Real-world data on cabozantinib in metastatic renal cell carcinoma (mRCC) is limited. This study (CABOREAL) reports treatment patterns and outcomes for patients treated with cabozantinib through the ...French Early Access Program.
This multicentre (n = 26), observational, retrospective study enrolled patients with mRCC who had received ≥1 dose of cabozantinib. Overall survival (OS) was estimated using the Kaplan–Meier method; subgroups were compared using the log-rank test. A multiple Cox regression model assessed predictive factors of OS after cabozantinib initiation.
Four hundred and ten recruited patients started treatment between September 2016 and February 2018: the Eastern Cooperative Oncology Group Performance Status ≥2, 39.3%; poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 31.7%; 0–1, 2 and ≥3 previous treatment lines, 25.3%, 33.4% and 41.2%, respectively; bone metastases, 55.9%; brain metastases, 16.8%. Median (min–max) follow-up was 14.4 (0–30) months. Overall, 57.0% of patients had a dose reduction, 15.6% an alternative dose schedule. The median average daily dose was 40.0 mg. Median (quartile Q1–Q3) treatment duration was 7.6 (0.1–29.1) months, median OS was 14.4 months, and the 12-month OS rate was 56.5% (95% confidence interval: 51.5–61.2). Most patients (54.4%) received subsequent treatment. Predictive factors associated with longer OS were body mass index ≥25 kg/m2 (p = 0.0021), prior nephrectomy (p = 0.0109), favourable or intermediate IMDC risk (p < 0.0001) and cabozantinib initiation at 60 mg/day (p = 0.0486).
In the largest real-world study to date, cabozantinib was effective in unselected, heavily pretreated patients with mRCC. Initiation at 60 mg/day was associated with improved outcomes.
NCT03744585.
•CABOREAL is the largest real-world study of cabozantinib in metastatic renal cell carcinoma to date.•Cabozantinib was effective in these unselected, heavily pretreated patients.•Patients received cabozantinib for a median duration of 7.6 months.•Dose modifications were necessary in 59% of patients, mainly to manage adverse events.•Initiation of cabozantinib at 60 mg/day was associated with improved outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Until recently, immunotherapy has been the standard of care for patients with nonresectable metastatic renal cell carcinoma (mRCC); however, immunotherapy is associated with a low response rate and ...significant toxicity. Because of their demonstrated ability to prolong progression-free survival, agents targeting vascular endothelial growth factor receptors or the mammalian target of rapamycin now have become standard therapies for patients with mRCC. Attaining lasting clinical benefits, however, requires multiple lines of therapy. This case study reports the case of a 52-year-old man with mRCC who remained free of disease progression for 48 months while receiving sequential therapy of sunitinib, everolimus, sorafenib, and temsirolimus.
Summary Background Early risk-stratified chemotherapy is a standard treatment for breast, colorectal, and lung cancers, but not for high-risk localised prostate cancer. Combined docetaxel and ...estramustine improves survival in patients with castration-resistant prostate cancer. We assessed the effects of combined docetaxel and estramustine on relapse in patients with high-risk localised prostate cancer. Methods We did this randomised phase 3 trial at 26 hospitals in France. We enrolled patients with treatment-naive prostate cancer and at least one risk factor (ie, stage T3–T4 disease, Gleason score of ≥8, prostate-specific antigen concentration >20 ng/mL, or pathological node-positive). All patients underwent a staging pelvic lymph node dissection. Patients were randomly assigned (1:1) to either androgen deprivation therapy (ADT; goserelin 10·8 mg every 3 months for 3 years) plus four cycles of docetaxel on day 2 at a dose of 70 mg/m2 and estramustine 10 mg/kg per day on days 1–5, every 3 weeks, or ADT only. The randomisation was done centrally by computer, stratified by risk factor. Local treatment was administered at 3 months. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was relapse-free survival in the intention-to-treat population. Follow-up for other endpoints is ongoing. This study is registered with ClinicalTrials.gov , number NCT00055731. Findings We randomly assigned 207 patients to the ADT plus docetaxel and estramustine group and 206 to the ADT only group. Median follow-up was 8·8 years (IQR 8·1–9·7). 88 (43%) of 207 patients in the ADT plus docetaxel and estramustine group had an event (relapse or death) versus 111 (54%) of 206 in the ADT only group. 8-year relapse-free survival was 62% (95% CI 55–69) in the ADT plus docetaxel and estramustine group versus 50% (44–57) in the ADT only group (adjusted hazard ratio HR 0·71, 95% CI 0·54–0·94, p=0·017). Of patients who were treated with radiotherapy and had data available, 31 (21%) of 151 in the ADT plus docetaxel and estramustine group versus 26 (18%) of 143 in the ADT only group reported a grade 2 or higher long-term side-effect (p=0·61). We recorded no excess second cancers (26 13% of 207 vs 22 11% of 206; p=0·57), and there were no treatment-related deaths. Interpretation Docetaxel-based chemotherapy improves relapse-free survival in patients with high-risk localised prostate cancer. Longer follow-up is needed to assess whether this benefit translates into improved metastasis-free survival and overall survival. Funding Ligue Contre le Cancer, Sanofi-Aventis, AstraZeneca, Institut National du Cancer.
