Novel CDK4/6 Inhibitor Combos Shape Future for HR+/HER2– Breast Cancer

Komal Jhaveri, MD

Despite the success of CDK4/6 inhibitors in patients with advanced hormone receptor (HR)–positive, HER2-negative breast cancer, acquired resistance develops in many. For these patients, research indicates that treatment sequencing may soon include agents that act on implicated pathways of resistance.

Komal Jhaveri, MD, explained 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 as a means of overcoming drug resistance.

Impact of CDK4/6 Inhibitors 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,” said Jhaveri. “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.”

Two approved CDK4/6 inhibitors, ribociclib (Kisqali) and abemaciclib (Verzenio), have also demonstrated the ability to prolong OS. According to findings from the phase 3 MONALEESA-3 trial (NCT02422615), 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 (hazard ratio, 0.724; 95% CI, 0.568-0.924; P = .00455).¹ Findings from the MONALEESA-7 trial (NCT02278120) showed that the median OS was not reached with ribociclib versus 40.9 months with endocrine therapy alone as first-line therapy in premenopausal women with advanced HR-positive, HER2-negative breast cancer (hazard ratio, 95% CI, 37.8–not estimable).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 HR-positive, HER2-negative breast cancer who progressed on prior endocrine therapy (hazard ratio, 0.757; 95% CI, 0.606-0.945; P = .01).³

Rationale for Combination Therapy

Such findings have set the stage for investigation into combinations with CDK4/6 inhibitors and novel targets, such as FGFR, explained Jhaveri. She cited data from key phase 3 trials of palbociclib (Ibrance) and ribociclib in HR-positive settings that indicate certain baseline tumor characteristics may predict therapy resistance.

“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 pointed to research led by Carlos Arteaga, MD, of 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 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 are scheduled for presentation 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 with ER-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 (ORR) of 1.3%, a clinical benefit rate (CBR) of 9.1%, and a median progression-free survival (PFS) 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 ORR of 5.4%, a CBR of 18.9%, and a median PFS of 3.5 months (95% CI, 1.8-5.5).

“This was the first study that evaluated and presented the results for an oral SERD in combination with both a CDK4/6 inhibitor and also a combination with alpelisib, the α-specific PI3K inhibitor,” said Jhaveri.

_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 premenopausal 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 abemaciclib 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 Y-S, 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 after endocrine therapy (ET). Ann Oncol. 2020;31(suppl 2):S62. doi:10.1016/j.annonc.2020.03.311}