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Review

The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results

by
Kenji Nakano
Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan
Int. J. Mol. Sci. 2023, 24(23), 16823; https://doi.org/10.3390/ijms242316823
Submission received: 29 October 2023 / Revised: 22 November 2023 / Accepted: 23 November 2023 / Published: 27 November 2023
(This article belongs to the Special Issue Molecular Research of Osteosarcoma Pathology and the Latest Therapies)
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Abstract

:
Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB, is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody–drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described.

1. Development of HER2-Targeted Therapy in Oncology

1.1. HER2 Biology

Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene ERBB2 (located at chromosome 17q21), is a receptor tyrosine-protein kinase and a member of the family of epidermal growth factor receptor (EGFR) tyrosine kinases, which consists of EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (Erb4). Unlike other EGFR family members, specific ligand binding to HER2 is not known; HER2 acts to form homodimers when binding to other HER2 molecules or heterodimers when binding to other EGFR family members, activating downstream cell proliferation signaling pathways such as the mitogen-activated protein kinase (MAPK) and phosphatidylinositol bisphosphate 3 kinase (PI3K) pathways [1]. The role of overexpressed ERBB2 as an oncogene was clarified with the use of transgenic mouse models [2].
The most common cancer known to include an HER2-positive population is breast cancer, for which HER2-targeted treatment strategies have been established [3]. As with the treatment strategies, the pathological evaluation of HER2 overexpression has been standardized for clinical decisions regarding the indications for HER2-targeted therapy [4], and pathological evaluation of HER2 overexpression is now applied to other malignant diseases. Gastroesophageal adenocarcinoma includes an HER2-positive subtype, and its treatment strategies have been divided into those for HER2-positive versus HER2-negative populations [5]. Although less common than breast and gastroesophageal cancers, a number of patients with other carcinomas have been observed to be HER2-positive (Table 1) [1,6,7]. As next-generation sequence (NGS) and whole-genome profiling have become widely used in clinical practice, various rare HER2 mutations other than amplification/overexpression have been recognized, such as ERBB2 fusion genes [8].

1.2. Development of HER2-Targeted Drugs

Based on the results obtained in basic research and the findings described above, many HER2-targeted drugs have been investigated and approved over the past 20 years, including monoclonal antibodies (mAbs), low-molecular-weight tyrosine kinase inhibitors (TKIs), and antibody–drug conjugates (ADCs). Most of these drugs were approved first for the treatment of breast cancer, and some of them have shown clinical benefits for other malignant diseases and are approved or recommended in some guidelines. The HER2-targeted drugs that have been approved by the U.S. Food and Drug Administration (FDA) as of 2023 are listed in Table 2.
Trastuzumab is the pioneer of molecular-targeted drugs; it was approved by the FDA in 1998 and was the first mAb used to treat malignant diseases. Trastuzumab has been shown to be useful in a wide range of circumstances, including recurrent cases and pre- and postoperative adjuvant chemotherapy for HER2-positive breast cancer, making it an indispensable drug in clinical practice [3]. Trastuzumab has also been approved by the FDA for the treatment of HER2-positive gastroesophageal cancer in combination with chemotherapy for recurrent or metastatic cases [9]. Several clinical trials have evaluated trastuzumab’s efficacy against other cancers, and guideline recommendations or indication approval by the FDA have been applied for some cancers, including colorectal cancer and salivary gland cancer [6,10]. Trastuzumab is a drug of great significance in cancer treatment in the sense that it opened up the therapeutic system of HER2-targeted therapy. Along with the widespread use of trastuzumab and the increased demand for cancer treatment, a trastuzumab biosimilar was developed and received FDA approval in 2017 [11,12]. A convenient subcutaneous injection formulation of trastuzumab is also being developed [13,14].
Pertuzumab is a mAb that targets the binding site of dimers including HER2, and it is usually administered in combination with trastuzumab. Pertuzumab has been shown to be effective in rescue therapy and adjuvant chemotherapy for recurrent and metastatic breast cancer [15,16]. The efficacy of pertuzumab in combination with trastuzumab against malignant diseases other than breast cancer is under investigation [17], and subcutaneous formulations have been developed and approved, as with trastuzumab [18]. The mAb margetuximab has shown benefit with cytotoxic chemotherapy for HER2-positive breast cancer patients with a history of multiple chemotherapies including other HER2-targeted therapy [19,20].
Lapatinib, neratinib, and tucatinib are oral low molecular TKIs that target HER2 and other EGFR-family receptor tyrosine kinases. Lapatinib has demonstrated antitumor activity in combination with the cytotoxic anticancer drug capecitabine and is approved for the treatment of breast cancer [21]. Neratinib is also used with capecitabine to treat recurrent/metastatic breast cancer, but it is used as monotherapy in extended adjuvant therapy; for perioperative therapy with neratinib, the selection of indications as precision medicine based on patient profiles has been investigated [22,23,24]. Tucatinib is prescribed in combination with capecitabine and trastuzumab, and it has demonstrated a promising effect on brain metastases [25,26]. Tucatinib and trastuzumab combination therapy was also approved for HER2-positive colorectal cancer in 2023 [27].
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) in which the microtubule inhibitor DM1 is bound as a cytotoxic payload by the linker to trastuzumab. T-DM1 showed efficacy for patients with advanced HER2-positive breast cancer after trastuzumab treatment, and it was superior to lapatinib and capecitabine [28]. As perioperative therapy, T-DM1 is administered to patients who have residual invasive disease after neoadjuvant chemotherapy including trastuzumab [29].
All of the HER2-targeted drugs mentioned above are now approved for the treatment of breast cancer, but their efficacy against other HER2-positive cancers varies; although there has been a study in which HER2-targeted therapy showed promising efficacy similar to that of trastuzumab for salivary gland cancers [10], there is also the case that HER2-targeted therapy effective to HER2-positive breast cancer is not effective to other HER2-positive cancers, such as T-DM1 to gastroesophageal cancer [30]. Until the introduction of trastuzumab deruxtecan (T-DXd, discussed below in Section 3), the prognostic impact of HER2 expression and the efficacy of targeted therapy was essentially considered tumor specific, not tumor agnostic [6].

