ABSTRACT
Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4-1.7) compared to 1.5 months (95% CI 1.4-1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2-1.6) versus 1.6 months (95% CI 1.3-1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.
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PURPOSE: Treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid dMMR/MSI tumors and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. PATIENTS AND METHODS: Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol (DRUP), a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response (OR) or stable disease ≥ 16 weeks). Whole-genome sequencing and RNA-sequencing were performed on pre-treatment tumor biopsies. RESULTS: 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% (95% CI: 53 - 70) with an OR in 45% (95% CI: 36 - 54). After a median follow-up of 14.5 months (95% CI: 13 - 19), median progression-free survival was 18 months (95% CI 9 - not reached) and median overall survival was not reached. While CB was not or only weakly associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, where markers of adaptive immunity dominated the biomarker landscape. CONCLUSIONS: Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor-type specific biomarkers for guiding immunotherapy.
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Colorectal cancer (CRC) raises considerable clinical challenges, including a high mortality rate once the tumor spreads to distant sites. At this advanced stage, more accurate prediction of prognosis and treatment outcome is urgently needed. The role of cancer immunity in metastatic CRC (mCRC) is poorly understood. Here, we explore cellular immune cell status in patients with multi-organ mCRC. We analyzed T cell infiltration in primary tumor sections, surveyed the lymphocytic landscape of liver metastases, and assessed circulating mononuclear immune cells. Besides asking whether immune cells are associated with survival at this stage of the disease, we investigated correlations between the different tissue types; as this could indicate a dominant immune phenotype. Taken together, our analyses corroborate previous observations that higher levels of CD8+ T lymphocytes link to better survival outcomes. Our findings therefore extend evidence from earlier stages of CRC to indicate an important role for cancer immunity in disease control even after metastatic spreading to multiple organs. This finding may help to improve predicting outcome of patients with mCRC and suggests a future role for immunotherapeutic strategies.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Male , Female , Liver Neoplasms/secondary , Liver Neoplasms/immunology , Liver Neoplasms/mortality , Aged , Middle Aged , Prognosis , CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasm Metastasis , AdultABSTRACT
PURPOSE: Although eligibility criteria are essential in trial design, overly restrictive criteria contribute to low accrual and limited generalizability. To enhance trial inclusivity, there has been growing interest in broadening eligibility criteria, especially for patients with advanced or treatment-refractory disease. Yet, the impact on patient safety remains uncertain. In the Drug Rediscovery Protocol (DRUP), protocol exceptions are frequently requested and occasionally granted. Here we describe the impact of these waivers on treatment safety and efficacy. PATIENTS AND METHODS: DRUP is a multicenter, non-randomized clinical basket trial treating therapy-refractory cancer patients with molecularly targeted- and immunotherapies outside their registered indications (NCT02925234). Here, all granted waivers were revised, analyzed in terms of safety and efficacy outcome, and compared with outcomes of included patients that did not receive a waiver. RESULTS: Between September 1st 2016 and September 1st 2021, protocol waivers were granted for 82 patients (8%) out of 1019 included patients in DRUP. Most waivers (45%) were granted for general- or drug-related eligibility criteria, other categories were out-of-window testing, treatment and testing exceptions. Serious adverse event rate was similar between patients that received a waiver (pW) and patients that did not (pNW): 39% vs. 41%, respectively (P=0.81). The clinical benefit (either objective response or stable disease ≥ 16 weeks) rate of pW was 40% versus 33% in pNW (P=0.43). CONCLUSION: Safety and clinical benefit were preserved in patients for whom a waiver was granted. These data support a more personalized approach in assessing eligibility criteria, especially in trials with widely used and approved drugs accruing patients without other treatment options.
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BACKGROUND: A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes. METHODS: Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1). RESULTS: Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94-61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43-21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06-6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26-4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival. CONCLUSIONS: Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.
Subject(s)
Exercise , Neoplasms , Smartphone , Humans , Neoplasms/therapy , Neoplasms/mortality , Female , Male , Middle Aged , Aged , Adult , Clinical Trials, Phase II as Topic , Clinical Trials, Phase I as Topic , Treatment OutcomeABSTRACT
BACKGROUND AND PURPOSE: The Drug Rediscovery Protocol (DRUP) is a Dutch, pan-cancer, nonrandomized clinical trial that aims to investigate the efficacy and safety of targeted and immunotherapies outside their registered indication in patients with advanced or metastatic cancer. PATIENTS: Patients with advanced or metastatic cancer are eligible when there are no standard of care treatment options left and the tumor possesses a molecular genomic variant for which commercially available anticancer treatment is accessible off-label in DRUP. Clinical benefit is the study's primary endpoint, characterized by a confirmed objective response or stable disease after at least 16 weeks of treatment. RESULTS: More than 2,500 patients have undergone evaluation, of which over 1,500 have started treatment in DRUP. The overall clinical benefit rate (CBR) remains 33%. The nivolumab cohort for patients with microsatellite instable metastatic tumors proved highly successful with a CBR of 63%, while palbociclib or ribociclib in patients with tumors harboring CDK4/6 pathway alterations showed limited efficacy, with a CBR of 15%. The formation of two European initiatives (PCM4EU and PRIME-ROSE) strives to accelerate implementation and enhance data collection to broaden equitable access to anticancer treatments and gather more evidence. CONCLUSION: DRUP persists in improving patients access to off-label targeted or immunotherapy in the Netherlands and beyond. The expansion of DRUP-like clinical trials across Europe provides countless opportunities for broadening the horizon of precision oncology.
