Research Highlight |
Featured
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Research Highlight |
Mirvetuximab soravtansine has activity in platinum-sensitive epithelial ovarian cancer
- Diana Romero
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Research Highlight |
FIRSTMAPPP prospectively charts the efficacy of sunitinib for phaeochromocytoma and paraganglioma
- David Killock
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Review Article |
FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions
FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.
- Masuko Katoh
- , Yohann Loriot
- & Masaru Katoh
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Review Article |
BRAF — a tumour-agnostic drug target with lineage-specific dependencies
Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAFV600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.
- Aphrothiti J. Hanrahan
- , Ziyu Chen
- & David B. Solit
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Review Article |
Exploring the next generation of antibody–drug conjugates
Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.
- Kyoji Tsuchikama
- , Yasuaki Anami
- & Chisato M. Yamazaki
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Review Article |
Management of patients with advanced-stage HER2-positive breast cancer: current evidence and future perspectives
The discovery of ERBB2 as a gene frequently amplified and/or overexpressed in breast cancers and of its product HER2 as a biomarker has spurred the development of various targeted therapies. As a result, the prognosis of patients with advanced-stage HER2-positive breast cancer has greatly improved in the past decades. The authors of this Review describe the development of the current treatment landscape for these patients and discuss how to address resistance to further improve outcomes.
- Antonio Marra
- , Sarat Chandarlapaty
- & Shanu Modi
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Research Highlight |
Mirvetuximab soravtansine superior to chemotherapy in platinum-resistant epithelial ovarian cancer
- Peter Sidaway
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News & Views |
Pyrotinib in combination with first-line trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer: a new therapeutic option?
Recent results from the phase III PHILA trial demonstrate a benefit in terms of progression-free survival derived from the addition of pyrotinib to first-line chemotherapy plus trastuzumab in patients with metastatic HER2-positive breast cancer. Dual HER2 blockade with pyrotinib and trastuzumab is an effective therapeutic strategy but might increase the risk of gastrointestinal toxicity; therefore, the risk-to-benefit ratio should be carefully evaluated.
- Pier Paolo M. Berton Giachetti
- & Giuseppe Curigliano
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Review Article |
Pharmacological reactivation of p53 in the era of precision anticancer medicine
p53, encoded by TP53, the commonest mutated gene in cancer, is an appealing target for systemic anticancer therapies including those designed to restore p53 function. Thus far, and despite promising preclinical data and several clinical trials, no p53-restoring systemic therapy has been approved for therapeutic use. Despite this limited success, several research efforts are ongoing. In this Review, the authors summarize the role of p53 in cancer with a focus on the complexity of p53 function and how this relates to clinical attempts to restore at least some of these functions.
- Amos Tuval
- , Charlotte Strandgren
- & Klas G. Wiman
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Research Highlight |
Tovorafenib effective against low-grade gliomas harbouring BRAF fusions
- Peter Sidaway
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Research Highlight |
Patients with uncommon EGFR mutations also benefit from first-line osimertinib
- Diana Romero
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Review Article |
Molecular tumour boards — current and future considerations for precision oncology
According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.
- Apostolia M. Tsimberidou
- , Michael Kahle
- & Funda Meric-Bernstam
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Review Article |
Heterogeneity and treatment landscape of ovarian carcinoma
Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.
- Ana C. Veneziani
- , Eduardo Gonzalez-Ochoa
- & Amit M. Oza
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Perspective |
Drug-tolerant persister cells in cancer: the cutting edges and future directions
Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.
- Yi Pu
- , Lu Li
- & Shensi Shen
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Comment |
Complicated regulatory decision-making following inconsistent trial results: the issue with ibrutinib for mantle cell lymphoma
In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.
- Edward R. Scheffer Cliff
- , Talal Hilal
- & Aaron S. Kesselheim
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Research Highlight |
Dabrafenib–trametinib is effective in paediatric high-grade glioma
- Diana Romero
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Research Highlight |
Early promising results with the novel KRASG12C inhibitor divarasib
- Diana Romero
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News & Views |
Harnessing potent therapies with care: enfortumab vedotin plus pembrolizumab for advanced-stage urothelial carcinoma
Following the recent FDA Accelerated Approval of enfortumab vedotin (EV) plus pembrolizumab for patients with advanced-stage urothelial carcinoma who are cisplatin-ineligible, herein we highlight key clinical outcomes with this combination based on results from Cohort K of the pivotal phase Ib/II EV-103 trial. We also discuss treatment sequencing, de-escalation strategies and toxicity management as EV–pembrolizumab becomes widely used in clinical practice.
