New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?
Abstract
:1. Introduction
- The drugs that directly target HER2, include novel anti-HER antibodies characterized with an increased affinity, antibody-drug conjugates (ADC), bispecific antibodies, as well as more potent or more specific HER2 tyrosine kinase inhibitors (TKI), and targeted radio-immunotherapy.
- The drugs that indirectly target HER2 include novel therapeutics modulating HER2-connected pathways, which may synergize with direct anti-HER2 targeting through innovative associations, such as immune check point inhibitors (ICIs), cell cycle inhibitors, and PI3K inhibitors.
2. Novel Anti-HER2 Antibodies
2.1. Antibody-Drug Conjugates
2.1.1. Trastuzumab-Deruxtecan
Mechanism of Action
Clinical Outcomes
2.1.2. Trastuzumab Duocarmazine
Mechanism of Action
Clinical Outcomes
2.1.3. Other Antibody-Drug Conjugates
2.2. Margetuximab (MGAH22)
2.2.1. Mechanism of Action
2.2.2. Clinical Outcomes
2.3. Bispecific Antibodies
2.3.1. Zenocutuzumab (MCLA 128)
Mechanism of Action
Clinical Outcomes
- HER2-positive MBC failing 2–4 prior HER2 therapies (including T-DM1): doublet with MCLA-128 and trastuzumab, or triplet with MCLA-128, trastuzumab, and vinorelbine.
- HR+/HER2-low expression MBC failing ≥1 prior endocrine therapy + CDK4-6 inhibitor: MCLA-128 and endocrine therapy.
2.3.2. Azymetric (ZW25)
Mechanism of Action
Clinical Outcomes
- First-in-human, three-part trial: ZW25 alone and combined with selected chemotherapy agents (capecitabine, vinorelbine, or paclitaxel) in patients with HER2-expressing MBC (cohort 4–6) (NCT02892123).
- Phase II trial: ZW25 with palbociclib plus fulvestrant in patients with HER2-positive/HR-positive ABC (NCT04224272)
- Phase I/II trial: ZW25 in combination with docetaxel in patient with HER2-positive BC, tislelizumab and chemotherapy in patients with HER2+ gastroesophageal adenocarcinoma (NCT04276493).
2.3.3. PRS-343
Mechanism of Action
Clinical Outcomes
2.3.4. Other Bispecific Antibodies
2.4. More Potent or More Specific HER2 TKI
2.4.1. Neratinib
Mechanism of Action
Clinical Outcomes
2.4.2. Tucatinib (ONT-380)
Mechanism of Action
Clinical Outcomes
2.4.3. Pyrotinib
Mechanism of Action
Clinical Outcomes
2.4.4. Poziotinib (NOV120101)
Mechanism of Action
Clinical Outcomes
2.5. Targeted Radio-Immunotherapy
2.5.1. Mechanism of Action
2.5.2. Clinical Outcomes
3. Innovative Associations Co-Targeting HER2 and Connected Pathways
3.1. Immunotherapy
3.1.1. Rational for Inhibiting Immune Checkpoint in HER2-Positive
3.1.2. Clinical Outcome
Pembrolizumab
Atezolizumab
Nivolumab
3.2. Cell Cycle Inhibitors
3.2.1. Rational for Inhibiting Cell Cycle via CDK4/6 Inhibitors in HER2-Positive BC
3.2.2. Clinical Outcomes
3.3. PI3K/mTOR Inhibitors
3.3.1. Rational for Targeting the PI3K/AKT/mTOR Pathway in HER2-Positive BC
3.3.2. Clinical Outcomes
mTOR Inhibitors
PI3K Inhibitors
4. Perspective of Integration of Novel Anti-HER2 Therapeutics in Clinical Practice
- The changing landscape in systemic treatment at the early stage, since it may increasingly incorporate pertuzumab and trastuzumab emtansine, both being major components of therapeutic management in the advanced setting, with documented major overall survival gain. Thus, pertuzumab-trastuzumab combo, which improves pathological complete response rate in the neoadjuvant setting [100], was recently confirmed to increase disease-free survival in node-positive disease, whatever the expression of hormone receptors, when administered in the adjuvant setting [101]. In addition, trastuzumab emtansine, when used in the post-neoadjuvant setting in the presence of residual invasive disease, increased significantly survival outcome. Accordingly, those patients relapsing after being exposed to these drugs may require alternative therapeutic algorithm, and potential early introduction of most recent drugs with efficacy after pertuzumab and trastuzumab emtansine exposure.
