A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 ...(PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.
In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.
Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio HR 0·74 95% CI 0·57–0·96; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76–1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3–4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.
Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.
F Hoffmann–La Roche Ltd and Genentech Inc.
PI3K-Akt-mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We ...therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC.
Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors.
rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths.
In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.
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In a randomized trial involving previously untreated patients with metastatic intermediate- or poor-risk renal-cell cancer, nivolumab plus ipilimumab was associated with higher response rates, longer ...overall survival, and greater improvement in quality of life than sunitinib.
•Why: in the HRD condition PARP inhibition promotes an interactive mechanism, defined “synthetic lethality” phenomenon, which is now the cornerstone of targeting DDR pathways in cancer ...treatment;•What: DDR pathway somatic alterations were detected in about 20% of mCRPC (germline 7%), and BRCA1-2 and ATM are the most frequent affected genes;•Where: the most appropriate could be fresh tumor tissue, compared with fixed tumor tissue or ctDNA; however, integrating of both approaches may be the preferred choice when available;•When: patients with a positive family history for cancer, patients with known DDR mutations in family (eg, BRCA2), patients with metastatic PC (even if negative family history) should be tested;•Who: FDA approved olaparib and rucaparib for mCRPC with HRR gene mutations (germline or somatic) following treatment with androgen-receptor-targeting agents;
DNA–damage repair (DDR) pathways alterations, a growing area of interest in oncology, are detected in about 20% of patient with prostate cancer and are associated with improved sensitivity to poly(ADP ribose) polymerases (PARP) inhibitors. In May 2020, the Food and Drug Administration (FDA) approved two PARP inhibitors (olaparib and rucaparib) for prostate cancer treatment. Moreover, germline aberrations in DDR pathways genes have also been related to familial or hereditary prostate cancer, requiring tailored health-care programs. These emerging scenarios are rapidly changing diagnostic, prognostic and therapeutic approaches in prostate cancer management. The aim of this review is to highlight the five W-points of DDR pathways in prostate cancer: why targeting DDR pathways in prostate cancer; what we should test for genomic profiling in prostate cancer; “where” testing genetic assessment in prostate cancer (germline or somatic, solid or liquid biopsy); when genetic testing is appropriate in prostate cancer; who could get benefit from PARP inhibitors; how improve patients outcome with combinations strategies.
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell ...carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.
In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months IQR 13·4–36·3), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached 95% CI 35·6–not estimable vs 26·6 months 22·1–33·4; hazard ratio HR 0·66 95% CI 0·54–0·80, p<0·0001), progression-free survival (median 8·2 months 95% CI 6·9–10·0 vs 8·3 months 7·0–8·8; HR 0·77 95% CI 0·65–0·90, p=0·0014), and the proportion of patients achieving an objective response (178 42% of 425 vs 124 29% of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached 95% CI not estimable vs 37·9 months 32·2–not estimable; HR 0·71 95% CI 0·59–0·86, p=0·0003), progression-free survival (median 9·7 months 95% CI 8·1–11·1 vs 9·7 months 8·3–11·1; HR 0·85 95% CI 0·73–0·98, p=0·027), and the proportion of patients achieving an objective response (227 41% of 550 vs 186 34% of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 10% of 547), increased amylase (31 6%), and increased alanine aminotransferase (28 5%), whereas in the sunitinib group they were hypertension (90 17% of 535), fatigue (51 10%), and palmar-plantar erythrodysaesthesia (49 9%). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.
The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.
Bristol-Myers Squibb and ONO Pharmaceutical.
We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive ...metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. ...Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss.
We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238.
Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo–abiraterone group and 547 (50%) to the ipatasertib–abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0–33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo–abiraterone group and 260 in the ipatasertib–abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9–17·0) in the placebo–abiraterone group and 18·5 months (16·3–22·1) in the ipatasertib–abiraterone group (hazard ratio HR 0·77 95% CI 0·61–0·98; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6–19·1) in the placebo–abiraterone group and 19·2 months (16·5–22·3) in the ipatasertib–abiraterone group (HR 0·84 95% CI 0·71–0·99; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo–abiraterone group and in 386 (70%) of 551 patients in the ipatasertib–abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo–abiraterone group and 116 (21%) in the ipatasertib–abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction n=1 and lower respiratory tract infection n=1) in the placebo–abiraterone group and in two patients (<1%; hyperglycaemia n=1 and chemical pneumonitis n=1) in the ipastasertb–abiraterone group.
Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis.
F Hoffmann-La Roche and Genentech.
In the so-called “antiangiogenic era” of recent years, a number of targeted therapies have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Emerging information about the ...immunological features of mRCC and the immunomodulating properties of antiangiogenic agents, one of the standard treatments for mRCC, indicates that a more rational design of potentially synergistic combinations should be pursued. Indeed, immunotherapy has undergone a resurgence in clinical practice. In this narrative review, we discuss the immunological features of mRCC and the potential interactions that antiangiogenic agents may also exert on host immunity and tumor immunogenicity, possibly working on both sides of this complex cross-talk. Hence, the recall to Gianus, the ancient two-faced Roman God who was looking both at the future and the past. Treatment strategies will be also critically discussed.
A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor ...receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.
Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.
The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio HR, 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥ 5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).
These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib.
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