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Model shows nivolumab plus ipilimumab cost effective in mRCC
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.
“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.
The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.
“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.
Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.
After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.
With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.
“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.
The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.
The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.
SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.
REPORTING FROM JAMA ONCOLOGY
Tivozanib has PFS benefit over sorafenib in hard-to-treat RCC
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
SAN FRANCISCO – The risk-benefit profile of the novel vascular endothelial growth factor (VEGF) inhibitor tivozanib when used as later-line therapy for renal cell carcinoma (RCC) appears to be similar to when it is used earlier, according to eagerly awaited results of the TIVO-3 trial.
Tivozanib, an oral tyrosine kinase inhibitor of the VEGF family of receptors with a long half-life, is designed both to optimize receptor blockade and minimize off-target toxicities, lead investigator Brian I. Rini, MD, said at the the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Positive progression-free survival results of the TIVO-1 trial (J Clin Oncol. 2013;31:3791-9) led to approval of this agent as first-line therapy for RCC in Europe. However, the Food and Drug Administration rejected approval because of a trend toward poorer overall survival, which was likely related to imbalanced cross-over to active treatment.
The TIVO-3 trial enrolled 350 patients with advanced clear-cell RCC who had experienced failure of two or three prior regimens, including a VEGF receptor tyrosine kinase inhibitor. They were randomized evenly to open-label tivozanib (1.5 mg q.d., 3 weeks on and 1 week off) or sorafenib (Nexavar) (400 mg b.i.d. continuously).
Main results showed that progression-free survival was about 2 months longer with tivozanib, compared with sorafenib. The difference translated to a 27% reduction in risk of events, reported Dr. Rini, professor of medicine at Case Western Reserve University, Cleveland, and leader of the genitourinary oncology program at the Cleveland Clinic.
The benefit was similar for most subgroups. The tivozanib group had a higher incidence of hypertension, but lower incidences of diarrhea, hand-foot syndrome, and rash.
“Tivozanib significantly improved progression-free survival and objective response rate compared to sorafenib in patients with treatment-refractory advanced RCC. It was superior in the subset of patients previously treated with checkpoint inhibitors, as well as the subset who had had two prior TKIs,” Dr. Rini said. “Responses to tivozanib, perhaps most impressively, were more durable than those with sorafenib. Tivozanib was very well tolerated, with on-target hypertension as the most common adverse event, but lower rates of off-target toxicities.”
Overall survival data at present show a trend toward shorter survival with tivozanib, but are not yet mature. Definitive results are expected later this year.
Study details
About 60% of patients in TIVO-3 had received two prior lines of therapy, Dr. Rini reported at the symposium. The proportion stopping study treatment because of adverse events was 13% in the tivozanib group and 23% in the sorafenib group.
Median progression-free survival according to an independent review committee was 5.6 months and 3.9 months, respectively (hazard ratio, 0.73; P = .0165). Corresponding 1-year rates were 28% and 11%.
Among patients previously treated with an immune checkpoint inhibitor, median progression-free survival according to an independent review committee was 7.3 months with tivozanib and 5.1 months with sorafenib (hazard ratio, 0.55; P = .028). Corresponding 1-year rates were 35% and 4%.
In the entire trial population, the overall response rate was 18% for tivozanib versus 8% for sorafenib (P = .02). Median duration of response was not reached, compared with 5.7 months.
An interim analysis showed a median overall survival of 16.4 months in the tivozanib group and 19.7 months in the sorafenib group.
The rate of any-grade treatment-related adverse events was 84% with tivozanib and 94% with sorafenib. Tivozanib had a higher rate of grade 3 or 4 hypertension (20% vs. 14%), but lower rates of grade 3 or 4 diarrhea (2% vs. 9%), hand-foot syndrome (1% vs. 10%), and rash (0% vs. 8%).
Dr. Rini reported that he has a consulting role with Aveo, which sponsored the trial, and financial relationships with several other companies.
SOURCE: Rini BI et al. GUCS 2019, Abstract 541.
