Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib.

Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 (METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1-56.3%], the DCR was 81.3% (95% CI: 63.6-92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6-9.7) and 17.0 month (95% CI: 10.3-not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

Pyrotinib and trastuzumab plus palbociclib and fulvestrant in HR+/HER2+ breast cancer patients with brain metastasis.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients are at a high risk of developing metastases in the brain. However, research focusing on treatment strategies for hormonal receptor positive (HR+), HER2+ BC patients with brain metastases (BM) remains limited. Thus, a multi-center, prospective trial was conducted in China. Women over the age of 18 who were naive to whole brain radiotherapy and had estrogen receptor (ER)/progesterone-receptor (PgR) positive, HER2+ BM were treated with palbociclib, fulvestrant, trastuzumab and pyrotinib, until disease progression or the development of intolerable side effects. The primary endpoint was objective response rate (ORR) in the central nervous system (CNS). This ongoing study is still recruiting participants and is registered with ClinicalTrials.gov (NCT04334330). This report presents the findings from an interim analysis. From December 4, 2020, to November 2, 2022, 15 patients were enrolled. Among the 14 patients who were evaluable for clinical response, the ORR was 35.7% (95% CI: 12.8-64.9%), with a CNS-ORR of 28.6% (95% CI: 8.4-58.1%). The median follow-up period was 6.3 months (range, 2.1-14.3 months), during which the median progression-free survival (PFS) was 10.6 months (95% CI: 4.3-16.9 months), and the median time to CNS progression was 8.5 months (95% CI: 5.9-11.1 months). The most common adverse event was diarrhea (93%), with 33% having grade 3 and 6.7% having grade 4. The study suggests that the combination of palbociclib, trastuzumab, pyrotinib and fulvestrant offers a promising chemo-free treatment strategy for HR+, HER2+ BC patients with BM.

Screening optimal candidates with operable, early-stage triple-negative breast cancer benefitting from capecitabine maintenance: A post-hoc analysis of the SYSUCC-001 study.

BACKGROUND: To explore whether specific clinicopathological covariates are predictive for a benefit from capecitabine maintenance in early-stage triple-negative breast cancer (TNBC) in the SYSUCC-001 phase III clinical trial. METHODS: Candidate covariates included age, menstrual status, type of surgery, postoperative chemotherapy regimen, Ki-67 percentage, histologic grade, primary tumor size, lymphovascular invasion, node status, and capecitabine medication. Their nonlinear effects were modeled by restricted cubic spline. The primary endpoint was disease-free survival (DFS). A survival prediction model was constructed using Cox proportional hazards regression analysis. RESULTS: All 434 participants (306 in development cohort and 128 in validation cohort) were analyzed. The estimated 5-year DFS in development and validation cohorts were 77.8 % (95 % CI, 72.9%-82.7 %) and 78.2 % (95 % CI, 70.9%-85.5 %), respectively. Age and node status had significant nonlinear effects on DFS. The prediction model constructed using four covariates (node status, lymphovascular invasion, capecitabine maintenance, and age) demonstrated satisfactory calibration and fair discrimination ability, with C-index of 0.722 (95 % CI, 0.662-0.781) and 0.764 (95 % CI, 0.668-0.859) in development and validation cohorts, respectively. Moreover, patient classification was conducted according to their risk scores calculated using our model, in which, notable survival benefits were reported in low-risk subpopulations. An easy-to-use online calculator for predicting benefit of capecitabine maintenance was also designed. CONCLUSIONS: The evidence-based prediction model can be readily assessed at baseline, which might help decision making in clinical practice and optimize patient stratification, especially for those with low-risk, capecitabine maintenance might be a potential strategy in the early-disease setting.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Optimal Sequential Strategies for Antibody-Drug Conjugate in Metastatic Breast Cancer: Evaluating Efficacy and Cross-Resistance.

BACKGROUND: The optimal sequential strategy for antibody-drug conjugates (ADCs) in breast cancer remains uncertain. This study aimed to evaluate the efficacy and potential resistance of second ADC (ADC2) following the first ADC (ADC1) in human epidermal growth factor receptor 2 (HER2)-positive and HER2-low MBC. METHODS: This retrospective, multicenter, real-world study enrolled patients with MBC who received at least 2 different types of ADCs in 3 hospitals in China between July 1, 2017 and May 1, 2023. Outcomes included the objective response rate (ORR) for ADC1 and ADC2, progression free survival 2 (PFS2), defined as the time from initiation of ADC2 to progression, and overall survival (OS). RESULTS: Seventy-nine female patients were included, 64 of whom had HER2-positive disease. The ORR for ADC2 with similar payload of ADC1 was found to be 5.3%. When switching to a different payload, the ORR of ADC2 increased to 22.6%. The PFS2 for ADC2 remained similar regardless of whether the payload was similar or different. Switching to different payload showed a higher ORR in patients with rapid progression and a durable response longer than 6 months (41.2% vs 15.0%). Specifically, significantly longer PFS2 and OS were seen in patients treated with trastuzumab deruxtecan (T-Dxd) compared to those treated with disitamab vedotin (RC48) after progression from trastuzumab emtansine (T-DM1; median PFS2 5.37 months vs 3.30 months, HR = 0.40, 95% CI 0.17-0.93, P = .034; median OS 50.6 months vs 20.2 months, HR = 0.27, 95% CI 0.08-0.91, P = .034). For patients who progressed after T-Dxd, the median PFS2 was 6.05 months for those treated with RC48 versus 0.93 months for those treated with T-DM1 (HR = 0.03, 95% CI 0.002-0.353, P = .0093). Genomic analysis revealed that alternation of retinoblastoma1 was significantly associated with superior PFS. CONCLUSION: The alternation of payload achieves different responses in different settings. T-Dxd followed by RC48 may be a potentially beneficial strategy in HER2-positive disease. Further research is needed to elucidate the mechanism of cross-resistance.

A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study.

BACKGROUND: Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS: In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS: Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS: This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY: To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial.

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

Assessment of the expression pattern of HER2 and its correlation with HER2-targeting antibody-drug conjugate therapy in urothelial cancer.

Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to anti-HER2 therapy in many tumors. RC48- antibody-drug conjugate (ADC) has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC). The characteristic expression and scoring systems of HER2 are nonexistent in UC. We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC. Methods: A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2, respectively, from March 2009 to December 2018. The patients in cohort 2 were enrolled in a phase II study of RC48-ADC. UC samples were tested for HER2 status using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC. Results: The HER2-positive (IHC 2+ or 3+) rate was 24.1% (33/137). In HER2 IHC 2+ or 3+ patients, the HER2 gene amplification rate was 31% (13/42). The objective response rates (ORRs) in RC48-ADC-treated patients with IHC 3+, IHC 2+ and FISH+, IHC 2+ and FISH- were 58.8%, 66.7% and 40%, respectively. The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification (61.5% vs. 44.8%, P = 0.059). The heterogeneity of HER2 expression in the primary tumor was 55.5% (15/27), and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity. Conclusions: IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy. There was a trend toward a better benefit for patients with HER2 amplification, and tumor heterogeneity did not influence the drug efficacy.