Emerging Therapies in Breast Cancer Excite the Field

Targeted Therapies in Oncology, October 1, 2022,
Pages: 28

Despite advances in the treatment of breast cancer, challenges remain, such as the development of resistance to existing therapies, serious adverse events, and suboptimal treatment adherence.

Many novel therapeutic agents for endocrine therapy–resistant breast cancer are in the clinical trial stage of development, promising more options for patients in the near future.

A key disease management strategy for patients with hormone receptor–positive disease—the most common subtype of breast cancer—has been to modulate estrogen synthesis and/or estrogen receptor (ER) activity, because most hormone receptor–positive cancers depend on ER signaling for tumor growth and progression.1-4 This strategy offers patients with ER-positive metastatic breast cancer the opportunity to avoid chemotherapy until later lines of therapy.5

These endocrine therapies remain the mainstay of treatment options for patients with hormone receptor– positive breast cancer, and combinations with CDK4/6 inhibitors are a common standard-of-care first-line regimen in ER-positive metastatic disease.1,5

“We have come a long way in the treatment of all breast cancer subtypes in the past few years [SEE PAGES 69-80]. We have seen incredible gains in overall [survival (OS)] and progression-free survival [PFS] with the use of CDK4/6 inhibitors and antibody- drug conjugates [ADCs], as well as in PFS with PI3K inhibitors,” said Komal Jhaveri, MD, FACP, section head for the Endocrine Therapy Research Program and clinical director for the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, New York, during an interview with Targeted Therapies in OncologyTM.

Despite advances in the treatment of breast cancer, challenges remain, such as the development of resistance to existing therapies, serious adverse events (AEs), and suboptimal treatment adherence.1,5 There is a clear need for therapies with improved efficacy that prevent or overcome resistance to current agents, reduce/postpone the need for more toxic chemotherapy, optimize patients’ quality of life, and improve treatment outcomes.1,6

Emerging Agents in Development

Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are a growing class of therapeutics that comprise a humanized monoclonal antibody bound to a cytotoxic agent via a molecular linker. When the antibody component of the ADC binds to its target antigen on the cell surface, it induces the internalization of the ADC through endocytosis. The linker is then cleaved, releasing the payload portion inside the cancer cells. This target-dependent activation of the cytotoxic agent produces tumor selectivity, signifi cantly reducing systemic AEs.7

“The recent reports about the activity of ADCs across different subtypes, including HER2-negative and HER2-positive (low and high), as well as triple- negative breast cancer [TNBC], demonstrate that these drugs are active in breast cancer. I think we are going to hear a lot about these studies in the near future and that ADCs are here to stay,” said Jhaveri.

There are several next-generation HER2-targeted ADCs under investigation in clinical trials. These agents have been designed with different payloads and linker technologies to further improve their efficacy and tolerability.7 The FDA a ccepted a biologics license application for [vic-]trastuzumab duocarmazine (SYD985) for patients with HER2-positive unresectable locally advanced or metastatic breast cancer, based on results from the phase 3 TULIP trial (NCT03262935).8 The ADC’s antibody component, trastuzumab (Herceptin), was the first HER2-targeting monoclonal antibody developed and is used in many ADCs. Its payload is duocarmycin, a potent DNA-alkylating molecule that is membrane permeable and thus can enter neighboring cells regardless of HER2 expression.9 T he TULIP trial results showed a significant PFS improvement of 2.1 months (7.0 months vs 4.9 months, respectively; HR, 0.64; 95% CI, 0.49-0.84; P = .002), as well as supportive OS results (HR, 0.83; 95% CI, 0.62-1.09; P = .153), with SYD985 compared with physician’s choice of treatment in heavily pretreated patients.8,10 The most prevalent AE was ocular toxicity (78.1%) and interstitial lung disease/pneumonitis (7.6%) in SYD985-treated patients.10 The Prescription Drug User Fee Act target action date for [vic-]trastuzumab duocarmazine is May 12, 2023.8

Ladiratuzumab is a monoclonal antibody that targets the zinc transporter LIV-1, which is expressed in breast tumors. The expression of LIV-1 is linked to the epidermal-to-mesenchymal transition and, therefore, to poor prognosis and metastasis.11 Conjugation of ladiratuzumab to a cytotoxic payload consisting of monomethyl auristatin E (aka vedotin) produces the LIV-1–targeted ADC ladiratuzumab vedotin (LV; aka SGN-LIV1A). Monotherapy with LV is being investigated for patients with metastatic breast cancer in a phase 1 trial (NCT01969643).12 Among trial participants with TNBC, there was an objective response rate (ORR) of 32%, a disease control rate (DCR) of 64%, and a median PFS of 11.3 weeks. Additionally, a DCR of 59% was observed for patients with hormone receptor–positive, HER2-negative breast cancer.12 The combination of LV with pembrolizumab (Keytruda), a PD-1 inhibitor, is also being evaluated in patients with locally advanced or metastatic TNBC in the phase 1b/2 SGNLVA-002 trial (NCT03310957). There are promising preliminary results for both clinical trials.11-14

