Over the past decade, the lung cancer landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). Despite these scientific and clinical advances, there are still many unmet needs underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this concept has been the leading view, preclinical and clinical observations are demonstrating that only a nascent mechanistic understanding of these agents exists. In this review, we discuss the underlying biology of ADCs and their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing, and mechanisms of resistance, as well as management of unique ADC-associated toxicities.
{"title":"Antibody-drug conjugates in advanced lung cancer: Is this a new frontier?","authors":"Joshua E Reuss, Samuel Rosner, Benjamin P Levy","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Over the past decade, the lung cancer landscape has been dominated by targeted and immunotherapeutic approaches that have drastically shifted treatment paradigms for patients with advanced non-small cell lung cancer (NSCLC). Despite these scientific and clinical advances, there are still many unmet needs underscoring the importance of novel strategies. Antibody-drug conjugates (ADCs) represent one such strategy that is beginning to alter the therapeutic strategies for patients with advanced NSCLC. The rationale of ADCs is simple: selectively deliver cytotoxic payloads through an antibody-mediated process to target antigens expressed by cancer cells, sparing normal tissue and inflicting damage to tumors. Although this concept has been the leading view, preclinical and clinical observations are demonstrating that only a nascent mechanistic understanding of these agents exists. In this review, we discuss the underlying biology of ADCs and their structure and potential mechanisms of action, examine approved and promising ADC targets in lung cancer, and review emerging ADC targets and combinatorial strategies. Importantly, we address the unanswered questions surrounding ADCs in lung cancer, including biomarker selection, treatment sequencing, and mechanisms of resistance, as well as management of unique ADC-associated toxicities.</p>","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 5","pages":"217-226"},"PeriodicalIF":1.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"STEAP1 as a potential target for new therapies in prostate cancer.","authors":"Wm Kevin Kelly","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 5","pages":"243-244"},"PeriodicalIF":1.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.
{"title":"Improving survival in metastatic colorectal cancer through optimized patient selection.","authors":"Tanios S Bekaii-Saab, Afsaneh Barzi, Mike Cusnir","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The systemic treatment options for patients with metastatic colorectal cancer have recently expanded with the US Food and Drug Administration approval of fruquintinib being added to previously approved trifluridine/tipiracil with or without bevacizumab and regorafenib. These therapies are recommended for use based on the initial clinical trials that focused on their safety and efficacy in extending overall survival of patients with refractory metastatic disease, as well as later studies, including the ReDOS study that confirmed the dose-escalation strategy of regorafenib to be key in optimizing duration of therapy and preventing side effects. Although more research is needed on how to sequence third-line therapies, data from real-world studies showed that switching from regorafenib to trifluridine/tipiracil with or without bevacizumab allowed patients to have a chemotherapy-free break and led to improved survival, suggesting that there may be a benefit for using regorafenib first. Current treatment guidelines state that each therapy can be given before or after the others. Generally, sequencing considerations in the refractory setting include multiple variables such as tumor characteristics, toxicities, factors that are important to the patient, response to prior lines of therapy, and extent of disease.</p>","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 Suppl 4 5","pages":"1-20"},"PeriodicalIF":1.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Beryl L Manning-Geist, Tal Cantor, Róisín E O'Cearbhaill, Rachel N Grisham
Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.
低级别浆液性癌是一种罕见的上皮性卵巢癌亚型,具有独特的临床、组织学和分子特征。对这一疾病亚型的进一步了解促使治疗方案取得了最新进展。虽然低级别浆液性癌历来按照高级别浆液性癌的模式进行治疗,但新的数据对铂类再治疗的效用提出了质疑,探讨了一线激素治疗的可能性,并提出了针对低级别肿瘤中 MAPK 通路和细胞周期蛋白 D 激酶的治疗方案。正在进行的研究工作旨在利用低分化浆液性癌的独特特征,完善这一罕见肿瘤亚型患者的治疗方案。
{"title":"Redefining the standard of care for low-grade serous ovarian cancer.","authors":"Beryl L Manning-Geist, Tal Cantor, Róisín E O'Cearbhaill, Rachel N Grisham","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.</p>","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 5","pages":"205-226"},"PeriodicalIF":1.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Locally advanced gastrointestinal (GI) malignancies have conventionally been treated in a multimodal fashion that combines (neo)adjuvant chemotherapy with or without radiation and definitive surgical resection. Clinical data have demonstrated the reduced responsiveness of GI malignancies with microsatellite instability (MSI) to both adjuvant and neoadjuvant systemic chemotherapy when compared with microsatellite stable (MSS) disease. The elevated tumor mutational burden associated with MSI tumors of all types sensitizes these tumors to the effects of immune checkpoint blockade in the metastatic setting, which led to tumor-agnostic approval of immune checkpoint inhibitors in this context. The recent demonstration of greater sensitivity and high pathologic complete response rates to neoadjuvant immunotherapy in locally advanced GI malignancies may ultimately establish a novel treatment paradigm and herald potential nonoperative management of this distinct subgroup of GI malignancies. This article provides an overview of immune checkpoint inhibitor therapy in locally advanced MSI GI malignancies. It also covers the clinical significance of MSI status across the GI cancer spectrum, the available data demonstrating differential responses of MSI and MSS disease to conventional chemotherapy, and the biological rationale for novel strategies utilizing immunotherapy in the neoadjuvant, adjuvant, and nonoperative settings.
