Professor James Larkin
Honorary Faculty: Melanoma and Kidney Cancer
Biography
Professor James Larkin is a Medical Oncologist specialising in the treatment of melanoma and cancers of the kidney.
Professor Larkin grew up in North Cornwall before taking a first in Natural Sciences from Cambridge University. He undertook clinical training at Oxford University, qualifying in 1996. General medical training was undertaken in London and in 2001 he won a Medical Research Council Fellowship for a Clinician, carrying out laboratory research at the Institute of Cancer Research leading to a PhD. Specialist training was completed at The Royal Marsden and he was appointed a Consultant in 2008.
His research interests involve trying to understand cancer and its consequences better, as well as developing improved treatments, particularly with targeted therapies and immunotherapies. In the past he has served on the Medical Oncology Specialist Advisory Committee for the Joint Royal Colleges of Physicians Training Board, as the NIHR National Specialty Lead for Early Phase Oncology Trials and Chair of both the NCRI Renal Cancer Clinical Studies Group and The Royal Marsden/Institute of Cancer Research Committee for Clinical Research.
In 2018 he was elected as a Fellow of the Academy of Medical Sciences and in 2020 as an NIHR Senior Investigator. In 2022 he was appointed to roles as Head of The Royal Marsden Skin Unit, Joint Training Programme Director for Medical Oncology and Lead of the Cancer Immunotherapy Theme at The Royal Marsden/Institute of Cancer Research NIHR Biomedical Research Centre. Professor Larkin serves as a medical advisor to the patient advocacy group Melanoma UK, as a trustee of Action Kidney Cancer and sits on the Medical Advisory Board of the International Kidney Cancer Coalition.
Related pages
Types of Publications
Journal articles
BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.
PURPOSE: A Phase II study to screen for anti-melanoma activity of the heat shock protein 90 (HSP90) inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin) was performed. The primary endpoint was the rate of disease stabilisation in patients with progressive, metastatic melanoma treated with 17-AAG. Secondary endpoints were to determine: the toxicity of 17-AAG, the duration of response(s), median survival and further study the pharmacokinetics and pharmacodynamics of 17-AAG. PATIENTS AND METHODS: Patients with metastatic melanoma (progressive disease documented ≤6 months of entering study) were treated with weekly, intravenous 17-AAG. A Simon one sample two stage minimax design was used. A stable disease rate of ≥25% at 6 months was considered compatible with 17-AAG having activity. RESULTS: Fourteen patients (8 male: 6 female) were entered, eleven received 17-AAG (performance status 0 or 1). Median age was 60 (range 29-81) years. The majority (93%) received prior chemotherapy and had stage M1c disease (71%). Toxicity was rarely ≥ Grade 2 in severity and commonly included fatigue, headache and gastrointestinal disturbances. One of eleven patients treated with 17-AAG had stable disease for 6 months and median survival for all patients was 173 days. The study was closed prematurely prior to completion of the first stage of recruitment and limited planned pharmacokinetic and pharmacodynamic analyses. CONCLUSION: Some evidence of 17-AAG activity was observed although early study termination meant study endpoints were not reached. Stable disease rates can be incorporated into trials screening for anti-melanoma activity and further study of HSP90 inhibitors in melanoma should be considered.
Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.
Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare, distinctive renal neoplasm characterized by an admixture of cuboidal cells in tubules and sheets of spindle cells, typically with low-grade nuclei and a myxoid or mucinous background. It is characteristically of low malignant potential, and only rare metastatic cases have been reported. We describe a case in which the patient presented with extensive regional and distant metastases, but both primary and metastatic tumor showed the typical histomorphology of bland cuboidal or spindle cells lacking pleomorphism, mitoses, and necrosis. Almost all previous cases of metastatic MTSCCs have shown nuclear atypia or sarcomatoid morphology of the primary tumor; and metastatic renal MTSCC in which the primary neoplasm does not display atypical features is exceptional, serving to highlight that these rare tumors can behave aggressively even with "indolent" histological appearances.
Metastatic renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is intrinsically resistant to chemotherapy and radiotherapy. Although therapies targeted to the molecules vascular endothelial growth factor and mammalian target of rapamycin have shown clinical effectiveness, their effects are variable and short-lived, underscoring the need for improved treatment strategies for RCC. Here, we used quantitative phosphoproteomics and immunohistochemical profiling of 346 RCC specimens and determined that Src kinase signaling is elevated in RCC cells that retain wild-type von Hippel-Lindau (VHL) protein expression. RCC cell lines and xenografts with wild-type VHL exhibited sensitivity to the Src inhibitor dasatinib, in contrast to cell lines that lacked the VHL protein, which were resistant. Forced expression of hypoxia-inducible factor (HIF) in RCC cells with wild-type VHL diminished Src signaling output by repressing transcription of the Src activator protein tyrosine phosphatase 1B (PTP1B), conferring resistance to dasatinib. Our results suggest that a HIF-regulated VHL-PTP1B-Src signaling pathway determines the sensitivity of RCC to Src inhibitors and that stratification of RCC patients with antibody-based profiling may identify patients likely to respond to Src inhibitors in RCC clinical trials.
