Susan London

A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.

“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”

In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.

Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.

“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.

The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.

“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”

“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.

Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.

“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”

Study details

The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.

The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.

In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.

At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).

In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).

The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.

Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.

SOURCE: Peterson et al. ASCO 2018, Abstract 6063.

A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.

“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”

In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.

Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.

“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.

The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.

“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”

“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.

Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.

“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”

Study details

The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.

The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.

In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.

At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).

In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).

The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.

Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.

SOURCE: Peterson et al. ASCO 2018, Abstract 6063.

A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.

“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”

In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.

Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.

“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.

The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.

“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”

“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.

Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.

“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”

Study details

The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.

The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.

In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.

At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).

In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).

The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.

Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.

SOURCE: Peterson et al. ASCO 2018, Abstract 6063.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

Comprehensive testing of newly diagnosed metastatic non–small cell lung cancer (NSCLC) with next-generation sequencing (NGS) for known lung cancer–related genomic alterations is cost-saving relative to single-gene testing strategies and often faster, a new study finds.

“We know now that genomic testing for all patients with advanced NSCLC is the standard of care to help detect oncogenic drivers, to inform treatment decisions,” lead study author Nathan A. Pennell, MD, PhD, codirector of the Cleveland Clinic lung cancer program, said in a press briefing leading up to the ASCO annual meeting. But the optimal strategy for this testing is unclear.

He and his colleagues conducted a decision analytic modeling study among hypothetical insurance plans having 1 million enrollees. Outcomes were compared between NGS testing and three single-gene testing strategies.

Data indicated that compared with exclusionary, sequential, or hot-spot panel testing approaches, NGS testing simultaneously for eight genomic alterations having Food and Drug Administration–approved or investigational targeted therapies could save up to $2.1 million among Medicare beneficiaries and up to $250,842 among patients covered by commercial insurance. The costs to payers decreased as the percentage of patients receiving NGS testing increased. Moreover, the wait time for results was similar or roughly half as long with NGS.

“Our results showed that there were substantial cost savings associated with upfront NGS testing compared to all other strategies,” Dr. Pennell said. “In addition, NGS had a faster turnaround time than either sequential or exclusionary testing, which is critically important for sick lung cancer patients, to make sure they get their treatment as quickly as possible. Waiting a month or longer is simply no longer viable for patients because they get sick very quickly and these treatments work very well.”

Of note, the model indicated that some patients undergoing initial single-gene testing strategies never had their genomic alterations detected because tissue for testing ran out and they were too sick to undergo another biopsy.

“The bottom line is, ultimately, using the best single test upfront results in the fastest turnaround time, the highest percentage of patients with targetable alterations identified, and overall the lowest cost to payers,” he summarized.

Study details

For NSCLC, there are currently approved treatments that target alterations in EGFR, ALK, ROS1, and BRAF, and investigational treatments in clinical trials that target alterations in MET, HER2, RET, and NTRK1.

In the model Dr. Pennell and his colleagues developed, patients with newly diagnosed metastatic NSCLC received testing for programmed death ligand 1 (PD-L1) plus testing for the above known lung cancer–related genes using one of four strategies:

• NGS testing (testing of all eight genes plus KRAS simultaneously).
• Sequential testing (testing one gene at a time starting with EGFR).
• Exclusionary testing (testing for KRAS mutation, the most common genomic alteration, followed by sequential testing for changes in other genes only if KRAS was not mutated).
• Hot-spot panel testing (combined testing for EGFR, ALK, ROS1, and BRAF), followed by either single-gene or NGS testing for alterations in other genes.

Model results indicated that among 1 million hypothetical plan enrollees, 2,066 patients covered by the Centers for Medicare & Medicaid Services and 156 covered by U.S. commercial insurers would have newly diagnosed metastatic NSCLC and therefore be eligible for testing.

SOURCE: Pennell et al., ASCO Annual Meeting Abstract 9031.

Comprehensive testing of newly diagnosed metastatic non–small cell lung cancer (NSCLC) with next-generation sequencing (NGS) for known lung cancer–related genomic alterations is cost-saving relative to single-gene testing strategies and often faster, a new study finds.

“We know now that genomic testing for all patients with advanced NSCLC is the standard of care to help detect oncogenic drivers, to inform treatment decisions,” lead study author Nathan A. Pennell, MD, PhD, codirector of the Cleveland Clinic lung cancer program, said in a press briefing leading up to the ASCO annual meeting. But the optimal strategy for this testing is unclear.