Subject(s)
Neoplasms , Precision Medicine , Humans , Neoplasms/drug therapy , Neoplasms/genetics , Precision Medicine/methods , Netherlands , Immunotherapy/methods , Medical Oncology/methods , Medical Oncology/trends , Piperazines/therapeutic use , Pyridines/therapeutic use , Nivolumab/therapeutic use , Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy/methodsABSTRACT
BACKGROUND: In the two European Union (EU)-funded projects, PCM4EU (Personalized Cancer Medicine for all EU citizens) and PRIME-ROSE (Precision Cancer Medicine Repurposing System Using Pragmatic Clinical Trials), we aim to facilitate implementation of precision cancer medicine (PCM) in Europe by leveraging the experience from ongoing national initiatives that have already been particularly successful. PATIENTS AND METHODS: PCM4EU and PRIME-ROSE gather 17 and 24 partners, respectively, from 19 European countries. The projects are based on a network of Drug Rediscovery Protocol (DRUP)-like clinical trials that are currently ongoing or soon to start in 11 different countries, and with more trials expected to be established soon. The main aims of both the projects are to improve implementation pathways from molecular diagnostics to treatment, and reimbursement of diagnostics and tumour-tailored therapies to provide examples of best practices for PCM in Europe. RESULTS: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: PCM4EU and PRIME-ROSE were launched in January and July 2023, respectively. Educational materials, including a podcast series, are already available from the PCM4EU website (http://www.pcm4eu.eu). The first reports, including an overview of requirements for the reimbursement systems in participating countries and a guide on patient involvement, are expected to be published in 2024. CONCLUSION: European collaboration can facilitate the implementation of PCM and thereby provide affordable and equitable access to precision diagnostics and matched therapies for more patients.
Subject(s)
Neoplasms , Precision Medicine , Humans , Precision Medicine/methods , Europe , Neoplasms/therapy , European Union , Drug Repositioning , Clinical Trials as Topic/organization & administrationABSTRACT
BACKGROUND: The epidemiology of colorectal cancer (CRC) has changed rapidly over the years. The aim of this study was to assess the trends in incidence, treatment, and relative survival (RS) of patients diagnosed with CRC in the Netherlands between 2000 and 2021. PATIENTS AND METHODS: 2 75667 patients diagnosed with CRC between 2000 and 2021 were included from the Netherlands Cancer Registry. Analyses were stratified for disease extent (localised: T1-3N0M0; regional: T4N0M0/T1-4N1-2M0; distant: T1-4N0-2M1) and localisation (colon; rectum). Trends were assessed with joinpoint regression. RESULTS: CRC incidence increased until the mid-2010s but decreased strongly thereafter to rates comparable with the early 2000s. Amongst other trend changes, local excision rates increased for patients with localised colon (2021: 13.6 %) and rectal cancer (2021: 34.9 %). Moreover, primary tumour resection became less common in patients with distant colon (2000-2021: 60.9-12.5 %) or rectal cancer (2000-2021: 47.8-6.9 %), while local treatment of metastases rates increased. Five-year RS improved continuously for localised and regional colon (97.7 % and 72.0 % in 2017, respectively) and rectal cancer (95.2 % and 76.3 % in 2017, respectively). The rate of anti-cancer treatments decreased in distant colon (2010-2021: 80.3 % to 67.2 %; p < 0.001) and rectal cancer (2011-2021: 86.0 % to 77.0 %; p < 0.001). The improvement of five-year RS stagnated for distant colon (2010-2017: 11.2 % to 11.9 %; average percentage of change [APC]: 2.1, 95 % confidence interval [CI]: -7.6, 4.7) and rectal cancer (2009-2017: 12.7 % to 15.6 %; APC: 1.4, 95 % CI: -19.1, 5.5). CONCLUSIONS: Major changes in the incidence and treatment of CRC between 2000 and 2021 were identified and quantified. Five-year RS increased continuously for patients with localised and regional CRC, but stagnated for patients with distant CRC, likely caused by decreased rates of anti-cancer treatment in this group.