Datopotamab deruxtecan (Dato-DXd; DS-1062a) targets the trophoblast cell surface antigen-2 (Trop-2), which is highly expressed in various malignancies, including breast cancer. This ADC is composed of anti–Trop-2 IgG1 monoclonal antibody attached to a topoisomerase 1 inhibitor payload via a tetrapeptide-based cleavable linker.15 Compared with sacituzumab govitecan (Trodelvy), an FDA-approved Trop-2–targeting ADC, Dato-DXd has a longer half-life, and is thought to deliver the payload with greater efficiency, thereby reducing systemic toxicities, such as neutropenia.

In the phase 1 TROPION-PanTumor01 trial evaluating Dato-DXd (NCT03401385), the ORR was 34% in patients with previously treated advanced TNBC and 52% in patients not previously exposed to a topoisomerase 1 inhibitor ADC. The safety profi le was manageable, including grade 3 or higher treatment-related AEs in 23% of patients and low rates of neutropenia and diarrhea.16 This agent is being evaluated in a number of trials, including TROPION-Breast02 (NCT05374512), a phase 3, open-label, randomized trial assessing first-line Dato-DXd treatment in patients with locally recurrent, inoperable, or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibition.17 The BEGONIA trial (NCT03742102) is investigating Dato-DXd in combination with the checkpoint inhibitor durvalumab (Imfi nzi) in the first-line setting for patients with locally advanced or metastatic TNBC.18 Finally, the phase 3 TROPION-Breast01 trial (NCT05104866) is evaluating Dato-DXd in patients with previously treated HER2-negative breast cancer.19

XMT-2056 is an ADC that delivers a stimulator of interferon genes (STING) agonist to the tumor microenvironment. The STING pathway mediates the innate immune response and is capable of inducing antitumor immune activity. In XMT-2056, a novel STING agonist payload is linked to HT-19, an HER2-targeting monoclonal antibody that binds to a novel epitope on HER2 and does not compete for binding with either trastuzumab or pertuzumab (Perjeta).20 XMT-2056 demonstrated robust antitumor activity as a monotherapy in preclinical models with both high and low HER2 expression, with enhanced efficacy when used in combination with multiple approved agents.20

Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate made up of a CD166-directed monoclonal antibody conjugated to DM4, a cytotoxic microtubule inhibitor. The peptide mask of the agent limits target engagement with normal tissue.21 This ADC is being investigated for treatment of patients with solid tumors in the phase 1/2 PROCLAIM-CX-2009 trial (NCT03149549). Among patients with hormone receptor–positive, HER2-negative breast cancer, praluzatamab ravtansine showed an ORR of 15% and a clinical benefit rate of 40% in a phase 2 study of patients with advanced breast cancers (CTMX-2009-002; NCT04596150).21-23 However, ORRs in patients with advanced TNBC were less than 10%, resulting in the discontinuation of the TNBC treatment arm.

Selective Estrogen Receptor Degraders

Patients with endocrine therapy–resistant breast cancer may still respond to subsequent therapies that target the ER via a different mechanism, because these tumors often remain dependent on ER signaling for growth and survival. Selective estrogen receptor degraders (SERDs) are high-affi nity competitive antagonists of the ER that immobilize and target the ER for proteasome-dependent degradation, and prevent ER signaling, thereby providing more potent inhibition of the ER.1

“Oral SERDs might have a role post CDK4/6 [inhibitor] therapy; combinations are being evaluated to further assess efficacy. These agents are also being evaluated in the adjuvant setting,” noted Jhaveri.

Elacestrant is a nonsteroidal SERD that has complex dose-related ER agonist/antagonist activity and is being developed for hormone receptor–positive breast cancer,24,25 was evaluated in 2 first-in-human studies (Study 001 [EudraCT: 2007-006547-41] and Study 004 [EudraCT: 2014-001699-67]) that demonstrated its safety and tolerability in healthy postmenopausal women.26 Furthermore, elacestrant demonstrated single-agent activity in a phase 1 study (NCT02338349) of heavily pretreated, postmenopausal patients with hormone receptor–positive, HER2-negative, advanced breast cancer.26 The promising results from these early studies supported further assessment, which is under way in the phase 3 EMERALD trial (NCT03778931).27,28