He and his colleagues conducted a decision analytic modeling study among hypothetical insurance plans having 1 million enrollees. Outcomes were compared between NGS testing and three single-gene testing strategies.

Data indicated that compared with exclusionary, sequential, or hot-spot panel testing approaches, NGS testing simultaneously for eight genomic alterations having Food and Drug Administration–approved or investigational targeted therapies could save up to $2.1 million among Medicare beneficiaries and up to $250,842 among patients covered by commercial insurance. The costs to payers decreased as the percentage of patients receiving NGS testing increased. Moreover, the wait time for results was similar or roughly half as long with NGS.

“Our results showed that there were substantial cost savings associated with upfront NGS testing compared to all other strategies,” Dr. Pennell said. “In addition, NGS had a faster turnaround time than either sequential or exclusionary testing, which is critically important for sick lung cancer patients, to make sure they get their treatment as quickly as possible. Waiting a month or longer is simply no longer viable for patients because they get sick very quickly and these treatments work very well.”

Of note, the model indicated that some patients undergoing initial single-gene testing strategies never had their genomic alterations detected because tissue for testing ran out and they were too sick to undergo another biopsy.

“The bottom line is, ultimately, using the best single test upfront results in the fastest turnaround time, the highest percentage of patients with targetable alterations identified, and overall the lowest cost to payers,” he summarized.

Study details

For NSCLC, there are currently approved treatments that target alterations in EGFR, ALK, ROS1, and BRAF, and investigational treatments in clinical trials that target alterations in MET, HER2, RET, and NTRK1.

In the model Dr. Pennell and his colleagues developed, patients with newly diagnosed metastatic NSCLC received testing for programmed death ligand 1 (PD-L1) plus testing for the above known lung cancer–related genes using one of four strategies:

• NGS testing (testing of all eight genes plus KRAS simultaneously).
• Sequential testing (testing one gene at a time starting with EGFR).
• Exclusionary testing (testing for KRAS mutation, the most common genomic alteration, followed by sequential testing for changes in other genes only if KRAS was not mutated).
• Hot-spot panel testing (combined testing for EGFR, ALK, ROS1, and BRAF), followed by either single-gene or NGS testing for alterations in other genes.

Model results indicated that among 1 million hypothetical plan enrollees, 2,066 patients covered by the Centers for Medicare & Medicaid Services and 156 covered by U.S. commercial insurers would have newly diagnosed metastatic NSCLC and therefore be eligible for testing.

SOURCE: Pennell et al., ASCO Annual Meeting Abstract 9031.

Comprehensive testing of newly diagnosed metastatic non–small cell lung cancer (NSCLC) with next-generation sequencing (NGS) for known lung cancer–related genomic alterations is cost-saving relative to single-gene testing strategies and often faster, a new study finds.

“We know now that genomic testing for all patients with advanced NSCLC is the standard of care to help detect oncogenic drivers, to inform treatment decisions,” lead study author Nathan A. Pennell, MD, PhD, codirector of the Cleveland Clinic lung cancer program, said in a press briefing leading up to the ASCO annual meeting. But the optimal strategy for this testing is unclear.

He and his colleagues conducted a decision analytic modeling study among hypothetical insurance plans having 1 million enrollees. Outcomes were compared between NGS testing and three single-gene testing strategies.

Data indicated that compared with exclusionary, sequential, or hot-spot panel testing approaches, NGS testing simultaneously for eight genomic alterations having Food and Drug Administration–approved or investigational targeted therapies could save up to $2.1 million among Medicare beneficiaries and up to $250,842 among patients covered by commercial insurance. The costs to payers decreased as the percentage of patients receiving NGS testing increased. Moreover, the wait time for results was similar or roughly half as long with NGS.

“Our results showed that there were substantial cost savings associated with upfront NGS testing compared to all other strategies,” Dr. Pennell said. “In addition, NGS had a faster turnaround time than either sequential or exclusionary testing, which is critically important for sick lung cancer patients, to make sure they get their treatment as quickly as possible. Waiting a month or longer is simply no longer viable for patients because they get sick very quickly and these treatments work very well.”

Of note, the model indicated that some patients undergoing initial single-gene testing strategies never had their genomic alterations detected because tissue for testing ran out and they were too sick to undergo another biopsy.