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Summary Background Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition ...of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer. Methods In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m2 intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00104715. Findings Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39–63). Median overall survival was 58·9 months (95% CI 50·8–69·1) in the group given ADT plus docetaxel and 54·2 months (42·2–not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75–1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 21%), febrile neutropenia (six 3%), abnormal liver function tests (three 2%), and neutropenia with infection (two 1%). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group. Interpretation Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer. Funding French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.
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Three drug combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi), and avelumab-axitinib (Ave-Axi), have received regulatory approval in the USA and Europe for the ...treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in a first-line setting. We conducted a systematic search in PubMed, the Cochrane Library, and clinicaltrials.gov for any randomized controlled trials of treatment-naïve patients with mRCC, from January 2015 to October 2019. The process was performed according to PRISMA guidelines. We performed a Bayesian network meta-analysis with two different approaches, a contrast-based model comparing HRs and ORs between studies and arm-based using parametric modeling. The outcomes for the analysis were overall survival, progression-free survival (PFS), and objective response rate. Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA = 83%) and Pembro-Axi (SUCRA = 80%) exhibited the best ranking probabilities for PFS. For overall survival (OS), Pembro-Axi (SUCRA = 96%) was the most preferable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA: 94%) and Pembro-Axi as the second best option. In the parametric models, the risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterwards. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Overall evidence suggests that pembrolizumab plus axitinib seems to have a slight advantage over the other two combinations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
To the best of our knowledge, this study is the first to compare dual inhibition of PI3K/mammalian target of rapamycin (mTOR) by apitolisib (GDC-0980) against single inhibition of mTORC1 by ...everolimus in metastatic renal cell carcinoma (mRCC).
Patients with clear-cell mRCC who progressed on or after vascular endothelial growth factor-targeted therapy were randomly assigned to apitolisib 40 mg once per day or to everolimus 10 mg once per day. End points included progression-free survival, safety, overall survival, and objective response rate. Biomarker assessments were conducted.
Eighty-five patients were randomly assigned. After 67 events, stratified analysis revealed that median progression-free survival was significantly shorter for apitolisib than for everolimus (3.7 v 6.1 months; hazard ratio, 2.12 95% CI, 1.23 to 3.63; P < .01); apitolisib was not favored in any stratification subgroup. Median overall survival was not significantly different but trended in favor of everolimus (16.5 v 22.8 months; hazard ratio, 1.77 95% CI, 0.97 to 3.24; P = .06). The objective response rate was 7.1% for apitolisib and 11.6% for everolimus. Patients administered apitolisib with a greater incidence of grade 3 to 4 adverse events were more likely to discontinue treatment (31% v 12% for everolimus). No drug-related deaths were observed. Apitolisib in comparison with everolimus was associated with substantially more high-grade hyperglycemia (40% v 9%) and rash (24% v 2%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High hypoxia-inducible factor 1α protein expression was associated with better outcome in both arms.
This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than was everolimus in mRCC, likely because full blockade of PI3K/mTOR signaling resulted in multiple on-target adverse events. VHL mutation and hypoxia-inducible factor 1α expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required.
Primary tumour response may impact therapeutic strategies in metastatic renal cell carcinoma (mRCC) but remains unknown in the era of immune checkpoint inhibitors. We aimed to describe the response ...of the primary tumour in patients who did not undergo upfront cytoreductive nephrectomy (uCN) and were treated with nivolumab in the GETUG-AFU-26 NIVOREN phase 2 trial. Primary tumour response was prospectively assessed, as well as the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Among 720 patients, 111 did not undergo uCN, mainly patients with intermediate (45%) and poor (49%) International mRCC Database Consortium (IMDC) risk. In the 111 patients, nivolumab was used in the second line for 63% of patients and the third line or more for 37%, with an ORR of 16% (95% confidence interval CI 1025%); with a median follow-up of 24.5 mo (95% CI 21.6–27.1), median PFS was 2.7 mo (95% CI 2.5–4.0) and median OS was 15.9 mo (95% CI 9.5–19.8). A total of 67 patients had an evaluable primary renal lesion, four of whom (6%) experienced shrinkage of more than 30%. Overall, patients who did not undergo uCN had adverse baseline characteristics and nivolumab activity against the primary tumour was limited.
In this report, we observed that nivolumab was associated with a limited response of the primary tumour in previously treated patients with metastatic kidney cancer.
Nivolumab showed limited activity on the primary renal tumour in patients with metastatic renal cell carcinoma who already failed previous systemic therapy. Evidence of long-term responses suggest feasibility of surgical approaches on a case-by-case basis. Ongoing trials with immunotherapy combinations may reveal potential for perioperative strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises ...normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour.
To validate and clinically qualify plasma lpWGS for mCRPC.
Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study).
lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments.
Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08–2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss.
Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further.
We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a “genetic scar” in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes.
Tumour fraction, independent from cell-free DNA concentration and other clinical variables, is prognostic, with low-pass whole-genome sequencing profiles detecting abiraterone/enzalutamide-induced emerging genomic instability that is likely to be acquired as a result of tumour development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • Five antiangiogenic drugs are recommended as initial treatment of metastatic renal cell carcinoma patients. • The meta-analysis highlights that sunitinib, pazopanib, axitinib and ...bevacizumab + interferon alpha-2a yield a similar survival benefit but are associated with different safety profiles. • These results may provide guidance to optimize treatment choices.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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