- Pooja Ghatalia
- & Elizabeth R. Plimack
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Review Article |
TAM family kinases as therapeutic targets at the interface of cancer and immunity
The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) have diverse cancer-promoting functions in malignant cells as well as immune cells and other cell types in the tumour microenvironment, presenting an attractive opportunity for both direct and immune-mediated therapeutic activity manifest through inhibition of a single target. Accordingly, a variety of agents designed to selectively target TAM RTKs are entering clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians. The authors comprehensively review the various roles of TAM RTKs in cancer, the evidence supporting their potential as therapeutic targets, and the translational development of TAM-targeted agents as cancer treatments.
- Deborah DeRyckere
- , Justus M. Huelse
- & Douglas K. Graham
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Review Article |
Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer
Despite improved outcomes owing to advances in systemic targeted therapies, patients with brain metastases from oncogene-driven non-small-cell lung cancer continue to have a poor prognosis. This situation largely reflects the limited central nervous system (CNS) penetrance of most targeted therapies, a limitation that is beginning to be addressed with the development of later-generation agents. In this Review, the authors describe the CNS activity of targeted therapies for patients with oncogene-driven non-small-cell lung cancers, including discussions of novel agents with improved CNS penetrance and the potential of intrathecal administration for patients with leptomeningeal disease.
- Kelsey Pan
- , Kyle Concannon
- & Xiuning Le
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Research Highlight |
First-line pembrolizumab plus lenvatinib is effective in non-clear-cell RCC
- Diana Romero
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Research Highlight |
BRAF plus MEK inhibition effective in papillary craniopharyngioma
- Peter Sidaway
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News & Views |
A new era for glioma therapy — targeting mutant IDH
Hotspot point mutations in IDH1 occur in the vast majority of adult grade 2–3 gliomas. The understanding of their role in tumour biology continues to evolve. Therapeutic targeting of mutant IDH1 with vorasidenib demonstrated highly encouraging efficacy and minimal toxicity in a recent, randomized phase III trial involving patients with low-grade gliomas.
- David A. Reardon
- & Daniel P. Cahill
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Review Article |
Optimizing the safety of antibody–drug conjugates for patients with solid tumours
Advances in technology have enabled the development of several novel antibody–drug conjugates (ADCs) with encouraging clinical activity in patients with advanced-stage solid tumours. Indications for these therapies are expanding rapidly to earlier lines of therapy. Nonetheless, the toxicities of these various agents are not trivial and can be fatal, even in patients with early stage disease. In this Review, the authors summarize the toxicities of ADCs in patients with solid tumours both as monotherapies and in combination with other agents and discuss various ongoing research efforts attempting to optimize the therapeutic index of these agents.
- Paolo Tarantino
- , Biagio Ricciuti
- & Sara M. Tolaney
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Review Article |
Early stage gastric adenocarcinoma: clinical and molecular landscapes
Long-term survival rates of patients with gastric cancer remain low, particularly in Western countries. This lack of progress, among other aspects, is likely to reflect a focus on empirical approaches that fail to account for the heterogeneity of gastric cancers. In this Review, the authors summarize the available evidence on the management of patients with early stage gastric cancers, with an emphasis on understanding the underlying biology in order to improve the outcomes in patients with these historically difficult-to-treat tumours.
- Yuki Hirata
- , Ayesha Noorani
- & Jaffer A. Ajani
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Research Highlight |
Venetoclax–obinutuzumab combinations are effective in fit patients with CLL
- Diana Romero
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Review Article |
Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours
Antibody–drug conjugates (ADCs) have demonstrated efficacy in patients with various cancers, although their antitumour activity in the central nervous system (CNS) might be limited by the blood–brain barrier. In this Review, the authors describe the available clinical data emphasizing the heterogeneous activity of ADCs against primary or secondary brain tumours and ongoing clinical trials in this area. In addition, they discuss physical, biological and molecular determinants of the CNS activity of ADCs, as well as potential strategies to improve delivery of these agents to brain tumours.
- Maximilian J. Mair
- , Rupert Bartsch
- & Matthias Preusser
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Review Article |
Rare molecular subtypes of lung cancer
Lung cancers harbouring ‘rare’ alterations (defined as those with a prevalence of <5% of oncogene-driven lung cancers) can be detected in around a third of all oncogene-driven lung cancers and are diagnosed in thousands of patients each year. Advances in our understanding of tumour biology, diagnosis and the development of novel therapies are enabling increasing use of specific therapies targeting these alterations. In this Review, the authors provide an overview of the epidemiology, diagnosis, prognosis and treatment of patients with lung cancers harbouring these rare alterations. The importance of expedited drug approval pathways and cooperation between multiple stakeholders is also emphasized.
- Guilherme Harada
- , Soo-Ryum Yang
- & Alexander Drilon
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Repotrectinib effective in ROS1-fusion-positive NSCLC
ROAR brings in a new histology-agnostic approval for rare cancers
New data confirm clinical utility of ctDNA