REPORTING FROM GUCS 2019
First-line avelumab/axitinib for RCC benefits wide range of patients
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
“For first-line therapy of metastatic clear-cell renal cancer, we now have two regimens that have demonstrated a survival advantage over first-line sunitinib,” Walter M. Stadler, MD, said in an interview. For first-line therapy, there is the combination of nivolumab and ipilimumab in intermediate- and poor-risk patients and also the combination of pembrolizumab and axitinib.
Dr. Stadler is the Fred C. Buffett Professor of Medicine and Surgery, chief of the section of hematology/oncology, director of the genitourinary oncology program, and deputy director of the Comprehensive Cancer Center at the University of Chicago.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
SAN FRANCISCO – subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.
Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).
JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.
Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.
In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.
“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”
JAVELIN Renal 101 complemented two other noteworthy trials exploring first-line checkpoint inhibitors for which new data were reported at the symposium. One, KEYNOTE-426 (NCT02853331), established that the combination of the immune checkpoint inhibitor pembrolizumab (Keytruda) and axitinib was superior to sunitinib. The other, CheckMate 214 (NCT02231749), established that the combination of two immune checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy), was superior to sunitinib.
Weighing new options
“So a new standard of care in 2019 is present: The majority of patients with advanced clear cell RCC will be eligible to receive the combination of a checkpoint inhibitor and axitinib,” commented invited discussant Lori Wood, MD, a professor in the division of medical oncology at Dalhousie University, Halifax, Canada. “The questions now are: Which treatment should we choose? can we afford it? and perhaps more importantly, can we safely deliver this therapy to all patients?”
When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.
Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.
Safely administering the combinations – through use of education, judicious patient selection, and attention to logistics – is a challenge, she maintained. “I tell the residents, you can probably give cisplatin/gemcitabine to 10 patients and you can probably give sunitinib to 20 patients and get a good sense of what’s going to happen. But every single patient that I have put on immune therapy, I learn something new.”
Evolving issues, such as nuanced differences among the immune checkpoint inhibitors and whether the doses used in trials are really needed, have yet to be worked through. But combining these agents is likely better than sequencing them because only about half of RCC patients given first-line therapy go on to get second-line therapy, “so we might as well use our best therapy up front,” Dr. Wood said. Finally, it’s unclear whether cytoreductive nephrectomy is needed to achieve a complete response with these combinations because all trials predated the CARMENA trial (NCT00930033), so most patients underwent this surgery.
“These are exciting times. I think that for the first-line metastatic renal cell patient with favorable-, intermediate-, or poor-risk disease, a checkpoint inhibitor/axitinib combination will be a new standard of care in many parts of the world, not all,” she summarized. “For intermediate- and poor-risk patients, there’s no clear winner in my mind at this current time between ipilimumab/nivolumab and checkpoint inhibitor/axitinib. Decisions will need to be based on overall survival, complete response rates, toxicities, and then practical aspects, as well as costs.”
“But we cannot safely and effectively deliver this new standard of care without true infrastructure and system changes to accommodate more doctor and nurse visits, more infusion time, all of these extra visits, and more education for everybody who is both delivering and receiving these agents,” Dr. Wood concluded.
Study details
The subgroup analyses showed that, compared with sunitinib, avelumab/axitinib yielded better progression-free survival across patients differing with respect to IMDC risk group (range of hazard ratios, 0.539-0.736), MSKCC risk group (range of HRs, 0.495-0.715), tumor PD-L1 status (range of HRs, 0.626-0.827), prior nephrectomy status (range of HRs, 0.673-0.748), smoking status (range of HRs, 0.663-0.711), and body mass index (range of HRs, 0.667-0.674), Dr. Choueiri reported at the symposium. However, the 95% confidence intervals crossed 1 in some cases.
Overall, 20.8% of the avelumab/axitinib group and 39.2% of the sunitinib group went on to receive a follow-up anticancer drug therapy. The most common was cabozantinib (Cabometyx) in the former and nivolumab (Opdivo) in the latter.
The rate of progression-free survival 2 could not be estimated for the avelumab/axitinib group and was 18.4 months for the sunitinib group (HR, 0.56). “In theory, the first-line treatment could change the biology of the disease and therefore lead to substantially shorter benefit of second-line treatment, and progression-free survival 2 is actually a potentially important endpoint for regulatory and reimbursement evaluation,” Dr. Choueiri explained. “This suggests at least no negative impact of first-line treatment with the combination on subsequent benefit from second-line treatment.”
