BACKGROUND: Cancer predisposition due to constitutional (germline) genetic variants in high-risk or moderate-risk cancer predisposition genes presents clinical opportunities for risk mitigation. Focusing genetic testing...BACKGROUND: Cancer predisposition due to constitutional (germline) genetic variants in high-risk or moderate-risk cancer predisposition genes presents clinical opportunities for risk mitigation. Focusing genetic testing only on patients who are most likely to be positive for germline variants might enhance the clinical utility of positive results, but this approach could fail to assess the rate and pattern of such variants in patients with cancer overall. We aimed to assess the frequency and nature of constitutional variants in cancer predisposition genes in patients with cancer in the UK health-care system. METHODS: In this retrospective cohort study, we analysed data from participants with cancer from the 100 000 Genomes Project research environment. We included participants recruited from 14 genomic medicine centres operating within the UK National Health Service. Cancer predisposition genes (n=109) were curated to include those for which pathogenic variants were consistent with neoplasia as a primary presenting feature. We developed a detailed, semi-automated workflow for variant interpretation based on American College of Medical Genetics and Genomics guidance. This workflow used cancer and gene-specific adaptions developed by the Cancer Variant Interpretation Group UK and the US-based resource ClinGen. Multiple external reference sources (including the databases ClinVar and Gnomad, as well as functional studies) were used to inform the application of the guidance in the assessment of variants as pathogenic or likely pathogenic. Tumour type was assessed to ascertain associations between tumours and pathogenic or likely pathogenic variants. Fisher's exact tests were used for some elements of variant assessment. FINDINGS: 14 765 participants recruited into the 100 000 Genomes Project between Nov 29, 2016, and Feb 26, 2020, were included in the study (8315 [56%] female and 6450 [44%] male). Ancestry designation was European in 13 219 (90%) participants. The most frequent cancer types were breast (2908 [20%]), colorectal (2605 [18%]), and lung (1522 [10%]). Mean age at diagnosis was 62·9 years (SD 16·1). 711 (5%) participants were identified with a cancer predisposition gene variant assessed as pathogenic or likely pathogenic, with a total of 727 pathogenic or likely pathogenic variants. The genes with the most frequently detected pathogenic or likely pathogenic variants were CHEK2 (121 [0·82%] participants) and BRCA2 (110 [0·75%]), which are both associated with breast cancer. The rate of pathogenic or likely pathogenic variants varied widely between tumour types, with the highest proportion (for which >50 diagnoses were observed in the cohort) found in ovarian cancer (53 [9%] of 610 cases). 326 (45%) of 727 pathogenic or likely pathogenic variants had a known association with the tumour diagnosed in that participant, with proportions varying considerably between genes. INTERPRETATION: Understanding the frequency and nature of variants in cancer predisposition genes is important for planning of clinical services. Our analysis highlights the implications of more expansive genetic testing and the variant interpretation considerations necessary to yield benefit and avoid harm (eg, unnecessary surveillance) for patients. FUNDING: UK National Institute for Health and Care Research Cambridge Biomedical Research Centre.