- The clinical presentation of the disease balanced with the toxicity profile of emerging drugs. Thus, because of its outstanding activity but also its potential for significant chemo-like toxicities, including potentially severe pulmonary toxicity, trastuzumab-deruxtecan could be predominantly proposed to patients with aggressive diseases but keeping a good performance status with a satisfactory respiratory function. In contrast, tucatinib in combination with trastuzumab and capecitabine could be first offered to more fragile patients and/or with more indolent diseases. In addition, regarding to the highly significant improvement in OS for patients with brain metastases, this combination may be preferred in this subgroup. Even though the neratinib-capecitabine combination may have significant activity in CNS disease, the high level of digestive toxicity, notably diarrheas, and the marginal clinical benefit registered to date, clearly make it an inferior option to consider in this setting.
- The evaluation of available or emerging biomarkers. While additional molecular information might better orient prescription in a near future, the presence of HER2 overexpression/amplification remains the only validated biomarker for efficacy of anti-HER2 therapeutics. Thus, the levels of HER2 mRNA or protein did not predict efficacy of either dual blockade or trastuzumab emtansine, but was identified as a prognostic factor, a lower HER2 expression being associated with worse outcome [102]. In addition, the presence of heterogeneity in HER2 expression was recently associated with lower efficacy of trastuzumab emtansine [103,104]. However, both of these features might be less relevant for predicting efficacy of novel ADCs, in which a bystander effect is suspected and activity in a low-HER2 context is demonstrated [105]. Another potential important biomarker in HER2-positive ABC is the expression of hormone receptors, identifying the so-called “triple-positive” breast cancer. This luminal HER2-positive subtype, possibly better approximated by PAM50 gene expression signature, might be particularly sensitive to endocrine therapy-based with or without CDK4/6 inhibitors approaches [106,107]. Other molecular alterations with potential therapeutic interest include those associated with PI3K pathway, including PIK3CA mutations and/or PTEN loss and/or AKT1 mutation, which might guide the future use of PI3K/mTOR/AKT inhibitors in this subtype [93]. Finally, PD-L1 expression as well as presence of TILs could identify HER2-positive ABC with potential sensitivity to ICIs [78,79].
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Trial | Phase | Population | Arms | Primary Endpoint |
---|---|---|---|---|
DESTINY-Breast 02 [16] (NCT03523585) | III | HER2+ ABC pretreated with T-DM1 | T-DXd vs. Investigator’s choice (capecitabine with trastuzumab or lapatinib) | PFS, OS, ORR, CBR, duration of response |
DESTINY-Breast 03 [17] (NCT03529110) | III | HER2 + MBC previously treated with trastuzumab and taxane | T-DXd vs. T-DM1 | PFS, OS, ORR, CBR, duration of response |
DAISY (NCT04132960) | II | HER2 high and low HER2 ABC | monotherapy T-DXd | Best ORR in three cohorts according HER2 expression. Biomarkers analysis to characterize response and resistance to therapy. |
