In a double-blind, randomized trial involving nearly 1000 patients followed for a median of 2 years, pembrolizumab injections for 1 year after surgery led to improved disease-free survival at 24 ...months as compared with placebo (77% vs. 68%). Almost one third of patients in the pembrolizumab group had a grade 3 adverse event, but no deaths were due to pembrolizumab.
Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We ...report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8
T cells from systemic circulation. Within the liver, activated antigen-specific Fas
CD8
T cells undergo apoptosis following their interaction with FasL
CD11b
F4/80
monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8
T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.
MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to ...compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.
We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.
Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6–12) than in the sunitinib group (5·6 months, 3–7; hazard ratio for progression or death 0·60, 0·37–0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.
Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.
National Institutes of Health and National Cancer Institute.
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is ...mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
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•CDK12 biallelic inactivating mutations define a distinct subtype of prostate cancer•CDK12 loss is associated with genomic instability and focal tandem duplications•CDK12 loss leads to increased gene fusions, neoantigen burden, and T cell infiltration•Patients with CDK12 mutant tumors may benefit from immune checkpoint inhibition
Loss of both alleles of the CDK12 gene defines a molecular subtype of metastatic castration-resistant prostate cancer that is potentially targetable with immune checkpoint inhibitors.
Background
CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis ...assesses the long‐term clinical benefits of nivolumab versus everolimus.
Methods
The randomized, open‐label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression‐free survival (PFS), safety, and health‐related quality of life (HRQOL).
Results
Eight hundred twenty‐one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow‐up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months 95% CI, 22.2‐29.8 months vs 19.7 months 95% CI, 17.6‐22.1 months; hazard ratio HR, 0.73; 95% CI, 0.62‐0.85) with 5‐year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 23% vs 17 of 411 4%; P < .001). PFS also favored nivolumab (HR, 0.84; 95% CI, 0.72‐0.99; P = .0331). The most common treatment‐related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with nivolumab but remained the same or deteriorated with everolimus.
Conclusions
The superior efficacy of nivolumab over everolimus is maintained after extended follow‐up with no new safety signals, and this supports the long‐term benefits of nivolumab monotherapy in patients with previously treated aRCC.
LAY SUMMARY
CheckMate 025 compared the effects of nivolumab (a novel immunotherapy) with those of everolimus (an older standard‐of‐care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy.
After 5 years of study, nivolumab continues to be better than everolimus in extending the lives of patients, providing a long‐lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
The results of the 5‐year follow‐up analysis of the CheckMate 025 trial demonstrate that the clinical benefits are sustained with nivolumab over everolimus in previously treated patients with advanced renal cell carcinoma in the long term. Overall survival, progression‐free survival, and objective response rate benefits are maintained with nivolumab versus everolimus, and more patients treated with nivolumab experience improved health‐related quality of life; meanwhile, the safety of nivolumab is manageable and compares favorably with that of everolimus.
Cross-sectional X-ray imaging has become the standard for staging most solid organ malignancies. However, for some malignancies such as urinary bladder cancer, the ability to accurately assess local ...extent of the disease and understand response to systemic chemotherapy is limited with current imaging approaches. In this study, we explored the feasibility that radiomics-based predictive models using pre- and post-treatment computed tomography (CT) images might be able to distinguish between bladder cancers with and without complete chemotherapy responses. We assessed three unique radiomics-based predictive models, each of which employed different fundamental design principles ranging from a pattern recognition method via deep-learning convolution neural network (DL-CNN), to a more deterministic radiomics feature-based approach and then a bridging method between the two, utilizing a system which extracts radiomics features from the image patterns. Our study indicates that the computerized assessment using radiomics information from the pre- and post-treatment CT of bladder cancer patients has the potential to assist in assessment of treatment response.
The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic ...alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported.
Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety.
Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label.
Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.
Cyclin-dependent kinase 12 (CDK12) loss occurs in 3–7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are ...not well established.
To determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.
A retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).
Patients were stratified by mutation status (CDK12, homologous recombination deficiency HRD; BRCA1/2 and ATM, TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.
The median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p = 0.004) and development of castration-resistant disease (median = 32.7 mo, p < 0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p = 0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.
Our data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.
In this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ≥8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.
We compared clinical characteristics of prostate cancer patients harboring cyclin-dependent kinase 12 (CDK12) mutations with those having canonical homologous recombination deficiency and TP53 mutations. CDK12-mutated cancers were more aggressive, with more Gleason ≥8 tumors, and with shorter time to development of metastasis and castration resistance.
Clinical trials have demonstrated higher complete response rates in the immuno-oncology-based combination arms than in the tyrosine kinase inhibitor arms in patients with metastatic renal cell ...carcinoma. We aimed to characterize real-world patients who experienced complete response to the contemporary first-line therapies.
Using the International Metastatic Renal Cell Carcinoma Database Consortium, response-evaluable patients who received frontline immuno-oncology-based combination therapy or tyrosine kinase inhibitor monotherapy were analyzed. Baseline characteristics of patients and post-landmark overall survival were compared based on best overall response, as per RECIST 1.1.
A total of 52 (4.6%) of 1,126 and 223 (3.0%) of 7,557 patients experienced complete response to immuno-oncology-based and tyrosine kinase inhibitor therapies, respectively (
005). An adjusted odds ratio for complete response achieved by immuno-oncology-based combination therapy (vs tyrosine kinase inhibitor monotherapy) was 1.56 (95% CI 1.11-2.17;
009). Among patients who experienced complete response, the immuno-oncology-based cohort had a higher proportion of non-clear cell histology (15.9% and 4.7%;
016), sarcomatoid dedifferentiation (29.8% and 13.5%;
014), and multiple sites of metastases (80.4% and 50.0%;
001) than the tyrosine kinase inhibitor cohort. Complete response was independently associated with post-landmark overall survival benefit in both the immuno-oncology-based and tyrosine kinase inhibitor cohorts, giving respective adjusted hazard ratios of 0.17 (95% CI 0.04-0.72;
016) and 0.28 (95% CI 0.21-0.38;
001).
The complete response rate was not as high in the real-world population as in the clinical trial population. Among those who experienced complete response, several adverse clinicopathological features were more frequently observed in the immuno-oncology-based cohort than in the tyrosine kinase inhibitor cohort. Complete response was an indicator of favorable overall survival.
Germline inactivation of the Von Hippel-Lindau (
) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic
mutations are ...also observed in patients with sporadic RCC. Loss of function
mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.
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