Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay
Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay
Global PharmaPoint HER2 Positive Breast Cancer Drug report Forecast and Analysis to 2023 SummaryHER2-positive breast cancer is the second most common cancer in the world and the most common cancer in women worldwide. This report focuses on the current treatment landscape, unmet needs, current pipeline, and commercial opportunities in the HER2-positive breast cancer market, with coverage of multiple settings of the disease including neoadjuvant, adjuvant, first-, second-, third-, and fourth-line metastatic.To Browse a Full Report with Toc: http://www.
researchmoz.us/pharmapoint-her2-positive-breast-cancer-global-drug-forecast-and-market-analysis-to-2023-report.htmlSince its introduction in 1998, Roches gold standard therapy, Herceptin (trastuzumab), a monoclonal antibody, revolutionized the treatment of the disease. Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. The realization that targeting the HER2 receptor could significantly improve disease-free survival (DFS) has created a large market for HER2-directed therapies. In 2013, Roche dominated the HER2-positive market, with a share of 95%. With Herceptins patent expiry looming in Europe Roche launched Perjeta and Kadcyla in 2012 and 2013 to maintain its leadership.
Key Questions Answered- What are the R&D strategies being used by drug makers- How is the disease management evolving? What impact for drug manufacturers- What opportunities remain for future players- How large are the neoadjuvant, adjuvant, and metastatic markets for HER2 targeting agents, and which one is growing the fastest- What exciting, innovative approaches are being investigated in HER2-positive breast cancer- What to KOLs think about the latest therapies and drug development strategiesKey Findings- The HER2-positive breast cancer market will increase by 2.5-fold, reaching $12.63bn by 2023, at…
ORDER A PLAGIARISM-FREE PAPER NOW
The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay.Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.
Introduction
A better understanding of tumor biology and HER2 signaling has led to the development and approval of new HER2-targeted agents that, together with the use of continued anti-HER2 therapy beyond progression, have resulted in unpreceded survival outcomes in patients with advanced HER2-positive breast cancer.1
The addition of trastuzumab to standard therapy dramatically improved prognosis for patients with HER2-positive breast cancer, and became a landmark in the treatment of these patients.2,3 The second anti-HER2 agent that was incorporated into routine practice of advanced HER2-positive disease was lapatinib, an oral tyrosine kinase inhibitor (TKI) that reversibly inhibits HER1 or epidermal growth factor receptor (EGFR) and HER2 kinases. The approval of lapatinib was based on the improvement in progression-free survival (PFS) found in a phase III trial when combined with capecitabine versus capecitabine alone though no improvement in overall survival (OS) was observed.4 Pertuzumab is a humanized monoclonal antibody that binds to HER2 on extracellular domain II, a different domain than trastuzumab, preventing homo- and heterodimer formations and blocking one of the most powerful heterodimers, HER2/HER3, that activates several intracellular signaling cascades including cell proliferation and survival.Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. The addition of pertuzumab to a taxane and trastuzumab combination compared with taxane and trastuzumab therapy alone as a first-line treatment in advanced HER2-positive breast cancer resulted in an improvement not only in PFS but also in OS by almost 16 months, reaching a median survival of nearly 5 years and establishing this regimen as the preferred regimen in the first-line setting.1 Finally, trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprised of trastuzumab covalently linked to a maytansine derivate (DM1), a potent antimitotic agent that binds microtubules.5 After selectively binding to HER2, the conjugate is internalized within endocytic vesicles and degraded in the lysosomes, releasing the active payload within the cell. This results in cell death by mitotic catastrophe.6 T-DM1 significantly improved both PFS and OS compared with lapatinib plus capecitabine as a second-line treatment7 and as a later line in patients with advanced HER2-positive breast cancer previously treated with trastuzumab.8 Based on those results, T-DM1 is currently the only ADC approved to treat breast cancer and the standard second-line therapy for advanced HER2-positive disease. To date, there is no standard of care treatment for patients with advanced HER2-positive tumors following treatment with trastuzumab, pertuzumab and T-DM1. Treatment options at this point include lapatinib plus capecitabine, combinations of trastuzumab with other chemotherapies (such as vinorelbine or gemcitabine), or dual-blockade combinations without chemotherapy, such as trastuzumab with lapatinib or endocrine therapy with either trastuzumab or lapatinib in patients with hormone receptor (HR)-positive disease.
Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies alone or as dual HER2-blockade in the standard treatment of advanced disease, most patients ultimately develop progressive disease and die. Furthermore, up to 40–50% of patients with advanced HER2-positive breast cancer will develop brain metastases during their disease course. Better options for the prevention and treatment of brain metastases are clearly needed.9 A growing understanding of the underlying mechanisms of primary and acquired resistance to anti-HER2 therapies and compensatory pathways as well as tumor heterogeneity and the tumor microenvironment is essential for the development of novel therapeutic strategies. A substantial number of novel anti-HER2 treatments are being investigated extensively in the preclinical and clinical settings to further improve patient outcomes. Here, we review the rationale and latest evidence of those novel treatments and approaches to overcome resistance in advanced HER2-positive breast cancer. Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay.
Mechanisms of resistance and response heterogeneity to anti-HER2 therapy
Many potential resistance mechanisms to anti-HER2 therapy have been described that ultimately lead to reactivation of the HER2 pathway or its downstream signaling, through pathway redundancy or stimulation of alternative survival pathways.10 Some of these mechanisms include incomplete blockade of the HER2 receptor that activates compensatory mechanisms within the HER family (such as HER3), activation of alternative receptor tyrosine kinases (RTKs) or other membrane receptors outside of the HER family [such as insulin-like growth factor 1 receptor (IGF-1R)11 and MET12], and alterations in downstream signaling pathways, such as hyperactivation of the PI3K/AKT/mTOR pathway13,14 by reduced levels of tumor suppressor genes (like PTEN and INPP4-B), or by activating mutations in PIK3CA (phosphatidylinositol-4,5 bisphosphate 3-kinase catalytic subunit).15 Several other biologic features have been associated with response heterogeneity to anti-HER2 therapy, including HER2 mRNA or protein levels,16 tumor intrinsic subtype,17 alterations in the HER2-receptor (such as p95HER2),18 and host and tumor microenvironment components, such as tumor infiltrating lymphocytes (TILs)19 and FCγR polymorphisms.20 In the CLEOPATRA trial for instance, high HER2 protein and high HER2 and HER3 mRNA levels were associated with a significantly better outcome (p < 0.05). In contrast, PIK3CA mutation was identified as a strong negative prognostic biomarker, despite deriving benefit from pertuzumab and trastuzumab treatment.21 In the EMILIA trial, a greater benefit in OS was also observed in patients treated with T-DM1 and high HER2 mRNA expression.22Notably, PIK3CA mutations were associated with significantly shorter PFS and OS in patients treated with capecitabine plus lapatinib, but not in T-DM1 treated patients (median PFS 10.9 vs. 9.8 months; OS, not reached in mutant or wild type).22 Regarding TILs, an increased quantity of stromal TILs was significantly associated with improved OS in patients with advanced HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab or placebo in the CLEOPATRA trial.19
It has also been demonstrated that the cyclin D1-CDK4 pathway can mediate resistance to HER2-targeting therapies in vitro and in vivo and that targeting resistant tumor cells with CDK 4/6 inhibitors re-sensitizes them to anti-HER2 therapy and delays tumor recurrence in HER2-driven breast cancers in vivo in patient-derived xenograft tumors.23As discussed below, trials are currently underway to evaluate the efficacy of combined HER2 and CDK4/6 inhibition in HER2-positive breast cancer. Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay.