Agent | Antibody | Cytotoxic payload | Trial | Phase | Population |
---|---|---|---|---|---|
SYD985 [19] | Vic-Trastuzumab | Duocarmazine (irreversible alkylation of the DNA in tumor cells) | NCT02277717 [20] | I | MBC regardless HER2 and ER statutes, in the 3rd ou 4th line with HER2 targeting |
NCT03262935 TULIP | III | HER2-positive ABC beyond the second line therapy | |||
XMT-1522 [22] | XMT-1519 (novel anti-HER2 monoclonal antibody) | 10–15 molecules of the payload AF-HPA, an auristatin-derivative (anti tubulin). | NCT02952729 | Ib | ABC and other advanced tumors expressing HER2 |
ARX788 [23] | Anti HER2 Mab | Amberstatin269 or AS269 (a potent cytotoxic tubulin inhibitor) | NCT02512237 [24] | I | Two cohorts with different ABC HER+ expansion cohorts, and one cohort with advanced HER+ gastric cancer. |
NCT03255070 | I | HER+ MBC or gastric cancer. | |||
DHES0815A | Trastuzumab | PBD-MA (alkylator) | NCT03451162 | I | Heavily pretreated HER2-positive ABC |
Trial | Phase | Population | Experimental Arm | Standard Arm | Status |
---|---|---|---|---|---|
NCT04034589 | II | HR+/HER2+ MBC | Pyrotinib + Fulvestrant | NA | Recruiting |
NCT03691051 | II | HER2+ MBC with brain metastases | Pyrotinib + Capecitabine | NA | Not yet recruiting |
NCT03997539 | II R* | HER2+ ABC previously treated by Trastuzumab-Based Therapy | Pyrotinib + Vinorelbine | Treatment of physician’s choice | Not yet recruiting |
NCT04246502 | II R | First-line treatment of HER2+ MBC | Pyrotinib + Capecitabine | Capecitabine, trastuzumab, and pertuzumab | Not yet recruiting |
NCT03876587 | II | First-line Treatment of HER2+ MBC | Pyrotinib + Docetaxel | NA | Not yet recruiting |
NCT03993964 | II | HER2+ MBC | SHR6390 + Pyrotinib SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway | Not yet recruiting | |
NCT03863223 | III R | First-line treatment of HER2+ MBC | Pyrotinib + Trastuzumab and Docetaxel | Placebo + trastuzumab and docetaxel | Recruiting |
NCT04033172 | II | HR+/HER2+ MBC | Pyrotinib + Fulvestrant | NA* | Recruiting |
NCT04001621 | II | Trastuzumab-resistant HER2+ ABC | Pyrotinib + Capecitabine | NA | Recruiting |
NCT03910712 | II R | First-line Treatment of HER2+/HR+ MBC | Pyrotinib + Trastuzumab + Aromatase inhibitors | trastuzumab + Aromatase inhibitors | Not yet recruiting |
TKI | Randomized Trial | Phase | n | Arms | ORR | 1-year PFS | HR |
---|---|---|---|---|---|---|---|
Neratinib | NALA trial [49] (NCT01808573) | III | 621 | Neratinib + Capecitabine vs. Lapatinib + Capecitabine | 33% vs. 27% | 29% vs. 15% | 0.76; 95% CI, 0.63–0.93; p = 0.0059 |
Tucatinib | HER2CLIMB [59] (NCT02614794). | III | 603 | Capecitabine + trastutuzumab +/− Tucatinib | 33% vs. 12% | 40% vs. 22.8% | 0.54; 95% CI, 0.42–0.71; p < 0.001 |
Pyrotinib | PHENIX [65] (NCT02973737) | III | 279 | Capecitabine-Pyrotinib vs. Capecitabine-placebo | 68.6% vs. 16.0% | 0.18; 95% CI, 0.13–0.26; p < 0.001 | |
(NCT02422199) [64] | II | 128 | Capecitabine-Pyrotinib vs. Capecitabine-Lapatinib | 78% vs. 57% | 18 vs. 7% | 0.36; 95% CI, 0.23–0.58; p = 0. 001 |
Trial | Phase | Population | Regimens | Primary Endpoint |
---|---|---|---|---|
PATINA [86] (NCT02947685) | III Randomized | HR+/HER2+ MBC after induction treatment | anti-HER2 therapy ± Palbociclib | PFS |
PATRICIA [87] (NCT02448420) | II | previously treated HR+/HER2+ ABC | Palbociclib + Trastuzumab ± Létrozole | PFS |
