The Christie School of Oncology: Christie Research Publications Repository
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First-line tislelizumab plus chemotherapy for esophageal squamous cell carcinoma with programmed death-Ligand 1 expression ≥ 1%: a retrospective analysis of RATIONALE-306
No full textINTRODUCTION: The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against the use of programmed cell death protein-1 inhibitors for first-line treatment of advanced or metastatic unresectable esophageal squamous cell carcinoma (ESCC) with a programmed death-ligand 1 (PD-L1) expression Tumor Area Positivity (TAP) score < 1% or combined positive score < 1 due to an unfavorable benefit-risk profile observed across the phase 3 CheckMate 648, KEYNOTE-590, and RATIONALE-306 trials. Therefore, we conducted a retrospective analysis of RATIONALE-306 to evaluate the efficacy and safety of tislelizumab plus investigator-chosen chemotherapy (ICC) versus placebo plus ICC in patients with advanced or metastatic unresectable ESCC and a PD-L1 TAP score ≥ 1%. METHODS: Adult patients with advanced or metastatic unresectable ESCC enrolled in the global, randomized, phase 3 RATIONALE-306 trial randomly received tislelizumab 200 mg every 3 weeks plus ICC or matched placebo plus ICC. Efficacy and safety outcomes were evaluated among patients who were retrospectively assessed for PD-L1 expression defined by a TAP score ≥ 1%. RESULTS: At primary analysis data cutoff (February 28, 2022), a clinically meaningful improvement in median overall survival was observed among 230 patients in the tislelizumab plus ICC arm {16.8 [95% confidence interval (CI) 15.3-20.8] months} versus 248 patients in the placebo plus ICC arm [9.6 (95% CI 8.9-11.8) months] [stratified hazard ratio 0.64 (95% CI 0.51-0.80)]; this was maintained at a 3-year follow-up data cutoff (November 24, 2023). Similar findings at primary analysis were observed for progression-free survival, objective response rate, disease control rate, and duration of response. Tislelizumab plus ICC was tolerable and no new safety signals were observed. CONCLUSIONS: Tislelizumab plus ICC is an effective and well tolerated first-line treatment option for patients with advanced or metastatic unresectable ESCC and a tumor PD-L1 TAP score ≥ 1%. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03783442
External validation of deep learning-derived 18F-FDG PET/CT delta biomarkers for loco-regional control in head and neck cancer
No full textBACKGROUND AND PURPOSE: Delta biomarkers that reflect changes in tumour burden over time can support personalised follow-up in head and neck cancer. However, their clinical use can be limited by the need for manual image segmentation. This study externally evaluates a deep learning model for automatic determination of volume change from serial 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans to stratify patients by loco-regional outcome. Patient/material and methods: An externally developed deep learning algorithm for tumour segmentation was applied to pre- and post-radiotherapy (RT, with or without concomitant chemoradiotherapy) PET/CT scans of 50 consecutive head and neck cancer patients from The Christie NHS Foundation Trust, UK. The model, originally trained on pre-treatment scans from a different institution, was deployed to derive tumour volumes at both time points. The AI-derived change in tumour volume (ΔPET-Gross tumour volume (GTV)) was calculated for each patient. Kaplan-Meier analysis assessed loco-regional control based on ΔPET-GTV, dichotomised at the cohort median. In a separate secondary analysis confined to the pre‑treatment scans, a radiation oncologist qualitatively evaluated the AI‑generated PET‑GTV contours. RESULTS: Patients with higher ΔPET-GTV (i.e. greater tumour shrinkage) had significantly improved loco-regional control (log-rank p = 0.02). At 2 years, control was 94.1% (95% CI: 83.6-100%) vs. 53.6% (95% CI: 32.2-89.1%). Only one of nine failures occurred in the high ΔPET-GTV group. Clinician review found AI volumes acceptable for planning in 78% of cases. In two cases, the algorithm identified oropharyngeal primaries on pre-treatment PET-CT before clinical identification. INTERPRETATION: Deep learning-derived ΔPET-GTV may support clinically meaningful assessment of post-treatment disease status and risk stratification, offering a scalable alternative to manual segmentation in PET/CT follow-up
629. AGGRESSIVE LYMPHOMAS, IMMUNOTHERAPY INCLUDING BISPECIFIC ANTIBODIES Epcoritamab (epcor) monotherapy offers long-term disease control in large B-cell lymphoma (LBCL): NHL-1 subgroup analysis in patients with prior chimeric antigen receptor T-cell (CAR T) therapy from the 3-year follow-up
No full textPathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry
No full textProstate cancer (PCa) germline testing, while gaining momentum, is ancestry restrictive and African exclusive. Through whole genome sequencing for 217 African ancestral cases (186 southern African, 31 Pan representative), we identify 172 potentially pathogenic variants in 78 DNA damage repair or PCa related genes. Prevalence for reported (13/217, 5.99%) and cumulative predicted (24/217, 11.06%) variants of significance (11 genes) falls below that reported for non-Africans. Conversely, BRCA1, HOXB13, CDK12, MLH1, MSH2, and BRIP1 remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B and ATM. Besides notable impact of DNA polymerases, including POLG, Fanconi anaemia genes include FANCD2, FANCA, FANCG, ERCC4, FANCE and FANCI, while DNA mismatch repair genes MSH3 and PMS1 outranked known namesakes MSH6 and PMS2. This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing
Safety and efficacy of combining midostaurin and gemtuzumab ozogamicin with induction chemotherapy in FLT3-mutated AML
No full textDespite the use of FMS-like tyrosine kinase 3 (FLT3) inhibitors, outcomes for patients with FLT3-mutated (FLT3(mut)) acute myeloid leukemia (AML) remain suboptimal because of high rates of relapse. We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO), and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3(mut) AML in the UK National Cancer Research Institute AML19 trial. A total of 195 patients were randomized to receive DA with either 1 or 2 doses of GO (DAGO1 and DAGO2). Overall, 77 had an FLT3 mutation and received midostaurin for 2 weeks after each chemotherapy course and then as maintenance for 1 year unless they received a transplant. A total of 39 patients received DAGO1+m and 38 DAGO2+m. Their median age was 51 years (range, 20-74), and 16 (20%) were aged >60 years. The overall response rate was 91%. Day 60 mortality was 0%, with no increase in toxicity compared with patients treated contemporaneously with DAGO1 and DAGO2 without midostaurin. Two-year overall survival was 77%. Two-year event-free survival and cumulative incidence of relapse were 62% and 31%, respectively. Measurable residual disease (MRD) clearance was enhanced compared with patients with FLT3(mut) AML treated with DAGO without midostaurin. Overall, 81% of evaluable patients were NPM1 MRD negative in the peripheral blood after course 2 (76% with DAGO1+m, and 86% with DAGO2+m), 79% were MRD negative in the bone marrow by FLT3-ITD next-generation sequencing, and all patients had FLT3-MRD levels <0.01%. DAGO+m appears safe and effective. DAGO2+m will now be evaluated in a randomized study. This trial was registered at www.isrctn.com as #ISRCTN78449203
Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial
No full textOBJECTIVES: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23%) and 29 (17%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30% was two-fold higher with sotorasib than docetaxel (33.3% vs 15.4%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population. CONCLUSIONS: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population. CLINICAL TRIALS REGISTRATION NUMBER: NCT04303780
Hypo-fractionated radiotherapy to the cavity for resected brain metastases: a UK series
No full textAIMS: With improved systemic disease control, the incidence of brain metastases in patients with cancer is increasing. Neurosurgical resection is recommended in selected cases, although local control following surgery remains an ongoing concern. Both fractionated radiotherapy and stereotactic radiosurgery (SRS) improve local control after surgical resection. Although postoperative SRS can avoid whole brain radiotherapy-associated toxicity, due to lack of survival and quality of life data, the optimum strategy remains debated. Furthermore, some cavities may be too large for SRS. MATERIALS AND METHODS: In this multicentre study, patients following surgery for brain metastases were treated with a hypo-fractionated radiotherapy regimen (25Gy given in 5 fractions/30Gy in 6 fractions) to the surgical cavity. RESULTS: Sixty-five patients were identified from electronic patient notes with a median follow-up of 23.6 months (95% CI: 20.1-28.6). The 6-, 12-, 24- and 36-month freedom from local failure rates were 92.7% (95% CI: 81.7-97.2%), 77.3% (95% CI: 61.0-87.4%) and 70.6% (both 24- and 36-months, 95% CI: 52.9-82.5%), respectively. The 6-, 12- and 24-month overall survival rates were 80.0% (95% CI: 68.0-87.9%), 53.7% (95% CI: 40.6-65.2%) and 27.7% (95% CI: 16.0-40.7%), respectively. During follow-up, 10.8% (7/65 patients) developed leptomeningeal disease (LMD) and 3% (2/65 patients) developed radiation necrosis (RN). Treatment with hypo-fractionated radiotherapy to the surgical cavity was well tolerated; there was one episode of grade 3 toxicity (vomiting) in this patient cohort. CONCLUSION: In this multicentre series of postoperative hypo-fractionated radiotherapy to the surgical cavity following resection of a brain metastasis, we demonstrated good rates of local control, with low risk of LMD and RN. Therefore, this radiotherapy regimen is a reasonable alternative to cavity SRS in patients with large cavity volumes or complete gross total resection within the UK. This should be investigated further within a prospective trial
Corrigendum to 'Electrochemotherapy for cutaneous Kaposi Sarcoma: a European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT)'
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