Renal Cell Carcinoma

Germline mutations in patients with advanced renal cell carcinoma may be more common than previously suspected.

In a single-center cohort of 254 patients with advanced renal cell carcinoma (RCC) who received matched tumor-germline DNA sequencing, over a third (35.7%) of patients who had mutations in genes associated with RCC had not met current clinical criteria for testing.

In all, pathogenic germline mutations were identified in 41 patients (16.1%), with 14 patients’ mutations (5.5%) in genes known to be associated with RCC. For the remaining 27 patients (10.5%), the mutations were in non–RCC-associated genes, investigators reported in JAMA Oncology.

Of the non–RCC-associated mutations, CHEK2 was particularly common among patients with clear cell RCC (ccRCC), occurring in eight patients with ccRCC and two with non ccRCC (nccRCC). The overall odds ratio for this mutation among the study cohort was 3.0, compared with the general population (95% confidence interval 1.3-5.8; P = .003). “Although there are currently no RCC-specific screening recommendations for individuals with CHEK2 mutations, there may be incremental screening for other cancers, justifying including this gene on RCC panel tests,” wrote Maria Carlo, MD, and her coauthors.

Germline FH mutations were seen in seven patients, all with nccRCC. This higher rate of hereditary leiomyomatosis and RCC (HLRCC) was higher than previously reported in the literature, and clinical cues to the diagnosis were few among the study patients. Even though clues pointing to HLRCC were seen when tumor samples were submitted for histopathology to the genitourinary specialists at the study site, “it is unclear whether nonspecialist pathologists would be able to draw the same conclusions,” wrote Dr. Carlo and her colleagues.

Renal cell cancer–associated mutations were significantly more common in patients with nccRCC than in the ccRCC group: 9/74 (11.7%) nccRCC patients had an RCC-associated mutation, compared with 3/177 of the ccRCC group (P = .001).

The patient’s course of therapy could be guided by the mutation identified in 10% (eight) of the nccRCC patients, “none of which would have been identified with somatic-only sequencing,” wrote Dr. Carlo and associates. “Our results suggest that germline mutations in cancer-associated genes in patients with advanced RCC may be prevalent, and many of these mutations can be used to guide therapy.”

The 254 patients (median age 56 years, 70.5% male, 83.1% non-Hispanic white) were drawn from 267 patients with American Joint Committee on Cancer (AJCC) stage III or IV RCC participating in clinical trials at Memorial Sloan Kettering Cancer Center, New York, where Dr. Carlo practices as an oncologist. The patients included in the cohort were those who consented to germline sequencing and results disclosure.

To determine which pathogenic variants were identified by the study protocol that would have been missed by current testing standards, the investigators assumed that for those who met guidelines, the multigene test panel would probe for VHL, VH, FLCN, MET, SDHB, SDHD, BAP1, TSC1, TSC2, TP53, and MITF. If another mutation was picked up by the next-generation sequencing used in the study, or if a mutation was found in an individual who otherwise would not have been tested, the finding was considered incremental and attributable to the study protocol.

Implications of the additional mutations picked up by the tumor-germline sequencing approach go beyond the patient, said the researchers, who have seen several of the study participants’ family members receive positive test results for cancer-associated mutations as well. “Relatives who are also found to carry FH mutations should be considered for RCC screening. Early detection may increase the likelihood of cure and survivorship,” wrote Dr. Carlo and her coinvestigators.

Dr. Carlo reported serving as a consultant for Pfizer. Other authors reported multiple associations with pharmaceutical companies. The study was funded by the National Institutes of Health, the J. Randall and Kathleen L. MacDonald Kidney Cancer Research Fund, and the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center.

SOURCE: Carlo M et al. JAMA Oncol. 2018 Jul 5. doi: 10.1001/jamaoncol.2018.1986.

Germline mutations in patients with advanced renal cell carcinoma may be more common than previously suspected.

In a single-center cohort of 254 patients with advanced renal cell carcinoma (RCC) who received matched tumor-germline DNA sequencing, over a third (35.7%) of patients who had mutations in genes associated with RCC had not met current clinical criteria for testing.

In all, pathogenic germline mutations were identified in 41 patients (16.1%), with 14 patients’ mutations (5.5%) in genes known to be associated with RCC. For the remaining 27 patients (10.5%), the mutations were in non–RCC-associated genes, investigators reported in JAMA Oncology.

Of the non–RCC-associated mutations, CHEK2 was particularly common among patients with clear cell RCC (ccRCC), occurring in eight patients with ccRCC and two with non ccRCC (nccRCC). The overall odds ratio for this mutation among the study cohort was 3.0, compared with the general population (95% confidence interval 1.3-5.8; P = .003). “Although there are currently no RCC-specific screening recommendations for individuals with CHEK2 mutations, there may be incremental screening for other cancers, justifying including this gene on RCC panel tests,” wrote Maria Carlo, MD, and her coauthors.

Germline FH mutations were seen in seven patients, all with nccRCC. This higher rate of hereditary leiomyomatosis and RCC (HLRCC) was higher than previously reported in the literature, and clinical cues to the diagnosis were few among the study patients. Even though clues pointing to HLRCC were seen when tumor samples were submitted for histopathology to the genitourinary specialists at the study site, “it is unclear whether nonspecialist pathologists would be able to draw the same conclusions,” wrote Dr. Carlo and her colleagues.