Compared with sunitinib, avelumab/axitinib also yielded better odds of objective response regardless of IMDC risk group (range of odds ratios, 3.099-3.556), MSKCC risk group (range of ORs, 3.061-4.686), PD-L1 status (range of ORs, 2.240-3.594), prior nephrectomy status (range of ORs, 2.592-3.249), smoking status (range of ORs, 2.649-3.798), and body mass index (range of ORs, 3.086-3.292). Here, virtually all 95% confidence intervals excluded 1.
Mean duration of response was more than 4 months longer with the combination than with sunitinib. Moreover, responses were deeper for the combination patients.
In updated safety results, the avelumab/axitinib group had higher rates of any-grade treatment-related diarrhea (54% vs. 45%) and hypothyroidism (24% vs. 13%). But there were few of these adverse events of grade 3 or 4 in either group.
Dr. Choueiri disclosed that he receives honoraria from, has a consulting or advisory role with, and receives institutional research funding from Merck and Pfizer – among other disclosures. The trial was sponsored by Pfizer.
SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.
REPORTING FROM GUCS 2019
Pembrolizumab-axitinib nearly halves risk of death in RCC
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of pembrolizumab and axitinib has similar safety and better efficacy than single-agent sunitinib, the current standard of care, according to findings of the KEYNOTE-426 trial that will be reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.
“Axitinib is usually licensed and usually used in sunitinib-refractory disease. However, there is data for both pembrolizumab and axitinib in the frontline setting,” said lead author Thomas Powles, MBBS, MRCP, MD, of Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London. A phase 1b trial testing the combination showed an impressive 73% objective response rate and acceptable toxicity (Lancet Oncol. 2018;19:405-15), prompting further investigation.
The 861 patients in KEYNOTE-426, a phase 3, randomized, controlled trial, were evenly assigned to combination therapy with the immune checkpoint inhibitor pembrolizumab (Keytruda), which targets programmed death–1, plus the tyrosine kinase inhibitor axitinib (Inlyta), which targets vascular endothelial growth factor and platelet-derived growth factor, or to monotherapy with the tyrosine kinase inhibitor sunitinib (Sutent), which also targets those growth factors.
Main results reported in a presscast held before the symposium showed that, with a median follow-up of 12.8 months, pembrolizumab-axitinib reduced the risk of progression-free survival events by a relative 31% and the risk of death by a relative 47%, compared with sunitinib. The combination had a rate of grade 3-5 treatment-related adverse events similar to the rate with sunitinib alone.
“The benefit of pembrolizumab plus axitinib was seen irrespective of IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk group or PD-L1 [programmed death–ligand 1] status,” Dr. Powles noted. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”
“This is a very significant trial, and it’s going to impact on patient management going forward, as it works through the regulatory process,” commented ASCO Expert and presscast moderator Robert Dreicer, MD, MS, MACP, FASCO, who is also deputy director and associate director of clinical research at the University of Virginia Cancer Center and a professor of medicine and urology at the University of Virginia, Charlottesville.
Study details
Patients in KEYNOTE-426 had newly diagnosed or recurrent stage IV clear cell RCC and had not received any previous systemic treatment for their advanced disease. They were randomized to pembrolizumab (200 mg intravenously every 3 weeks up to 35 cycles) plus axitinib (5 mg orally twice daily), or to sunitinib (50 mg orally once daily for first 4 weeks of each 6-week cycle).
Median overall survival was not reached in either group, but the 12-month rate was 89.9% with pembrolizumab-axitinib versus 78.3% with sunitinib, Dr. Powles reported in the presscast. The difference corresponded to a near halving of the risk of death with the combination (hazard ratio, 0.53; P less than .0001).
Median progression-free survival was 15.1 months with pembrolizumab-axitinib and 11.1 months with sunitinib. The difference corresponded to a nearly one-third reduction in the risk of events with the combination (HR, 0.69; P = .0001). “The 11.1 months is quite long for a control arm, so there’s nothing from these data to suggest that sunitinib underperformed in this trial,” he noted.