(NCT 02657343) | II | HER+ MBC not responded to standard treatment | Ribociclib + Trastuzumab vs T-DM1 ± Fulvestrant | MTD and/or recommended Phase II dose CBR |
(NCT03054363) [88] | Ib/II | first or second line of therapy in HR+/HER+ MBC | Tucatinib + Palbociclib, + Letrozole | adverse events PFS |
Drug | Trial | Phase | Regimens | Population | Activity | Toxicities |
---|---|---|---|---|---|---|
Alpelisib | NCT02038010 [96] | I | Alpelisib + T-DM1 | HER2+ MBC Progressing on prior trastuzumab and taxane-based therapy | Median PFS (months): No prior T-DM1 (n = 11): 6 Prior T-DM1 (n = 6): 4.3 | Hyperglycemia (53%), fatigue (53%), nausea (35%), and rash (47%) |
NCT02167854 [97] | I | LJM716 + alpelisib + Trastuzumab | HER2+ MBC | SD in 5/6 evaluable patients | Significant toxicities (and worst grades): diarrhea, hyperglycemia hypokalemia, mucositis, transaminitis | |
NCT04208178 | III | Alpelisib + Trastuzumab + Pertuzumab | Maintenance therapy in patients with HER2+ ABC with a PIK3CA mutation | unknown | unknown | |
Taselisib | NCT02390427 | Ib | Arm A: Taselisib + Trastuzumab + T-DM1 Arm B: Taselisib + T-DM1 + Pertuzumab Arm C: Taselisib + Pertuzumab + Trastuzumab Arm D: Taselisib + Pertuzumab + Trastuzumab + Paclitaxel | HER2+ ABC | unknown | unknown |
Copanlisib | NCT02705859 [98] | Ib/2 | Copanlisib + Trastuzumab | HER2+ MBC | SD in 9/12 patients. Six patients continued treatment ≥ 16 weeks | G3 hypertension (33%), G3 infections (36%), hepatic toxicities |
MEN1611 | NCT03767335 [99] | Ib | MEN1611 + Trastuzumab +/− Fulvestrant | PIK3CA mutated HER2+ ABC progressed to anti-HER2 based therapy | unknown | unknown |
Class | Treatment | ORR | PFS (months) |
---|---|---|---|
Antibody-drug conjugates | T-DXd | 60.9% | 16.4 |
SYD985 | 33% | 7.6 | |
Margetuximab | Margetuximab + chemotherapy | 25.2% | 5.8 |
Bispecific antibodies | MCLA 128 | 77.7% | unknown |
ZW25 | 54% | unknown | |
HER2 TKI | Neratinib + Capecitabine | 33% | 8.5 |
Tucatinib + Capecitabine + Trastutuzumab | 33% | 7.8 | |
Tucatinib + T-DM1 | 47% | 8.2 | |
Pyrotinib + Capecitabine | 68.6% | 11.1 | |
Poziotinib | 75.5% | 4 | |
ICIs | Pembrolizumab | 25% in the PD-L1 positive cohort | 2.7 |
Atezolizumab + T-DM1 | no benefit | ||
Nivolumab | unknown | unknown | |
Cell cycle inhibitors | Abemaciclib + Trastuzumab +/− Fulvestrant | 35.4% | 8.3 |
mTOR inhibitors | Everolimus + Trastuzumab + Vinorelbine | 7 | |
Alpelisib + T-DM1 | 6 if no prior T-DM1 4.3 if prior T-DM1 | ||
LJM716 + Alpelisib +Trastuzumab | 5/6 | unknown | |
Copanlisib + Trastuzumab | 9/12 | unknown |
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Mezni, E.; Vicier, C.; Guerin, M.; Sabatier, R.; Bertucci, F.; Gonçalves, A. New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices? Cancers 2020, 12, 1573. https://doi.org/10.3390/cancers12061573
Mezni E, Vicier C, Guerin M, Sabatier R, Bertucci F, Gonçalves A. New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices? Cancers. 2020; 12(6):1573. https://doi.org/10.3390/cancers12061573
Chicago/Turabian StyleMezni, Essia, Cécile Vicier, Mathilde Guerin, Renaud Sabatier, François Bertucci, and Anthony Gonçalves. 2020. "New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?" Cancers 12, no. 6: 1573. https://doi.org/10.3390/cancers12061573