adequate surgical treatment. Patients are randomized to receive sacituzumab govitecan vs physician’s choice of capecitabine, platinum-based chemotherapy, or observation.

The primary endpoint is iDFS, and secondary endpoints include OS, distant DFS, iDFS and OS in subgroups, and safety. It will be interesting to see whether there is evidence supporting the selection of postoperative adjuvant therapy in patients with residual disease.

Turning now to clinical trials investigating immunotherapy, the phase III KEYNOTE-756 trial is comparing pembrolizumab vs placebo in combination with neoadjuvant chemotherapy and adjuvant ET in patients newly diagnosed with high-risk ER-positive/HER2-negative EBC (NCT03725059).³⁶ Patients were stratified by region, PD-L1 status, nodal status, and anthracycline dose and randomized to receive pembrolizumab or placebo for 8 cycles of neoadjuvant therapy plus paclitaxel during cycles 1-4 and doxorubicin or epirubicin plus cyclophosphamide for cycles 5-8. After cycle 8, all patients went on to surgery before receiving 9 cycles of adjuvant ET with pembrolizumab or placebo. ET in both arms can continue for ≤10 years.

The coprimary endpoints are pCR (ypT0/Tis ypN0) and EFS, and secondary endpoints include pCR (ypT0 ypN0, ypT0/Tis, ypT0/Tis ypN0), OS, health-related quality of life, safety, and tolerability.

The phase III CheckMate 7FL trial is comparing neoadjuvant nivolumab or placebo with chemotherapy followed by adjuvant nivolumab or placebo with ET in 1200 patients newly diagnosed with high-risk ER-positive/HER2-negative grade 2-3 breast cancer (NCT04109066).³⁷ Stratification was based on PD-L1 expression on tumor-infiltrating lymphocytes, tumor grade, nodal status, and anthracycline plus cyclophosphamide. Patients are randomized to receive 4 cycles of nivolumab plus paclitaxel or placebo plus paclitaxel followed by 4 cycles of nivolumab or placebo alone prior to surgery. Following surgery, patients receive 7 cycles of either nivolumab plus ET or placebo plus ET.

The primary endpoints are pCR (ypT0/is ypN0) and EFS, and secondary endpoints include OS, DFS, ORR, adverse events, and quality of life.