“The bottom line is, ultimately, using the best single test upfront results in the fastest turnaround time, the highest percentage of patients with targetable alterations identified, and overall the lowest cost to payers,” he summarized.

Study details

For NSCLC, there are currently approved treatments that target alterations in EGFR, ALK, ROS1, and BRAF, and investigational treatments in clinical trials that target alterations in MET, HER2, RET, and NTRK1.

In the model Dr. Pennell and his colleagues developed, patients with newly diagnosed metastatic NSCLC received testing for programmed death ligand 1 (PD-L1) plus testing for the above known lung cancer–related genes using one of four strategies:

• NGS testing (testing of all eight genes plus KRAS simultaneously).
• Sequential testing (testing one gene at a time starting with EGFR).
• Exclusionary testing (testing for KRAS mutation, the most common genomic alteration, followed by sequential testing for changes in other genes only if KRAS was not mutated).
• Hot-spot panel testing (combined testing for EGFR, ALK, ROS1, and BRAF), followed by either single-gene or NGS testing for alterations in other genes.

Model results indicated that among 1 million hypothetical plan enrollees, 2,066 patients covered by the Centers for Medicare & Medicaid Services and 156 covered by U.S. commercial insurers would have newly diagnosed metastatic NSCLC and therefore be eligible for testing.

SOURCE: Pennell et al., ASCO Annual Meeting Abstract 9031.

SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.

An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.

Susan London/Frontline Medical News

Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.

Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

KEYNOTE-045 trial update

Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).

Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.

Susan London/Frontline Medical News

Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).

IMvigor 211 trial biomarker analyses

The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.

At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).

Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.

“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.

Susan London/Frontline Medical News

Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.

New data, new insights

“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”

The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”

Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.

Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.

“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.

Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”

Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.

“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”

“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”

SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.

SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.

An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.

Susan London/Frontline Medical News

Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.

Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

KEYNOTE-045 trial update

Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).

Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.

Susan London/Frontline Medical News

Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).

IMvigor 211 trial biomarker analyses

The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.

At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).

Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.

“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.

Susan London/Frontline Medical News

Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.

New data, new insights

“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”

The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”

Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.

Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.

“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.

Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”

Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.

“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”

“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”

SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.

SAN FRANCISCO – Emerging data from phase 3 clinical trials are better clarifying the efficacy and safety of immunotherapy in advanced urothelial cancer and helping identify patients most likely to benefit.

An updated analysis of the KEYNOTE-045 trial showed that, compared with chemotherapy, pembrolizumab (Keytruda), an antibody to programmed death-1 (PD-1), almost doubled the 2-year survival rate in patients with recurrent or advanced urothelial cancer. No cumulative toxicity was seen.

Susan London/Frontline Medical News

Biomarker analyses from the IMvigor 211 trial showed that, compared with chemotherapy, atezolizumab (Tecentriq), an antibody to programmed cell death ligand 1 (PD-L1), prolonged survival by more than 7 months in patients with platinum-treated locally advanced or metastatic disease whose tumors were positive for this ligand and had a high mutational burden. The difference translated to a halving of the risk of death.

Results of both trials were reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

KEYNOTE-045 trial update

Initial results of KEYNOTE-045, at a median follow-up of 14.1 months, provided level I evidence for the safety and efficacy of pembrolizumab over chemotherapy as second-line therapy for recurrent, advanced urothelial cancer (N Engl J Med. 2017;376:1015-26), leading to approval for that indication. (Pembrolizumab is also approved as first-line therapy for cisplatin-ineligible patients).

Lead investigator Joaquim Bellmunt, MD, PhD, an associate professor of medicine at Harvard Medical School and director of the Bladder Cancer Center, Dana-Farber Cancer Institute, both in Boston, reported a trial update, now at a median follow-up of 27.7 months.

Susan London/Frontline Medical News

Results among 542 patients showed that the initial overall survival benefit of pembrolizumab over chemotherapy (vinflunine, paclitaxel, or docetaxel) (hazard ratio, 0.73; P = .0022) was sustained and in fact now somewhat greater with longer follow-up (HR, 0.70; P = .00017).

IMvigor 211 trial biomarker analyses

The IMvigor 211 trial enrolled 931 patients with locally advanced or metastatic urothelial carcinoma who had experienced progression during or after platinum-based chemotherapy and had received at most two prior lines of therapy.

