Novel Combinations Carry CDK4/6 Inhibitors Into the Future in HR+/HER2- Breast Cancer

Patients with advanced hormone receptor–positive, HER2-negative breast cancer still face acquired resistance, even with the most effective agents, namely CDK4/6 inhibitors, which have demonstrated unprecedented overall survival (OS) benefit in the metastatic setting. Investigators in the field, however, are continuing to explore pathways implicated in resistance, said Komal Jhaveri, MD, explaining that FGFR inhibitors, PI3K inhibitors, and selective estrogen receptor downregulators (SERDs) are just a few of the therapeutic classes under investigation in combination with CDK4/6 inhibitors.

“We’re really trying to understand how to appropriately treat our patients and [determine] the next line of therapy for a patient who progresses on a CDK4/6 inhibitor. [To that end], we’re trying to understand the genomic alterations and the next-generation sequencing data from tissue and plasma to better address that question,” Jhaveri, a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York, New York, said in an interview with OncLive®.

Before diving into some of the novel combinations under investigation, she spoke to the profound effects that CDK4/6 inhibitors have had on the field.

“The unprecedented, near doubling if not more of progression-free survival compared with endocrine therapy alone in the first-line setting has certainly changed our treatment paradigm,” Jhaveri said. “For patients who haven’t seen a CDK4/6 inhibitor in the first line, even in the second-line setting, we’ve been able to show a statistically significant progression-free [survival] benefit, justifying the use of this class of agents in the first- or second-line settings.”

At the European Society for Medical Oncology Congress 2019, two approved CDK4/6 inhibitors—ribociclib (Kisqali) and abemaciclib (Verzenio)—were shown to prolong OS as well. According to findings from the phase 3 MONALEESA-3 trial (NCT02422615), the median OS was not reached with ribociclib versus 40 months with fulvestrant (Faslodex) alone in postmenopausal women with advanced HR-positive, HER2-negative breast cancer (HR, 0.724; 95% CI, 0.568-0.924; P = .00455).¹ These data were presented shortly after the 2019 American Society of Clinical Oncology Annual Meeting, where findings from the MONALEESA-7 trial (NCT02278120) showed that the median OS was not reached with ribociclib versus 40.9 months (95% CI, 37.8-not reached), with endocrine therapy alone as first-line therapy in premenopausal women with advanced hor-mone receptor–positive, HER2-negative breast cancer (HR, 0.71; 95% CI, 0.54-0.95; P = .00973) (TABLE^1,2).²

Table. Efficacy Results in MONALEESA Trials^1,2

Moreover, in the phase 3 MONARCH 2 trial (NCT02107703), abemaciclib led to a median OS of 46.7 months versus 37.3 months with fulvestrant alone in patients with advanced hormone receptor–positive, HER2-negative breast cancer who progressed on prior endocrine therapy (HR, 0.757; 95% CI, 0.606-0.945; P = .01).3 Such findings have set the stage for investigation into combinations with CDK4/6 inhibi-tors and novel targets, such as FGFR, explained Jhaveri.

“There is some [indication] from the PALOMA-3 [NCT01942135] and MONALEESA-2 [NCT01958021] trials, and other preclinical data, that perhaps FGFR1 amplification is a mechanism of resistance [to CDK4/6 inhibitors] and a benefit [might be seen] if one were to potentially target it with an FGFR inhibitor,” said Jhaveri.

Jhaveri also pointed to research led by Carlos Arteaga, MD, director of the Simmons Comprehensive Cancer Center and associate dean of Oncology Programs at UT Southwestern Medical Center, which suggests a potential role for triplet therapy with an FGFR inhibitor and CDK4/6 inhibitor plus endocrine therapy.

Such research is being investigated in a phase 1 trial (NCT03238196) evaluating the addition of erdafitinib (Balversa) to palbociclib (Ibrance) and fulvestrant in women with FGFR-amplified estrogen receptor (ER)–positive, HER2-negative breast cancer. To be eligible for enrollment, patients must have had at least 1 line of therapy in the metastatic setting. Notably, prior CDK4/6 inhibition will not serve as an exclusion criterion. As such, the preliminary results from the trial, which will be presented at the 2020 San Antonio Breast Cancer Symposium, will not only illustrate the activity of the triplet in an FGFR-amplified population but also potentially inform the utility of continuing CDK4/6 inhibition upon progression.

“There are many important questions that we’re still now trying to understand in the clinic, and these research efforts are underway, including whether there’s a role for continuing CDK4/6 beyond progression,” said Jhaveri. “The paradigm that we use in HER2-positive metastatic breast cancer is that targeting the HER2 pathway remains important and we continue anti-HER2 therapy beyond progression. The same is not yet clear for the utilization of CDK4/6 inhibitors beyond CDK4/6 [progression]. That’s something we’re actively evaluating in ongoing trials, such as MAINTAIN [NCT02632045].”

Another approach under investigation is that of combined PI3K and CDK4/6 inhibition, explained Jhaveri.

“CDK4/6 is downstream of the PI3K/AKT/mTOR pathway, so if one were to consider dually vertically inhibiting these pathways together, we might be able to see better synergistic activity,” she said.

Key trials in this regard include PASTOR (NCT02599714), PIPA (NCT02389842), LeeBLet (NCT02154776), and TRINITI-1 (NCT02732119), among others.

ESR1 mutations are another viable target, arising in approximately 30% of women who have received prior aromatase inhibitors. Oral SERDs are currently the subject of investigation in this setting, but whether they will pan out, either as single agents or in combination, has yet to be determined, said Jhaveri.

Although the data are still in early stages, findings from a phase 1/1b trial (NCT02734615) indicated that the oral SERD LSZ102 was well tolerated and was active in combination with ribociclib or alpelisib (Piqray) in patients withER-positive breast cancer who had progressed on endocrine therapy. In the 3-arm study, investigators evaluated LSZ102 alone (arm A), in combination with ribociclib (arm B), and in combination with alpelisib (arm C). In arm A, LSZ102 elicited an objective response rate of 1.3%, a clinical benefit rate of 9.1%, and a medi-an progression-free survival of 1.8 months (95% CI, 1.7-2).⁴

In arm B, the addition of LSZ102 to ribociclib led to a 15.8% ORR and a CBR of 35.5%; the median PFS was 6.2 months (95% CI, 4.4-6.4). The combination of LSZ102 and alpelisib demonstrated an objective response rate of 5.4%, a clinical benefit rate of 18.9%, and a median progression-free survival of 3.5 months (95% CI, 1.8-5.5).

References

1. Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2–) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Ann Oncol. 2019;30(suppl 5):V856-V857. doi:10.1093/annonc/mdz394.007
2. Hurvitz SA, Im S-A, Lu Y-S, et al. Phase III MONALEESA-7 trial of premenopaus- al patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: overall survival (OS) results. J Clin Oncol. 2019;37(suppl 18):LBA1008. doi:10.1200/JCO.2019.37.18_suppl.LBA1008
3. Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: overall survival of abemaci- clib plus fulvestrant in patients with HR+, HER2 advanced breast cancer. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394.006
4. Jhaveri K, Juric D, Yap YS, et al. Interim results of a phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader, in combination with ribociclib (RIB) or alpelisib (ALP) in patients with ER+ breast cancer (BC) who had progressed af- ter endocrine therapy (ET). Ann Oncol. 2020;31(suppl 2):S62. doi:10.1016/j.an- nonc.2020.03.311