Renal cell cancer–associated mutations were significantly more common in patients with nccRCC than in the ccRCC group: 9/74 (11.7%) nccRCC patients had an RCC-associated mutation, compared with 3/177 of the ccRCC group (P = .001).

The patient’s course of therapy could be guided by the mutation identified in 10% (eight) of the nccRCC patients, “none of which would have been identified with somatic-only sequencing,” wrote Dr. Carlo and associates. “Our results suggest that germline mutations in cancer-associated genes in patients with advanced RCC may be prevalent, and many of these mutations can be used to guide therapy.”

The 254 patients (median age 56 years, 70.5% male, 83.1% non-Hispanic white) were drawn from 267 patients with American Joint Committee on Cancer (AJCC) stage III or IV RCC participating in clinical trials at Memorial Sloan Kettering Cancer Center, New York, where Dr. Carlo practices as an oncologist. The patients included in the cohort were those who consented to germline sequencing and results disclosure.

To determine which pathogenic variants were identified by the study protocol that would have been missed by current testing standards, the investigators assumed that for those who met guidelines, the multigene test panel would probe for VHL, VH, FLCN, MET, SDHB, SDHD, BAP1, TSC1, TSC2, TP53, and MITF. If another mutation was picked up by the next-generation sequencing used in the study, or if a mutation was found in an individual who otherwise would not have been tested, the finding was considered incremental and attributable to the study protocol.

Implications of the additional mutations picked up by the tumor-germline sequencing approach go beyond the patient, said the researchers, who have seen several of the study participants’ family members receive positive test results for cancer-associated mutations as well. “Relatives who are also found to carry FH mutations should be considered for RCC screening. Early detection may increase the likelihood of cure and survivorship,” wrote Dr. Carlo and her coinvestigators.

Dr. Carlo reported serving as a consultant for Pfizer. Other authors reported multiple associations with pharmaceutical companies. The study was funded by the National Institutes of Health, the J. Randall and Kathleen L. MacDonald Kidney Cancer Research Fund, and the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center.

SOURCE: Carlo M et al. JAMA Oncol. 2018 Jul 5. doi: 10.1001/jamaoncol.2018.1986.

Germline mutations in patients with advanced renal cell carcinoma may be more common than previously suspected.

In a single-center cohort of 254 patients with advanced renal cell carcinoma (RCC) who received matched tumor-germline DNA sequencing, over a third (35.7%) of patients who had mutations in genes associated with RCC had not met current clinical criteria for testing.

In all, pathogenic germline mutations were identified in 41 patients (16.1%), with 14 patients’ mutations (5.5%) in genes known to be associated with RCC. For the remaining 27 patients (10.5%), the mutations were in non–RCC-associated genes, investigators reported in JAMA Oncology.

Of the non–RCC-associated mutations, CHEK2 was particularly common among patients with clear cell RCC (ccRCC), occurring in eight patients with ccRCC and two with non ccRCC (nccRCC). The overall odds ratio for this mutation among the study cohort was 3.0, compared with the general population (95% confidence interval 1.3-5.8; P = .003). “Although there are currently no RCC-specific screening recommendations for individuals with CHEK2 mutations, there may be incremental screening for other cancers, justifying including this gene on RCC panel tests,” wrote Maria Carlo, MD, and her coauthors.

Germline FH mutations were seen in seven patients, all with nccRCC. This higher rate of hereditary leiomyomatosis and RCC (HLRCC) was higher than previously reported in the literature, and clinical cues to the diagnosis were few among the study patients. Even though clues pointing to HLRCC were seen when tumor samples were submitted for histopathology to the genitourinary specialists at the study site, “it is unclear whether nonspecialist pathologists would be able to draw the same conclusions,” wrote Dr. Carlo and her colleagues.

Renal cell cancer–associated mutations were significantly more common in patients with nccRCC than in the ccRCC group: 9/74 (11.7%) nccRCC patients had an RCC-associated mutation, compared with 3/177 of the ccRCC group (P = .001).

The patient’s course of therapy could be guided by the mutation identified in 10% (eight) of the nccRCC patients, “none of which would have been identified with somatic-only sequencing,” wrote Dr. Carlo and associates. “Our results suggest that germline mutations in cancer-associated genes in patients with advanced RCC may be prevalent, and many of these mutations can be used to guide therapy.”

The 254 patients (median age 56 years, 70.5% male, 83.1% non-Hispanic white) were drawn from 267 patients with American Joint Committee on Cancer (AJCC) stage III or IV RCC participating in clinical trials at Memorial Sloan Kettering Cancer Center, New York, where Dr. Carlo practices as an oncologist. The patients included in the cohort were those who consented to germline sequencing and results disclosure.

To determine which pathogenic variants were identified by the study protocol that would have been missed by current testing standards, the investigators assumed that for those who met guidelines, the multigene test panel would probe for VHL, VH, FLCN, MET, SDHB, SDHD, BAP1, TSC1, TSC2, TP53, and MITF. If another mutation was picked up by the next-generation sequencing used in the study, or if a mutation was found in an individual who otherwise would not have been tested, the finding was considered incremental and attributable to the study protocol.

Implications of the additional mutations picked up by the tumor-germline sequencing approach go beyond the patient, said the researchers, who have seen several of the study participants’ family members receive positive test results for cancer-associated mutations as well. “Relatives who are also found to carry FH mutations should be considered for RCC screening. Early detection may increase the likelihood of cure and survivorship,” wrote Dr. Carlo and her coinvestigators.