2. HER2 in Osteosarcoma

2.1. HER2 Amplification or Overexpression in Osteosarcoma

Osteosarcoma is a malignant disease that occurs mainly in children and young adults. It is the most common primary bone tumor but it is rare; for example, there are approx. 400 new osteosarcoma cases/year in the United States. Since the 1980s, the use of cytotoxic anticancer agents (methotrexate, doxorubicin, cisplatin, and ifosfamide) for pre- and postoperative adjuvant chemotherapy has improved the prognoses of osteosarcoma patients, but the development of molecular-targeted therapy for osteosarcomas has lagged behind that of other solid tumors [31]. One reason for this is that the genetic variation in osteosarcomas is so great that it is difficult to find a common specific target molecule or mutation [32]. Among the osteosarcomas, mutations to HER2 have been detected at a relatively high rate, but the reported frequency of HER2 amplification or overexpression in osteosarcoma varies (although most reports are in the 30–60% range, there have been reports of 0–100%). This wide range of values may depend on the evaluation method (e.g., immunohistochemistry [IHC] techniques such as staining vs. fluorescence in situ hybridization [FISH]) and patient background (initial presentation, distant metastasis, etc.) [33]. It has been noted that HER2 tends to be expressed in the cytoplasm in osteosarcoma cell lines [34]. This differs from HER2-positive breast cancer and other solid tumors, which may also contribute to the positivity rate’s variability.
Since HER2 is known to have carcinogenic function, the value of HER2 mutation as a prognostic factor in osteosarcoma has been investigated, but the prognostic significance of HER2 in osteosarcoma is still a matter of controversy [33].

2.2. HER2-Targeted Therapies for Osteosarcoma

There are very few clinical data on HER2-targeted therapies for osteosarcoma compared to other carcinomas, due in part to its rarity; in addition, osteosarcoma is predominant in children and young adults, and safety and optimal dosage evaluations for HER2-targeted drugs must be considered separately in the development of such drugs.
As mentioned above, trastuzumab is the first and representative HER2-targeted antitumor agent, and it is the only HER2-targeted agent whose efficacy has been evaluated in prospective clinical trials for osteosarcoma prior to the advent of trastuzumab deruxtecan. In the phase II trial carried out by the Children’s Oncology Group, 96 newly diagnosed metastatic osteosarcoma patients (41 with HER2 overexpression shown by IHC) received both standard chemotherapy (a combination of cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide); trastuzumab (weekly for a total of 34 cycles) was added to the treatment of 34 of the HER2-positive patients. The 30-month event-free survival and overall survival rates of the HER2-positive patients were 32% and 59%, respectively, which were not significantly different from the rates of the HER2-negative patients (32% and 50%) [35]. Although the efficacy of trastuzumab cannot be evaluated in a randomized controlled trial since the study did not directly compare the efficacy of trastuzumab with or without trastuzumab in HER2-positive patients, the results of the Children’s Oncology Group study did not indicate that trastuzumab would be effective for the treatment of HER2-positive osteosarcoma. Other than the phase II trial of trastuzumab cited above, data from prospective clinical trials of HER2-targeted therapies have not been available, and preclinical studies remain few and far between [36].
It was against this backdrop that a new HER2-targeted ADC, i.e., trastuzumab deruxtecan (T-DXd) emerged, as discussed next.

3. Trastuzumab Deruxtecan (T-DXd) for the Treatment of Osteosarcoma

3.1. The Mechanism of Action and Clinical Efficacy of T-DXd

Trastuzumab deruxtecan (T-DXd) is a new HER2-targeted ADC with a novel linker-payload system. The cytotoxic payload is a topoisomerase I inhibitor exatecan derivative (DXd), which differs from the cytotoxic payload of a previous HER2-targeted ADC, i.e., T-DM1, in which the microtubule inhibitor is linked as payload [37]. Due to the cell membrane permeability effect, there is not only a direct cytotoxic effect of T-DXd against the target HER2-positive cancer cells to which trastuzumab directly binds as an HER2-targeted antibody; T-DXd also has the ability to kill cancer cells in the vicinity, as a so-called bystander effect [38]. A preclinical study of T-DXd demonstrated the bystander effect, which is considered to be a characteristic of this drug [39]. As expected from the results of preclinical studies, T-DXd has shown promising effects on various HER2-positive solid tumors, which had not been regarded as the subjects of HER2-targeted therapies in the early phase of investigation [40].
First, in HER2-positive breast cancer, T-DXd treatment produced a very high response rate of 60% in patients who had received multiple HER2-targeted therapies, including trastuzumab and T-DM1, and T-DXd was then approved by the FDA for the treatment of HER2-positive breast cancer in 2019 [41]. In a subsequent phase III trial, T-DXd treatment provided extended survival in patients after T-DM1 treatment [X], and in another phase III trial T-DXd showed superiority to T-DM1 [42]. Based on these results, T-DXd is gradually being used in previous lines of therapy in patients with recurrent or metastatic disease. T-DXd has also shown efficacy against trastuzumab-resistant HER2-positive gastroesophageal cancer, and it was approved by the FDA for the treatment of this disease in 2021 [43]. In addition, high response rates have been reported for T-DXd in settings in which HER2-targeted therapy had not been approved. Clinical trials for HER2-positive patients with non-small cell lung cancer (NSCLC) and HER2-positive patients with colorectal cancer have shown high response rates [44,45], and T-DXd was approved by the FDA for the treatment of NSCLC in 2022. Other clinical trials are underway for gynecologic cancer [46] and biliary tract cancer [47]. In a single-arm meta-analysis of T-DXd as a treatment for HER2-positive solid tumors (breast cancer, gastroesophageal cancer, colorectal cancer, NSCLC, and biliary tract cancer), the pooled overall response rate was 47.91%, and the median durations of progression-free and overall survival combined were 9.63 months and 10.71 months, respectively [48].
As noted above, the efficacy of HER2-targeted therapy has been thought to vary between tumors of different primary origin, but the results demonstrating efficacy in such a wide range of areas has raised expectations for the tumor-agnostic effects of T-DXd [49]. In 2023, the DESTINY-PanTumor02 study was initiated as a phase II trial of T-DXd enrolling HER2-positive (IHC 2+ or IHC 3+) solid tumors for which HER2-targeted therapies had rarely or never been evaluated, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other tumors [50]. The trial’s overall response rate (primary endpoint) for all patients (IHC 3+ and IHC 2+) and IHC 3+ was 37.1% and 61.3%, respectively. There were variations in the efficacy of T-DXd among the types of carcinoma, with pancreatic cancer, in particular, having an exceptionally low response rate at 4.0%, but, in general, a high response rate was achieved with T-DXd in each of the HER2-positive tumors enrolled, regardless of their primary origins.
Until recently, HER2-targeted therapy had been known to be more effective in cases with higher HER2 expression, and its efficacy was regarded as clinically meaningful only for patients with high HER2 expression (IHC 3+ or FISH-positive, defined as “HER2-positive”), and thus the clinical trials of HER2-targeted therapies before the advent of T-DXd had been limited to these patients. This was also true for T-DM1, the first HER2-targeted ADC. However, T-DXd has been shown to be effective even in patients with low HER2 expression, and its efficacy was demonstrated in clinical trials of breast cancer patients with low HER2 expression; its approval has established a new population called “HER2-low” [51]. Clinical trials have also been conducted in patients with other cancers with low HER2 expression, and promising results have been obtained [52].
Although a high response rate and clinical benefit have been observed for T-DXd in a broad range of malignant diseases, the management of adverse events is a major challenge, especially in interstitial lung disease (ILD) [53,54].