Pembrolizumab-axitinib was also associated with a higher objective response rate (59.3% vs. 35.7%; P less than .0001). The median duration of response was not reached with the former, compared with 15.2 months with the latter.
“Pembrolizumab and axitinib had a manageable safety profile,” Dr. Powles said. The rate of grade 3-5 treatment-related adverse events was 62.9% with the combination and 58.1% with sunitinib monotherapy.
The rate of events leading to death was similar at 0.9% and 1.6%, respectively. The rate of events leading to discontinuation of any treatment was 25.9% for pembrolizumab-axitinib and 10.1% for sunitinib, and the rate of events leading to discontinuation of both drugs in the combination was 8.2%.
Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from Astra-Zeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
SOURCE: Powles T et al. GUCS 2019, Abstract 543.
REPORTING FROM GUCS 2019
Key clinical point: The combination of pembrolizumab and axitinib may become a new first-line standard of care in advanced renal cell carcinoma.
Major finding: Compared with sunitinib monotherapy, pembrolizumab and axitinib combination therapy prolonged progression-free survival (hazard ratio, 0.69; P = .0001) and overall survival (HR, 0.53; P less than .0001).
Study details: A phase 3, randomized, controlled trial among 861 patients with untreated locally advanced or metastatic renal cell carcinoma (KEYNOTE-426).
Disclosures: Dr. Powles reported that he has a consulting or advisory role with Genentech/Roche, Bristol-Myers Squibb, Merck, Novartis, and AstraZeneca; has a nonspecified relationship with Ipsen and Bristol-Myers Squibb; receives honoraria from Roche/Genentech, Bristol-Myers Squibb, and Merck; and receives research funding from AstraZeneca/MedImmune and Roche/Genentech. The study was funded by Merck.
Source: Powles T et al. GUCS 2019, Abstract 543.
Severe adverse events seen in placebo arm of cancer clinical trials
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
A significant number of patients who receive only a placebo in a clinical trial of cancer immunotherapy still experience grade three or grade four adverse events, research suggests.
Writing in JAMA Network Open, researchers reported the outcomes of a systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled, phase 3 trials of targeted therapy or immunotherapy drugs for cancer, in which patients in the placebo group were treated only with placebo and no other anticancer drugs.
Among the 4,873 patients who were randomized to placebo, a mean of 85.1% experienced some sort of placebo adverse event. The overall incidence of grade 3-4 placebo adverse events was 18% but was as high as 25% in two trials – one in renal cell carcinoma and one in melanoma – and as low as 11% in one trial.
Hypertension was the most frequent grade 3-4 adverse event among patients on placebo, experienced by a mean of 2.8% of patients, followed by fatigue (1%) and diarrhea (0.8%).
Neither route of administration nor cancer type made a significant difference in terms of the rate of placebo adverse events. No deaths attributed to the placebo were reported, but the mean rate of discontinuation due to placebo adverse events was 3.9%, and was higher than 5% for four trials.
The median duration of placebo administration ranged from 10 to 15 months for all but one study, and the authors noted that the longer the placebo exposure, the higher the proportion of grade 3-4 adverse events.
The investigators – Matías Rodrigo Chacón, MD, and his colleagues in the research department at the Argentine Association of Clinical Oncology – said that studies with a lower incidence of grade 3-4 adverse events in the treatment arm also had a lower incidence of grade 3-4 placebo adverse events, while the higher incidences of placebo adverse events were seen in studies that also had a higher incidence of treatment-related adverse events.
They suggested that “contextual factors,” such as the information given during the informed consent process, could contribute to negative expectations of adverse events.
“To illustrate this point, in an RCT [randomized controlled trial] of aspirin as a treatment for unstable angina, a higher incidence of gastrointestinal irritation was reported in centers that specified its potential occurrence in the informed consent compared with research units that did not include that risk,” they wrote.
They also suggested that patients may experience anxiety associated with the uncertainty about whether they had received active treatment or placebo, and this could also affect their distress levels.