Dr. Carlo reported serving as a consultant for Pfizer. Other authors reported multiple associations with pharmaceutical companies. The study was funded by the National Institutes of Health, the J. Randall and Kathleen L. MacDonald Kidney Cancer Research Fund, and the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center.

SOURCE: Carlo M et al. JAMA Oncol. 2018 Jul 5. doi: 10.1001/jamaoncol.2018.1986.

CHICAGO – Pembrolizumab monotherapy shows promising efficacy and tolerability in treatment-naive patients with advanced clear cell renal cell carcinoma (accRCC), according to findings from the phase 2 KEYNOTE-427 study.

At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“The disease control rate was 59%,” he said.

Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.

“Most tumor responses occurred early in the course of therapy,” he noted.

The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.

An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.

“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”

In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.

“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.

Median progression-free survival was 8.7 months, and median overall survival has not been reached.

Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.

Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.

Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.

Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.

KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.

The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.

“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.

Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.

SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.

CHICAGO – Pembrolizumab monotherapy shows promising efficacy and tolerability in treatment-naive patients with advanced clear cell renal cell carcinoma (accRCC), according to findings from the phase 2 KEYNOTE-427 study.

At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“The disease control rate was 59%,” he said.

Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.

“Most tumor responses occurred early in the course of therapy,” he noted.

The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.

An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.

“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”

In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.

“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.

Median progression-free survival was 8.7 months, and median overall survival has not been reached.

Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.

Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.

Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.

Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.

KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.

The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.

“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.

Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.

SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.

CHICAGO – Pembrolizumab monotherapy shows promising efficacy and tolerability in treatment-naive patients with advanced clear cell renal cell carcinoma (accRCC), according to findings from the phase 2 KEYNOTE-427 study.

At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“The disease control rate was 59%,” he said.

Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.

“Most tumor responses occurred early in the course of therapy,” he noted.

The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.

An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.

“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”

In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.

“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.

Median progression-free survival was 8.7 months, and median overall survival has not been reached.

Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.

Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.

Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.

Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.

KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.

The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.

“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.

Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.

SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.

Levels of activity of a protein linked to malignancy could help predict if and when patients with renal cell carcinoma are likely to experience a recurrence, investigators report.

In a retrospective cohort study, the researchers looked at surgical specimens from 303 patients with localized clear cell renal cell carcinoma who had surgery between 1993 and 2011. The specimens were stained for antibodies against three key proteins; eukaryotic initiation factor 4E (eIF4E), eukaryotic initiation factor 4E binding protein 1 (4EBP1), and phospho eukaryotic initiation factor 4E binding protein 1 (p-4EBP1), reported Osamu Ichiyanagi, MD, of Yamagata (Japan) University, and colleagues. The study was published in Clinical Genitourinary Cancer.

The 4EBP1/eIF4E axis is known to regulate protein synthesis associated with malignant behavior. Researchers found that while the expression levels for the three proteins were similar between the recurrence-free and recurrence groups, patients who did not experience a recurrence had significantly lower activity in the 4EBP1/eIF4E axis.

The analysis showed that having intermediate or strong activation of the 4EBP1/eIF4E axis was an independent predictor of the risk of recurrence, as was Fuhrman grade 3/4 and pathological T stage of pT1b or above.

Only two patients who had weak activation of the 4EBP1/eIF4E axis experienced a recurrence (one early, one late).

Overall, 31 patients experienced an early recurrence – defined as recurrence within 5 years – and 16 patients experienced a recurrence after 5 years. Strong activation of the 4EBP1/eIF4E axis was an independent predictor of early recurrence.

About one-third of patients with nonmetastatic renal cell carcinoma who are curatively treated with nephrectomy experience a tumor recurrence, most commonly a distant metastasis. Late recurrence is known to occur in 6%-12% of patients.

“We show here for the first time that activation level of the 4EBP1/eIF4E axis in localised ccRCC may contribute not only to tumour recurrence but also to the timing of recurrence following curative nephrectomy,” wrote Dr. Ichiyanagi and coauthors. “Our data indicate that this activation may impact ER [early recurrence] and LR [late recurrence] events differentially.”

The study also found that more patients experienced recurrence after curative nephrectomy, suggesting that the 4EBP1/eIF4E axis became strongly activated after this.

The study was supported by Yamagata University Faculty of Medicine and the Japan Society for Promotion of Science. No conflicts of interest were declared.

SOURCE: Ichiyanagi O et al. Clin Genitourin Cancer. 2018 June 8. doi: 10.1016/j.clgc.2018.06.002.

Levels of activity of a protein linked to malignancy could help predict if and when patients with renal cell carcinoma are likely to experience a recurrence, investigators report.

In a retrospective cohort study, the researchers looked at surgical specimens from 303 patients with localized clear cell renal cell carcinoma who had surgery between 1993 and 2011. The specimens were stained for antibodies against three key proteins; eukaryotic initiation factor 4E (eIF4E), eukaryotic initiation factor 4E binding protein 1 (4EBP1), and phospho eukaryotic initiation factor 4E binding protein 1 (p-4EBP1), reported Osamu Ichiyanagi, MD, of Yamagata (Japan) University, and colleagues. The study was published in Clinical Genitourinary Cancer.