3.2. T-DXd Treatment for Osteosarcoma—An Unexpected Result

The above-described background has provided an opportunity to evaluate the efficacy of T-DXd in osteosarcoma, which is known to contain HER2-positive cases. However, HER2-targeted therapies have not been developed for osteosarcoma. In a preclinical study conducted by the Pediatric Preclinical Testing Consortium, six of seven xenograft models of osteosarcoma with HER2 mRNA positivity achieved prolonged event-free survival, suggesting that clinical trials may be beneficial [55].
Nevertheless, the results of the PEPN1924 phase II trial of T-DXd were disappointing. Recurrent, unresectable osteosarcoma patients with >10% of tumor cells with cytoplasmic or membranous HER2 expression were treated with T-DXd (5.4 mg/kg every 3 weeks), but none of nine patients enrolled at the first step showed an objective response; on the contrary, seven of them were evaluated as having progressive disease at the first response evaluation (after only two infusions of T-DXd), and one of the remaining two patients withdrew consent before the first evaluation; the other barely reached the definition of stable diseases at 24 weeks after the introduction of T-DXd, which was the primary endpoint of the trial. As a result, the trial was terminated without proceeding to the second step [56].
Why was T-DXd, which has been shown to be effective in almost all HER2-positive cancers, not effective in osteosarcoma? Several reasons should be considered. An initial question is, were the inclusion criteria of the PEPN1924 trial appropriate? The definition of the inclusion criteria for “HER2-positive” status in the PEPN1924 trial differs from the definition used for other HER2-positive cancers (represented by breast cancer). As discussed earlier in Section 2.1, HER2 in osteosarcoma tends to be expressed in the cytoplasm rather than on the cell membrane surface, which may have influenced the efficacy of T-DXd. In preclinical studies, T-DXd was shown to prolong event-free survival in the xenograft model, but the effect of tumor shrinkage was limited to stable disease [55]. However, it is expected that T-DXd will have an antitumor bystander effect, and we can judge the degree to which the HER2 expression status affects the efficacy of T-DXd only by considering the results of past and future clinical trials.
Is it possible that the antitumor effect of the payload in T-DXd is not active against osteosarcoma? The payload of T-DXd is an exatecan derivative (DC-8951 derivative, DXd), which is a topoisomerase I inhibitor similar to irinotecan [37], but irinotecan is not approved for the treatment of osteosarcoma. In a retrospective analysis of patients treated at the Memorial Sloan-Kettering Cancer Center in which the efficacy of irinotecan for treating pediatric solid tumors was evaluated, seven osteosarcoma patients (six of whom had an evaluable response) were included and none of them showed any clinical benefit; the outcome for all six evaluable patients was progressive disease [57]. However, the efficacy expected from the mechanism of action of the payload does not necessarily match the efficacy of the ADC. For example, topoisomerase inhibitors including irinotecan have not been approved for breast cancer (for which T-DXd is markedly effective), and conversely, there are carcinomas such as pancreatic cancer for which irinotecan is used as standard therapy (including liposomal formulations), but T-DXd was not effective [58].
Whether the dose of T-DXd is appropriate is also open to consideration. Several doses of T-DXd are currently approved for use: 6.4 mg/kg and 5.4 mg/kg, depending on the carcinoma. The PEPN1924 trial used the 5.4 mg/kg dose, but it is unclear whether the dose intended for adults is effective and safe in children, which is especially important because osteosarcomas have developed in many pediatric patients. The majority of the patients in the PEPN1924 trial ended the study with early progression, and it is thus more likely that underdosing resulted in a lack of efficacy rather than in adverse events due to overdosing. However, T-DXd is a drug with a high incidence of adverse events—especially pulmonary toxicity as typified by ILD—and a carefully designed phase I trial is necessary if efficacy with increased doses is to be achieved.
Another possibility to consider is that the role that HER2 plays in the cancer cell signaling pathway in osteosarcoma may play a different role than in other HER2-positive solid tumors. For example, BRAF V600 mutation is now approved as the tumor-agnostic target [59,60], but differences in efficacy are observed among tumor origins, especially in colorectal cancer. Interestingly, unlike other BRAF-mutated cancers, it is known that the co-inhibition of EGFR (upstream of BRAF) is indispensable to the clinical response of colorectal cancers, and, on the other hand, the co-inhibition of MEK (downstream of BRAF) might not contribute to the improved efficacy in BRAF-mutated colorectal cancers [61,62]. Indeed, regorafenib, a multi-kinase inhibitor, has shown some efficacy in osteosarcoma, suggesting that multiple cell surface tyrosine kinases and their downstream signaling pathways are involved in tumor growth [63,64]. Investigations of how other signaling pathways associated with HER2 are involved in cancer progression may help identify osteosarcoma patients who will benefit from T-DXd in the future.
In any case, the evidence available at present does not indicate that T-DXd is effective against HER2-positive osteosarcoma, and it is not a drug that will change the treatment system as significantly as other malignant diseases.

4. Future Direction of HER2-Targeted Therapy Development to Osteosarcoma

Although HER2-targeted therapies (i.e., mAbs and ADCs) have made great strides in cancer treatment with results extending beyond breast cancer, osteosarcoma has not yet benefited from them. New therapeutic strategies targeting HER2 are still being developed, some of which target osteosarcoma. The next section is an overview of the prospects for HER2-targeted therapy as a potential new treatment for osteosarcoma (Figure 1).