{"title":"Immune checkpoint inhibitor therapy in locally advanced MSI GI malignancies.","authors":"Emily C Harrold, Fergus Keane, Andrea Cercek","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Locally advanced gastrointestinal (GI) malignancies have conventionally been treated in a multimodal fashion that combines (neo)adjuvant chemotherapy with or without radiation and definitive surgical resection. Clinical data have demonstrated the reduced responsiveness of GI malignancies with microsatellite instability (MSI) to both adjuvant and neoadjuvant systemic chemotherapy when compared with microsatellite stable (MSS) disease. The elevated tumor mutational burden associated with MSI tumors of all types sensitizes these tumors to the effects of immune checkpoint blockade in the metastatic setting, which led to tumor-agnostic approval of immune checkpoint inhibitors in this context. The recent demonstration of greater sensitivity and high pathologic complete response rates to neoadjuvant immunotherapy in locally advanced GI malignancies may ultimately establish a novel treatment paradigm and herald potential nonoperative management of this distinct subgroup of GI malignancies. This article provides an overview of immune checkpoint inhibitor therapy in locally advanced MSI GI malignancies. It also covers the clinical significance of MSI status across the GI cancer spectrum, the available data demonstrating differential responses of MSI and MSS disease to conventional chemotherapy, and the biological rationale for novel strategies utilizing immunotherapy in the neoadjuvant, adjuvant, and nonoperative settings.</p>","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 4","pages":"162-173"},"PeriodicalIF":1.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Improving outcomes in pediatric NTRK gene fusion-positive solid tumors: importance of genomic testing and targeted therapy with the TRK inhibitor larotrectinib.","authors":"Theodore W Laetsch","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 Suppl 3 4","pages":"1-11"},"PeriodicalIF":1.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ammanuel Taye, Ahmed Elkhanany, Erica Stringer-Reasor
Black women diagnosed with breast cancer experience a disproportionately high mortality rate. The disparity in outcomes between Black and White women is multifactorial, with a large portion attributed to lower participation of minorities in clinical trials. The lack of diversity in clinical trials continues to both reflect and contribute to health care inequities, limiting the generalizability of research findings. In addition, women who do not enroll in clinical trials miss out on the standard-of-care or often better patient care provided in these trials. Barriers to enrolling diverse populations encompass system-, provider-, and patient-level barriers. Identifying these barriers and providing actionable solutions are key to bolstering enrollment in clinical trials and ultimately eliminating cancer disparities. This review elucidates the barriers to clinical trial participation in Black women diagnosed with breast cancer and discusses ways to overcome these challenges.
{"title":"Increasing inclusion and equity for Black women in breast cancer clinical trials.","authors":"Ammanuel Taye, Ahmed Elkhanany, Erica Stringer-Reasor","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Black women diagnosed with breast cancer experience a disproportionately high mortality rate. The disparity in outcomes between Black and White women is multifactorial, with a large portion attributed to lower participation of minorities in clinical trials. The lack of diversity in clinical trials continues to both reflect and contribute to health care inequities, limiting the generalizability of research findings. In addition, women who do not enroll in clinical trials miss out on the standard-of-care or often better patient care provided in these trials. Barriers to enrolling diverse populations encompass system-, provider-, and patient-level barriers. Identifying these barriers and providing actionable solutions are key to bolstering enrollment in clinical trials and ultimately eliminating cancer disparities. This review elucidates the barriers to clinical trial participation in Black women diagnosed with breast cancer and discusses ways to overcome these challenges.</p>","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 4","pages":"175-182"},"PeriodicalIF":1.1,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PROTAC drugs in cancer care.","authors":"Peter A Fasching","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 4","pages":"188-190"},"PeriodicalIF":1.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Liver transplant in patients with metastatic colorectal cancer.","authors":"Bashar A Aqel","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":51585,"journal":{"name":"Clinical Advances in Hematology & Oncology","volume":"22 4","pages":"183-184"},"PeriodicalIF":1.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140917224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}