The 4EBP1/eIF4E axis is known to regulate protein synthesis associated with malignant behavior. Researchers found that while the expression levels for the three proteins were similar between the recurrence-free and recurrence groups, patients who did not experience a recurrence had significantly lower activity in the 4EBP1/eIF4E axis.

The analysis showed that having intermediate or strong activation of the 4EBP1/eIF4E axis was an independent predictor of the risk of recurrence, as was Fuhrman grade 3/4 and pathological T stage of pT1b or above.

Only two patients who had weak activation of the 4EBP1/eIF4E axis experienced a recurrence (one early, one late).

Overall, 31 patients experienced an early recurrence – defined as recurrence within 5 years – and 16 patients experienced a recurrence after 5 years. Strong activation of the 4EBP1/eIF4E axis was an independent predictor of early recurrence.

About one-third of patients with nonmetastatic renal cell carcinoma who are curatively treated with nephrectomy experience a tumor recurrence, most commonly a distant metastasis. Late recurrence is known to occur in 6%-12% of patients.

“We show here for the first time that activation level of the 4EBP1/eIF4E axis in localised ccRCC may contribute not only to tumour recurrence but also to the timing of recurrence following curative nephrectomy,” wrote Dr. Ichiyanagi and coauthors. “Our data indicate that this activation may impact ER [early recurrence] and LR [late recurrence] events differentially.”

The study also found that more patients experienced recurrence after curative nephrectomy, suggesting that the 4EBP1/eIF4E axis became strongly activated after this.

The study was supported by Yamagata University Faculty of Medicine and the Japan Society for Promotion of Science. No conflicts of interest were declared.

SOURCE: Ichiyanagi O et al. Clin Genitourin Cancer. 2018 June 8. doi: 10.1016/j.clgc.2018.06.002.

Levels of activity of a protein linked to malignancy could help predict if and when patients with renal cell carcinoma are likely to experience a recurrence, investigators report.

In a retrospective cohort study, the researchers looked at surgical specimens from 303 patients with localized clear cell renal cell carcinoma who had surgery between 1993 and 2011. The specimens were stained for antibodies against three key proteins; eukaryotic initiation factor 4E (eIF4E), eukaryotic initiation factor 4E binding protein 1 (4EBP1), and phospho eukaryotic initiation factor 4E binding protein 1 (p-4EBP1), reported Osamu Ichiyanagi, MD, of Yamagata (Japan) University, and colleagues. The study was published in Clinical Genitourinary Cancer.

The 4EBP1/eIF4E axis is known to regulate protein synthesis associated with malignant behavior. Researchers found that while the expression levels for the three proteins were similar between the recurrence-free and recurrence groups, patients who did not experience a recurrence had significantly lower activity in the 4EBP1/eIF4E axis.

The analysis showed that having intermediate or strong activation of the 4EBP1/eIF4E axis was an independent predictor of the risk of recurrence, as was Fuhrman grade 3/4 and pathological T stage of pT1b or above.

Only two patients who had weak activation of the 4EBP1/eIF4E axis experienced a recurrence (one early, one late).

Overall, 31 patients experienced an early recurrence – defined as recurrence within 5 years – and 16 patients experienced a recurrence after 5 years. Strong activation of the 4EBP1/eIF4E axis was an independent predictor of early recurrence.

About one-third of patients with nonmetastatic renal cell carcinoma who are curatively treated with nephrectomy experience a tumor recurrence, most commonly a distant metastasis. Late recurrence is known to occur in 6%-12% of patients.

“We show here for the first time that activation level of the 4EBP1/eIF4E axis in localised ccRCC may contribute not only to tumour recurrence but also to the timing of recurrence following curative nephrectomy,” wrote Dr. Ichiyanagi and coauthors. “Our data indicate that this activation may impact ER [early recurrence] and LR [late recurrence] events differentially.”

The study also found that more patients experienced recurrence after curative nephrectomy, suggesting that the 4EBP1/eIF4E axis became strongly activated after this.

The study was supported by Yamagata University Faculty of Medicine and the Japan Society for Promotion of Science. No conflicts of interest were declared.

SOURCE: Ichiyanagi O et al. Clin Genitourin Cancer. 2018 June 8. doi: 10.1016/j.clgc.2018.06.002.

In hindsight, a widely used prognostic model for patients with metastatic renal cell carcinoma (mRCC) has been shown to be effective at stratifying patient risk, and may inform the design of future clinical trials.

By retrospectively comparing clinical outcomes with risk categories determined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, Brian I Rini, MD, of the Cleveland Clinic, and his colleagues found notable differences in progression-free survival, overall survival, and objective response rates between the different risk categories among patients with mRCC treated with sunitinib (Sutent) in a major clinical trial.

“These benchmark values can aid current and future design and interpretation of clinical trials in mRCC. Results of this analysis demonstrate clear differences in patient outcomes based on IMDC prognostic risk group,” they wrote. The report was published in Clinical Genitourinary Cancer.

They also found that the Memorial Sloan Kettering Cancer Center (MSKCC) model appeared to be similar in prognostic utility to the IMDC model, and that either model could be useful for counseling patients about prognosis and treatment options.

They based their conclusions on an analysis of data from a phase 3 clinical trial comparing sunitinib with interferon alfa in patients with mRCC. Patients in this study were grouped according to prognostic risk category by the MSKCC criteria, which overlap with the IMDC criteria in five of six areas.

