Jivadco (trastuzumab duocarmazine)

Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

P1/2, N=48, Completed, Byondis B.V. | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jun 2023 | Trial primary completion date: Dec 2023 --> Apr 2023

Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration.

Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.

Methods The TULIP trial randomly assigned patients with HER2-positive locally advanced or MBC with ≥2 previous HER2-targeting MBC regimens or pretreated with T-DM1, in a 2:1 ratio between T-Duo (1.2 mg/kg q3w) and PC. PC could be either trastuzumab combined with capecitabine or vinorelbine or eribulin or lapatinib plus capecitabine...The final OS results confirm a trend towards a numerically prolonged OS (statistically non-significant) in the T-Duo group compared with PC group. Safety was aligned with the primary analysis, with no new signals identified.

P1, N=32, Completed, Byondis B.V. | Active, not recruiting --> Completed | N=120 --> 32

P3, N=436, Completed, Byondis B.V. | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Aug 2022

P1, N=120, Active, not recruiting, Byondis B.V. | Trial completion date: Dec 2023 --> Jun 2023

P2, N=64, Completed, Byondis B.V. | Active, not recruiting --> Completed

Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients. Trastuzumab emtansine, the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy. Despite the progress in treatment development, most patients develop resistance and eventually relapse. Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer.

P2, N=60, Active, not recruiting, Byondis B.V. | Trial completion date: Dec 2022 --> May 2023 | Trial primary completion date: Dec 2022 --> Apr 2023

P1, N=120, Active, not recruiting, Byondis B.V. | Trial completion date: Jan 2023 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.

P1/2, N=48, Active, not recruiting, Byondis B.V. | Recruiting --> Active, not recruiting | N=196 --> 48

T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer...Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines...In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved anti-tumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression.

Although an early clinical study failed to demonstrate benefit of adjuvant trastuzumab for ERBB2-low disease, several novel anti-ERBB2 therapies have shown efficacy in ERBB2-low breast cancer, including the antibody-drug conjugate trastuzumab deruxtecan in a phase 3 trial, and trastuzumab duocarmazine and the bispecific antibody zenocutuzumab in early-phase studies. This review suggests that ERBB2-low may be a distinct, clinically relevant breast cancer entity warranting reassessment of traditional diagnostic and therapeutic paradigms. Ongoing clinical trials and further investigations may provide optimized strategies for diagnosing and treating ERBB2-low breast cancer, including reproducible, consistent definitions to identify patients in this diagnostic category and demonstration of benefits of emerging therapies.

P1/2, N=196, Recruiting, Byondis B.V. | Active, not recruiting --> Recruiting | N=48 --> 196

P1, N=120, Active, not recruiting, Byondis B.V. | Trial primary completion date: Jul 2022 --> Dec 2022

P1/2, N=48, Active, not recruiting, Byondis B.V. | Recruiting --> Active, not recruiting | N=180 --> 48

P3, N=436, Active, not recruiting, Byondis B.V. | Trial completion date: May 2022 --> Oct 2022

P2, N=60, Active, not recruiting, Byondis B.V. | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2022 --> Dec 2022

There were statistically significant differences regarding estrogen (p = 0.00) and progesterone (p = 0.02) receptors...The prevalence of hormonal receptors in HER2-low tumors was consistent with previous data in the literature. Although retrospective, the data suggest that HER2-low tumors should be regarded as a distinct biological subtype and more research is warranted.

The randomized DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1) in patients previously treated with trastuzumab and a taxane...For subsequent lines, trastuzumab duocarmazine, neratinib plus capecitabine or the continuation of trastuzumab with different chemotherapy partners are valid options...For those relapsing between 6 and 12 months after non-pertuzumab-based adjuvant treatment, we recommend first-line THP. Finally, for patients with active brain metastasis, tucatinib-based combination represents a suitable second-line option.

A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

P1, N=120, Active, not recruiting, Byondis B.V. | Recruiting --> Active, not recruiting

P1/2, N=180, Recruiting, Byondis B.V. | Not yet recruiting --> Recruiting | Initiation date: Sep 2021 --> Jan 2022

Our data does not support HER2-low as a biologically distinct BC subtype, with no prognostic value on survival outcomes and no predictive effect for pCR after conventional NACT.

-The preliminary overall survival (OS) results are supportive. -Safety data obtained in the trial will be discussed

P2; Trial completion date: Dec 2026 --> Dec 2031 | Trial primary completion date: Dec 2025 --> Dec 2030

P1/2, N=180, Not yet recruiting, Byondis B.V.

A narrative review is also performed regarding the rationale behind the consolidated and ongoing clinical trials studying anti-HER2 agents in combination with unrelated agents, such as immunotherapy, endocrine therapy, and CDK4/6 inhibitors. Hopefully, all this ongoing research effort will be able to extend the survival benefits seen with anti-HER2 agents in HER2-positive disease, at least to some degree, to the greater proportion of patients with HER2-low BC.

P2, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P1 --> P2

Recently, the US Food and Drug Administration (FDA) approved three new drugs for the treatment of HER2-positive MBC: the antibody-drug conjugate trastuzumab deruxtecan and the two tyrosine kinase inhibitors neratinib and tucatinib...Furthermore, novel antibody-drug conjugates and small molecules against HER2 are discussed. These developments coupled with new combination strategies (eg, with CDK4/6 inhibitors or immunotherapy) will change the treatment landscape for patients with HER2-positive MBC very soon and will hopefully further improve clinical outcomes.

P1, N=4000, Recruiting, QuantumLeap Healthcare Collaborative | Phase classification: P2 --> P1

Recently, the results of Phase I studies with novel antibody drug conjugates targeting HER2 (Trastuzumab-deruxtecan and trastuzumab-duocarmazine) have suggested a benefit in HER2-low patients with advanced breast cancer. In this cohort, 31% of patients were HER2-low. There were no substantial differences in demographic/pathologic terms between HER2-low and HER2-0 patients. HER2-low status did not impact pCR rates or RFS of luminal and triple negative tumors treated with neoadjuvant chemotherapy.

P3, N=436, Active, not recruiting, Byondis B.V. | Recruiting --> Active, not recruiting | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: Jul 2020 --> Jul 2021

P2, N=60, Recruiting, Byondis B.V. | Not yet recruiting --> Recruiting

Preclinical data strongly supports these ADCs and ongoing clinical trials will shed further light into the potential of making these drugs part of current standard practice and providing our patients with a higher level of personalized cancer care.

ILD is a well-described adverse drug reaction associated with several anti-HER2 drugs. Published ILD management guidelines are available for few anti-HER2 treatment regimens; however, guidance for monitoring for anti-HER2 drug-induced ILD is lacking.

Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation.

P1, N=120, Recruiting, Byondis B.V. | Not yet recruiting --> Recruiting