EMERALD was the fi rst study to demonstrate greater efficacy for an oral SERD over fulvestrant (Faslodex); an FDA-approved intramuscular SERD and another type of endocrine therapy termed aromatase inhibitors (AIs) in patients who had progressed on a CDK4/6 inhibitor and an endocrine therapy.5,28 Elacestrant demonstrated a statistically signifi cant benefi t in median PFS compared with the AI group, the risk of progression or death was reduced by 30% in the overall population (P = .0018) and by 45% in patients harboring ESR1 mutations (P = .0005). Elacestrant also showed superior 12-month PFS rates compared with AIs both in the overall cohort (22.3% vs 9.4%, respectively) and in the subgroup of patients with ESR1-mutated tumors (12-month PFS rate, 26.8% vs 8.2%) (TABLE28). These results suggest that patients with partial endocrine sensitivity after progression on CDK4/6 inhibitors, especially those with ESR1 mutations, derive greater benefi t from elacestrant than with other endocrine monotherapies.5,28 This finding will likely change the standard of care in the second-line metastatic setting and prompt a precision medicine approach when other targetable mutations are also present.5

In August 2022, the FDA granted a priority review to elacestrant in ER-positive, HER2-negative advanced or metastatic breast cancer, based on the results of EMERALD.29

Amcenestrant (SAR439859) is a nonsteroidal, orally bioavailable SERD that was initially developed as a treatment for hormone receptor–positive, HER2-negative breast cancer, either alone or in combination with a CDK4/6 inhibitor.30-32 H owever, its development was recently discontinued based on results of an interim analysis of findings from the phase 3 AMEERA-5 trial (NCT04478266). An independent data monitoring committee found that the combination of amcenestrant and palbociclib (Ibrance) did not meet the prespecified boundary for continuation compared with palbociclib and letrozole.33

Camizestrant (AZD9833), another potent, orally delivered, nonsteroidal SERD, developed for the treatment of hormone receptor–positive breast cancer, was designed to further improve on the ER degradation and avoid the ER agonism observed with first-generation oral SERDs.34 An ongoing, phase 1, doseescalation study (SERENA-1; NCT03616587) is evaluating the safety and tolerability of camizestrant alone or in combination with palbociclib, everolimus (Afinitor), abemaciclib (Verzenio), or capivasertib in patients with endocrine-resistant, ER-positive, HER2-negative breast cancer that is not amenable to treatment with curative intent.35,36 Reduction of ER and PR protein levels occurred in all dose cohorts, indicating modulation of ER signaling, and the tolerability profi le of the combination with palbociclib was consistent with those of both camizestrant and palbociclib alone.35,36 Clinical benefit was also reported with camizestrant at various dose levels, but response rates were modest. A phase 3 study (SERENA-4; NCT04711252) and 2 phase 2 studies are under way.36,37

Giredestrant (GDC-9545), a highly potent, nonsteroidal, orally bioavailable SERD, was developed for the treatment of hormone receptor–positive breast cancer.1 Results from an ongoing phase 1 study (GO39932; NCT03332797) showed that giredestrant, alone and in combination with palbociclib, was well tolerated; no dose-limiting toxicities were reported, and no maximum tolerated dose was reached. Furthermore, all tested dose levels of giredestrant demonstrated encouraging antitumor activity in patients with hormone receptor–positive advanced or metastatic breast cancer. This activity was independent of patients’ ESR1 mutation status and whether they had received prior treatment with chemotherapy or CDK4/6 inhibitors.38,39 Giredestrant is being evaluated in phase 3 clinical trials alone (lidERA Breast Cancer; NCT04961996) and with palbociclib (persevERA Breast Cancer; NCT04546009).40,41

Structure-guided investigations driven by activity in breast cancer cell lines contributed to the development of rintodestrant (G1T48), another orally bioavailable, nonsteroidal SERD, which has shown efficacy in both ESR1-mutated and wild-type preclinical models.1,42 Rintodestrant is being evaluated alone and in combination with palbociclib in an ongoing phase 1 trial (NCT03455270) in postmenopausal patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.42 The study showed a favorable safety profile and preliminary evidence of antitumor activity in patients following progression on several lines of endocrine therapy, including in patients with tumors harboring ESR1 mutations.42

Borestrant (ZB716) is another next-generation SERD that has demonstrated preclinical activity and is being evaluated in a phase 1/2, open-label, multicenter study (ENZENO; NCT04669587).43 The aim of the study is to obtain safety and tolerability data for borestrant, alone and in combination with palbociclib, in patients with ER-positive, HER2-negative advanced breast cancer.44

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) act by reducing the effects of estradiol via competitive binding of the ER.1 Tamoxifen, the original SERM, is the most prescribed therapeutic agent for ER-positive breast cancer.45 Bazedoxifene is a SERM/SERD hybrid approved for the management of osteoporosis and postmenopausal hot fl ashes.43,46