In the current study, Dr. Rini and his associates applied the IMDC criteria to the same population, and derived benchmark values for outcomes by IMDC risk groups based on radiologic tumor progression measurements performed by independent reviewers on images of patients in the intention-to-treat population.

They also conducted an analysis of data from investigator measurements of tumor progression, and compared the results with the independently reviewed radiologic data for patients outcomes according to the MSKCC model.

SOURCE: Rini B et al. Clin Genitourin Cancer. 2018 May 3. doi: 10.1016/j.clgc.2018.04.005.

In hindsight, a widely used prognostic model for patients with metastatic renal cell carcinoma (mRCC) has been shown to be effective at stratifying patient risk, and may inform the design of future clinical trials.

By retrospectively comparing clinical outcomes with risk categories determined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, Brian I Rini, MD, of the Cleveland Clinic, and his colleagues found notable differences in progression-free survival, overall survival, and objective response rates between the different risk categories among patients with mRCC treated with sunitinib (Sutent) in a major clinical trial.

“These benchmark values can aid current and future design and interpretation of clinical trials in mRCC. Results of this analysis demonstrate clear differences in patient outcomes based on IMDC prognostic risk group,” they wrote. The report was published in Clinical Genitourinary Cancer.

They also found that the Memorial Sloan Kettering Cancer Center (MSKCC) model appeared to be similar in prognostic utility to the IMDC model, and that either model could be useful for counseling patients about prognosis and treatment options.

They based their conclusions on an analysis of data from a phase 3 clinical trial comparing sunitinib with interferon alfa in patients with mRCC. Patients in this study were grouped according to prognostic risk category by the MSKCC criteria, which overlap with the IMDC criteria in five of six areas.

In the current study, Dr. Rini and his associates applied the IMDC criteria to the same population, and derived benchmark values for outcomes by IMDC risk groups based on radiologic tumor progression measurements performed by independent reviewers on images of patients in the intention-to-treat population.

They also conducted an analysis of data from investigator measurements of tumor progression, and compared the results with the independently reviewed radiologic data for patients outcomes according to the MSKCC model.

SOURCE: Rini B et al. Clin Genitourin Cancer. 2018 May 3. doi: 10.1016/j.clgc.2018.04.005.

In hindsight, a widely used prognostic model for patients with metastatic renal cell carcinoma (mRCC) has been shown to be effective at stratifying patient risk, and may inform the design of future clinical trials.

By retrospectively comparing clinical outcomes with risk categories determined by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, Brian I Rini, MD, of the Cleveland Clinic, and his colleagues found notable differences in progression-free survival, overall survival, and objective response rates between the different risk categories among patients with mRCC treated with sunitinib (Sutent) in a major clinical trial.

“These benchmark values can aid current and future design and interpretation of clinical trials in mRCC. Results of this analysis demonstrate clear differences in patient outcomes based on IMDC prognostic risk group,” they wrote. The report was published in Clinical Genitourinary Cancer.

They also found that the Memorial Sloan Kettering Cancer Center (MSKCC) model appeared to be similar in prognostic utility to the IMDC model, and that either model could be useful for counseling patients about prognosis and treatment options.

They based their conclusions on an analysis of data from a phase 3 clinical trial comparing sunitinib with interferon alfa in patients with mRCC. Patients in this study were grouped according to prognostic risk category by the MSKCC criteria, which overlap with the IMDC criteria in five of six areas.

In the current study, Dr. Rini and his associates applied the IMDC criteria to the same population, and derived benchmark values for outcomes by IMDC risk groups based on radiologic tumor progression measurements performed by independent reviewers on images of patients in the intention-to-treat population.

They also conducted an analysis of data from investigator measurements of tumor progression, and compared the results with the independently reviewed radiologic data for patients outcomes according to the MSKCC model.

SOURCE: Rini B et al. Clin Genitourin Cancer. 2018 May 3. doi: 10.1016/j.clgc.2018.04.005.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

For adults with metastatic, treatment-naive renal clear cell carcinoma, an alternate (2 weeks on, 1 week off) oral sunitinib schedule might be more tolerable than the approved 4:2 schedule, according to the results of a single-arm, multicenter, phase 2 trial.

After a median follow-up of 17 months, 25% of 59 patients had experienced grade 3 fatigue, hand-foot syndrome, or diarrhea, 37% had required dose reductions, and only 10% had stopped treatment because of toxicity. Rates of treatment discontinuation and dose reduction compared favorably with those seen with the 4:2 schedule in the pivotal COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial (37% and 51%, respectively), reported Eric Jonasch, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his associates in the Journal of Clinical Oncology.

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, is standard first-line therapy for metastatic clear cell renal cell carcinoma. But side effects impede treatment, and moderate to severe diarrhea, fatigue, and hand-foot syndrome are especially hard to manage without dose-reducing or interrupting therapy. These and other toxicities tend to peak during the second half of the Food and Drug Administration–approved 4-week treatment cycle, the investigators noted. Building on retrospective studies that have reported less toxicity with an alternate 2:1 schedule, they powered their trial to test whether this schedule would produce grade 3 or worse diarrhea, fatigue, or hand-foot syndrome in no more than 15% of patients.

Despite missing this endpoint, “the initial 2:1 schedule and subsequent schedule and dose alterations ensured that 90% [of patients] could continue treatment and avoid protracted high-grade toxicities,” the investigators said. Sunitinib showed “robust” efficacy – a 57% overall response rate and 13.7-month median progression-free survival – even though most patients were intermediate risk (67%) or poor risk (10%), they added. The nonrandomized data support using the alternate 2:1 schedule to maintain quality of life and extend treatment duration, they concluded.