BACKGROUND: Epothilones are cytotoxic macrolides that share a similar mechanism of action with the taxanes but demonstrate antitumor activity in taxane-resistant settings. Six epothilones are in early clinical trials for cancer treatment. DESIGN: This review summarizes data from phase II clinical studies of the epothilones ixabepilone (BMS-247550), patupilone (EPO906), and KOS-862. Data were identified by searches of PubMed and of the proceedings of the American Society of Clinical Oncology annual meetings and the Federation of European Cancer Societies biennial conference for the period 2000-2006. Studies were included if safety and efficacy data were available for at least 10 patients with a given tumor type in a standard phase II design. RESULTS: Epothilones have demonstrated activity in lung, ovarian, breast, prostate, and renal carcinomas and in non-Hodgkin's lymphoma in phase II studies. Little or no evidence of clinical activity has been reported in studies of epothilones in other tumor types. Preliminary data indicate that epothilones can be combined safely with other cytotoxic agents such as carboplatin. CONCLUSIONS: The epothilones may play a role as an alternative to taxanes if activity in resistant settings can be confirmed together with an acceptable toxicity profile. Randomized studies are awaited to investigate the utility of epothilones in single-agent and combination regimens.
PURPOSE: We present the Royal Marsden Hospital experience of cerebral metastases from primary epithelial ovarian carcinoma (EOC) over the last 20 years and examine the evidence for an increasing incidence of EOC metastasizing to this site. PATIENTS AND METHODS: A total of 3,690 women with EOC were seen at the Royal Marsden Hospital from 1980 to 2000. Eighteen of these patients developed cerebral metastases. RESULTS: Median age at diagnosis of EOC was 52 years (range, 39 to 67). All patients received at least one line of platinum-based chemotherapy; 56% (10 of 18) received more than one line of treatment; 17% (three of 18), two lines; 11% (two of 18), three lines; and 28% (five of 18), four lines. The median treatment interval between each line of chemotherapy was 12, 18, and 4 months. The median interval between diagnosis and CNS relapse was 46 months (range, 12 to 113), in comparison with 5 and 7.5 months for hematogenous relapse in lung or liver, respectively (P <.001). The incidence of CNS metastases in our population from 1980 to 1984 was 0.2%; from 1985 to 1989, 0%; from 1990 to 1994, 0.3%; and from 1995 to 1999, 1.3% (P <.001). An analysis of data from the literature also suggests that the incidence of cerebral metastases from EOC has increased over time. CONCLUSION: CNS metastases in EOC are a rare and late manifestation of the disease, occurring in patients with a prolonged survival caused by repeated chemosensitive relapses. An analysis of our data and the data from the literature suggests that the incidence of metastasis at this site in patients with EOC is increasing.
Uveal melanoma (UM) is a rare disease with a distinct molecular profile. About half of the patients with UM eventually develop metastatic disease. The prognosis of these patients remains poor. Treatment options are limited and none of them have been able to show a survival benefit. Ipilimumab was the first agent to show a survival benefit in patients with cutaneous melanoma in a randomized trial; however, there is limited published evidence for its role in the management of advanced UM. Here, we report our experience of ipilimumab in five patients with advanced UM treated at an academic cancer centre in the UK. Two patients had durable stable disease and three developed progressive disease. Of the patients with stable disease, one maintained disease control at 11 months from the commencement of treatment with ∼10% reduction in tumour volume compared with the baseline, and the second patient progressed after 15 months. We also examined the tumour kinetics and response patterns that resembled that of ipilimumab in cutaneous melanoma. Given the lack of randomized trial data, our findings indicate that ipilimumab might be a reasonable treatment option for patients with advanced UM.
Systemic treatment of renal cell carcinoma has changed dramatically since 2007, with the development and approval of six new agents, which target complex molecular pathways regulating tumour angiogenesis and cell proliferation and survival. These treatments have significantly improved survival times in metastatic renal cell carcinoma, but remain palliative. A number of newer agents are in clinical development, which offer theoretical advantages over existing treatments, and research methodologies are adapting with the aim of defining an individualised approach to therapy which exploits the underlying tumour biology. This review will provide an overview of current and emerging systemic treatments and how they might be integrated with surgical therapy, with a particular focus on advanced, clear cell metastatic renal cell carcinoma.
PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.
Fatigue is one of the most common symptoms associated with cancer. Persistent fatigue can impair multiple aspects of daily functioning and quality of life, and patients report that treatment-related fatigue has a greater impact than other symptoms, including pain, nausea, and depression. Thus, management of fatigue is recognized as an important component of care for patients with cancer. Treatment of advanced and metastatic renal cell carcinoma (RCC) was, until recently, limited to cytokine-based therapies, which are associated with modest response rates and significant toxicity, including high rates of treatment-related fatigue. The paradigm for RCC treatment has shifted dramatically in the last 5 years with the advent of efficacious targeted therapies. These agents provide the promise of better tolerability because of their more selective mechanisms of action. However, there is considerable variation in the selectivity of targeted agents for RCC, and a review of randomized clinical trials in patients with advanced and/or metastatic disease reveals that there is considerable variation in the tolerability of these agents. Fatigue remains a prominent toxicity with current targeted therapies. Future agents that show better selectivity and potency than current targeted therapies should help to provide better efficacy and tolerability.