Johnson ML, Patel MR, Falchook GS
… +13 more, Koyama T, Gutierrez M, Awad MM, Piha-Paul SA, Friedman CF, Satoh T, Okamoto N, Singh J, Yoshizuka N, Windish HP, Qian M, Tran BP, Doi T
BACKGROUND: Ifinatamab deruxtecan is a novel B7-H3-directed antibody-drug conjugate that leverages the clinically validated deruxtecan technology. We report dose-escalation results from a trial of ifinatamab deruxtecan i...BACKGROUND: Ifinatamab deruxtecan is a novel B7-H3-directed antibody-drug conjugate that leverages the clinically validated deruxtecan technology. We report dose-escalation results from a trial of ifinatamab deruxtecan in patients with solid tumours. METHODS: In this two-part, multicentre, open-label, first-in-human, phase 1/2 study of ifinatamab deruxtecan conducted at clinics in ten hospitals and cancer centres in the USA and Japan, we recruited patients aged 18 years or older who had advanced treatment-refractory solid tumours (small-cell lung cancer, oesophageal squamous cell carcinoma, castration-resistant prostate cancer, squamous non-small-cell lung cancer, head and neck squamous cell carcinoma, bladder cancer, sarcoma, endometrial cancer, melanoma, or breast cancer), and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received ifinatamab deruxtecan at doses of 0·8-16·0 mg/kg intravenously every 3 weeks. The primary outcome of dose escalation was the safety profile, which was evaluated in patients who received one or more dose of ifinatamab deruxtecan. Antitumour activity (per Response Evaluation Criteria in Solid Tumours version 1.1; secondary outcome) was evaluated in patients receiving ifinatamab deruxtecan at doses of 4·8 mg/kg or higher. The data cutoff was Jan 31, 2023. This trial is registered with ClinicalTrials.gov (NCT04145622) and is ongoing. FINDINGS: Between Oct 25, 2019, and July 13, 2022, 97 patients were enrolled and treated. 77 (79%) patients were male and 20 (21%) were female, 56 (58%) patients were White, and 31 (32%) were Asian. Three patients (3%) had dose-limiting toxicities; however, on the basis of protocol-defined criteria, the maximum tolerated dose was not reached. The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were anaemia (17 [18%] patients), neutropenia (four [4%]), lymphocyte count decreased (three [3%]), and neutrophil count decreased (three [3%]). Serious TEAEs occurred in 31 (32%) patients. TEAEs associated with death were reported in five patients (5%; pneumonia, pneumonia aspiration, COVID-19 pneumonia, interstitial lung disease, and one death of undesignated cause); death due to interstitial lung disease was considered related to study medication by the investigator. After a median follow-up of 8·6 months (IQR 4·1-12·9), the confirmed objective response rate across tumour types was 34% (95% CI 23-47; 24 of 70 evaluable patients). INTERPRETATION: The maximum tolerated dose was not reached with ifinatamab deruxtecan; however, one death due to treatment-related interstitial lung disease highlights the importance of prompt evaluation and careful management of patients who develop interstitial lung disease. Promising antitumour activity was observed across various solid tumours. These findings support further evaluation of ifinatamab deruxtecan in randomised controlled trials. FUNDING: Funding for this study was provided by Daiichi Sankyo Company (Daiichi Sankyo) and Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA.
Sandhu S, Joshua AM, Emmett L
… +27 more, Bressel M, Anton A, Spain L, Horvath LG, Pasam A, Tolmeijer SH, Akhurst TJ, Alipour R, Banks P, Buteau JP, Cassidy E, Crumbaker M, Dhiantravan N, Xu W, Chan J, Hitchen N, Scalzo M, Ravi Kumar AS, Kong G, Wallace R, Williams N, Williams S, Haynes NM, Neeson P, Wyatt AW, Hicks RJ, Hofman MS
BACKGROUND: Lutetium-177 [Lu]-prostate-specific membrane antigen (PSMA)-617 improves overall survival and progression-free survival in metastatic castration resistant prostate cancer (mCRPC), whereas immune checkpoint in...BACKGROUND: Lutetium-177 [Lu]-prostate-specific membrane antigen (PSMA)-617 improves overall survival and progression-free survival in metastatic castration resistant prostate cancer (mCRPC), whereas immune checkpoint inhibitors (ICIs) have limited activity. Preclinical evidence suggests radioligand therapy might induce immunogenic cell death that can be enhanced with ICIs. This study evaluates the activity and adverse event profile associated with multiple doses of [Lu]Lu-PSMA-617 with pembrolizumab. METHODS: PRINCE was a multicentre, single-arm, phase 1b/2 trial of [Lu]Lu-PSMA-617 and pembrolizumab. Eligible participants were aged 18 years or older, had mCRPC, an Eastern Cooperative Oncology Group performance status of 0-1, previous androgen receptor pathway inhibitor therapy with previous docetaxel allowed, and high PSMA expression. Participants received up to six cycles of [Lu]Lu-PSMA-617 intravenously every 6 weeks with 200 mg of pembrolizumab intravenously every 3 weeks for up to 24 months. Co-primary endpoints were safety and 50% prostate-specific antigen (PSA) response rate. All participants who received treatment were included in the analysis. The trial is registered with ClinicalTrials.gov, NCT03658447, and has been completed. FINDINGS: Between Aug 22, 2019 and Dec 16, 2020, 37 participants (median age 72 years, IQR 67-76; 27 [73%] docetaxel pretreated) received a median of six cycles (IQR 4-6) of [Lu]Lu-PSMA-617 and a median of 12 cycles (IQR 6-24) of pembrolizumab. Median follow up was 30 months (IQR 28-31). A decline in PSA of 50% or greater from baseline was observed in 28 (76%, 95% CI 59-88) of the 37 participants. Common treatment-related adverse events were grade 1-2. Grade 3 adverse events included anaemia in one (3%) participant and immune-related adverse events in 11 (30%) participants, including two cases each of fatigue (5%), colitis (5%), and increased serum amylase (5%), and one case (3%) each of pancreatitis, pneumonitis, type 1 diabetes, nephritis, myasthenia gravis, and mucosal pemphigus attributable to pembrolizumab. One participant had co-occurring myasthenia gravis and colitis. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Multicycle [Lu]Lu-PSMA-617 and pembrolizumab showed encouraging activity with manageable toxicity that was consistent with [Lu]Lu-PSMA-617 or pembrolizumab, and the combination might provide durable clinical benefit in a subset of patients. FUNDING: Victorian Cancer Agency, Merck Sharp & Dohme, and Novartis.