Pfizer makes sunitinib and funded the study. Dr. Jonasch disclosed research funding, travel reimbursement, and an advisory relationship with Pfizer.
 

SOURCE: Jonasch E et al. J Clin Oncol. 2018 Apr 11. doi: 10.1200/JCO.2017.77.1485.

A second interim analysis of data from the phase 3 ADAPT trial for the treatment of newly diagnosed metastatic renal cell carcinoma has led to discontinuation of the trial.

In ADAPT, 462 patients with previously untreated advanced or metastatic renal cell carcinoma (mRCC) were randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib versus sunitinib monotherapy, after undergoing cytoreductive nephrectomy.

In February 2017, the trial’s Independent Data Monitoring Committee had reviewed the data and concluded that the trial was unlikely to demonstrate a statistically significant improvement in median overall survival in the combination arm and recommended halting the trial. However, the principal investigators and the company, Argos Therapeutics, considered the data too immature to observe the delayed effects associated with immunotherapy and decided to continue the trial. They submitted a protocol amendment to the Food and Drug Administration adding additional co-primary endpoints, and in April of last year, met with the Food and Drug Administration, which accepted the amendment and agreed to continuation of the trial, according to a company press release issued in November.

In the latest interim analysis, which was conducted following an additional 51 deaths, median overall survival for the intent-to-treat patient population was 28.2 months for the combination arm (95% confidence interval, 23.4, 35.2) compared with 31.2 months (95% CI, 23.0, 44.5) for the control arm; this was one of four new co-primary endpoints. The hazard ratio was 1.10 (95% CI, 0.85, 1.42).

Other co-primary endpoints that were evaluated, including overall survival for the patients who remained alive at the time of the February 2017 interim analysis and overall survival for all patients for whom at least 12 months of follow-up was available, did not demonstrate a favorable result, Argos Therapeutics said in a recent press release.

Rocapuldencel-T “consists of autologous dendritic cells programmed with amplified RNA from a patient’s primary tumor” and is “designed to overcome immunosuppression and induce broadly reactive, long-lasting anti-tumor memory T cells” according to the early interim analysis presented at the European Society for Medical Oncology (ESMO) 2017. The drug is also being evaluated in non–small cell lung cancer and bladder cancer.

[email protected]

A second interim analysis of data from the phase 3 ADAPT trial for the treatment of newly diagnosed metastatic renal cell carcinoma has led to discontinuation of the trial.

In ADAPT, 462 patients with previously untreated advanced or metastatic renal cell carcinoma (mRCC) were randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib versus sunitinib monotherapy, after undergoing cytoreductive nephrectomy.

In February 2017, the trial’s Independent Data Monitoring Committee had reviewed the data and concluded that the trial was unlikely to demonstrate a statistically significant improvement in median overall survival in the combination arm and recommended halting the trial. However, the principal investigators and the company, Argos Therapeutics, considered the data too immature to observe the delayed effects associated with immunotherapy and decided to continue the trial. They submitted a protocol amendment to the Food and Drug Administration adding additional co-primary endpoints, and in April of last year, met with the Food and Drug Administration, which accepted the amendment and agreed to continuation of the trial, according to a company press release issued in November.

In the latest interim analysis, which was conducted following an additional 51 deaths, median overall survival for the intent-to-treat patient population was 28.2 months for the combination arm (95% confidence interval, 23.4, 35.2) compared with 31.2 months (95% CI, 23.0, 44.5) for the control arm; this was one of four new co-primary endpoints. The hazard ratio was 1.10 (95% CI, 0.85, 1.42).

Other co-primary endpoints that were evaluated, including overall survival for the patients who remained alive at the time of the February 2017 interim analysis and overall survival for all patients for whom at least 12 months of follow-up was available, did not demonstrate a favorable result, Argos Therapeutics said in a recent press release.

Rocapuldencel-T “consists of autologous dendritic cells programmed with amplified RNA from a patient’s primary tumor” and is “designed to overcome immunosuppression and induce broadly reactive, long-lasting anti-tumor memory T cells” according to the early interim analysis presented at the European Society for Medical Oncology (ESMO) 2017. The drug is also being evaluated in non–small cell lung cancer and bladder cancer.

[email protected]

A second interim analysis of data from the phase 3 ADAPT trial for the treatment of newly diagnosed metastatic renal cell carcinoma has led to discontinuation of the trial.

In ADAPT, 462 patients with previously untreated advanced or metastatic renal cell carcinoma (mRCC) were randomized 2:1 between combination treatment with Rocapuldencel-T and sunitinib versus sunitinib monotherapy, after undergoing cytoreductive nephrectomy.

In February 2017, the trial’s Independent Data Monitoring Committee had reviewed the data and concluded that the trial was unlikely to demonstrate a statistically significant improvement in median overall survival in the combination arm and recommended halting the trial. However, the principal investigators and the company, Argos Therapeutics, considered the data too immature to observe the delayed effects associated with immunotherapy and decided to continue the trial. They submitted a protocol amendment to the Food and Drug Administration adding additional co-primary endpoints, and in April of last year, met with the Food and Drug Administration, which accepted the amendment and agreed to continuation of the trial, according to a company press release issued in November.