4.1. Bispecific Antibody Including HER2

The development of bispecific antibodies that inhibit multiple targets is progressing, with practical approval achieved in hematologic diseases [65,66,67]. Although bispecific antibodies for solid tumors are still under development and appropriate target molecules have not been established, HER2, for which molecular-targeted therapy with antibody drugs has already been established as discussed above, is one of the candidates [68,69].
Another potential candidate for treating osteosarcoma is disialoganglioside (GD2), which is a glycosphingolipid expressed on the surface of various malignant tumors including osteosarcoma [70]. The development of GD2-targeted therapy has focused on pediatric oncology, including neuroblastomas and osteosarcomas; as a treatment for neuroblastoma, the anti-GD2 antibody dinutuximab showed the improvement of event-free survival as maintenance therapy with alternating granulocyte-macrophage colony-stimulating factor (GM-CSF) and intravenous interleukin-2 (IL-2) and was approved by the FDA in 2015 [71]. Unfortunately, dinutuximab for recurrent osteosarcoma did not show efficacy in a phase II trial [72], but the development of bispecific antibodies that inhibit HER2 and GD2 is underway, and their efficacy is expected to be evaluated [73]. Attempts have also been made to evaluate the GD2 expression on images [74], which is a technique that is beneficial in osteosarcoma, a primary bone cancer that can be more difficult to evaluate with the use of molecular pathologic markers compared to other solid tumors. As described in the example of BRAF-targeted therapy for colorectal cancer, it is possible that a combination of targeted agents can inhibit cancer growth even if individual targeted therapies do not work. However, in the development of bispecific antibodies, clinical research should not be conducted by combining targets in the dark; basic and translational research should also be conducted to determine how much of a synergy effect can be expected from co-targeted therapy.

4.2. Immunotherapy Targeted to HER2 in Osteosarcoma

Cancer immunotherapy progressed remarkably in the 2010s, due mainly to the development of immune checkpoint inhibitors [75]. However, for bone and soft tissue sarcomas, the immune checkpoint inhibitors have not yet shown meaningful clinical benefit, except for some specific subtypes of soft tissue sarcomas [76,77]. Immunotherapies such as T-cell treatments and vaccines for bone and soft tissue tumors continue to be developed, some of which target HER2.
Chimeric antigen receptor T-cell (CAR-T) therapy treats cancer by taking the patient’s own T cells and administering them to the patient with modified T cells (CAR-T cells) that can produce a special protein called chimeric antigen receptor (CAR) [78]. Formulations targeting the transmembrane protein CD19 and B-cell maturation antigen (BCMA) are now approved for hematologic diseases, but development is also underway for solid tumors, and HER2 is included as a candidate target antigen. Safety evaluations have already been conducted for osteosarcoma, and efficacy data are expected to be obtained in the future [79].
Cancer vaccines are also being actively developed in the field of cancer immunotherapy, and clinical trials have begun for those targeting HER2 [80,81]. Most of these vaccines are being tested in breast and gastric cancers, but as their efficacy is demonstrated, it is expected that they will be tested in a wide range of HER2-positive solid tumors, as is the case with T-DXd.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflict of interest.

Abbreviations

ADC: antibody–drug conjugate, BCMA: B-cell maturation antigen, CAR-T: chimeric antigen receptor T-cell, FDA: Food and Drug Administration, FISH: fluorescence in situ hybridization, GD2: disialoganglioside, HER2: human epidermal growth factor receptor 2, IHC: immunohistochemistry, ILD: interstitial lung disease, MAPK: mitogen-activated protein kinase, NSCLC: non-small-cell lung cancer, PI3K: phosphatidylinositol bisphosphate 3 kinase, p.o.: per os, T-DXd: trastuzumab deruxtecan.