At a median follow-up of 17.3 months, the trial did not meet its primary endpoint of significantly better overall survival with atezolizumab versus chemotherapy (vinflunine, docetaxel, or paclitaxel) in patients having PD-L1–positive tumors, defined as immunohistochemical staining of 2 or 3 (HR, 0.87; 95% confidence interval, 0.63-1.21; P = .41) (Lancet. 2018;391:748-57).

Findings were similar in the entire intention-to-treat population (HR, 0.85; 95% CI, 0.73-0.99) and in the subset with tumors having PD-L1–negative tumors, defined as immunohistochemical staining of 0 or 1 (HR, 0.84; 0.71-1.00). In an unexpected finding, PD-L1 positivity was associated with better outcome in both treatment arms.

“So PD-L1 is a classic prognostic, not predictive, biomarker,” commented lead investigator Thomas Powles, MBBS, MRCP, MD, a clinical professor of genitourinary oncology with Barts Health NHS Trust, St. Bartholomew’s Hospital, London. The investigators therefore conducted a series of analyses in the intent-to-treat population to identify predictive biomarkers.

Susan London/Frontline Medical News

Results were essentially the same with the tumor gene expression 3 (tGE3) signature, an RNA signature that captures expression of the genes encoding interferon gamma, a chemokine ligand, and PD-L1, and that is a marker for preexisting T-cell immunity. And they were also similar with the DNA damage response (DDR) biomarker.

New data, new insights

“We already know the KEYNOTE-045 trial is positive,” commented the invited discussant, Dr. Jones. “This longer follow-up data is important because we need to better describe the magnitude of benefit.”

The updated survival findings are exciting because they resemble those seen with ipilimumab in melanoma, with about a fifth of patients still alive several years out, he said. Longer follow-up is needed, but “the data we see today are in keeping with the possibility that we might be seeing a similar long-term tail – the so-called immuno-oncology tail – of survival for patients with urothelial cancer as well.”

Although not statistically significant, the difference in progression-free survival is clinically important, according to Dr. Jones. This benefit is driven by both higher response rate and longer duration of response with pembrolizumab.

Long-term toxicity, especially immune-related toxicity, is also a consideration. “There is a small increment in the number of some of these toxicities, but essentially it hasn’t changed. So it would appear that there is certainly not an unexpected peak of latent immunotoxicity with this treatment,” he noted.

“Our confidence in the data for second-line pembrolizumab, if it needed to be further increased, is increased. This does help our patients make an informed decision about whether or not to accept this treatment,” he summarized.

Turning to the IMvigor 211 biomarker study, Dr. Jones said, “I would argue that the choice of second-line therapy in advanced urothelial cancer is not a clinically important decision. The reason for saying that is the case for second-line chemotherapy is poor. We’ve all used it, but we’ve never had high level evidence of benefit. … But it’s important because when we consider moving into the first-line setting, where there are active alternatives, or maybe even more into the perioperative setting, it actually could be vitally important.”

Studies of immunotherapies and targeted therapies in other cancers suggest that a clinically useful predictive biomarker will identify patients who will derive at least a doubling of favorable outcome or a halving of unfavorable outcome when given the drug as compared with a control. “So it appears that the bar has been set quite high,” Dr. Jones said.

“These IMvigor 211 data are exploratory, and they would need further independent validation, in my view,” he said. Nevertheless, “this may provide us the opportunity to use combinations of biomarkers where now we are seeing a hazard ratio of 0.50 [for risk of death] combining PD-L1 with high tumor mutational burden (TMB). That hazard ratio is bringing it into the area where it may be of a magnitude big enough to use in clinical practice, if this could be validated.”

“I would say that none of these data support a role for second-line cytotoxics after failure of platinum, at least not in preference to a checkpoint inhibitor,” Dr. Jones concluded. “There is still no biomarker to inform a choice in second-line treatment. However, TMB, either alone or in combination with other markers, shows promise, which we need to validate in future randomized trials.”

SOURCE: Bellmunt J et al. GUC 2018 Abstract 410; Powles T et al. GUC 2018, Abstract 409.

SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.

In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.

Susan London/Frontline Medical News

As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.

TACTICS trial

“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”

The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.

They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.

Susan London/Frontline Medical News

The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).

“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.

CELESTIAL trial

The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.

Susan London/Frontline Medical News

Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.

The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.

Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.

Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.

New treatments increase options, complexity

The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.

“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”

The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”

Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”

In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.

Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.

The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”

All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.

Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”

SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.

SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.

In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.

Susan London/Frontline Medical News

As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.

TACTICS trial

“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”

The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.

They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.