Bazedoxifene functions as a high-affi nity ERα antagonist in breast tumors and promotes ER degradation.46-48 Bazedoxifene showed antitumor activity in laboratory-based models of tamoxifen-resistant breast cancer,46,49 leading to a phase 2 clinical trial to evaluate its safety and efficacy in patients with metastatic breast cancer who progressed on prior endocrine therapy (NCT02448771).50

Lasofoxifene is a next-generation SERM with improved bioavailability compared with tamoxifen but similar characteristics in terms of ER binding and inhibition of coactivators.51 Initially developed for osteoporosis, lasofoxifene was found to retain antagonist activity without evidence of resistance in cancer cells harboring ESR1 mutations in preclinical models.52 These results led to the clinical evaluation of lasofoxifene in patients with ESR1-mutant metastatic breast cancer in the ELAINE (NCT03781063; monotherapy) and ELAINEII (NCT04432454; in combination with abemaciclib) trials, which are under way. A phase 3 trial of the combination is planned.53-55

In the ELAINE trial, lasofoxifene showed a median PFS of 6.04 months in patients with ER-positive, HER2-negative metastatic breast cancer harboring an ESR1 mutation, vs 4.04 months in patients treated with fulvestrant (HR, 0.699; 95% CI, 0.445-1.125; P = .138).55 The ORR was 13.2% for lasofoxifene compared with 2.9% for fulvestrant (P = .12), with 1 complete response noted in the lasofoxifene arm. AEs were mostly grade 1 or 2.

Proteolysis-Targeting Chimeras

Proteolysis-targeting chimeras (PROTACs), also known as bivalent chemical protein degraders, are heterobifunctional molecules that degrade specific endogenous proteins via the E3 ubiquitin ligase pathway.56 PROTACs provide an alternative strategy for blocking protein function that moves beyond the restrictions of traditional pharmacology.56

ARV-471, an oral ER-targeting PROTAC, was designated an investigational new drug by the FDA in 2019.57 ARV-471 is designed to selectively target the ER for the treatment of patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer.57 A phase 1/2 trial (NCT04072952) of ARV-471 alone and in combination with palbociclib is under way.58 The phase 1 dose-escalation study showed that ARV-471 was well tolerated with no dose-limiting toxicities. Furthermore, there was robust ER degradation (89% reduction) and encouraging activity, including a clinical benefit rate of 40% in CDK4/6 inhibitor–pretreated patients.59,60

Another promising PROTAC for ER-positive breast cancer is ERD-308. Preclinical studies found that ERD-308 is a highly potent and effective ER-targeting PROTAC, inducing more than 95% ER degradation at concentrations as low as 5 nM in breast cancer cell lines. Additionally, ER degradation displayed time and dose dependence, with faster degradation kinetics and more complete degradation than fulvestrant.61

In preclinical studies, AC682 demonstratedcpotent ER degradation, diminishedcexpression of ER-regulated genes, and subsequentc cell growth inhibition. Moreover, animal studies showed oral bioavailability and tolerance of AC682, as well as dose-dependent tumor growth inhibition/regression and concomitant tumor ER protein reduction in estradiol-dependent MCF7 xenograft tumors. There was clear synergy when AC682 was administered in combination with palbociclib in both estradiol-dependent and tamoxifen-resistant MCF7 models.62 A phase 1 clinical trial (NCT05080842) evaluating the safety and effectiveness of AC682 for the treatment of locally advanced or metastatic ER-positive breast cancer is under way.63

PI3K Inhibitors

Breast tumors frequently exhibit dysregulation of the PI3K pathway, leading to either increased or decreased activity.64 This dysregulation may also contribute to resistance to a variety of anticancer agents.65

The novel, orally available, α-selective PI3K inhibitor MEN1611 (PA799) was evaluated in 2 preclinical breast cancer models: HER2-positive, PIK3CA-mutated breast cancer cell lines and patient-derived xenografts. MEN1611 demonstrated activity in these models both as monotherapy and in combination with HER2-targeted therapy.66 The combination exhibited synergy, including protein depletion of the α isoform and a pro-inflammatory macrophage phenotype in both model systems. A phase 1b study, B-PRECISE-01 (NCT03767335), aims to determine the appropriate dose of MEN1611 to be used in combination with trastuzumab with or without fulvestrant for the treatment of patients with advanced or metastatic HER2-positive breast cancer.67

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36. Baird R, Oliveira M, Gil EMC, et al. Abstract PS11-05: Updated data from SERENA-1: A Phase 1 dose escalation and expansion study of the next generation oral SERD AZD9833 as a monotherapy and in combination with palbociclib, in women with ER-positive, HER2-negative advanced breast cancer. Cancer Res. 2021;81(4_Supplement):PS11-05. doi:10.1158/1538-7445.Sabcs20-ps11-05

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