No conflicts of interest were declared.
SOURCE: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
FROM JAMA NETWORK OPEN
Key clinical point: Serious adverse events can occur in patients treated only with placebo in cancer clinical trials.
Major finding: The incidence of grade 3-4 placebo adverse events was 18% in cancer clinical trials.
Study details: Systematic review and meta-analysis of 10 randomized, placebo-controlled, double-blind trials.
Disclosures: No conflicts of interest were declared.
Source: Chacón M et al. JAMA Network Open. 2018 Dec 7. doi: 10.1001/jamanetworkopen.2018.5617.
‘Optimal’ pazopanib levels linked to lower toxicity in RCC patients
In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.
Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.
The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.
Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.
The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.
The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.
Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.
One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).
A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.
No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.
Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.
Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.
Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.
In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.
“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”
Dr. Terada and coauthors said they had no conflicts of interest to report.
SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.
In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.
Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.
The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.
Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.
The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.
The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.
Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.
One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).
A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.
No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.
Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.
Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.
Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.
In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.
“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”
Dr. Terada and coauthors said they had no conflicts of interest to report.
SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.
In patients with renal cell carcinoma, trough concentrations of pazopanib in a specific target range were associated with better safety and comparable efficacy, versus higher concentrations of the drug, authors of an exploratory investigation have reported.
Fewer serious toxicities were seen in patients with pazopanib concentrations in the 20- to 50-mcg/mL range, yet overall response rate was similar compared to patients with concentrations over 50 mcg/mL, according to results of the retrospective study.
The findings suggest therapeutic drug monitoring to achieve a specific trough concentration may be useful to optimize pazopanib dosing, according to investigator Tomohiro Terada, PhD, of Shiga University of Medical Science Hospital, Japan, and coinvestigators.
Therapeutic drug monitoring for sunitinib in RCC patients was recently covered by medical insurance in Japan, Dr. Terada and colleagues wrote in Clinical Genitourinary Cancer.
The strategy may be especially suited to adjusting the dose of pazopanib, which is often associated with severe toxicities and has pharmacokinetics that suggest a wide variation between individuals, they added.
The retrospective study by Dr. Terada and colleagues included 27 renal cell carcinoma patients who received pazopanib at doses of 400, 600, or 800 mg daily based on the recommendation of the treating physician, with doses reduced or discontinued based on adverse events or progression.
Trough concentrations of pazopanib 3 months after starting the treatment ranged from a low of 10.6 mcg/mL to a high of 106 mcg/mL, with a median of 49.1 mcg/mL, according to the report.
One-third of patients experienced grade 3 or greater toxicities, including anorexia, hypertension, anemia, and thrombocytopenia, among others. The median pazopanib concentration for those nine patients was 69.3 mcg/mL, compared with 41.2 mcg/mL for those not experiencing serious toxicities (P less than .05).
A concentration over 50.3 mcg/mL predicted grade 3 or greater toxicity, statistical analysis showed, with 8 out of 13 patients with concentrations above that threshold experiencing serious toxicities. By contrast, 1 of 14 patients below that threshold experienced grade 3 or greater toxicities.
No responses were observed in three patients with pazopanib concentrations below 20.5 mcg/mL, a concentration level considered to be subtherapeutic based on previous investigations.
Overall response rates were similar for patients with concentrations in the “optimal” 20.5- and 50.3-mcg/mL range and those with concentrations over 50.3 mcg/mL, according to the investigators.
Among 11 patients in that “optimal” range, partial responses were seen in 5, they reported, while for the 13 patients with high concentrations of the drug, partial responses were seen in 4 patients and a complete response was seen in 1 patient.
Trough concentrations may not predict all types of toxicities, according to the investigators, who said that the results of their small, retrospective analysis should be validated in a large, prospective study.
In particular, there was no significant relationship between trough concentration of pazopanib and development of grade 2 or greater hepatotoxicity, a common and specific side effect of the drug.
“Based on these findings, pazopanib-induced hepatotoxicity may not be related to the pharmacokinetics of pazopanib,” they wrote. “Therefore, pharmacogenomics testing is needed to predict pazopanib-induced hepatotoxicity.”
