New Data Augment the Treatment Paradigm in HR+/HER2– Breast Cancer

Mark Pegram, MD

The utility of continued CDK4/6 inhibition, selective estrogen receptor degraders (SERDs) as monotherapy or combination partners, and antibody-drug conjugates (ADCs) spanning new classifications of hormone receptor–positive (HR+) disease are all avenues that researchers are hopeful will improve the 5-year overall survival (OS) rate for patients with HR+, HER2-negative (HER2–) breast cancer, which currently sits at just 24%.¹

“[Biomarker testing] in the metastatic setting is critically important and is completely different from the genomic assays we use for early-stage breast cancer,” Mark Pegram, MD, said. “It’s important to document first metastasis by biopsy to secure the diagnosis histopathologically and not run into the trouble of another tumor type that metastasized in the same patient or a benign condition that mimics metastasis. Consequently, that gives you an opportunity to repeat estrogen and progesterone receptor and HER2 status because that can change. These are dynamic variables. They are not static. They can change, and that can impact metastatic treatment decisions in the first or later lines.”

During a recent OncLivePeer Exchange^®, a panel of expert breast cancer clinicians discussed data updates in HR+, HER2– breast cancer in the context of new findings from clinical trials presented during the 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024), which took place from May 31 to June 4 in Chicago, Illinois. The panelists primarily highlighted recent results from studies in advanced and metastatic HR+, HER2– breast cancer.

First-Line Advanced and Metastatic HR+/HER2–Breast Cancer

In the frontline setting of advanced or metastatic HR+, HER2– breast cancer, CDK4/6 inhibitors in combination with endocrine therapy are the standard of care and there are a variety of agents to choose from, allowing for better tailored care to individual patients. Since March 2017, palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali) have all received FDA approval in combination with endocrine therapy in this disease setting. The regulatory decisions were supported by findings from the phase 3 PALOMA-2 (NCT01740427), MONARCH 3 (NCT02246621), and MONALEESA-7 (NCT02278120) trials, respectively (Figure).^2-4

Figure

During ASCO 2024, investigators presented findings from the Italian PALMARES-2 study. The retrospective, real-world study is the largest study to date that demonstrates that palbociclib, abemaciclib, and ribociclib have differing efficacy for the frontline treatment of patients with HR+, HER2– breast cancer. The study included adult women with inoperable, locally advanced, or metastatic HR+, HER2– breast cancer who did not receive prior chemotherapy for advanced disease and had a minimum of 3 months of follow-up after beginning endocrine therapy in combination with a CDK4/6 inhibitor. The primary objective was to compare the real-world efficacy of the 3 agents in terms of real-world progression-free survival (PFS).⁵

“PALMARES-2 was interesting, [although] it wasn’t a randomized study, so there were selection biases as I understand it, where patients with higher-risk disease tended to go on abemaciclib,” Sara A. Hurvitz, MD, FACP, said. “But it was interesting to see that in that data set, abemaciclib and ribociclib beat out palbociclib in terms of PFS. It was concordant with the data that we’re seeing; my go-to tends to be ribociclib, because patients are less aware they’re on it due to the gastrointestinal [toxicities], but you have to be careful about drug-drug interactions.”

Findings from PALMARES-2 showed that the median real-world PFS and median OS in the overall population (n = 1850) was 34.7 months (95% CI, 31.1-36.7) and 66.6 months (95% CI, 61.4-not applicable [NA]), respectively. For the individual therapy comparisons, abemaciclib was favored over palbociclib (adjusted hazard ratio, 0.71; 95% CI, 0.56-0.90; P = .005) as well as ribociclib (adjusted hazard ratio, 0.91; 95% CI, 0.70-1.19; P = .505) in terms of real-world PFS, and ribociclib was favored vs palbociclib (adjusted hazard ratio, 0.81; 95% CI, 0.65-0.99; P = .048). Study authors noted that longer follow-up data from the study will include mature OS findings and will be key to confirm the results.

“It was very interesting that abemaciclib was being used in patients who are at a higher risk for progression, [such as] those with visceral metastatic disease, and the abemaciclib did really well,” Kelly E. McCann, MD, PhD, said. “There will be some new drugs coming out, including CDK4 inhibitors, and there’s also a CDK2/4/6 inhibitor. It will be very interesting to delve down into what makes abemaciclib different from palbociclib and ribociclib if they are, in fact, very different.”

“I won’t switch my patients who are already on palbociclib, but my new start-ups are going to go to ribociclib. Having said that, if there are some toxicity concerns, palbociclib is the better tolerated of the three and I will switch those patients,” Virginia Kaklamani, MD, added.