Substantial preclinical and clinical studies support the bidirectional cross-talk between HER2 and estrogen receptor (ER) signaling when both receptors are expressed in breast cancer cells.24 Tumors that express both ER and HER2 are less sensitive to endocrine therapy than ER-positive and HER2-negative tumors, and ER can act as an escape pathway to HER2 inhibition.25,26 Concurrent inhibition of ER together with dual anti-HER2 therapy can improve outcomes, as demonstrated in several trials in early and advanced HER2-positive breast cancer.27–29
The HER2Δ16 splice variant is a major oncogenic driver that promotes trastuzumab resistance. Preclinical data suggest trastuzumab-resistant HER2Δ16 cells are sensitive to the SRC kinase inhibitor dasatinib and data from a phase I/II (GEICAM/2010-04) study suggest there may be a signal for activity when dasatinib is combined with trastuzumab and paclitaxel in the first-line treatment for patients with advanced HER2-positive breast cancer.30,31 In addition, SRC activation by itself has been associated with trastuzumab resistance.32
The mechanisms that contribute to T-DM1 resistance are not fully understood. There are multiple components to consider when identifying mechanisms of resistance for ADCs, such as the ones related to the antibody, the linker or the payload. Preclinical studies have shown that CDK1/cyclin B1 activity is needed for T-DM1 action. Silencing cyclin B1 induces resistance to T-DM1 while increasing the levels of cyclin B1 in resistant cells partially restores sensitivity.33 Other potential mechanisms of T-DM1 resistance have been proposed including the reduction of the intracellular DM1 payload due to upregulation of multidrug resistance proteins (e.g. MDR1),34 impaired lysosomal proteolytic activity35 or lysosomal transporter loss (e.g. SLC46A3).34
Interestingly, molecular imaging seems promising not only to further our understanding of tumor heterogeneity in advanced HER2-positive breast cancer but also to identify patients who will unlikely benefit from T-DM1.36 In the prospective ZEPHIR trial, striking levels of inter- and intrapatient heterogeneity in HER2 expression were observed, with one-third of patients having little or no trastuzumab-zirconium uptake (HER2-Positron emission tomography (PET)/computed tomography (CT) scan [PET/CT scan]) across their metastatic sites.Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. Moreover, the combined use of HER2-PET/CT scan and early fluorodeoxyglucose-PET/CT scan discriminated patients treated with T-DM1 with a median time to treatment failure (TTF) of 2.8 months from those with 15 months of TTF.36 Despite the extensive translational research being conducted, most of the mechanisms of HER2 resistance and potential biomarkers of response or resistance either have not been clinically validated, or the results are contradictory.37 To date, no biomarker beyond HER2 exists for patient selection for anti-HER2 therapy in HER2-positive breast cancer. Of note, the interpretation of mechanisms of resistance based solely in preclinical models can be challenging due to tumor heterogeneity, the complex nature of drug resistance and compensatory pathways, and the use of different tumor cell lines. Moreover, multiple mechanisms of resistance may coexist in the same cell.
Novel strategies to overcome resistance to HER2-targeted therapy
Replacement of current anti-HER2 therapies for improved anti-HER2 drugs
ADCs
ADCs are a therapeutic class that provide wider therapeutic window by more efficient and specific drug delivery. ADCs exploit target selectivity of monoclonal antibodies (MAbs) to deliver cytotoxic drugs to antigen-expressing cells to improve tumor selectivity and reduce damage to normal cells.38 The success observed with the first-in-class T-DM1 has led to a rapid and extensive development of new ADCs. Table 1lists several anti-HER2 ADCs in clinical development.7,39–41
Table 1.
HER2-directed ADCs in clinical development.
| Agent | Anti-HER2 MAb/payload (target) | Drug to antibody ratio | Linker drug | Phase of development | ORR in HER2-positive |
ORR in HER2 low (IHC1+/2+/ISH-) |
|---|---|---|---|---|---|---|
| Trastuzumab-DM1 (T-DM1)7 | Trastuzumab/ DM1 (anti-tubulin) |
3.5 | Noncleavable | US FDA Approved | 43.6% | ——— |
| Trastuzumab duruxtecan(DS-8201a) 39 |
Trastuzumab/ exatecan derivative (topoisomerase I inhibitor) | 8 | Cleavable | II/III NCT03248492 NCT03529110 NCT03523585 |
54.5% | 50% |
| SYD985 40 | Duocarmycin derivative (alkylating agent) | 2.8 | Cleavable | III NCT03262935 |
33% | HR + 27% HR − 40% |
| XMT-1522 41 | XMT-1519/ monomethyl auristatin (anti-tubulin) | 12 | Cleavable | I NCT02952729 |
unknown | unknown |
| ARX788 | Anti-HER2 MAb/ auristatin analog 269 (AS269) (anti-tubulin) | 1.9 | Non-cleavable | I NCT03255070 |
unknown | unknown |
| DHES0815A | Trastuzumab/ alkylator | 2 | Cleavable | I NCT03451162 |
unknown | unknown |
ADC, antibody–drug conjugate; HR+, hormone receptor positive; HR−, hormone receptor negative; IHC, immunohistochemistry; ISH, In Situ Hybridization; MAb, monoclonal antibody; NCT, ClinicalTrials.gov identifier; ORR, overall response rate; US FDA, United States Food and Drug Administration.