Susan London/Frontline Medical News

The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).

“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.

CELESTIAL trial

The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.

Susan London/Frontline Medical News

Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.

The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.

Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.

Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.

New treatments increase options, complexity

The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.

“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”

The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”

Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”

In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.

Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.

The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”

All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.

Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”

SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.

SAN FRANCISCO – Two new therapies that target vascular endothelial growth factor signaling are efficacious and may expand the treatment armamentarium for intermediate and advanced hepatocellular carcinoma, data from a pair of randomized trials suggest.

In the phase 2 TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination With Sorafenib) trial, median progression-free survival, using a new, more narrow definition of progression, was almost a year longer when the oral tyrosine kinase inhibitor sorafenib (Nexavar) was added to transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), translating to a 41% reduction in risk of events. This benefit came at the price of higher rates of certain grade 3 adverse events, but the combination was overall feasible and safe.

Susan London/Frontline Medical News

As welcome as such new therapeutic options are, they will likely increase the complexity of the treatment landscape for HCC and could muddy the ability of future trials to establish survival benefit, Jordi Bruix, MD, PhD, cautioned in an invited discussion. In addition, patients who cannot receive anti–vascular endothelial growth factor (VEGF) therapy because of comorbidities still represent an unmet need, underscoring the importance of continued research on other fronts.

TACTICS trial

“Because TACE has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors,” said TACTICS lead investigator Masatoshi Kudo, MD, professor and chairman of the department of gastroenterology and hepatology at Kindai University, Osaka, Japan. “Since TACE and sorafenib have been shown to prolong survival in patients with unresectable HCC, their combination may improve clinical outcomes.”

The 156 patients enrolled in the TACTICS trial, sponsored by the Japan Liver Oncology Group, had unresectable HCC, a Child-Pugh score of 7 or lower, and no vascular invasion or extrahepatic spread.

They were randomly assigned to as-needed TACE alone or TACE plus sorafenib, which inhibits VEGF receptors, platelet-derived growth factor receptors, and Raf kinases, reducing growth signaling and angiogenesis. Sorafenib therapy was interrupted only for several days before and after each TACE session.

Susan London/Frontline Medical News

The trial’s positive results contrast with those of the earlier randomized Post-TACE trial, SPACE trial, and TACE 2 trial, noted Dr. Kudo. This may be due to both the new, narrower definition of progression and the longer duration of sorafenib therapy in TACTICS (median 38.7 weeks) as compared with those trials (17.0-21.0 weeks).

“The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate-stage HCC,” he concluded.

CELESTIAL trial

The 707 patients in the phase 3 CELESTIAL trial, sponsored by Exelixis, had advanced HCC with Child-Pugh class A and had previously received sorafenib. About 70% had received only one prior systemic regimen for their advanced disease, according to lead investigator Ghassan K. Abou-Alfa, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center, New York.

Susan London/Frontline Medical News

Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (HR, 0.76; P = .0049). Median progression-free survival was 5.2 months and 1.9 months, respectively (HR, 0.44; P less than .0001). For both outcomes, benefit was similar across most patient subgroups and among patients whose only prior therapy was sorafenib.

The objective response rate was 4% with cabozantinib (all partial responses) and 0.4% with placebo. Median time to subsequent systemic anticancer therapy – most commonly cytotoxic chemotherapy – was 6.6 months with the drug and 3.3 months with placebo.

Median duration of treatment was 3.8 months and 2.0 months, respectively. The rate of discontinuation from treatment-related adverse events was 16% and 3%.

Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group (mainly hand-foot syndrome, hypertension, and gastrointestinal events) and 36% in the placebo group. Six patients in the former group and one in the latter group had grade 5 treatment-related adverse events, most due to worsening of hepatic function.

New treatments increase options, complexity

The new endpoint of unTACEable progression used in TACTICS “is an interesting potential surrogate endpoint for survival. It probably needs to be refined. I would not follow exactly the Japanese methodology,” said Dr. Bruix, the invited discussant.

“More importantly, it needs to be validated,” he added. “The survival data need to be there to see what is the value of the surrogate intermediate endpoint.”

The pattern of overall survival thus far suggests that an early advantage from adding sorafenib to TACE is lost over time. “Potentially, what we have here is the treatment maintained a bit beyond what would be recommended in the Western guidelines,” proposed Dr. Bruix, professor of medicine at the University of Barcelona and director of the Barcelona Clinic Liver Cancer Group. “The longer duration of sorafenib obviously may be related to the specific management in Japan, but also to the fact that progression recognition is delayed. If you delay recognition, you delay the definition of treatment interruption.”