References

  1. Raghav, K.P.S.; Moasser, M.M. Molecular pathways and mechanisms of HER2 in cancer therapy. Clin. Cancer Res. 2023, 29, 2351–2361. [Google Scholar] [CrossRef]
  2. Guy, C.T.; Webster, M.A.; Schaller, M.; Parsons, T.J.; Cardiff, R.D.; Muller, W.J. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc. Natl. Acad. Sci. USA 1992, 89, 10578–10582. [Google Scholar] [CrossRef] [PubMed]
  3. Giordano, S.H.; Franzoi, M.A.B.; Temin, S.; Anders, C.K.; Chandarlapaty, S.; Crews, J.R.; Kirshner, J.J.; Krop, I.E.; Lin, N.U.; Morikawa, A.; et al. Systemic therapy for advanced human epidermal growth factor receptor 2-positive breast cancer: ASCO guideline update. J. Clin. Oncol. 2022, 40, 2612–2635. [Google Scholar] [CrossRef] [PubMed]
  4. Wolff, A.C.; Somerfield, M.R.; Dowsett, M.; Hammond, M.E.H.; Hayes, D.F.; McShane, L.M.; Saphner, T.J.; Spears, P.A.; Allison, K.H. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO-College of American Pathologists Guideline Update. J. Clin. Oncol. 2023, 41, 3867–3872. [Google Scholar] [CrossRef] [PubMed]
  5. Bartley, A.N.; Washington, M.K.; Colasacco, C.; Ventura, C.B.; Ismaila, N.; Benson, A.B., 3rd; Carrato, A.; Gulley, M.L.; Jain, D.; Kakar, S.; et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: Guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J. Clin. Oncol. 2017, 35, 446–464. [Google Scholar] [CrossRef] [PubMed]
  6. Oh, D.Y.; Bang, Y.J. HER2-targeted therapies—A role beyond breast cancer. Nat. Rev. Clin. Oncol. 2020, 17, 33–48. [Google Scholar] [CrossRef] [PubMed]
  7. Li, Z.; Chen, S.; Feng, W.; Luo, Y.; Lai, H.; Li, Q.; Xiu, B.; Li, Y.; Li, Y.; Huang, S.; et al. A pan-cancer analysis of HER2 index revealed transcriptional pattern for precise selection of HER2-targeted therapy. EBioMedicine 2020, 62, 103074. [Google Scholar] [CrossRef]
  8. Schubert, L.; Elliott, A.; Le, A.T.; Estrada-Bernal, A.; Doebele, R.C.; Lou, E.; Borghaei, H.; Demeure, M.J.; Kurzrock, R.; Reuss, J.E.; et al. ERBB family fusions are recurrent and actionable oncogenic targets across cancer types. Front. Oncol. 2023, 13, 1115405. [Google Scholar] [CrossRef]
  9. Bang, Y.-J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010, 376, 687–697. [Google Scholar] [CrossRef]
  10. Takahashi, H.; Tada, Y.; Saotome, T.; Akazawa, K.; Ojiri, H.; Fushimi, C.; Masubuchi, T.; Matsuki, T.; Tani, K.; Osamura, R.Y.; et al. Phase II trial of trastuzumab and docetaxel in patients with human epidermal growth factor receptor 2-positive salivary duct carcinoma. J. Clin. Oncol. 2019, 37, 125–134. [Google Scholar] [CrossRef]
  11. Bennett, C.L.; Schoen, M.W.; Hoque, S.; Witherspoon, B.J.; Aboulafia, D.M.; Hwang, C.S.; Ray, P.; Yarnold, P.R.; Chen, B.K.; Schooley, B.; et al. Improving oncology biosimilar launches in the EU, the USA, and Japan: An updated Policy Review from the Southern Network on Adverse Reactions. Lancet Oncol. 2020, 21, e575–e588, Erratum in Lancet Oncol. 2021, 22, e42. [Google Scholar] [CrossRef] [PubMed]
  12. Triantafyllidi, E.; Triantafillidis, J.K. Systematic review on the use of biosimilars of trastuzumab in HER2+ breast cancer. Biomedicines 2022, 10, 2045. [Google Scholar] [CrossRef] [PubMed]
  13. Ismael, G.; Hegg, R.; Muehlbauer, S.; Heinzmann, D.; Lum, B.; Kim, S.-B.; Pienkowski, T.; Lichinitser, M.; Semiglazov, V.; Melichar, B.; et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): A phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012, 13, 869–878. [Google Scholar] [CrossRef] [PubMed]
  14. Ataseven, B.; Azim, H.; Al-Sakaff, N.; Lauer, S.; Shing, M.; Koroveshi, D.; Bouzid, K.; Casalnuovo, M.; Cascallar, D.; Korbenfeld, E.P.; et al. Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study’s primary analysis of 2573 patients. Eur. J. Cancer 2017, 82, 237–246. [Google Scholar] [CrossRef]
  15. Baselga, J.; Cortés, J.; Kim, S.-B.; Im, S.-A.; Hegg, R.; Im, Y.-H.; Roman, L.; Pedrini, J.L.; Pienkowski, T.; Knott, A.; et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med. 2012, 366, 109–119. [Google Scholar] [CrossRef]
  16. Von Minckwitz, G.; Procter, M.; de Azambuja, E.; Zardavas, D.; Benyunes, M.; Viale, G.; Suter, T.; Arahmani, A.; Rouchet, N.; Clark, E.; et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N. Engl. J. Med. 2017, 377, 122–131, Erratum in N. Engl. J. Med. 2017, 377, 702; Erratum in N. Engl. J. Med. 2018, 379, 1585. [Google Scholar] [CrossRef] [PubMed]
  17. Sweeney, C.J.; Hainsworth, J.D.; Bose, R.; Burris, H.A.; Kurzrock, R.; Swanton, C.; Friedman, C.F.; Spigel, D.R.; Szado, T.; Schulze, K.; et al. MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + trastuzumab treatment of a tissue-agnostic cohort of patients with human epidermal growth factor receptor 2-altered advanced solid tumors. J. Clin. Oncol. 2023, in press. [Google Scholar] [CrossRef] [PubMed]
  18. Tan, A.R.; Im, S.-A.; Mattar, A.; Colomer, R.; Stroyakovskii, D.; Nowecki, Z.; De Laurentiis, M.; Pierga, J.-Y.; Jung, K.H.; Schem, C.; et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): A randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021, 22, 85–97, Erratum in Lancet Oncol. 2021, 22, e42. [Google Scholar] [CrossRef]
  19. Rugo, H.S.; Im, S.-A.; Cardoso, F.; Cortés, J.; Curigliano, G.; Musolino, A.; Pegram, M.D.; Wright, G.S.; Saura, C.; Escrivá-De-Romaní, S.; et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: A phase 3 randomized clinical trial. JAMA Oncol. 2021, 7, 573–584. [Google Scholar] [CrossRef]
  20. Royce, M.; Osgood, C.L.; Amatya, A.K.; Fiero, M.H.; Chang, C.G.; Ricks, T.K.; Shetty, K.A.; Kraft, J.; Qiu, J.; Song, P.; et al. FDA Approval Summary: Margetuximab plus chemotherapy for advanced or metastatic HER2-positive breast cancer. Clin. Cancer Res. 2022, 28, 1487–1492. [Google Scholar] [CrossRef]
  21. Ryan, Q.; Ibrahim, A.; Cohen, M.H.; Johnson, J.; Ko, C.W.; Sridhara, R.; Justice, R.; Pazdur, R. FDA drug approval summary: Lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 2008, 13, 1114–1119. [Google Scholar] [CrossRef] [PubMed]