Subject(s)
Colorectal Neoplasms , Registries , Humans , Netherlands/epidemiology , Male , Female , Incidence , Colorectal Neoplasms/mortality , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/therapy , Colorectal Neoplasms/pathology , Aged , Middle Aged , Registries/statistics & numerical data , Aged, 80 and over , Adult , Survival RateABSTRACT
Cancer and its associated treatment is a major stressor, leading to emotions such as anxiety or depressive mood. Human emotions have developed through the course of evolution because they facilitate adaptation to important events, such as cancer and its associated treatment. On the other hand, emotions can be maladaptive and interfere with adaptation to cancer. Emotions are maladaptive if they are disproportionally severe or persistent, and if they interfere with functioning. We aim to expand the conceptualization of adaptive and maladaptive emotions in patients with cancer. We draw on major theories in the field of mental disorder and mental health, and apply these theories to conceptualize adaptive and maladaptive emotions in patients with cancer. (i) Maladaptive emotions have two essential features: mental dysfunction and patient harm. Maladaptive emotions are characterized by a network of strongly associated emotional symptoms, which may include cancer-related somatic symptoms. The dysfunctional symptom network is hypothesized to be the result of disturbance of life goal pursuit caused by cancer. (ii) Adaptive emotions have two essential features: ability to deal with cancer and functioning well. The ability to use emotions in an adaptive way depends on skills to recognize, express, and regulate emotions in a flexible manner. A secure attachment style facilitates adaptive emotional responses to cancer. The present conceptualization of adaptive and maladaptive emotions is expected to contribute to better understanding and management of emotions in patients with cancer.
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PURPOSE: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). PATIENTS AND METHODS: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing. RESULTS: Seventy-two evaluable patients with 26 different histotypes were enrolled. CB rate was 13% in cohort A (3/24 with partial response (PR)), 21% in cohort B (3/24 with SD, 2/24 with PR), and 42% in cohort C (4/24 with SD, 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. CONCLUSION: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.
ABSTRACT
Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.
Subject(s)
Antigens, Neoplasm , Immunotherapy , Neoplasms , Open Reading Frames , Humans , Antigens, Neoplasm/immunology , Antigens, Neoplasm/genetics , Immunotherapy/methods , Neoplasms/immunology , Neoplasms/therapy , Peptides/immunologyABSTRACT
PURPOSE: Patients with cancer often experience multiple somatic and psychological symptoms. Somatic and psychological symptoms are thought to be connected and may reinforce each other. Network analysis allows examination of the interconnectedness of individual symptoms. The aim of this scoping review was to examine the current state of knowledge about the associations between somatic and psychological symptoms in patients with cancer and cancer survivors, based on network analysis. METHODS: This scoping review followed the five-stage framework of Arksey and O'Malley. The literature search was conducted in May, 2023 in PubMed, APA PsycINFO, Embase Cochrane central, and CINAHL databases. RESULTS: Thirty-two studies were included, with eleven using longitudinal data. Seventeen studies reported on the strength of the associations: somatic and psychological symptoms were associated, although associations among somatic as well as among psychological symptoms were stronger. Other findings were the association between somatic and psychological symptoms was stronger in patients experiencing more severe symptoms; associations between symptoms over time remained rather stable; and different symptoms were central in the networks, with fatigue being among the most central in half of the studies. IMPLICATIONS FOR CANCER SURVIVORS: Although the associations among somatic symptoms and among psychological symptoms were stronger, somatic and psychological symptoms were associated, especially in patients experiencing more severe symptoms. Fatigue was among the most central symptoms, bridging the somatic and psychological domain. These findings as well as future research based on network analysis may help to untangle the complex interplay of somatic and psychological symptoms in patients with cancer.
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BACKGROUND: In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'. METHODS: Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies. RESULTS: CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available. CONCLUSIONS: The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.
Subject(s)
Antibodies, Monoclonal, Humanized , Colorectal Neoplasms , Receptor, ErbB-2 , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Proto-Oncogene Proteins B-raf/genetics , Receptor, ErbB-2/genetics , Trastuzumab/adverse effects , Trastuzumab/therapeutic useABSTRACT
Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0-62.4) and 59.6% (95% CI, 51.3-67.5), respectively. ORR was 35.1% (95% CI, 27.5-43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.
