Studies Explore a New Role for CDK4/6 Inhibition in HR+/HER2+ Breast Cancer and TNBC

Priyanka Sharma, MD

DATA FROM EARLY CLINICAL studies suggest a role for CDK4/6 inhibitor-based combinations in hormone receptor (HR)- positive, HER2-positive breast cancer and triple-negative breast cancer (TNBC). These data signify a new, nonchemotherapeutic alternative to therapies currently in use if the class of agents continues to demonstrate its efficacy in ensuing trials, according to Priyanka Sharma, MD.¹

“In the HER2-positive space we have several effective regimens that are available and new drugs have recently been added to that menu, but resistance to HER2-targeted therapy is still an issue and chemotherapy-free options are always desired by patients and providers. That’s where CDK4/6 inhibitors come in,” Sharma said in an interview in advance of her presentation at the 19th Annual International Congress on the Future of Breast Cancer^® East, a virtual program hosted by Physicians’ Education Resource^®, LLC (PER^®).

This class of agents has efficacy in HR-positive/HER2-negative disease, where 3 anti-CDK4/6 agents—abemaciclib (Verzenio), palbociclib (Ibrance), and ribociclib (Kisqali)—are approved for use.² Oncologic investigations are ongoing to determine whether the advantage seen in HR-positive/HER2-negative breast cancer extends to HR-positive/HER2-positive disease. The rationale for testing CDK4/6 inhibition in HR-positive/ HER2-positive disease and TNBC is based in part on preclinical data demonstrating that CDK4/6 is downstream of “several of the proposed resistance mechanisms for HER2-targeted therapy,” and can “reverse resistance” to trastuzumab (Herceptin) in cell lines and xenograft models,1 added Sharma, a medical oncologist with expertise in breast cancer at the University of Kansas Medical Center in Kansas City.

These preclinical findings have prompted several investigations into the utility and clinical applicability of CDK4/6 inhibitors in the HR-positive/HER2-positive and TNBC spaces. In the HER2-positive setting, these include the phase 2 PATRICIA II (NCT02448420) and monarcHER studies (NCT02675231), among others.

“We’re seeing results from SOLTI-1303 PATRICIA [PATRICIA II], which showed that treatment with trastuzumab, a CDK4/6 inhibitor, and anti–estrogen therapy had early signals of efficacy,” Sharma said. SOLTI-1303 PATRICIA is a 2-stage study seeking to enroll 232 postmenopausal women with HER2-positive locally advanced or metastatic breast cancer who have received a minimum of 2 and a maximum of 4 prior lines of systemic treatment, at least 1 of which must have been trastuzumab. Investigators will test the hypothesis that the addition of palbociclib to standard therapy is well tolerated and can provide a progression-free survival (PFS) benefit.

The first stage of the trial enrolled 15 patients each to cohorts A, B1, and B2, which included individuals with HR-negative/HER2-positive, HR-positive/ HER2-positive, and HR-positive/HER2-positive disease, respectively. For stage I to be successful, at least 6 patients had to be progression-free at 6 months in each cohort. The 6-month PFS rate was 33.3% in cohort A (5 of 15), 40.0% in cohort B1 (6 of 15), and 53.3% in cohort B2 (8 of 15), with both of the HR-positive/HER2-positive groups meeting this threshold.

Following the completion of stage I, investigators are now preparing to test different therapeutic interventions across 3 treatment arms. Patients in arm A and arm B1 will be treated with trastuzumab and palbociclib, and individuals in cohort B2 will receive trastuzumab, palbociclib, and letrozole.

Investigators are additionally planning to add 2 adaptive cohorts, C1 and C2.³ Palbociclib, trastuzumab, and endocrine therapy will be administered in C1, and physician’s choice of ado-trastuzumab emtansine (T-DM1; Kadcyla) or chemotherapy in combination with trastuzumab in C2. Cohorts C will enroll patients with HR-positive/HER2-positive, PAM50- confirmed luminal intrinsic subtype breast adenocarcinoma who have completed a minimum of 1 and no more than 4 prior lines of anti–HER2 regimens for locally advanced disease or metastatic breast cancer, including trastuzumab, a taxane, and an antibody-drug conjugate. In these 2 cohorts, the adaptive design will be applied to compare arms of treatment in patients with luminal subtype locally advanced or metastatic breast cancer. The primary end point is PFS.