Dr. Terada and coauthors said they had no conflicts of interest to report.
SOURCE: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.
FROM CLINICAL GENITOURINARY CANCER
Key clinical point: Trough concentrations of pazopanib in approximately the 20- to 50-mcg/mL range were associated with less toxicity but a similar overall response rate, versus higher concentrations.
Major finding: The overall response rate was about 46% in patients with pazopanib concentrations in that range, and in patients with higher concentrations. One patient in the “optimal” range experienced a grade 3 or greater toxicity.
Study details: An exploratory analysis including 27 patients with renal cell carcinoma.
Disclosures: The authors reported no conflicts of interest.
Source: Noda S et al. Clin Genitourin Cancer. 2018 Dec 7. doi: 10.1016/j.clgc.2018.12.001.
Cytoreductive nephrectomy may benefit RCC patients with brain mets
While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.
Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program.
By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.
The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.
“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.
However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.
In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.
Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.
Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).
Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.
Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.
While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.
“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.
Dr. Bratslavsky and his coauthors listed no disclosures related to their research.
SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.
While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.
Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program.
By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.
The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.
“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.
However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.
In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.
Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.
Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).
Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.
Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.
While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.
“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.
Dr. Bratslavsky and his coauthors listed no disclosures related to their research.
SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.
While patients with renal cell carcinoma (RCC) brain metastases are traditionally thought of as having a grim prognosis, a subset of patients may experience durable long-term survival with cytoreductive nephrectomy, authors of a retrospective study have reported.
Specifically, patients with brain lesions and no additional metastatic disease sites who underwent cytoreduction had a 2-year survival rate of 52%, according to the researchers’ analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program.
By contrast, these patients with brain-only metastases who did not undergo the procedure had a 2-year survival of 14%, reported Gennady Bratslavsky, MD, of State University of New York, Syracuse, and his associates.
The findings are at odds with “previously accepted dogma” that surgery is inadvisable in patients with RCC with brain metastases, which is traditionally thought of as a poor-risk feature, according to Dr. Bratslavsky and his colleagues.
“These patients seem to benefit from cytoreductive nephrectomy and may potentially be excellent candidates for clinical trials,” they wrote in Urologic Oncology.
However, patient selection likely drove survival outcomes in this retrospective cohort, the authors acknowledged, adding that they did not intend to argue “for or against” the role of cytoreductive nephrectomy.
In their analysis, they identified 6,403 patients with metastatic RCC and complete information on sites of metastasis; of these, 775 (12.1%) had brain metastases.
Patients with brain metastases generally fared worse than did patients with other, non-brain metastases, with 2-year survival rates of 14.9% and 28.6%, respectively (P less than .0001); however, patients with brain-only metastases had a 2-year survival of 31% overall in this analysis.
Cytoreductive nephrectomy was performed in 40.8% of patients with brain-only metastases, versus 20.8% of patients with synchronous metastases (P less than .0001).
Brain-only metastases patients who underwent cytoreductive nephrectomy had 1-year survival of 67%, 2-year survival of 52%, and median survival of 33 months, the data show. In contrast, brain-only metastases patients who did not undergo the procedure had 1-year survival of 26%, 2-year survival of 14%, and median survival of just 5 months.
Even when the researchers included patients with brain metastases in addition to other sites, cytoreduction was associated with superior outcomes, compared with patients with non-brain metastases who did not undergo cytoreduction, the investigators said. The reported 2-year survival rates in that analysis were 34.1% for brain metastasis and cytoreduction versus 14.4% for non-brain metastasis and no cytoreduction.
While this study was retrospective and was based on limited patient data, these findings nevertheless suggest that patients with RCC and isolated brain metastases might benefit from the procedure, Dr. Bratslavsky and his coauthors said.
“We anticipate that this work will be helpful for patient counseling and for modifying future exclusion criteria in clinical trials,” they concluded.
Dr. Bratslavsky and his coauthors listed no disclosures related to their research.
SOURCE: Daugherty M et al. Urol Oncol. 2018 Dec 5. doi: 10.1016/j.urolonc.2018.10.021.
