-
The New England Journal of Medicine Mar 2019The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.
METHODS
In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
RESULTS
After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.
CONCLUSIONS
Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Humans; Intention to Treat Analysis; Kidney Neoplasms; Male; Middle Aged; Programmed Cell Death 1 Receptor; Progression-Free Survival; Single-Blind Method; Sunitinib; Survival Rate
PubMed: 30779529
DOI: 10.1056/NEJMoa1816714 -
The New England Journal of Medicine Mar 2019In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.
METHODS
We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.
RESULTS
A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.
CONCLUSIONS
Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).
Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Programmed Cell Death 1 Receptor; Progression-Free Survival; Single-Blind Method; Sunitinib; Survival Rate
PubMed: 30779531
DOI: 10.1056/NEJMoa1816047 -
The Lancet. Oncology Dec 2020The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.
BACKGROUND
The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.
METHODS
In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.
FINDINGS
Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.
INTERPRETATION
With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.
FUNDING
Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Carcinoma, Renal Cell; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Sunitinib; Time Factors
PubMed: 33284113
DOI: 10.1016/S1470-2045(20)30436-8 -
European Urology Nov 2023Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced...
Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma.
Topics: Humans; Carcinoma, Renal Cell; Axitinib; Sunitinib; Follow-Up Studies; Kidney Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37500340
DOI: 10.1016/j.eururo.2023.06.006 -
Journal of Clinical Oncology : Official... May 2023We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic...
PURPOSE
We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).
PATIENTS AND METHODS
Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis.
RESULTS
Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR). Two patients achieved PR after 6 months; thus, the ORR at 6 months was 14%. The median follow-up time for surviving patients was 22 months (95% CI, 16.6 to 39.1 months). The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months). Most common treatment-related adverse events (TRAEs) included fatigue (62%), hypertension (32%), and diarrhea (32%). Ten (29%) patients had serious TRAEs, all grade 3; four patients (12%) discontinued avelumab, and nine patients (26%) underwent axitinib dose reduction.
CONCLUSION
The study reached its primary end point with ≥4 PRs in 28 evaluable patients (confirmed ORR of 18%). The potential added benefit of avelumab to axitinib in ACC requires further investigation.
Topics: Humans; Axitinib; Carcinoma, Adenoid Cystic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized
PubMed: 36898078
DOI: 10.1200/JCO.22.02221 -
The Lancet. Oncology Jun 2019VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF...
BACKGROUND
VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma.
METHODS
This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0-1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2-10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual.
FINDINGS
Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1-19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6-79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1-90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths.
INTERPRETATION
Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.
FUNDING
Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.
Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Brain Neoplasms; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Salvage Therapy; Sarcoma, Alveolar Soft Part; Soft Tissue Neoplasms; Survival Rate
PubMed: 31078463
DOI: 10.1016/S1470-2045(19)30153-6 -
The Cochrane Database of Systematic... May 2023Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL).
OBJECTIVES
To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs).
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable.
DATA COLLECTION AND ANALYSIS
All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm.
MAIN RESULTS
We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB.
AUTHORS' CONCLUSIONS
Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.
Topics: Male; Female; Adult; Humans; Carcinoma, Renal Cell; Axitinib; Nivolumab; Network Meta-Analysis; Sunitinib
PubMed: 37146227
DOI: 10.1002/14651858.CD013798.pub2 -
Bulletin Du Cancer Dec 2018HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In... (Review)
Review
HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In the second-line setting, for patients who progressed on prior antiangiogenic therapy (mainly the VEGFR tyrosine kinase inhibitors (TKI) sunitinib or pazopanib), axitinib and everolimus have been recommended. Since 2015, other drugs have proven their efficacy and are currently considered the standard of care: cabozantinib (TKI that targets VEGFR, MET and AXL) and nivolumab (first anti-PD-1 check point inhibitor). Lenvatinib has also demonstrated promising results in association with everolimus, but this combination is not available in France. The optimal treatment choice for a given patient is challenging for the clinician when facing multiple options. In this article, we review the efficacy, safety and quality of life results of the main pivotal clinical studies involving advanced or metastatic RCC in the second-line setting, to help clinicians in selecting the most appropriate treatment. Beyond that, it is important to define all the sequencing strategy for patients to successively receive all the drugs that have demonstrated an increase in overall survival.
Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Clinical Trials as Topic; Everolimus; Humans; Immunotherapy; Indazoles; Kidney Neoplasms; Nivolumab; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Sulfonamides; Sunitinib
PubMed: 30595153
DOI: 10.1016/S0007-4551(18)30379-5 -
Nature Medicine Nov 2020We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006 ), which demonstrated significantly... (Randomized Controlled Trial)
Randomized Controlled Trial
We report on molecular analyses of baseline tumor samples from the phase 3 JAVELIN Renal 101 trial (n = 886; NCT02684006 ), which demonstrated significantly prolonged progression-free survival (PFS) with first-line avelumab + axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We found that neither expression of the commonly assessed biomarker programmed cell death ligand 1 (PD-L1) nor tumor mutational burden differentiated PFS in either study arm. Similarly, the presence of FcɣR single nucleotide polymorphisms was unimpactful. We identified important biological features associated with differential PFS between the treatment arms, including new immunomodulatory and angiogenesis gene expression signatures (GESs), previously undescribed mutational profiles and their corresponding GESs, and several HLA types. These findings provide insight into the determinants of response to combined PD-1/PD-L1 and angiogenic pathway inhibition and may aid in the development of strategies for improved patient care in aRCC.
Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Axitinib; Biomarkers, Tumor; Carcinoma, Renal Cell; Female; Gene Expression Regulation, Neoplastic; Humans; Kidney; Male; Middle Aged; Progression-Free Survival; Sunitinib; Transcriptome; Young Adult
PubMed: 32895571
DOI: 10.1038/s41591-020-1044-8 -
Annals of Oncology : Official Journal... Feb 2024Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC.
PATIENTS AND METHODS
Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety.
RESULTS
A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group.
CONCLUSION
In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.
Topics: Humans; Antibodies, Monoclonal, Humanized; Axitinib; Carcinoma, Renal Cell; Kidney Neoplasms; Sunitinib; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37872020
DOI: 10.1016/j.annonc.2023.09.3108