  22. Saura, C.; Oliveira, M.; Feng, Y.-H.; Dai, M.-S.; Chen, S.-W.; Hurvitz, S.A.; Kim, S.-B.; Moy, B.; Delaloge, S.; Gradishar, W.; et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Phase III NALA Trial. J. Clin. Oncol. 2020, 38, 3138–3149. [Google Scholar] [CrossRef] [PubMed]
  23. Chan, A.; Delaloge, S.; Holmes, F.A.; Moy, B.; Iwata, H.; Harvey, V.J.; Robert, N.J.; Silovski, T.; Gokmen, E.; von Minckwitz, G.; et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016, 17, 367–377. [Google Scholar] [CrossRef]
  24. Park, J.W.; Liu, M.C.; Yee, D.; Yau, C.; Veer, L.J.v.; Symmans, W.F.; Paoloni, M.; Perlmutter, J.; Hylton, N.M.; Hogarth, M.; et al. Adaptive randomization of neratinib in early breast cancer. N. Engl. J. Med. 2016, 375, 11–22. [Google Scholar] [CrossRef] [PubMed]
  25. Murthy, R.K.; Loi, S.; Okines, A.; Paplomata, E.; Hamilton, E.; Hurvitz, S.A.; Lin, N.U.; Borges, V.; Abramson, V.; Anders, C.; et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N. Engl. J. Med. 2020, 382, 597–609, Erratum in N. Engl. J. Med. 2020, 382, 586. [Google Scholar] [CrossRef] [PubMed]
  26. Lin, N.U.; Borges, V.; Anders, C.; Murthy, R.K.; Paplomata, E.; Hamilton, E.; Hurvitz, S.; Loi, S.; Okines, A.; Abramson, V.; et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial. J. Clin. Oncol. 2020, 38, 2610–2619. [Google Scholar] [CrossRef] [PubMed]
  27. Casak, S.J.; Horiba, M.N.; Yuan, M.; Cheng, J.; Lemery, S.J.; Shen, Y.L.; Fu, W.; Moore, J.N.; Li, Y.; Bi, Y.; et al. FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer. Clin. Cancer Res. 2023, 29, 4326–4330. [Google Scholar] [CrossRef] [PubMed]
  28. Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.-Y.; Diéras, V.; Guardino, E.; et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012, 367, 1783–1791, Erratum in N. Engl. J. Med. 2013, 368, 2442. [Google Scholar] [CrossRef]
  29. Von Minckwitz, G.; Huang, C.-S.; Mano, M.S.; Loibl, S.; Mamounas, E.P.; Untch, M.; Wolmark, N.; Rastogi, P.; Schneeweiss, A.; Redondo, A.; et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N. Engl. J. Med. 2019, 380, 617–628. [Google Scholar] [CrossRef]
  30. Thuss-Patience, P.C.; Shah, M.A.; Ohtsu, A.; Van Cutsem, E.; Ajani, J.A.; Castro, H.; Mansoor, W.; Chung, H.C.; Bodoky, G.; Shitara, K.; et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017, 18, 640–653. [Google Scholar] [CrossRef]
  31. Meltzer, P.S.; Helman, L.J. New horizons in the treatment of osteosarcoma. N. Engl. J. Med. 2021, 385, 2066–2076. [Google Scholar] [CrossRef] [PubMed]
  32. Mirabello, L.; Zhu, B.; Koster, R.; Karlins, E.; Dean, M.; Yeager, M.; Gianferante, M.; Spector, L.G.; Morton, L.M.; Karyadi, D.; et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in patients with osteosarcoma. JAMA Oncol. 2020, 6, 724–734. [Google Scholar] [CrossRef] [PubMed]
  33. Gill, J.; Hingorani, P.; Roth, M.; Gorlick, R. HER2-targeted therapy in osteosarcoma. Adv. Exp. Med. Biol. 2020, 1257, 55–66. [Google Scholar] [CrossRef] [PubMed]
  34. Hughes, D.P.; Thomas, D.G.; Giordano, T.J.; Baker, L.H.; McDonagh, K.T. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res. 2004, 64, 2047–2053, Erratum in Cancer Res. 2013, 73, 4169. [Google Scholar] [CrossRef] [PubMed]
  35. Ebb, D.; Meyers, P.; Grier, H.; Bernstein, M.; Gorlick, R.; Lipshultz, S.E.; Krailo, M.; Devidas, M.; Barkauskas, D.A.; Siegal, G.P.; et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: A report from the children’s oncology group. J. Clin. Oncol. 2012, 30, 2545–2551. [Google Scholar] [CrossRef] [PubMed]
  36. Long, X.-H.; Zhang, G.-M.; Peng, A.-F.; Luo, Q.-F.; Zhang, L.; Wen, H.-C.; Zhou, R.-P.; Gao, S.; Zhou, Y.; Liu, Z.-L. Lapatinib alters the malignant phenotype of osteosarcoma cells via downregulation of the activity of the HER2-PI3K/AKT-FASN axis in vitro. Oncol. Rep. 2014, 31, 328–334. [Google Scholar] [CrossRef]
  37. Ogitani, Y.; Aida, T.; Hagihara, K.; Yamaguchi, J.; Ishii, C.; Harada, N.; Soma, M.; Okamoto, H.; Oitate, M.; Arakawa, S.; et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin. Cancer Res. 2016, 22, 5097–5108. [Google Scholar] [CrossRef]
  38. Staudacher, A.H.; Brown, M.P. Antibody drug conjugates and bystander killing: Is antigen-dependent internalisation required? Br. J. Cancer 2017, 117, 1736–1742. [Google Scholar] [CrossRef]
  39. Ogitani, Y.; Hagihara, K.; Oitate, M.; Naito, H.; Agatsuma, T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016, 107, 1039–1046. [Google Scholar] [CrossRef]
  40. Tsurutani, J.; Iwata, H.; Krop, I.; Jänne, P.A.; Doi, T.; Takahashi, S.; Park, H.; Redfern, C.; Tamura, K.; Wise-Draper, T.M.; et al. Targeting HER2 with trastuzumab deruxtecan: A dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020, 10, 688–701, Erratum in Cancer Discov. 2020, 10, 1078. [Google Scholar] [CrossRef]
  41. Modi, S.; Saura, C.; Yamashita, T.; Park, Y.H.; Kim, S.-B.; Tamura, K.; Andre, F.; Iwata, H.; Ito, Y.; Tsurutani, J.; et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 2020, 382, 610–621. [Google Scholar] [CrossRef]
  42. Cortés, J.; Kim, S.-B.; Chung, W.-P.; Im, S.-A.; Park, Y.H.; Hegg, R.; Kim, M.H.; Tseng, L.-M.; Petry, V.; Chung, C.-F.; et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N. Engl. J. Med. 2022, 386, 1143–1154. [Google Scholar] [CrossRef] [PubMed]
  43. Shitara, K.; Bang, Y.-J.; Iwasa, S.; Sugimoto, N.; Ryu, M.-H.; Sakai, D.; Chung, H.-C.; Kawakami, H.; Yabusaki, H.; Lee, J.; et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N. Engl. J. Med. 2020, 382, 2419–2430. [Google Scholar] [CrossRef]
  44. Li, B.T.; Smit, E.F.; Goto, Y.; Nakagawa, K.; Udagawa, H.; Mazières, J.; Nagasaka, M.; Bazhenova, L.; Saltos, A.N.; Felip, E.; et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N. Engl. J. Med. 2022, 386, 241–251. [Google Scholar] [CrossRef] [PubMed]
  45. Siena, S.; Di Bartolomeo, M.; Raghav, K.; Masuishi, T.; Loupakis, F.; Kawakami, H.; Yamaguchi, K.; Nishina, T.; Fakih, M.; Elez, E.; et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial. Lancet Oncol. 2021, 22, 779–789. [Google Scholar] [CrossRef] [PubMed]