FROM UROLOGIC ONCOLOGY
Key clinical point: Renal cell carcinoma patients with brain-only metastases may experience durable long-term survival following cytoreductive nephrectomy.
Major finding: Two-year survival was 52% and 14%, respectively, for patients with brain-only metastases who did and did not undergo the procedure.
Study details: A retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) Program data including 6,403 patients with metastatic RCC and complete data on sites of metastasis.
Disclosures: Dr. Bratslavsky and coauthors listed no disclosures related to their research.
Source: Daugherty M et al. Urol Oncol. 2018 Dec 5.doi: 10.1016/j.urolonc.2018.10.021.
Lipoprotein ratio linked to poor survival in metastatic RCC
The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.
The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.
Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.
“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.
Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.
The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.
In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.
Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).
The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.
Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.
This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.
“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.
The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.
SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.
The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.
The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.
Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.
“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.
Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.
The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.
In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.
Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).
The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.
Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.
This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.
“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.
The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.
SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.
The ratio of apolipoproteins B and A1 (apo B/A1) is an independent prognostic factor in patients with metastatic renal cell carcinoma, according to authors of a recent retrospective study.
The apo B/A1 ratio, evaluated prior to cytoreductive nephrectomy, was significantly linked with poor progression-free survival and overall survival, according to Fan Zhang, MD, of the Chinese PLA General Hospital in Beijing and coauthors.
Those findings suggest that patients with metastatic RCC should receive “consistent follow-up” that includes evaluation of that ratio, Dr. Zhang and colleagues said.
“As a novel prognostic factor, the preoperative apo B/A1 ratio can be utilized as a supplement to improve the current prognostic evaluation and treatment decision for patients with metastatic RCC,” they wrote in Urologic Oncology.
Apo B and A1, which are predominant components of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), respectively, have “extensive connections” with cardiovascular disease, diabetes, and Alzheimer disease, the authors said.
The apo B/A1 ratio is a known risk index for cardiovascular disease, and in recent studies, it appeared to have some value in prognosis and prediction of gastric and colorectal cancer, among other neoplasms, they added.
In their retrospective study, Dr. Zhang and colleagues analyzed data on 287 metastatic RCC patients who underwent cytoreductive nephrectomy at the Chinese PLA General Hospital. The median age of the patients was 56 years, and the median apo B/A1 ratio was 0.859.
Significantly poorer progression-free survival was seen in the group of patients with a preoperative apo B/A1 ratio over the cutoff of 0.977 (P less than .0001) compared with those under the cutoff, the investigators reported. Likewise, overall survival was poorer for patients with an apo B/A1 ratio over a cutoff of 0.847 (P = .0005).
The apo B/A1 ratio was higher in patients with Fuhrman grade 3-4 versus grade 1-2 patients (P = .010), though the investigators said no significant differences in the ratio were seen in patients stratified by age, body mass index, fatty liver, number of metastases, among other subgroup analyses.
Multivariate analysis revealed that the two independent prognostic factors for progression-free survival were preoperative apo B/A1 ratio and Fuhrman grade, with hazard ratios of 3.131 and 1.906, respectively (P less than .001 for both), while independent prognostic factors for overall survival also included the apo B/A1 ratio (hazard ratio, 2.173; P less than .001) and Fuhrman grade, along with tumor necrosis and receiving targeted therapy.
This retrospective study was limited by relatively small samples from a single center, and the prognostic value of the apo B/A1 ratio needs to be verified in other studies, investigators said.
“Peripheral blood biomarkers only provide a supplement to the traditional prognostic factors in the prediction of the prognosis for patients with metastatic RCC, and are still unable to replace it,” Dr. Zhang and associates said.
The Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest related to the work.
SOURCE: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.
FROM UROLOGIC ONCOLOGY
Key clinical point: The ratio of apolipoproteins B and A1 (apo B/A1) was an independent prognostic factor in patients with metastatic renal cell carcinoma (RCC).
Major finding: The preoperative apo B/A1 ratio was independently prognostic for progression-free survival and overall survival, with hazard ratios of 3.131 and 2.173, respectively (P less than .001 for both).
Study details: A retrospective, single-center study including 287 patients with metastatic RCC who underwent cytoreductive nephrectomy.
