Novinky z X/Twitteru - výběr zajímavých recentních publikací a výsledků studií 12/23 - 1/24

Prevalence and Therapeutic Targeting of High Level ERBB2 Amplification in Non-Small Cell Lung Cancer

https://doi.org/10..../j.jtho.2023.12.019

• High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathological and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history, or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history.
• T-DXd is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification
• Two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy.

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer

https://www.nejm.or....1056/NEJMoa2303974

• A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P=0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.

Single-dose ¹⁷⁷Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial

https://doi.org/10....470-2045(23)00451-5

• In part A, patients were enrolled sequentially to one of three schedules in which a single dose of ¹⁷⁷Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule
• Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A, n=25 part B), with a median follow-up of 16·5 months (IQR 12·2–21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35–76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed.
• A single priming dose of ¹⁷⁷Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer.

Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism. A Randomized Clinical Trial

https://doi:10.1001/jamanetworkopen.2023.48692

• In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study’s findings may facilitate a more informed appraisal of the potential risks of TRT.

Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST)

https://doi.org/10.....annonc.2023.12.007

• Dynamic changes in circulating tumor DNA can be used to predict tumor response to therapeutic regimens in oncology.
• Liquid Biopsy Response Evaluation Criteria in Solid Tumors have been proposed and used in the context of clinical trials.
• promising approach is to incorporate dynamic changes in circulating tumor DNA (ctDNA), which occur early in the course of therapy and can predict tumor responses weeks before gross size changes manifest.
• Several challenges exist for clinical applicability and need to be addressed for a more standardized approach.

Association of Pancreatic Adenocarcinoma Location With DNA Damage Response Status and Response to Platinum-Based Therapy

https://ascopubs.or...10.1200/PO.22.00648

• Genomic alterations in the DNA DDR pathway were enriched in body and tail PDAC tumors (21.7% of 618) relative to head tumors (15.6% of 942)
• DDR pathway alterations including BRCA1/BRCA2/PALB2are known predictors of increased benefit from platinum-based chemotherapy. NGS testing for germline and somatic mutations remains important in pancreatic ductal adenocarcinoma, especially in BT tumors where DDR pathway alterations may be more common than in H tumors.
• mFOLFIRINOX may increas mPFS particularly in body and tail PDAC location

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial

https://ascopubs.or...0.1200/JCO.23.00339

• In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous next-generation hormonal agents.

Sotorasib in KRASp.G12C mutated advanced NSCLC: Real-world data from the Italian expanded access program

https://doi.org/10....lungcan.2023.107444

• G12C mutation is a druggable target in advanced NSCLC.
• Sotorasib is the first in class KRASp.G12C inhibitor approved in clinical practice.
• Sotorasib efficacy and tolerability in the real-word setting were similar to the CodeBreak200 trial.
• Sotorasib has intracranial activity but multidisciplinary management of brain metastasis is recommeded.
• The Italian ATLAS registry is a reliable source of NSCLC patients real-word evidence.
• Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients

Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study

https://ascopubs.or...10.1200/PO.23.00385

• Thirty-one patients with solid tumors with BRAFmutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a disease control rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an overal response rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥ one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury.
• Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAFV600E mutations.

2023 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting

https://link.spring.../s00520-023-08224-1

• The recommendations for patients receiving high-dose chemotherapy with stem cell transplants and patients undergoing multiple-day cisplatin were updated. For patients receiving high-dose chemotherapy for stem cell transplant, a combination of a 5-HT₃receptor antagonist with dexamethasone and aprepitant is recommended. Olanzapine could be considered part of the antiemetic regimen. Patients receiving multiple-day cisplatin should receive a 5-HT₃ receptor antagonist plus dexamethasone plus aprepitant plus olanzapine. For patients experiencing breakthrough nausea and vomiting, the available evidence suggests using a single dose of olanzapine daily for 3 days.

Precision medicine for KRAS wild-type pancreatic adenocarcinomas

https://doi.org/10..../j.ejca.2023.113497

• Compared toKRAS_m patients, KRAS_WT patients have higher survival rates.
• Liver is a less frequent metastatic site inKRAS_WT PDAC patients.
• KRAS_WTPDAC patients harbor more actionable molecular alterations.
• KRAS_WTPDAC patients receiving molecularly-matched treatments have longer survival.
• Precision medicine is an efficient approach forKRAS_WT PDAC patients.

Risk factors for early-onset pancreatic ductal adenocarcinoma: A systematic literature review

https://pubmed.ncbi...m.nih.gov/38154392/

• Potential non-heritable risk factors for early-onset PDAC included smoking, alcohol consumption, pancreatitis and hepatitis B infection.