Trastuzumab deruxtecan (DS-8201, Daiichi Sankyo, Inc.) is an ADC comprising trastuzumab, a cleavable drug linker, and a topoisomerase I payload that has a high drug to antibody ratio (7–8). In preclinical studies, DS-8201a showed a broader anti-tumor activity than T-DM1, including efficacy against low HER2-expressing tumors.Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. In an updated subgroup analysis from a phase I study with multiple expansion cohorts,42 DS-8201a demonstrated an overall response rate (ORR) of 54.5% (54/99 patients) in patients with HER2-positive metastatic breast cancer pretreated with T-DM1 (as well as trastuzumab and pertuzumab in the majority of cases). Median duration of response and median PFS had not yet been reached.39 Interestingly, in patients with HER2 low-expressing metastatic breast cancer [defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization (ISH)-negative], the ORR was 50% (17/34 patients). Trastuzumab deruxtecan was relatively well tolerated; common adverse events (AEs) included nausea (73.5%; 3.5% grade ⩾3), decreased appetite (59.5%; 4.5% grade ⩾3) and vomiting (39.5%; 1.5% grade ⩾3). In August 2017, trastuzumab deruxtecan received a United States Food and Drug Administration (US FDA) Breakthrough Therapy designation for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and, have progressed to T-DM1. DS-8201a is being evaluated in numerous trials, including two phase III studies: the DESTINY-Breast02 (ClinicalTrials.gov identifier: NCT03523585) is evaluating DS-8201a versus investigator’s choice (capecitabine with trastuzumab or lapatinib) for patients with HER2-positive, unresectable or metastatic breast cancer pretreated with prior T-DM1, and the DESTINY-Breast03 (ClinicalTrials.gov identifier: NCT03529110) is a randomized, open-label study of DS-8201a versus T-DM1 for patients with HER2-positive, metastatic breast cancer previously treated with trastuzumab and taxane.
SYD985 (Synthon Biopharmaceuticals BV) is a third generation ADC based on trastuzumab and a ‘cleavable’ linker – duocarmycin payload, which is present as an inactive prodrug (valine-citrulline-seco – DUocarmycin – hydroxyBenzamide – Azaindole -vc-seco-DUBA). Proteases present in endosomes result in the linker cleavage in SYD985 and the release of the membrane-permeable active toxin. It then binds to the minor groove of DNA, causing irreversible DNA alkylation. This results in cell death in both dividing and nondividing cells in the tumor microenvironment but also in neighboring tumor cells due to the bystander effect. SYD985 has shown impressive preclinical results in breast cancer (even more potent than T-DM1) and encouraging clinical activity. Results from a dose-escalation phase I trial showed encouraging activity in heavily pretreated patients43,44 and led the US FDA to grant the agent Fast Track designation in January 2018. Results from the expansion cohorts recently reported an ORR of 33% and a median PFS of 9.4 months40 in a cohort of patients with advanced HER2-positive disease, previously treated with a median of six lines of therapy for metastatic disease (n = 50). Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. Interestingly, SYD985 was also effective in patients with HER2-low metastatic breast cancer, with an ORR of 27% and 40% in the HR-positive, HER2-low, and in the HR-negative, HER2-low cohorts, respectively. Enrollment was based on central HER2 analysis by IHC and ISH and HER2 low was defined as IHC 1+/2+ and fluorescence in situ hybridization (FISH) negative. Most of the adverse drug reactions were mild or moderate, with ocular toxicity and fatigue being most frequently reported. A phase III pivotal study (TULIP) is ongoing (ClinicalTrials.gov identifier: NCT03262935) which compares SYD985 with the treatment of the physician’s choice in patients with HER2-positive metastatic breast cancer in the third line and beyond.