Options Following Disease Progression on CDK4/6 Inhibition and Endocrine Therapy

During ASCO 2024, investigators presented findings from clinical trials examining several treatment approaches for patients with progressive HR+, HER2– breast cancer, including CDK4/6 inhibitors with endocrine therapy; SERDs, both as monotherapy and as combination partners; and ADCs. The phase 3 postMONARCH trial (NCT05169567) examined abemaciclib plus fulvestrant (Faslodex) compared with fulvestrant plus placebo in patients with HR+, HER2– advanced breast cancer following disease progression on a previous CDK4/6 inhibitor in combination with endocrine therapy. The primary end point was investigator-assessed PFS; secondary end points included OS, objective response rate (ORR), disease control rate, and safety.⁶

Findings from the primary analysis of postMONARCH showed that patients who received abemaciclib plus fulvestrant (n = 182) achieved a median PFS of 6 months (95% CI, 5.6-8.6) compared with 5.3 months (95% CI, 3.7-5.6) among patients who received fulvestrant plus placebo (n = 186), conferring a reduction in the risk of progression or death of 27% (hazard ratio, 0.73; 95% CI, 0.57-0.95; P = .02). The 6-month PFS rates were 50% vs 37%, respectively, and the PFS benefit consistently favored the abemaciclib arm, according to results from a subgroup analysis. The ORR by blinded independent central review (BICR) was 23% vs 8% among patients with measurable disease in the combination (n = 131) and control (n = 127) arm (nominal P = .0008).

Study authors noted that postMONARCH was the first phase 3, randomized, placebo-controlled study with findings to demonstrate a benefit with continued CDK4/6 inhibition with abemaciclib plus fulvestrant after disease progression on a CDK4/6 inhibitor. “There are a lot of questions about this clinical trial,” Kaklamani said. “Most of the patients were [previously] on palbociclib. The patients [on] ribociclib were fewer, and the 95% CIs in the ribociclib arm were pretty low. Patients having bone-only disease didn’t seem to have that much of a benefit, so that’s another question. But this trial is underpowered to look at these questions. I had not been [using] this [combination] until I got the results from postMONARCH. Now I might use it in a select patient population but not for all patients.”

The phase 1b/2 ELECTRA trial (NCT05386108) built upon the strategy of CDK4/6 inhibition in HR+, HER2– breast cancer by combining the oral SERD elacestrant (Orserdu) with abemaciclib. The study enrolled adult patients who received at least 1 prior endocrine therapy, 2 or fewer prior chemotherapy regimens, and 2 or fewer CDK4/6 inhibitors excluding abemaciclib. The primary end point in the phase 1b portion was safety per dose-limiting toxicities and determining the recommended phase 2 dose (RP2D); the primary end point in the phase 2 portion was ORR in patients with brain metastases.⁷

Findings from the phase 1b portion of the study showed that the combination was well tolerated and the safety profile was consistent with that of the individual agents; no grade 4 treatment-emergent adverse effects (TEAEs) were observed, and most TEAEs were of grade 1 or 2 severity. Among patients evaluable for efficacy treated across all dose levels (n = 26), 1 patient achieved a complete response, 4 patients experienced partial responses (PRs), and 14 patients experienced stable disease. The RP2D of the combination was daily elacestrant 345 mg in combination with twice-daily abemaciclib 150 mg.

The phase 1b/2 ELEVATE study (NCT05563220) sought to further characterize the efficacy of elacestrant in locally advanced or metastatic HR+, HER2– breast cancer by evaluating it as a component of various combinations. ELEVATE examined the safety and efficacy of elacestrant in combination with everolimus (Afinitor), alpelisib (Piqray), ribociclib, palbociclib, or capivasertib. The primary end point in phase 1b was to determine the RP2D of elacestrant in combination with each of the other study drugs.⁸

Preliminary data from ELEVATE demonstrated that among patients evaluable for efficacy who received elacestrant plus everolimus across dose levels (n = 13), 4 patients experienced a PR and 7 experienced stable disease. In the elacestrant plus ribociclib arm (n = 18), only 1 patient achieved a PR and 10 experienced stable disease. The RP2D for the combination was determined to be elacestrant 345 mg plus everolimus 7.5 mg daily. Findings from the other combinations will be presented later, but elacestrant displayed the potential to be the endocrine therapy backbone of targeted therapy combinations, study authors noted.

In the phase 2 Saci-IO study (NCT04448886), investigators evaluated the TROP2-directed ADC sacituzumab govitecan-hziy (Trodelvy) with or without pembrolizumab (Keytruda) in patients with unresectable locally advanced or metastatic HR+, HER2– breast cancer. Eligible patients needed to have received at least 1 prior endocrine therapy for metastatic disease or experienced progression on or within 12 months of adjuvant endocrine therapy and no more than 1 prior chemotherapy regimen; brain metastases were permitted if patients completed locoregional therapy and discontinued steroids at least 1 week prior to receiving study therapy. The primary end point was PFS; the study was the first randomized trial to report efficacy findings for a topoisomerase I inhibitor ADC in combination with an immune checkpoint inhibitor in breast cancer.⁹

Findings from the study showed that patients who received sacituzumab govitecan plus pembrolizumab (n = 52) achieved a median PFS of 8.12 months (95% CI, 4.51-11.12) compared with 6.22 months (95% CI, 3.85-8.68) among patients who received the ADC alone (n = 52; hazard ratio, 0.81; 95% CI, 0.51-1.28; log-rank P = .37). Additionally, the median OS was 18.52 months (95% CI, 16.55-NA) vs 17.96 months (95% CI, 12.50-NA), respectively (hazard ratio, 0.65; 95% CI, 0.33-1.28; log-rank P = .21).