Privé BM, Noordzij W, Muselaers CHJ
… +18 more, de Jong IJ, van Oort IM, Janssen MJR, Van Rijk MC, van Gemert WA, Timmermans B, de Groot M, Mehra N, Gerritsen WR, Jonker MA, Alevroudis E, van der Gaag S, Koppes JCC, Sedelaar JPM, Vis AN, Vrachimis A, Oprea-Lager DE, Nagarajah J
BACKGROUND: [Lu]Lu-prostate-specific membrane antigen (PSMA)-617 (Lu-PSMA-617) is a novel treatment for metastatic castration-resistant prostate cancer. Here, we aimed to evaluate Lu-PSMA-617 in patients with PSMA-expres...BACKGROUND: [Lu]Lu-prostate-specific membrane antigen (PSMA)-617 (Lu-PSMA-617) is a novel treatment for metastatic castration-resistant prostate cancer. Here, we aimed to evaluate Lu-PSMA-617 in patients with PSMA-expressing oligometastatic hormone-sensitive prostate cancer (HSPC). METHODS: BULLSEYE was an open-label, randomised, phase 2 trial in three academic hospitals in the Netherlands (Radboud University Medical Center, University Medical Center Groningen, and University Medical Center Amsterdam) and one community hospital in Cyprus (German Oncology Center). Eligible participants were men, aged 18 years or older, with biochemically recurrent prostate cancer following radical prostatectomy or radiotherapy, Eastern Cooperative Oncology Group performance status score of 0-1, a PSA doubling time of less than 6 months and PSA amounts of over 1·0 μg/L. Paients aged 18 years or older with recurrent hormone sensitive prostate cancer following radical surgery or radiotherapy were randomly asigned (1:1) using a centralised web-based system with block randomisation to Lu-PSMA-617 (intervention) or standard of care (control) of deferred androgen deprivation therapy (ADT). The treatment group received two cycles of 7·4 GBq Lu-PSMA-617 every 6 weeks. 6 weeks after the second treatment cycle, patients with residual PSMA-expressing disease on PSMA-PET-CT, and no grade 3 or worse treatment-related adverse events received two additional cycles of 7·4 GBq Lu-PSMA-617 given 6 weeks apart.The control group did not receive treatment but underwent active monitoring for disease progression. Co-primary endpoints were the proportion of patients with disease progression, and time to disease progression with the same endpoint. Primary, secondary, and safety endpoints were assessed in the per-protocol population, who all received at least one 1 dose of 177Lu-PSMA-617. This trial is registered with ClinicalTrials.gov (NCT04443062) and has completed accrual. FINDINGS: Between April 20, 2020, and July 29, 2024, 78 males were screened and 58 were eligible (29 intervention and 29 control). 56 patients were white, one was Asian, and one was African. Patients in the intervention group received a median of four cycles (IQR 4-4) of Lu-PSMA-617. At data cutoff (March 31, 2025), median follow-up time was 27 months (IQR 18-32). During the first 30 weeks, disease progression was reported in two (7%) of 29 patients in the intervention group versus 27 (93%) of 29 patients in the control group (p<0·0001). Median progression-free survival (per-protocol) was 25 months (IQR 15 to not reached) for intervention group versus 5 months (IQR 3-7) for control (hazard ratio [HR] 0·07, 95% CI 0·03-0·17; p<0·0001). One (3%) patient in the intervention group developed grade 3 dry eyes, which resolved with supportive treatment, and grade 3 lymphocyte count decrease was observed in three (10%) patients in the treatment group. The control group had five (17%) patients with grade 3 hypertension, one (3%) patient with a grade 3 decrease in lymphocyte count, one (3%) patient with a grade 4 gallbladder infection, and one (3%) patient with a grade 4 myocardial infarction. There were no treatment-related grade 4 adverse events or deaths. No serious adverse events were reported in patients who received Lu-PSMA-617. The most common adverse events were grade 1 dry mouth in 19 (66%) patients in the treatment group versus three (10%) patients in the control group, fatigue in 16 (55%) patients in the treatment group versus six (21%) patients in the control group, and nausea in 14 (48%) patients in the treatment group versus three (10%) patients in the control group. No deaths were attributed to the treatment in either group. INTERPRETATION: Lu-PSMA-617 showed promising response rates and delayed disease progression in patients with oligometastatic HSPC in this trial. In addition, most treatment-related adverse events were low grade. FUNDING: Dutch Prostate Cancer Foundation (Prostaatkankerstichting) and Novartis.