MEDI4276 (Medimmune) is a bispecific ADC that targets two different domains of the HER2 receptor, resulting in crosslinking followed by internalization of the complex, cleavage of the linker, and release of the payload. MEDI-4276 comprises the single-chain variable fragment (scFv) of trastuzumab, which binds to domain IV of HER2, and the anti-HER2 Mab 39S, which binds to domain II of HER2. The bispecific antibody is then conjugated, via a cleavable linker, to the cytotoxic anti-microtubule agent tubulysin. Results from the phase I study (ClinicalTrials.gov identifier: NCT02576548) in patients with advanced HER2-positive breast or gastric cancer45 showed clinical activity, but also considerable toxicity with 28% of patients (12/43) having drug-related AEs of grade 3–4 severity; most common were grade 3 elevated aspartate transaminase (AST; 19%) and grade 3 elevated alanine transaminase (ALT; 12%). Given the challenges with toxicity, clinical testing with this agent has been discontinued for breast and gastric cancers. Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay.
ADCT-502 (ADC Therapeutics) is also a novel pyrrolobenzodiazepine (PBD)-based ADC that targets HER2-expressing solid tumors, including breast cancers.46 However, based on data from the phase I study (ClinicalTrials.gov identifier: NCT03125200) that showed that ADCT-502 did not meet the necessary efficacy and safety profile required for patient benefit, clinical testing of this drug was recently halted.
In preclinical models, another bivalent biparatopic HER2-targeting ADC that targets two nonoverlapping epitopes on HER2 and is conjugated with microtubule inhibitor demonstrated superior activity than T-DM1 in breast cancer models and was able to overcome T-DM1 resistance. This biparatopic ADC also demonstrated bystander killing activity.47
In contrast with T-DM1, most of these new ADCs have a cleavable drug linker (see Table 1) that mediates the bystander killing effect. This is the passive diffusion of the free cytotoxin from target-positive cancer cells into the tumor microenvironment, killing neighboring cancer cells that are insensitive to the ADC because of the lack or limited target expression. This desired feature of those novel HER2-targeting ADCs, given that heterogeneity is frequent in HER2-positive breast cancer, may be however, a double-edged sword with an increased toxicity.
Novel anti-HER2 antibodies
Margetuximab (MGAH22, MacroGenics) is an Fc-optimized chimeric monoclonal antibody that binds to the same epitope as trastuzumab. Margetuximab has enhanced Fcγ receptor-binding properties with an increased affinity for CD16A polymorphisms and a decreased affinity for FcγRIIB (CD16B), an inhibitory receptor, which allows it to bind more tightly to effector cells and increase antibody-dependent cell-mediated cytotoxicity (ADCC); it also preserves the antiproliferative properties of trastuzumab.48 A first-in-human phase I study demonstrated promising single-agent activity of margetuximab in heavily pretreated patients with HER2-positive solid tumors. Among 24 patients with metastatic breast cancer, the ORR was 17% and 3 out of the 4 responders remained on treatment for 39–54 months.49 The most common AEs were grade 1–2 constitutional symptoms and no cardiotoxicity was observed. Margetuximab is currently being evaluated in the randomized phase III SOPHIA trial (ClinicalTrials.gov identifier: NCT02492711) that compares margetuximab plus chemotherapy with trastuzumab plus chemotherapy as a third-line therapy in patients with HER2-positive breast cancer after prior treatment with trastuzumab, pertuzumab, and T-DM1.Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. The US FDA has granted Fast Track designation for the investigation of margetuximab for the treatment of patients with metastatic or locally advanced HER-positive breast cancer previously treated with anti-HER2-targeted therapy.
Bispecific antibodies
Bispecific antibodies (BsAbs) combine the functionality of two MAbs that target two different targets or epitopes, either in the same or in different receptors. BsAbs can interfere with two or more RTK signaling pathways, by inactivating either the RTKs or their ligand. Several are currently being studied in patients with advanced HER2-positive disease.
