“… 62 For patients who experience ILD/pneumonitis, follow-up CT imaging is recommended every 1-2 weeks or as clinically indicated. 6 , 20 , 62 Consultation with a pulmonary specialist for monitoring and treatment recommendations is necessary if T-DXd-induced ILD/pneumonitis is suspected or develops. Figure 2 Management of ILD/pneumonitis.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“… Figure 2 Management of ILD/pneumonitis. 20 , 59 , 61 , 62 The ‘Manage ILD/P’ portion of this figure is from Figure 3 of Swain SM, Nishino M, Lancaster LH, et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…May 2022;106:102378. 62 https://doi.org/10.1016/j.ctrv.2022.102378 , Creative Commons license and disclaimer available from https://creativecommons.org/licenses/by-nc-nd/4.0/ . BAL, bronchoalveolar lavage; CBC, complete blood count; CT, computed tomography; ILD/P, interstitial lung disease/pneumonitis; i.v., intravenous; PFT, pulmonary function test; PK, pharmacokinetics; q3w, every 3 weeks; T-DXd, trastuzumab deruxtecan.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…May 2022;106:102378. 62 https://doi.org/10.1016/j.ctrv.2022.102378 , Creative Commons license and disclaimer available from https://creativecommons.org/licenses/by-nc-nd/4.0/ .…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…Current T-DXd ILD/pneumonitis guidelines recommend starting steroids promptly upon detection for grade ≥2 ILD/pneumonitis and suggest consideration of steroid treatment of grade 1 cases ( Figure 2 ). 6 , 20 , 59 , 62 Steroid treatment may be warranted for some patients with grade 1 ILD/pneumonitis, including those with extensive lung involvement or those who are at increased risk for progression of ILD/pneumonitis. 62 Treatment of ILD/pneumonitis with systemic steroids may help mitigate progression to higher-grade ILD/pneumonitis.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
“… 62 For patients who experience ILD/pneumonitis, follow-up CT imaging is recommended every 1-2 weeks or as clinically indicated. 6 , 20 , 62 Consultation with a pulmonary specialist for monitoring and treatment recommendations is necessary if T-DXd-induced ILD/pneumonitis is suspected or develops. Figure 2 Management of ILD/pneumonitis.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“… Figure 2 Management of ILD/pneumonitis. 20 , 59 , 61 , 62 The ‘Manage ILD/P’ portion of this figure is from Figure 3 of Swain SM, Nishino M, Lancaster LH, et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…May 2022;106:102378. 62 https://doi.org/10.1016/j.ctrv.2022.102378 , Creative Commons license and disclaimer available from https://creativecommons.org/licenses/by-nc-nd/4.0/ . BAL, bronchoalveolar lavage; CBC, complete blood count; CT, computed tomography; ILD/P, interstitial lung disease/pneumonitis; i.v., intravenous; PFT, pulmonary function test; PK, pharmacokinetics; q3w, every 3 weeks; T-DXd, trastuzumab deruxtecan.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…May 2022;106:102378. 62 https://doi.org/10.1016/j.ctrv.2022.102378 , Creative Commons license and disclaimer available from https://creativecommons.org/licenses/by-nc-nd/4.0/ .…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
confidence: 99%
“…Current T-DXd ILD/pneumonitis guidelines recommend starting steroids promptly upon detection for grade ≥2 ILD/pneumonitis and suggest consideration of steroid treatment of grade 1 cases ( Figure 2 ). 6 , 20 , 59 , 62 Steroid treatment may be warranted for some patients with grade 1 ILD/pneumonitis, including those with extensive lung involvement or those who are at increased risk for progression of ILD/pneumonitis. 62 Treatment of ILD/pneumonitis with systemic steroids may help mitigate progression to higher-grade ILD/pneumonitis.…”
Section: Management Of T-dxd-related Aes Of Interestmentioning
ImportanceErb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 [human epidermal growth factor receptor 2]) is an important prognostic and predictive factor in breast cancer. Anti-ERBB2 therapies have improved outcomes in ERBB2-positive breast cancer. However, based on current definitions, tumors with low ERBB2 expression are included in the ERBB2-negative subtype, and therefore, are ineligible for anti-ERBB2 therapies; patients with ERBB2-low (immunohistochemistry [IHC] 1 positive [+] or IHC 2+/in situ hybridization [ISH] negative [−]) tumors account for up to approximately 50% of breast cancer cases. Although the prognostic role of ERBB2-low needs to be defined, ERBB2 offers a potential therapeutic target in these patients.ObservationsMost breast cancer tumors have some ERBB2 expression, with ERBB2-low being more common in hormone receptor–positive than in hormone receptor–negative breast cancer. 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. Although reports are conflicting, some differences in biology and patient outcomes have been found between ERBB2-low and ERBB2 IHC-0 breast cancer. Currently, no established guidelines exist for scoring ERBB2-low expression in breast cancer because the focus has been on binary classification as ERBB2-positive or ERBB2-negative. Additional interpretive cutoffs may be needed to select patients for treatment with effective agents in ERBB2-low breast cancer, along with standardized laboratory quality assurance programs to ensure consistent patient identification for eligibility for ERBB2-low targeting agents.Conclusions and RelevanceThis 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.
Bystander‐killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody‐drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander‐killing payloads, this model is utilized for score‐directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti‐tumor efficacy and bystander‐killing effect in vivo and in vitro. The optimal conjugate T‐VEd9 exhibited therapeutic efficacy superior to DS‐8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity.
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