In the latest interim analysis, which was conducted following an additional 51 deaths, median overall survival for the intent-to-treat patient population was 28.2 months for the combination arm (95% confidence interval, 23.4, 35.2) compared with 31.2 months (95% CI, 23.0, 44.5) for the control arm; this was one of four new co-primary endpoints. The hazard ratio was 1.10 (95% CI, 0.85, 1.42).

Other co-primary endpoints that were evaluated, including overall survival for the patients who remained alive at the time of the February 2017 interim analysis and overall survival for all patients for whom at least 12 months of follow-up was available, did not demonstrate a favorable result, Argos Therapeutics said in a recent press release.

Rocapuldencel-T “consists of autologous dendritic cells programmed with amplified RNA from a patient’s primary tumor” and is “designed to overcome immunosuppression and induce broadly reactive, long-lasting anti-tumor memory T cells” according to the early interim analysis presented at the European Society for Medical Oncology (ESMO) 2017. The drug is also being evaluated in non–small cell lung cancer and bladder cancer.

[email protected]

The Food and Drug Administration has granted approvals to checkpoint inhibitors nivolumab and ipilimumab in combination for the treatment of intermediate- or poor-risk, previously untreated advanced renal cell carcinoma.

The approvals were based on statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients receiving the combination of nivolumab and ipilimumab (n = 425), compared with those receiving sunitinib (n = 422) in CheckMate 214, the FDA said in a press statement.

[email protected]

The Food and Drug Administration has granted approvals to checkpoint inhibitors nivolumab and ipilimumab in combination for the treatment of intermediate- or poor-risk, previously untreated advanced renal cell carcinoma.

The approvals were based on statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients receiving the combination of nivolumab and ipilimumab (n = 425), compared with those receiving sunitinib (n = 422) in CheckMate 214, the FDA said in a press statement.

[email protected]

The Food and Drug Administration has granted approvals to checkpoint inhibitors nivolumab and ipilimumab in combination for the treatment of intermediate- or poor-risk, previously untreated advanced renal cell carcinoma.

The approvals were based on statistically significant improvements in overall survival (OS) and objective response rate (ORR) for patients receiving the combination of nivolumab and ipilimumab (n = 425), compared with those receiving sunitinib (n = 422) in CheckMate 214, the FDA said in a press statement.

[email protected]

Physicians receiving general payments from the company marketing a targeted cancer therapy were more likely to prescribe it in three out of six drugs evaluated, researchers reported.

Prescribing of sunitinib, dasatinib, and nilotinib was increased for physicians receiving such payments versus not receiving them, while prescribing of imatinib, sorafenib, and pazopanib were not, according to the analysis by Aaron P. Mitchell, MD, of the Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, and his coauthors.

In previous studies, pharmaceutical industry payments to physicians have been associated with “higher-cost, brand-name pharmaceutical prescribing,” Dr. Mitchell and his colleagues wrote. The report was published in JAMA Internal Medicine.

“Whether industry payments are associated with physician treatment choice in oncology is uncertain,” they said.

To evaluate the association between payments to oncologists and drug selection, Dr. Mitchell and his colleagues linked Open Payments data from the Centers for Medicare & Medicaid Services to data from Medicare Part D Prescriber Public Use File for the years 2013-2014.

The primary variable in the study was payments received during 2013, according to investigators, and the primary outcome of the analysis was prescriptions filled during 2014.

Open Payments reported in 2013 had a total dollar value of $4.08 billion, including $1.20 billion paid to physicians, according to CMS data.

The researchers focused on targeted therapies for two therapeutic areas: metastatic renal cell carcinoma (RCC), including sorafenib, sunitinib, and pazopanib; and chronic myeloid leukemia (CML), including imatinib, dasatinib, and nilotinib.

They limited their analysis to physicians listed as oncologists who filled at least 20 prescriptions for each of the three drugs in metastatic RCC (n = 354) or in CML (n = 2,225).

Receiving payments categorized as “general,” such as gifts, speaker fees, meals, and travel, increased the odds of prescribing drugs for both metastatic RCC (odds ratio, 2.05; 95% confidence interval, 1.34-3.14; P = .001) and for CML (odds ratio, 1.29; 95% CI, 1.13-1.47; P less than .001).

By contrast, research payments did not increase the odds of prescribing those drugs, the investigators reported.

Looking at specific drugs, they found that receipt of general payments from a drug’s manufacturer was associated with increased prescribing of sunitinib (50.5% versus 34.4%, P = .01), dasatinib (13.8% versus 11.4%, P = .02), and nilotinib (15.4% vs 12.5%, P = .01).

However, no such association was found for sorafenib or pazopanib.

For imatinib, by contrast, investigators said industry payments were associated with a prescribing decrease.

“This may reflect a strategy by the manufacturer of imatinib, which also produces nilotinib, to promote switching to nilotinib before the patent expiration of imatinib in 2015,” the researchers wrote.

Dr. Mitchell and his coauthors reported no conflict of interest disclosures related to the study.

SOURCE: Mitchell AP, et al. JAMA Intern Med. 2018 Apr 9. doi: 0.1001/jamainternmed.2018.0776.

Physicians receiving general payments from the company marketing a targeted cancer therapy were more likely to prescribe it in three out of six drugs evaluated, researchers reported.

Prescribing of sunitinib, dasatinib, and nilotinib was increased for physicians receiving such payments versus not receiving them, while prescribing of imatinib, sorafenib, and pazopanib were not, according to the analysis by Aaron P. Mitchell, MD, of the Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, and his coauthors.