MCLA-128 (Merus) is a full-length immunoglobulin (Ig)G1 BsAb with enhanced ADCC activity targeting both HER2 and HER3. Preliminary results from a phase I/II study in solid tumors (ClinicalTrials.gov identifier: NCT02912949) that include eight patients with heavily pretreated (median of five prior lines in the metastatic setting) HER2-positive metastatic breast cancer showed an encouraging clinical benefit rate of 70%.50 A phase II study (ClinicalTrials.gov identifier: NCT03321981) is ongoing to evaluate the activity of MCLA-128 in two metastatic breast cancer populations: in HER2-positive/amplified patients (cohort 1) in combination with trastuzumab ± chemotherapy, and in ER-positive/low-HER2 expression (cohort 2) in which MCLA-128 is administered in combination with endocrine therapy.
ZW25 (Zymeworks Inc.) is a novel Azymetric bispecific antibody biparatopic that binds to two different epitopes on the extracellular domain of HER2 ECD2 and ECD4. This results in increased tumor cell binding, blockade of ligand-dependent and independent growth, and improved receptor internalization and downregulation relative to trastuzumab. Also, in vivo studies demonstrate anti-tumor activity in HER2-low to high expressing models. Results from the phase I study (ClinicalTrials.gov identifier: NCT02892123) evaluating the safety and efficacy of single-agent ZW25 in separate expansion cohorts, including HER2-high (IHC 3+ or 2+/FISH+) breast, gastric/esophageal, and other cancers, demonstrated a promising anti-tumor activity and no dose-limiting toxicities were observed.Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay. In patients with heavily pretreated HER2-expressing breast cancers that had progressed to a median of five HER2-targeted regimens for metastatic disease, a partial response rate of 33% (6/18 patients) was observed with a disease control rate of 50%. The most common AEs were diarrhea and infusion reaction, all grade 1 or 2, with no treatment-related discontinuations.51
T-cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the invariant CD3 chain of the T-cell receptor (TCR) and to tumor-associated or tumor-specific antigens. Binding to the tumor antigen results in crosslinking of the TCR and subsequent lymphocyte activation and tumor cell killing. However, on-target off-tumor effects caused by redirected lymphocytes can result in severe toxicities. Several are currently in clinical development:
ORDER A PLAGIARISM-FREE PAPER NOW
GBR1302 (Glenmark Pharmaceuticals) is a HER2xCD3 bsAb developed to direct T-cells to HER2-expressing tumor cells. Preclinically, GBR1302 has demonstrated potent killing of HER2-positive human cancer cells, as well as growth suppression of the trastuzumab-resistant cell line JIMT-1. In contrast, the GBR1302 concentration required to kill primary cardiomyocytes with normal HER2 levels was up to 1000 times greater than the concentration needed to kill HER2 3+ tumor cell lines. A first-in-human phase I study of single-agent GBR1302 in progressive HER2-positive solid tumors is ongoing (ClinicalTrials.gov identifier: NCT02829372). Preliminary biomarker and pharmacodynamic data from this study were recently presented, demonstrating modulation of peripheral T-cell populations and cytokines.52
PRS-343 (Pieris Pharmaceuticals, Inc.) is a monoclonal antibody-bispecific protein targeting HER2 and the immune receptor CD137. CD137 is a key costimulatory immunoreceptor and a member of the tumor necrosis factor receptor superfamily. PRS-343 is designed to promote CD137 clustering by bridging CD137-positive T-cells with HER2-positive tumor cells, thereby providing a potent costimulatory signal to tumor antigen-specific T-cells that has demonstrated tumor inhibition and TIL expansion in a humanized mouse model.53 The two clinical studies evaluating PRS-343 in HER2-positive solid tumors are ongoing, either as a single-drug agent (ClinicalTrials.gov identifier: NCT03330561) or in combination with atezolizumab (ClinicalTrials.gov identifier: NCT03650348). Global Phamarpoint Her2 Positive Breast Cancer Drug Report Essay.