INTRODUCTION: Each year in the UK there are 8100 new cases of malignant melanoma, and 1800 deaths, largely as a result of metastatic disease. The median survival of people with metastatic melanoma is 6-9 months after diagnosis, with 10% of people alive at 5 years. Chemotherapy is given with palliative rather than curative intent for metastatic disease. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of chemotherapy for metastatic melanoma? What are the effects of immunotherapy for metastatic melanoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 23 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding interferon alfa (with or without interleukin-2) to chemotherapy; dacarbazine; single-agent or combination chemotherapy; supportive palliative care alone or with chemotherapy; and temozolomide.
In metastatic renal cell carcinoma (RCC) immunotherapy results in a small but important improvement in overall survival, but a need exists to develop more-effective systemic therapies. Recent developments in our understanding of the molecular biology of RCC have identified several pathways associated with the development of the disease. A number of strategies designed specifically to target these pathways have resulted. Initial studies have shown marked clinical benefits of so-called 'targeted therapies'. Sunitinib, sorafenib and axitinib are kinase inhibitors that inhibit the VEGF, platelet-derived growth factor and c-kit receptor tyrosine kinases. Bevacizumab is a monoclonal antibody that is directed against VEGF. Temsirolimus inhibits the mammalian target of rapamycin. These agents have all shown considerable activity with manageable toxicity in phase II and III studies in both previously treated and untreated patients. In phase III studies, sorafenib and bevacizumab have been associated with prolonged progression-free survival compared with placebo. Phase III data have shown improvements in progression-free and overall survival with sunitinib and temsirolimus, respectively, compared with interferon alfa. Additional studies are needed to determine the optimum utilization of these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.
Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma.
BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of kidney cancer. Here, we integrated an unbiased genome-wide RNA interference screen for ccRCC survival regulators with an analysis of recurrently overexpressed genes in ccRCC to identify new therapeutic targets in this disease. One of the most potent survival regulators, the monocarboxylate transporter MCT4 (SLC16A3), impaired ccRCC viability in all eight ccRCC lines tested and was the seventh most overexpressed gene in a meta-analysis of five ccRCC expression datasets. MCT4 silencing impaired secretion of lactate generated through glycolysis and induced cell cycle arrest and apoptosis. Silencing MCT4 resulted in intracellular acidosis, and reduction in intracellular ATP production together with partial reversion of the Warburg effect in ccRCC cell lines. Intra-tumoural heterogeneity in the intensity of MCT4 protein expression was observed in primary ccRCCs. MCT4 protein expression analysis based on the highest intensity of expression in primary ccRCCs was associated with poorer relapse-free survival, whereas modal intensity correlated with Fuhrman nuclear grade. Consistent with the potential selection of subclones enriched for MCT4 expression during disease progression, MCT4 expression was greater at sites of metastatic disease. These data suggest that MCT4 may serve as a novel metabolic target to reverse the Warburg effect and limit disease progression in ccRCC.
The BRAF inhibitor, vemurafenib, has demonstrated improved progression-free and overall survival compared with chemotherapy in a randomized trial, and represents a new standard of care in patients with advanced melanoma harboring a BRAF-V600 mutation. A BRAF-V600 mutation is identified in approximately half of patients with cutaneous melanoma, and is unequivocally a biomarker predictive of profound clinical benefit for these patients. However, acquired vemurafenib resistance is a major clinical challenge and therapy is not yet curative. A substantial body of translational research has been performed alongside clinical trials of vemurafenib, providing key insights into the molecular basis of response and resistance. This review summarizes the development of vemurafenib for the treatment of BRAF-V600 mutant melanoma and discusses how knowledge of critical signaling pathways will be applied for its optimal clinical use in future.
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.
Immunotherapy results in a small overall survival advantage in metastatic renal cell carcinoma (RCC), but there is a need to develop more effective systemic therapies. Angiogenesis has an important role in the pathophysiology of RCC and vascular endothelial growth factor (VEGF) is a key mediator of this process. Sorafenib (BAY 43-9006) is a new agent belonging to a class of drugs called kinase inhibitors and inhibits the VEGF, platelet-derived growth factor (PDGF), and c-KIT receptor tyrosine kinases, amongst others. Sorafenib has shown significant activity with manageable toxicity in metastatic RCC in phase 2 studies in patients pretreated with immunotherapy, whilst prolonged progression-free survival in comparison with placebo in a phase 3 study has been reported. Further phase 3 trials in advanced disease are ongoing and a trial of adjuvant sorafenib therapy in RCC is planned.