Prognostic impact of TP53 mutations in metastatic non-squamous non-small-cell lung cancer

https://doi.org/10..../j.cllc.2023.12.004

• Patients with TP53 mutation benefit more of immunotherapy alone than wild-type patients.
• We found similar outcomes in patients treated with chemotherapy alone or combined to immunotherapy.
• Survival outcomes of patients without TP53 mutation improved with the addition of chemotherapy to immunotherapy.

Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical CancerSubgroup Analyses from the KEYNOTE-826 Randomized Clinical Trial

https://jamanetwork...le-abstract/2813178

• A total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior chemoradiotherapy only (HR, 0.56; 95% CI, 0.39-0.81) and without prior chemoradiotherapy only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type.
• In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior chemoradiotherapy only (HR, 0.64; 95% CI, 0.45-0.91) and without prior chemoradiotherapy only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type.
• Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations.
• The findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer.

Response-guided neoadjuvant sacituzumab govitecan for localized triple negative breast cancer: results from the NeoSTAR trial

https://doi.org/10.....annonc.2023.11.018

• Neoadjuvant treatment with sacituzumab govitecan for localized TNBC is safe and feasible
• Approximately 2/3 of patients responded to neoadjuvant SG alone, and 30% achieved pCR without additional chemotherapy.
• Higher Ki-67 and TILs were predictive of pCR to SG, while TROP2 expression was not.
• In the first NA trial with an ADC in localized TNBC, SG demonstrated single-agent efficacy and feasibility of response-guided escalation/de-escalation. Further research on optimal duration of SG as well as NA combination strategies, including immunotherapy, are needed.

Disease-Free Survival of Patients With Muscle-Invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder-Preserving Therapy: A Nationwide Study

https://doi.org/10.....ijrobp.2023.07.027

• A total of 1432 patients were included, of whom 1101 underwent radical cystectomy (RC) and 331, bladder-preserving therapy (BPT). Median follow-up was 39 months (range, 27-51 months). The IPTW-adjusted 2-year DFS was 61.5% (95% CI, 53.5%-69.6%) with BPT and 55.3% (95% CI, 51.6%-59.1%) with RC, with an adjusted hazard ratio of 0.84 (95% CI, 0.69-1.05). The adjusted 2-year OS for patients treated with BPT versus RC was 74.0% (95% CI, 67.0%-80.9%) versus 66.0% (95% CI, 62.7%-68.8%), respectively, with an adjusted hazard ratio of 0.80 (95% CI, 0.64-0.98).
• There was no statistically significant difference between the 2-year DFS of patients treated with BPT and RC. We propose that both RC and BPT should be offered as a curative treatment option to eligible patients with nonmetastatic MIBC.

MRI in addition to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO): an international, multicentre, prospective, diagnostic accuracy trial

https://doi.org/10....470-2045(23)00572-7

• Between Dec 17, 2019, and July 31, 2021, 325 patients with colorectal liver metastases were assessed for eligibility. 298 patients were enrolled and included in the intention-to-treat population, including 177 males (59%) and 121 females (41%) with planned local therapy based on contrast-enhanced CT. A change in the local treatment plan based on liver contrast-enhanced MRI findings was observed in 92 (31%; 95% CI 26–36) of 298 patients. Changes were made for 40 patients (13%) requiring more extensive local therapy, 11 patients (4%) requiring less extensive local therapy, and 34 patients (11%) in whom the indication for curative-intent local therapy was revoked, including 26 patients (9%) with too extensive disease and eight patients (3%) with benign lesions on liver contrast-enhanced MRI (confirmed by a median follow-up of 21·0 months [IQR 17·5–24·0]).
• Liver contrast-enhanced MRI should be considered in all patients scheduled for local treatment for colorectal liver metastases on the basis of contrast-enhanced CT imaging.

Combination therapies in patients with favorable risk metastatic renal cell Carcinoma: A Systematic Review and Meta-Analysis

https://doi.org/10..../j.ctrv.2023.102667

• The efficacy of IO-based combination therapies in patients with IMDC favorable risk remains unclear.
• IO plus TKI combination was associated with a risk reduction in disease progression.
• Objective response rates were higher with IO-TKI combination.
• Combination treatment did not have an OS benefit.
• In patients with favorable risk metastatic renal cell carcinoma, there's a need for biomarkers to identify those who would benefit from monotherapy or combination therapy.

Childhood and adulthood passive and active smoking, and the ABO group as risk factors for pancreatic cancer in women

https://doi.org/10.1002/ueg2.12487

• During a 24-year median follow-up, 346 incident pancreatic cancer (PC) cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08–2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08–2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91–1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42–5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10–2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B blood groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant.