  46. Nishikawa, T.; Hasegawa, K.; Matsumoto, K.; Mori, M.; Hirashima, Y.; Takehara, K.; Ariyoshi, K.; Kato, T.; Yagishita, S.; Hamada, A.; et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2-expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): The STATICE Trial. J. Clin. Oncol. 2023, 41, 2789–2799. [Google Scholar] [CrossRef]
  47. Ohba, A.; Morizane, C.; Ueno, M.; Kobayashi, S.; Kawamoto, Y.; Komatsu, Y.; Ikeda, M.; Sasaki, M.; Okano, N.; Furuse, J.; et al. Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Future Oncol. 2022, 18, 2351–2360. [Google Scholar] [CrossRef] [PubMed]
  48. Kou, L.; Chen, X.; Xie, X.; Wen, Q.; Li, J.; Li, Y. The efficacy and safety of trastuzumab deruxtecan (T-DXd) in HER2-expressing solid tumours: A single-arm meta-analysis. Jpn. J. Clin. Oncol. 2023, 53, 722–729. [Google Scholar] [CrossRef]
  49. Jørgensen, J.T. The potential of trastuzumab deruxtecan as a tissue agnostic drug. Oncology 2023, in press. [Google Scholar] [CrossRef]
  50. Meric-Bernstam, F.; Makker, V.; Oaknin, A.; Oh, D.-Y.; Banerjee, S.N.; Martin, A.G.; Jung, K.H.; Lugowska, I.A.; Manso, L.; Manzano, A.; et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J. Clin. Oncol. 2023, 41, LBA3000. [Google Scholar] [CrossRef]
  51. Narayan, P.; Dilawari, A.; Osgood, C.; Feng, Z.; Bloomquist, E.; Pierce, W.F.; Jafri, S.; Kalavar, S.; Kondratovich, M.; Jha, P.; et al. US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer. J. Clin. Oncol. 2023, 41, 2108–2116. [Google Scholar] [CrossRef] [PubMed]
  52. Yamaguchi, K.; Bang, Y.-J.; Iwasa, S.; Sugimoto, N.; Ryu, M.-H.; Sakai, D.; Chung, H.C.; Kawakami, H.; Yabusaki, H.; Lee, J.; et al. Trastuzumab deruxtecan in anti-human epidermal growth factor receptor 2 treatment-naive patients with human epidermal growth factor receptor 2-low gastric or gastroesophageal junction adenocarcinoma: Exploratory cohort results in a phase II trial. J. Clin. Oncol. 2023, 41, 816–825. [Google Scholar] [CrossRef] [PubMed]
  53. Tarantino, P.; Modi, S.; Tolaney, S.M.; Cortés, J.; Hamilton, E.P.; Kim, S.-B.; Toi, M.; Andrè, F.; Curigliano, G. Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: A review. JAMA Oncol. 2021, 7, 1873–1881. [Google Scholar] [CrossRef] [PubMed]
  54. Abuhelwa, Z.; Alloghbi, A.; Alqahtani, A.; Nagasaka, M. Trastuzumab deruxtecan-induced interstitial lung disease/pneumonitis in ERBB2-positive advanced solid malignancies: A systematic review. Drugs 2022, 82, 979–987. [Google Scholar] [CrossRef] [PubMed]
  55. Hingorani, P.; Zhang, W.; Zhang, Z.; Xu, Z.; Wang, W.-L.; Roth, M.E.; Wang, Y.; Gill, J.B.; Harrison, D.J.; Teicher, B.A.; et al. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, is effective in pediatric malignancies: A report by the Pediatric Preclinical Testing Consortium. Mol. Cancer Ther. 2022, 21, 1318–1325. [Google Scholar] [CrossRef] [PubMed]
  56. Reed, D.R.; Janeway, K.A.; Minard, C.G.; Hall, D.; Crompton, B.D.; Lazar, A.J.; Wang, W.-L.; Voss, S.D.; Militano, O.; Gorlick, R.G.; et al. PEPN1924, a phase 2 study of trastuzumab deruxtecan (DS-8201a, T-DXd) in adolescents and young adults with recurrent HER2+ osteosarcoma: A Children’s Oncology Group pediatric early-phase clinical trial network study. J. Clin. Oncol. 2023, 41, 11527. [Google Scholar] [CrossRef]
  57. Cosetti, M.; Wexler, L.H.; Calleja, E.; Trippett, T.; LaQuaglia, M.; Huvos, A.G.; Gerald, W.; Healey, J.H.; Meyers, P.A.; Gorlick, R. Irinotecan for pediatric solid tumors: The Memorial Sloan-Kettering experience. J. Pediatr. Hematol. Oncol. 2002, 24, 101–105. [Google Scholar] [CrossRef] [PubMed]
  58. Mizrahi, J.D.; Surana, R.; Valle, J.W.; Shroff, R.T. Pancreatic cancer. Lancet 2020, 395, 2008–2020. [Google Scholar] [CrossRef]
  59. Hyman, D.M.; Puzanov, I.; Subbiah, V.; Faris, J.E.; Chau, I.; Blay, J.-Y.; Wolf, J.; Raje, N.S.; Diamond, E.L.; Hollebecque, A.; et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 2015, 373, 726–736, Erratum in N. Engl. J. Med. 2018, 379, 1585. [Google Scholar] [CrossRef]
  60. Subbiah, V.; Kreitman, R.J.; Wainberg, Z.A.; Gazzah, A.; Lassen, U.; Stein, A.; Wen, P.Y.; Dietrich, S.; de Jonge, M.J.A.; Blay, J.-Y.; et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: The phase 2 ROAR trial. Nat. Med. 2023, 29, 1103–1112. [Google Scholar] [CrossRef]
  61. Kopetz, S.; Grothey, A.; Yaeger, R.; Van Cutsem, E.; Desai, J.; Yoshino, T.; Wasan, H.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 2019, 381, 1632–1643. [Google Scholar] [CrossRef] [PubMed]
  62. Tabernero, J.; Grothey, A.; Van Cutsem, E.; Yaeger, R.; Wasan, H.; Yoshino, T.; Desai, J.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: Updated survival results and subgroup analyses from the BEACON Study. J. Clin. Oncol. 2021, 39, 273–284. [Google Scholar] [CrossRef] [PubMed]
  63. Davis, L.E.; Bolejack, V.; Ryan, C.W.; Ganjoo, K.N.; Loggers, E.T.; Chawla, S.; Agulnik, M.; Livingston, M.B.; Reed, D.; Keedy, V.; et al. Randomized double-blind phase ii study of regorafenib in patients with metastatic osteosarcoma. J. Clin. Oncol. 2019, 37, 1424–1431. [Google Scholar] [CrossRef] [PubMed]
  64. Duffaud, F.; Mir, O.; Boudou-Rouquette, P.; Piperno-Neumann, S.; Penel, N.; Bompas, E.; Delcambre, C.; Kalbacher, E.; Italiano, A.; Collard, O.; et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: A non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019, 20, 120–133. [Google Scholar] [CrossRef]
  65. Kantarjian, H.; Stein, A.; Gökbuget, N.; Fielding, A.K.; Schuh, A.C.; Ribera, J.-M.; Wei, A.; Dombret, H.; Foà, R.; Bassan, R.; et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 2017, 376, 836–847. [Google Scholar] [CrossRef] [PubMed]
  66. Thieblemont, C.; Phillips, T.; Ghesquieres, H.; Cheah, C.Y.; Clausen, M.R.; Cunningham, D.; Do, Y.R.; Feldman, T.; Gasiorowski, R.; Jurczak, W.; et al. Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in a phase I/II trial. J. Clin. Oncol. 2023, 41, 2238–2247. [Google Scholar] [CrossRef] [PubMed]