ABSTRACT
BACKGROUND: The prognosis of malignant primary high-grade brain tumors, predominantly glioblastomas, is poor despite intensive multimodality treatment options. In more than 50% of patients with glioblastomas, potentially targetable mutations are present, including rearrangements, altered splicing, and/or focal amplifications of epidermal growth factor receptor (EGFR) by signaling through the RAF/RAS pathway. We studied whether treatment with the clinically available anti-EGFR monoclonal antibody panitumumab provides clinical benefit for patients with RAF/RAS-wild-type (wt) glioblastomas in the Drug Rediscovery Protocol (DRUP). METHODS: Patients with progression of treatment refractory RAF/RASwt glioblastoma were included for treatment with panitumumab in DRUP when measurable according to RANO criteria. The primary endpoints of this study are clinical benefit (CB: defined as confirmed objective response [OR] or stable disease [SD] ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and up to 24 patients in stage 2 if at least 1 in 8 patients had CB in stage 1. RESULTS: Between 03-2018 and 02-2022, 24 evaluable patients were treated. CB was observed in 5 patients (21%), including 2 patients with partial response (8.3%) and 3 patients with SD ≥ 16 weeks (12.5%). After median follow-up of 15 months, median progression-free survival and overall survival were 1.7 months (95% CI 1.6-2.1 months) and 4.5 months (95% CI 2.9-8.6 months), respectively. No unexpected toxicities were observed. CONCLUSIONS: Panitumumab treatment provides limited CB in patients with recurrent RAF/RASwt glioblastoma precluding further development of this therapeutic strategy.
Subject(s)
Glioblastoma , Panitumumab , Humans , Panitumumab/therapeutic use , Panitumumab/adverse effects , Panitumumab/pharmacology , Female , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Glioblastoma/mortality , Male , Middle Aged , Aged , Adult , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , ras Proteins/genetics , raf Kinases/genetics , raf Kinases/antagonists & inhibitorsABSTRACT
The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p < 0.05, fold-change > 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p < 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib.
ABSTRACT
Circulating tumour DNA (ctDNA) is a potential biomarker that could contribute to more judicious patient selection for personalised treatment. This review and meta-analysis gives an overview of the current knowledge in the literature investigating the value of ctDNA in patients with colorectal liver metastases (CRLM). A systematic search was conducted in electronic databases for studies published prior to the 26th of May 2023. Studies investigating the association between ctDNA and oncological outcomes in patients undergoing curative-intent local therapy for CRLM were included. Meta-analyses were performed to pool hazard ratios (HR) for the recurrence-free survival (RFS) and overall survival (OS). A total of eleven studies were included and nine were eligible for meta-analyses. Patients with detectable ctDNA after surgery experienced a significantly higher chance of recurrence (HR 3.12, 95% CI 2.27-4.28, p < 0.000010) and shorter OS (HR 5.04, 95% CI 2.53-10.04, p < 0.00001) compared to patients without detectable ctDNA. A similar association for recurrence was found in patients with detectable ctDNA after the completion of adjuvant therapy (HR 6.39, 95% CI 2.13-19.17, p < 0.0009). The meta-analyses revealed no association between detectable ctDNA before surgery and the RFS and OS. These meta-analyses demonstrate the strong association between detectable ctDNA after treatment and oncological outcomes in CRLM patients.
Subject(s)
Circulating Tumor DNA , Colorectal Neoplasms , Liver Neoplasms , Humans , Circulating Tumor DNA/genetics , Biomarkers , Combined Modality Therapy , Liver Neoplasms/genetics , Colorectal Neoplasms/geneticsABSTRACT
Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically and pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response to EGFR blockade and identify alternative drug targets to overcome resistance. Both the tyrosine and global phosphoproteome as well as the proteome harbored distinctive response signatures. We found that increased pathway activity related to mitogen-activated protein kinase (MAPK) inhibition and abundant tyrosine phosphorylation of cell junction proteins, such as CXADR and CLDN1/3, in sensitive tumors, whereas epithelial-mesenchymal transition and increased MAPK and AKT signaling were more prevalent in resistant tumors. Furthermore, the ranking of kinase activities in single samples confirmed the driver activity of ERBB2, EGFR, and MET in cetuximab-resistant tumors. This analysis also revealed high kinase activity of several members of the Src and ephrin kinase family in 2 CRC PDX models with genomically unexplained resistance. Inhibition of these hyperactive kinases, alone or in combination with cetuximab, resulted in growth inhibition of ex vivo PDX-derived organoids and in vivo PDXs. Together, these findings highlight the potential value of phosphoproteomics to improve our understanding of anti-EGFR treatment and response prediction in mCRC and bring to the forefront alternative drug targets in cetuximab-resistant tumors.
Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Colorectal Neoplasms , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cetuximab/therapeutic use , Colorectal Neoplasms/metabolism , Drug Resistance, Neoplasm , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Signal Transduction , Phosphoproteins , ProteomeABSTRACT
The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.