Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have ...primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung cancer, but the broad applicability of TMB-H as a biomarker of response across all solid tumors is unclear. The FDA has approved the PD-1 inhibitor, pembrolizumab, as a therapy for all solid tumors with TMB equal to or greater than 10 mutations/megabase as measured by the FoundationOne CDx assay. This approval was based on an exploratory analysis of the KEYNOTE-158 study, which was a single-arm, phase II multi-cohort study of pembrolizumab for select, previously treated advanced solid tumors. Here, we elucidate the caveats of using TMB as a biomarker with a universal threshold across all solid tumors. While we recognize the importance of this and other FDA pan-cancer approvals, several questions about TMB as a predictive biomarker remain unanswered. In this perspective, we discuss clinical trial evidence in this area. We review the relationship between TMB and the tumor immune microenvironment. We highlight the risks of extrapolating evidence from a limited number of tumor histologies to all solid tumors, and we propose avenues for future research.
Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in ...males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor‐treating fields, delivering low‐intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood‐brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker‐enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.
Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO ...grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health ...Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs.
To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.• Treatment with antiangiogenic therapy versus placebo.• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy.
Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched.
RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG.
Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.
After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours.
In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.
The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or ...rearrangements form a unique sub-class, with anaplastic lymphoma kinase (
) and c-ros oncogene 1 (
) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (
), rearrangement during transfection (
), and neuregulin 1 (
) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (
) mutant and
-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.
Gliomas are the most common malignant primary brain tumor in adults. Despite advances in multimodality therapy, incorporating surgery, radiotherapy, systemic therapy, tumor treating fields and ...supportive care, patient outcomes remain poor, especially in glioblastoma where median survival has remained static at around 15 months, for decades. Low-grade gliomas typically harbor
(
) mutations, grow more slowly and confer a better prognosis than glioblastoma. However, nearly all gliomas eventually recur and progress in a way similar to glioblastoma. One of the novel therapies being developed in this area are poly(ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors belong to a class of drugs that target DNA damage repair pathways. This leads to synthetic lethality of cancer cells with coexisting homologous recombination deficiency. PARP inhibitors may also potentiate the cytotoxic effects of radiotherapy and chemotherapy, and prime the tumor microenvironment for immunotherapy. In this review, we examine the rationale and clinical evidence for PARP inhibitors in glioma and suggest therapeutic opportunities.
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. ...There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples.
The SARS-CoV-2 pandemic has resulted in considerable consequences for many cancer patients, exacerbating pre-existing systemic health system limitations as well as creating new challenges. From ...socially distanced clinics and the widespread introduction of telehealth, to the halting of clinical trials and the reassessment of what constitutes “essential” treatment, care in oncology has abruptly changed. There is currently limited analysis of cancer patients’ experiences of the pandemic and its impacts on illness, wellness, and everyday life. Through semi-structured interviews with 54 people living with cancer during the 2020 phase of the SARS-CoV-2 pandemic in Australia, we explore how patients experience illness and care in reflecting upon a range of pandemic challenges, including delay, distance, and vulnerability. We find that in some cases, these pandemic conditions redefined the meaning of essential cancer care, reconfigured expectations around clinical trials, constructed new affective distances, and amplified dread and fear for people living with cancer.
Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising ...single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma.
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