  67. Holstein, S.A.; Grant, S.J.; Wildes, T.M. Chimeric antigen receptor T-cell and bispecific antibody therapy in multiple myeloma: Moving into the future. J. Clin. Oncol. 2023, 41, 4416–4429. [Google Scholar] [CrossRef]
  68. Misorin, A.K.; Chernyshova, D.O.; Karbyshev, M.S. State-of-the-art approaches to heterologous expression of bispecific antibodies targeting solid tumors. Biochemistry 2023, 88, 1215–1231. [Google Scholar] [CrossRef]
  69. Sun, Y.; Yu, X.; Wang, X.; Yuan, K.; Wang, G.; Hu, L.; Zhang, G.; Pei, W.; Wang, L.; Sun, C.; et al. Bispecific antibodies in cancer therapy: Target selection and regulatory requirements. Acta Pharm. Sin. B 2023, 13, 3583–3597. [Google Scholar] [CrossRef]
  70. Roth, M.; Linkowski, M.; Tarim, J.; Piperdi, S.; Sowers, R.; Geller, D.; Gill, J.; Gorlick, R. Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer 2014, 120, 5548–5554. [Google Scholar] [CrossRef]
  71. Ladenstein, R.; Pötschger, U.; Valteau-Couanet, D.; Luksch, R.; Castel, V.; Yaniv, I.; Laureys, G.; Brock, P.; Michon, J.M.; Owens, C.; et al. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1617–1629. [Google Scholar] [CrossRef] [PubMed]
  72. Hingorani, P.; Krailo, M.; Buxton, A.; Hutson, P.; Sondel, P.M.; Diccianni, M.; Yu, A.; Morris, C.D.; Womer, R.B.; Crompton, B.; et al. Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children’s Oncology Group. Eur. J. Cancer 2022, 172, 264–275. [Google Scholar] [CrossRef] [PubMed]
  73. Park, J.A.; Cheung, N.V. GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma. J. Hematol. Oncol. 2020, 13, 172. [Google Scholar] [CrossRef] [PubMed]
  74. Trautwein, N.F.; Reischl, G.; Seitz, C.; Dittmann, H.; Seith, F.; Scheuermann, S.; Feuchtinger, T.; Dombrowski, F.; Handgretinger, R.; Fuchs, J.; et al. First-in-humans PET/MRI of in vivo GD2 expression in osteosarcoma. J. Nucl. Med. 2023, 64, 337–338. [Google Scholar] [CrossRef] [PubMed]
  75. Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoint blockade. Science 2018, 359, 1350–1355. [Google Scholar] [CrossRef] [PubMed]
  76. Le Cesne, A.; Marec-Berard, P.; Blay, J.-Y.; Gaspar, N.; Bertucci, F.; Penel, N.; Bompas, E.; Cousin, S.; Toulmonde, M.; Bessede, A.; et al. Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: Results from the PEMBROSARC study. Eur. J. Cancer 2019, 119, 151–157. [Google Scholar] [CrossRef] [PubMed]
  77. Tawbi, H.A.; Burgess, M.; Bolejack, V.; Van Tine, B.A.; Schuetze, S.M.; Hu, J.; D’Angelo, S.; Attia, S.; Riedel, R.F.; Priebat, D.A.; et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017, 18, 1493–1501, Erratum in Lancet Oncol. 2017, 18, e711; Erratum in Lancet Oncol. 2018, 19, e8. [Google Scholar] [CrossRef]
  78. Labanieh, L.; Mackall, C.L. CAR immune cells: Design principles, resistance and the next generation. Nature 2023, 614, 635–648, Erratum in Nature 2023, 619, E26. [Google Scholar] [CrossRef]
  79. Ahmed, N.; Brawley, V.S.; Hegde, M.; Robertson, C.; Ghazi, A.; Gerken, C.; Liu, E.; Dakhova, O.; Ashoori, A.; Corder, A.; et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 2015, 33, 1688–1696. [Google Scholar] [CrossRef]
  80. Disis, M.L.; Dang, Y.; Coveler, A.L.; Marzbani, E.; Kou, Z.C.; Childs, J.S.; Fintak, P.; Higgins, D.M.; Reichow, J.; Waisman, J.; et al. HER-2/neu vaccine-primed autologous T-cell infusions for the treatment of advanced stage HER-2/neu expressing cancers. Cancer Immunol. Immunother. 2014, 63, 101–109. [Google Scholar] [CrossRef]
  81. Disis, M.L.; Dang, Y.; Coveler, A.L.; Childs, J.S.; Higgins, D.M.; Liu, Y.; Zhou, J.; Mackay, S.; Salazar, L.G. A phase I/II trial of HER2 vaccine-primed autologous T-Cell infusions in patients with treatment refractory HER2-overexpressing breast cancer. Clin. Cancer Res. 2023, 29, 3362–3371. [Google Scholar] [CrossRef] [PubMed]
Ijms 24 16823 g001
Figure 1. Schema of future directions of the HER2-directed therapy to osteosarcoma.
Figure 1. Schema of future directions of the HER2-directed therapy to osteosarcoma.
Ijms 24 16823 g001
Table 1. Percentages of HER2 amplification, overexpression, or mutation in primary tumor types [6].
Table 1. Percentages of HER2 amplification, overexpression, or mutation in primary tumor types [6].
Tumor OriginHER2
Amplification (%)		HER2
Overexpression (%)		HER2
Mutation (%)
Salivary gland12–5217–441
Lung2–32.51–3
Breast2015–202
Stomach11–16203
Biliary tract5–15202
Pancreas226<1
Colorectum5.852
Bladder8.612.49
Prostate5.8–610<1
Ovary7271
Uterus4–6918–802
Cervix0.5–14213
Table 2. HER2-targeted drugs approved by the FDA as of 2023.
Table 2. HER2-targeted drugs approved by the FDA as of 2023.
DrugRoute(s)IndicationsYear of First
FDA Approval
TrastuzumabIntravenous,
subcutaneous		Breast cancer (early, advanced)
Gastroesophageal cancer		1998
Lapatinibp.o.Breast cancer (advanced)2007
PertuzumabIntravenous,
subcutaneous		Breast cancer (early, advanced)2012
Trastuzumab emtansine (T-DM1)IntravenousBreast cancer (early, advanced)2013
Neratinibp.o.Breast cancer (early, advanced)2017
Trastuzumab deruxtecan (T-DXd)IntravenousBreast cancer (advanced)
NSCLC		2019
Tucatinibp.o.Breast cancer (advanced)
Colorectal cancer		2020
MargetuximabIntravenousBreast cancer (advanced)2020
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Nakano, K. The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results. Int. J. Mol. Sci. 2023, 24, 16823. https://doi.org/10.3390/ijms242316823

AMA Style

Nakano K. The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results. International Journal of Molecular Sciences. 2023; 24(23):16823. https://doi.org/10.3390/ijms242316823

Chicago/Turabian Style

Nakano, Kenji. 2023. "The Future of HER2-Targeted Treatment for Osteosarcoma: Lessons from the Negative Trastuzumab Deruxtecan Results" International Journal of Molecular Sciences 24, no. 23: 16823. https://doi.org/10.3390/ijms242316823

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