In previous studies, pharmaceutical industry payments to physicians have been associated with “higher-cost, brand-name pharmaceutical prescribing,” Dr. Mitchell and his colleagues wrote. The report was published in JAMA Internal Medicine.

“Whether industry payments are associated with physician treatment choice in oncology is uncertain,” they said.

To evaluate the association between payments to oncologists and drug selection, Dr. Mitchell and his colleagues linked Open Payments data from the Centers for Medicare & Medicaid Services to data from Medicare Part D Prescriber Public Use File for the years 2013-2014.

The primary variable in the study was payments received during 2013, according to investigators, and the primary outcome of the analysis was prescriptions filled during 2014.

Open Payments reported in 2013 had a total dollar value of $4.08 billion, including $1.20 billion paid to physicians, according to CMS data.

The researchers focused on targeted therapies for two therapeutic areas: metastatic renal cell carcinoma (RCC), including sorafenib, sunitinib, and pazopanib; and chronic myeloid leukemia (CML), including imatinib, dasatinib, and nilotinib.

They limited their analysis to physicians listed as oncologists who filled at least 20 prescriptions for each of the three drugs in metastatic RCC (n = 354) or in CML (n = 2,225).

Receiving payments categorized as “general,” such as gifts, speaker fees, meals, and travel, increased the odds of prescribing drugs for both metastatic RCC (odds ratio, 2.05; 95% confidence interval, 1.34-3.14; P = .001) and for CML (odds ratio, 1.29; 95% CI, 1.13-1.47; P less than .001).

By contrast, research payments did not increase the odds of prescribing those drugs, the investigators reported.

Looking at specific drugs, they found that receipt of general payments from a drug’s manufacturer was associated with increased prescribing of sunitinib (50.5% versus 34.4%, P = .01), dasatinib (13.8% versus 11.4%, P = .02), and nilotinib (15.4% vs 12.5%, P = .01).

However, no such association was found for sorafenib or pazopanib.

For imatinib, by contrast, investigators said industry payments were associated with a prescribing decrease.

“This may reflect a strategy by the manufacturer of imatinib, which also produces nilotinib, to promote switching to nilotinib before the patent expiration of imatinib in 2015,” the researchers wrote.

Dr. Mitchell and his coauthors reported no conflict of interest disclosures related to the study.

SOURCE: Mitchell AP, et al. JAMA Intern Med. 2018 Apr 9. doi: 0.1001/jamainternmed.2018.0776.

Physicians receiving general payments from the company marketing a targeted cancer therapy were more likely to prescribe it in three out of six drugs evaluated, researchers reported.

Prescribing of sunitinib, dasatinib, and nilotinib was increased for physicians receiving such payments versus not receiving them, while prescribing of imatinib, sorafenib, and pazopanib were not, according to the analysis by Aaron P. Mitchell, MD, of the Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, and his coauthors.

In previous studies, pharmaceutical industry payments to physicians have been associated with “higher-cost, brand-name pharmaceutical prescribing,” Dr. Mitchell and his colleagues wrote. The report was published in JAMA Internal Medicine.

“Whether industry payments are associated with physician treatment choice in oncology is uncertain,” they said.

To evaluate the association between payments to oncologists and drug selection, Dr. Mitchell and his colleagues linked Open Payments data from the Centers for Medicare & Medicaid Services to data from Medicare Part D Prescriber Public Use File for the years 2013-2014.

The primary variable in the study was payments received during 2013, according to investigators, and the primary outcome of the analysis was prescriptions filled during 2014.

Open Payments reported in 2013 had a total dollar value of $4.08 billion, including $1.20 billion paid to physicians, according to CMS data.

The researchers focused on targeted therapies for two therapeutic areas: metastatic renal cell carcinoma (RCC), including sorafenib, sunitinib, and pazopanib; and chronic myeloid leukemia (CML), including imatinib, dasatinib, and nilotinib.

They limited their analysis to physicians listed as oncologists who filled at least 20 prescriptions for each of the three drugs in metastatic RCC (n = 354) or in CML (n = 2,225).

Receiving payments categorized as “general,” such as gifts, speaker fees, meals, and travel, increased the odds of prescribing drugs for both metastatic RCC (odds ratio, 2.05; 95% confidence interval, 1.34-3.14; P = .001) and for CML (odds ratio, 1.29; 95% CI, 1.13-1.47; P less than .001).

By contrast, research payments did not increase the odds of prescribing those drugs, the investigators reported.

Looking at specific drugs, they found that receipt of general payments from a drug’s manufacturer was associated with increased prescribing of sunitinib (50.5% versus 34.4%, P = .01), dasatinib (13.8% versus 11.4%, P = .02), and nilotinib (15.4% vs 12.5%, P = .01).

However, no such association was found for sorafenib or pazopanib.

For imatinib, by contrast, investigators said industry payments were associated with a prescribing decrease.

“This may reflect a strategy by the manufacturer of imatinib, which also produces nilotinib, to promote switching to nilotinib before the patent expiration of imatinib in 2015,” the researchers wrote.

Dr. Mitchell and his coauthors reported no conflict of interest disclosures related to the study.

SOURCE: Mitchell AP, et al. JAMA Intern Med. 2018 Apr 9. doi: 0.1001/jamainternmed.2018.0776.