Beyond PATRICIA II, Tolaney et al published results from the monarcHER study involving 237 patients with HR-positive/HER2-positive advanced breast cancer. “This trial again asked the question, ‘Can we improve upon the current available options in [the] third-line HR-positive/ HER2-positive [setting] with the use of a CDK4/6 inhibitor?’ ” Sharma said.

The monarcHER trial, which similarly cast PFS as its primary end point, evaluated the efficacy of abemaciclib in combination with trastuzumab and fulvestrant (Faslodex) in arm A, abemaciclib and trastuzumab in arm B, and trastuzumab and investigator’s choice of chemotherapy in arm C. Findings showed that the combination of abemaciclib, fulvestrant, and trastuzumab prolonged PFS compared with trastuzumab and standard-of-care chemotherapy in this patient population. Specifically, at a median follow-up of 19.0 months, the PFS was 8.3 months with the triplet therapy versus 5.7 months with trastuzumab and chemotherapy (hazard ratio, 0.67; P = .051). The median PFS was 5.7 months with abemaciclib and trastuzumab. Although there was no PFS benefit in arms B or C, the improvement in arm A was statistically significant at the prespecified 2-sided alpha of 0.2.¹

“The trial also showed that the [3-drug] combination was well tolerated with no new safety signals, and this is a chemotherapy-free regimen so this is very encouraging” Sharma said, adding that the field eagerly awaits the completion and final results of PATRICIA II, among other ongoing studies, to “see if CDK 4/6 inhibitors fit into the treatment paradigm for patients with HR-positive/HER2-positive disease.” Identifying predictive biomarkers of CDK4/6 benefit will also be an integral component of the determination of whether there is a place for these agents in HR-positive/HER2- positive cancer, Sharma concluded.

TNBC

Given TNBC’s high rate of genomic or functional loss of the Rb protein, the breast cancer subtype is considered to be a poor candidate for CDK inhibition. However, several preclinical studies involving these agents have shown efficacy and have specifically suggested that combining CDK4/6 inhibitors with PI3K-mTOR or other mTOR inhibitors or anti-EGFR agents could be fruitful. Administering CDK4/6 inhibitors with androgen receptor–targeting therapies might also hold promise, Sharma said. Investigators are awaiting clinical trials that will test these CDK4/6-based regimens, as well as the results of ongoing randomized studies.¹

Data from a phase 2 study (NCT02978716) of trilaciclib (G1T28), a novel CDK4/6 inhibitor, plus gemcitabine and cisplatin in 102 patients with metastatic TNBC have already yielded “very intriguing results,” Sharma said. Although the regimen did not meet the trial’s primary myelosuppression safety end points, failing to reduce the frequency and duration of severe (grade 4) neutropenia or improve PFS or objective response rates, it unexpectedly increased overall survival (OS) compared with chemotherapy alone. The median OS was 12.6 months with chemotherapy alone (group 1; n = 34), 20.1 months with chemotherapy and concurrent trilaciclib (group 2; n = 33), and 17.8 months with chemotherapy and trilaciclib, with additional subsequent doses of the CDK4/6 inhibitor (group 3; n = 35). The 12-month OS rate was 67% with concurrent chemotherapy and trilaciclib compared with chemotherapy alone (P = .028). Further the OS rate was 66% with concurrent chemotherapy plus additional trilaciclib compared with chemotherapy alone (P = .0023).

Confirmatory studies will be needed to not only validate the observed OS benefit, but also identify the mechanisms behind it, Sharma said. “This was a very interesting trial and we have arranged to see if these [data] can be confirmed in a randomized phase 3 trial,” she concluded.

1. Sharma P. CDK4/6 inhibitors for HER2-positive and triple-negative metastatic breast cancer. Presented at: 19th Annual International Congress on the Future of Breast Cancer^® East; July 17-18, 2020; virtual. 
2. Gao JJ, Cheng J, Bloomquist E, et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol. 2020;21(2):250-260. doi:10.1016/S1470-2045(19)30804-6
3. Study of palbociclib and trastuzumab with endocrine therapy in HER2-positive metastatic breast cancer. ClinicalTrials.gov. Updated July 28, 2020. Accessed August 12, 2020. https://clinicaltrials.gov/ct2/show/NCT02448420