Disclosures: Beijing Natural Science Foundation supported the study. Dr. Zhang and coauthors had no disclosed conflicts of interest.
Source: Zhang F et al. Urol Oncol. 2018 Nov 30. doi: 10.1016/j.urolonc.2018.11.010.
RCC strongly linked to melanoma, and vice versa
A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.
A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.
The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.
“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.
They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.
Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).
Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.
In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.
That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.
“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.
They reported that they had no conflicts of interest.
SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.
A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.
A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.
The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.
“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.
They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.
Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).
Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.
In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.
That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.
“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.
They reported that they had no conflicts of interest.
SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.
A review of registry data from a major cancer center revealed a strong, bidirectional association between renal cell carcinoma (RCC) and melanoma.
A greater than twofold risk of melanoma in patients with RCC, and a nearly threefold risk of RCC in melanoma patients, were found in the review of the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.
The incidence of subsequent melanomas or RCCs in this study was in line with other recent reports from cancer registry analyses, reported Kevin B. Kim, MD, and his coinvestigators.
“Clinicians should be more watchful for these secondary cancers in patients with a history of melanoma or RCC,” they wrote. The report is in Cancer Epidemiology.
They found a total of 13,879 patients with melanoma and 7,597 patients with RCC in their review. Of those patients, 89 had both a melanoma and an RCC diagnosis. About 30% were first diagnosed with RCC, 61% were first diagnosed with melanoma, and 9% had both diagnoses around the same time.
Among the RCC-first patients, the standardized incidence ratio for developing a second primary melanoma was 2.31 (95% confidence interval, 1.52-3.37; P less than .001), while for melanoma-first patients, for developing a second primary RCC, it was 2.87 (95% CI, 2.16-3.74; P less than .001).
Those statistics were consistent with other registry reports, according to Dr. Kim and his colleagues, who wrote that the standardized incidence ratios in those studies ranged from 1.28 to 2.5.
In the MD Anderson registry study, nearly one-third of patients with secondary primary melanoma or RCC had a history of additional secondary cancers, according to the researchers. Those diagnoses included nonmelanoma skin cancers, leukemias, prostate cancer, breast cancer, and colon cancer, among others.
That suggested the presence of possible common risk factors that may have included abnormal genetics, though the database lacked the genetic sequencing and family history data to explore that hypothesis further.
“It would be highly desirable to assess germline genetic information on patients and their families, and also somatic gene aberrations in the tumor lesions, in a more systematic way in order to better elucidate the contribution of the genetics in the association between melanoma and RCC,” Dr. Kim and his colleagues said.
They reported that they had no conflicts of interest.
SOURCE: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.
FROM CANCER EPIDEMIOLOGY
Key clinical point: Review of international tumor registry data demonstrated a strong and bidirectional association between renal cell carcinoma (RCC) and melanoma.
Major finding: Standardized incidence ratios were 2.31 for developing a second primary melanoma in patients who first had an RCC diagnosis, and 2.87 for developing a second primary RCC in patients who had melanoma first.
Study details: Analysis of 13,879 patients with melanoma and 7,597 patients with RCC in the International Tumor Registry Database at The University of Texas MD Anderson Cancer Center.
Disclosures: The authors reported that they had no conflicts of interest.
Source: Kim KB et al. Cancer Epidemiol. 2018 Oct 19;57:80-4.
RCC research has opened door to the future, but “much work remains to be done”
Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.
The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.
“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”
RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.
Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.
Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.
Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.
“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.
SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.
Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.
The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.
“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”
RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.
Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.
Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.
Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.
“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.
SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.
Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.
The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.
“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”
RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.
Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.
Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.
Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.
“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.
SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.
FROM UROLOGIC ONCOLOGY
Key clinical point: Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options but personalized medicine is still largely unavailable.
Major finding: There are still no validated biomarkers to select patient treatment, and in only rare cases does the knowledge of particular mutations in renal cell carcinoma lead to rational treatment selection.
Study details: A review article of mutations in renal cell carcinoma and associated treatment options.
Disclosures: This work was supported by the Canadian Cancer Society and the Canadian Institutes of Health.
Source: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.