Atezolizumab and bevacizumab for non-resectable or metastatic combined hepatocellular-cholangiocarcinoma: A multicentric retrospective study

https://doi.org/10.1002/ueg2.12503

• Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13 months and a median PFS of 3 months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease.
• The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA.

Primary analysis from the phase III, randomized INAVO-120 trial

https://www.targete...tated-breast-cancer

• Inavolisib + palbo + fulvestrant in PIK3CAmut HR+/HER2- with PD within 12 months of adj. ET was associated with significant PS 15 vs. 7.3 monts, HR 0.43

Pregnancy After Breast Cancer in Young BRCA CarriersAn International Hospital-Based Cohort Study

https://jamanetwork...le-abstract/2812828

• In this global study, 1 in 5 young BRCAcarriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

https://www.nejm.or...query=featured_home

• patients with chemorefractory metastatic colorectal cancer with mutated KRASG12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator’s choice of trifluridine–tipiracil or regorafenib (standard care; 54 patients). 
• After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib–panitumumab and 240-mg sotorasib–panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib–panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P=0.006), and the hazard ratio in the 240-mg sotorasib–panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P=0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib–panitumumab, 240-mg sotorasib–panitumumab, and standard-care groups, respectively.

Utility of Tumor Mutational Burden as a Biomarker for Response to Immune Checkpoint Inhibition in the VA Population

https://ascopubs.or...10.1200/PO.23.00176

• Overall survival (OS) was significantly longer for patients with TMB-H versus TMB low tumors in non–small-cell lung cancer (NSCLC; n = 1,593), head and neck (H&N) cancer (n = 222), and urothelial cancer (n = 332). OS was not significantly different based on TMB status in melanoma (n = 207) or esophageal/gastric cancer (n = 248).
• Consistent with previous studies, a predictive value of TMB ≥10 mut/Mb for ICI response was found in NSCLC and H&N, but not in esophageal/gastric cancer. Although inconclusive in the literature, significant association was found in urothelial cancer. The predictive value of TMB in melanoma was inconclusive. Our analysis does not support the use of a fixed threshold for TMB as a standalone predictive biomarker for ICI across all solid tumors.

Insomnia in adult patients with cancer: ESMO Clinical Practice Guideline

https://doi.org/10.....esmoop.2023.102047

• Insomnia is common in patients with cancer, with a higher prevalence than observed in the general population.
• Insomnia is often under-recognised and inadequately treated in patients with cancer.
• Brief validated screening tools are available for the evaluation of insomnia in clinical practice.
• First-line therapy should be based on international guidelines recommending cognitive behavioural therapy for insomnia.
• This Clinical Practice Guideline presents an up-to-date, evidence-based approach to assessing and managing insomnia disorder in patients with cancer and cancer survivors. The authors followed the levels of evidence and grades of recommendation as detailed in the ‘Methodology’ section.

First line talazoparib plus enzalutamide in HRR-deficient metastatic castration resistant prostate cancer: the phase 3 TALAPRO-2 trial

https://www.nature..../s41591-023-02704-x

• Median progression-free survival not reached in talazoparib group vs. 13.8 months in control, HR 0.45.
• Overall survival data remain immature, early signs are hopeful, HR 0.69
• Patients with BRCA1/2 alteration had an 80% lower risk of radiographic progression or death, HR 0.20

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial

https://doi.org/10....470-2045(23)00531-4

• 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46–57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0–14·5). An objective response was noted in 83 (98% [95% CI 92–100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. 
• Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer.

Translating immuno-onco-microbiome-based therapeutics: precision bugs for immune checkpoint drugs

https://doi.org/10.....annonc.2023.03.002

• In pursuit of augmenting responses, several ICI combination therapy approaches are being attempted that include combinations with targeted therapy (ICI+ v-Raf murine sarcoma viral oncogene homolog B inhibitor therapy in melanoma), with other immune checkpoints (PD-1 + cytotoxic T-lymphocyte-associated protein 4 or PD-1 + lymphocyte-activation gene 3), with anti-vascular endothelial growth factor (VEGF) therapies (ICI + bevacizumab, or ICI + multi-kinase VEGF inhibitors like lenvatinib), with chemotherapy (ICI + carboplatin + pemetrexed), other immune-modulating agents (cancer vaccines, adoptive cell transfer, and cytokines), and with radiotherapy for the abscopal effect.
• Beyond these strategies, microbiome-based interventions like fecal microbiota transplantation (FMT) or addition of probiotics can also amplify the immune system by altering the gut microbiome and boost the antitumor response to ICI.