Gregorc V, Majem M, Lo Russo G
… +22 more, Maio M, Salvagni S, Gutiérrez-Calderon V, Gonzalez-Cao M, Sandiego Contreras S, Koumarianou A, Bearz A, Bernabé-Caro R, Viteri S, de Sanmamed MF, Zagouri F, Morán Bueno T, Lazzari C, Martínez-Recio S, Giménez-Capitán A, Zhang Y, Shan Y, Zhu H, Zhao C, Shen H, Wang Y, Rosell R
BACKGROUND: Fulzerasib, a KRAS inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRAS inhibitor with an anti-EGFR antibody is effe...BACKGROUND: Fulzerasib, a KRAS inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRAS inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored. METHODS: This single-arm, phase 1b/2 trial enrolled patients at 30 medical centres in Spain, Italy, and Greece. Eligible patients had KRAS-mutated NSCLC with no previous systemic anti-tumour therapy for advanced or metastatic disease and were aged 18 years and older; had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; had an Eastern Cooperative Oncology Group performance status of 0 or 1; and had a life expectancy of 3 months or more. Enrolled patients received 600 mg oral fulzerasib twice daily plus 500 mg/m intravenous cetuximab every 2 weeks. The primary endpoint was investigator-assessed objective response rate per RECIST 1.1 assessed in the full response analysis set. The study was registered with ClinicalTrials.gov (NCT05756153) and is complete. FINDINGS: Between April 23, 2023, and April 15, 2024, a total of 60 patients were screened, and 47 patients (78%) received treatment. The median age was 68 years (IQR 59-72); 25 patients (53%) were male and 22 (47%) were female. 45 (95%) patients were current or former smokers. As of Jan 14, 2025, the median follow-up time and treatment duration were 12·8 months (90% CI 11·6-14·6) and 10·1 months (IQR 6·3-13·0) months, respectively. The confirmed objective response rate was 69% (90% CI 56-80). Treatment-related adverse events (TRAEs) occurred in 41 (87%) of the 47 patients (grade 3 in seven [15%]). No grade 4 or 5 TRAEs were observed. TRAEs led to drug discontinuation in three (6%) patients, with only cetuximab being discontinued. INTERPRETATION: In treatment-naive KRAS-mutated NSCLC, fulzerasib plus cetuximab showed encouraging activity with a favourable safety profile. The combination is currently being planned for investigation in a phase 3 study. FUNDING: Zhejiang GenFleet Therapeutics.
Lachenmeier DW, Arrandale VH, DeMarini DM
… +24 more, Ruksha T, Abdallah MA, Bettini G, Ishii Y, Ladeira C, Pi J, Rossner P, Ryan KR, Stefanska B, van Gerwen M, Venier M, de Conti A, Facchin C, Kunzmann AT, Madia F, Pasqual E, Wedekind R, Al Nahas A, Coutaz-Repland S, Ohene-Agyei P, Suonio E, Mattock H, Benbrahim-Tallaa L, Schubauer-Berigan MK
Lancet Oncol
· 2026 Mar · PMID 41911935
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