“This is interrogating in a proof-of-concept way whether adding immunotherapy [to an ADC] benefits patients,” Hurvitz said. “There was an interesting 1- or 2-month improvement in PFS by adding pembrolizumab to sacituzumab govitecan. [There was] no difference in OS, and the ORRs were overlapping CIs between the 2 arms. The data are interesting; [the combination] was tolerable. There are 2 ongoing phase 3 trials right now looking at sacituzumab govitecan with pembrolizumab in triple-negative breast cancer and in the metastatic setting. It’s unclear whether that’s positive; maybe we’ll see this move into the metastatic setting for hormone receptor–positive [disease].”

In the phase 3 DESTINY-Breast06 trial (NCT04494425), investigators evaluated another ADC, fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), vs investigator’s choice of chemotherapy in patients with HR+, HER2-low, or HER2-ultralow breast cancer who had received prior endocrine therapy. Patients were required to be chemotherapy naive in the metastatic breast cancer setting and to have received at least 2 lines of endocrine therapy with or without targeted therapy for metastatic breast cancer or 1 line of prior therapy and progression within 6 months of starting frontline CDK4/6 inhibition plus endocrine therapy or disease recurrence within 24 months of starting adjuvant endocrine therapy. The primary end point was PFS by BICR in patients with HER2-low disease; key secondary end points included PFS in the intention-to-treat (ITT) population (HER2-low and HER2-ultralow disease) and OS.¹⁰

Primary findings from DESTINY-Breast06 showed that patients with HER2-low disease who received T-DXd (n = 359) achieved a median PFS of 13.2 months compared with 8.1 months among patients who received physician’s choice of chemotherapy (n = 354; hazard ratio, 0.62; 95% CI, 0.51-0.74; P < .0001). Similarly, the median PFS in the ITT population was 13.2 months vs 8.1 months, respectively (hazard ratio, 0.63; 95% CI, 0.53-0.75; P < .0001). The confirmed ORRs in the ITT population were 57.3% vs 31.2%, respectively.

“The ADC class is a favorite of mine in terms of theoretical potential for future years, [as] there are many other therapeutic targets,” Pegram said in conclusion. “There are unique payloads that are nonchemotherapy payloads that are particularly exciting, especially immunologic payloads. That could be a game changer: the activation of human innate immunity. It’s been difficult to do that systemically because of off-target, inflammatory toxicity. But if you direct it only to the tumor, you might avoid a lot of the systemic toxicity, improve the pharmacokinetics, and improve the therapeutic index across the board.”

References

1. Cao LQ, Sun H, Xie Y, et al. Therapeutic evolution in HR+/HER2- breast cancer: from targeted therapy to endocrine therapy. Front Pharmacol. 2024;15:1340764. doi:10.3389/fphar.2024.1340764
2. Palbociclib (Ibrance). FDA. March 31, 2017. Accessed June 13, 2024. bit.ly/4crzHLI
3. FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer. FDA. February 26, 2018. Accessed June 13, 2024. bit.ly/3KR95bg
4. FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. FDA. July 18, 2018. Accessed June 13, 2024. bit.ly/3RBQmnQ
5. Vernieri C, Provenzano L, Giuliano M, et al. Comparison of antitumor efficacy of first-line palbociclib, ribociclib, or abemaciclib in patients with HR+/HER2- aBC: results of the multicenter, real-world, Italian study PALMARES-2. J Clin Oncol. 2024;42(suppl 16):1014. doi:10.1200/JCO.2024.42.16_suppl.1014
6. Kalinsky K, Bianchini G, Hamilton EP, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the phase 3 postMONARCH trial. J Clin Oncol. 2024;42(suppl 17):LBA1001. doi:10.1200/JCO.2024.42.17_suppl.LBA1001
7. Ibrahim NK, Hamilton EP, Kim SB, et al. Elacestrant in combination with abemaciclib in patients (pts) with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer: preliminary data from ELECTRA, an open-label, multicenter, phase 1b/2 study. J Clin Oncol. 2024;42(suppl 16):1064. doi:10.1200/JCO.2024.42.16_suppl.1064
8. Rugo HS, O’Shaughnessy J, Cortes J, et al. Elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (adv/mBC): preliminary data from ELEVATE, a phase 1b/2, open-label, umbrella study. J Clin Oncol. 2024;42(suppl 16):1069. doi:10.1200/JCO.2024.42.16_suppl.1069
9. Garrido-Castro AC, Kim SE, Desrosiers J, et al. SACI-IO HR+: a randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer. J Clin Oncol. 2024;42(suppl 17):LBA1004. doi:10.1200/JCO.2024.42.17_suppl.LBA1004
10. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000