Results of TACTICS probably will not lead to incorporation of sorafenib in clinical practice at this time, he concluded. “This will take a while. There is lots of noise in the chemoembolization trials, there are lots of discussions about what should be done.” In addition, “this should be studied in the West and in a large sample size.”

In the CELESTIAL trial, it would have been helpful to see biomarker data (given that tumor MET status may influence benefit from cabozantinib) and patient stratification according to reason for stopping prior sorafenib (intolerance versus progression), according to Dr. Bruix.

Furthermore, pattern of progression was not reported. “What drives a poorer outcome [in HCC] is the extrahepatic dissemination, meaning vascular invasion or extrahepatic spread. The trials, at least as a post hoc analysis, should have nowadays this kind of analysis that I think is not going to be available in the cabozantinib trial,” he said.

The fact that time to progression with cabozantinib was longer than time on the drug hints at possible safety and tolerability issues, according to Dr. Bruix. “This makes me suspect that some patients had something prior to progression that primed treatment interruption. This is something that I would like to see better explored … to understand to what extent the drug is safe, can be managed, or whether there are too many treatment interruptions that can lead to this discrepancy.”

All of the emerging systemic therapies for first- and second-line therapy in HCC, now also including immune checkpoint inhibitors, are likely to complicate the treatment landscape in the next few years, he cautioned. “The positioning of agents and the sequencing of treatments is different across the world. So there may be confusion in the field and that will affect all the trials that are going to be run by different companies, because if we do not maintain the discipline, patients will jump from one trial to the other and the follow-up after progression will be contaminated.” Ultimately, this could lead to noninformative trials.

Finally, “something that needs to be stated is that all the agents that are positive act on the VEGF pathway. This leaves a proportion of patients that cannot benefit from these agents because of comorbidity that are still in need of something that improves survival,” Dr. Bruix concluded. “We all should focus beyond VEGF and try to develop new strategies.”

SOURCE: Kudo M et al. GI Cancers Symposium, Abstract 206. Abou-Alfa GK et al. GI Cancers Symposium, Abstract 207.

SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.

“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”

The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).

With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.

Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.

Susan London/Frontline Medical News

Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.

Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”

The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.

 

Weighing the evidence

The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”

Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).

“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.

Susan London/Frontline Medical News

“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.

It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
 

Study details

Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.

Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.

Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).

Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).

“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).

The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.

Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

SOURCE: Hussain M et al. Abstract 3.

SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.

“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”

The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).

With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.

Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.

Susan London/Frontline Medical News

Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.

Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”

The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.

 

Weighing the evidence

The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”

Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).

“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.

Susan London/Frontline Medical News

“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.

It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
 

Study details

Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.

Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.

Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).

Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).

“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).

The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.

Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

SOURCE: Hussain M et al. Abstract 3.

SAN FRANCISCO – The androgen receptor inhibitor enzalutamide is efficacious for treating nonmetastatic castration-resistant prostate cancer accompanied by a rapidly rising prostate-specific antigen (PSA) level, according to results of the phase 3 PROSPER trial.

“Nonmetastatic castration-resistant prostate cancer is an area of unmet need with no currently approved therapies. The development of metastases is predictable in this group of patients and is associated with increasing baseline PSA and a PSA doubling time of less than 10 months,” said lead author Maha Hussain, MBChB, deputy director at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity and also prolong overall survival.”

The PROSPER investigators enrolled 1,401 men with nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less despite castrate levels of testosterone. They were randomized 2:1 to enzalutamide (Xtandi) or placebo, with continuation of androgen deprivation therapy in both groups. (At present, enzalutamide is approved by the Food and Drug Administration for untreated and docetaxel-treated metastatic castration-resistant prostate cancer).

With a median follow-up of 22 months, median metastasis-free survival (based on radiographic progression or death) was about 22 months longer with enzalutamide versus placebo, according to results reported at the 2018 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology. The difference translated to a 71% reduction in risk of events.

Relative to peers in the placebo group, patients in the enzalutamide group also had dramatically longer time to PSA progression (93% risk reduction) and time to first use of new antineoplastic therapy (79% risk reduction). An interim analysis showed a trend toward better overall survival with the drug as well, and it was well tolerated.

Susan London/Frontline Medical News

Although progression on PROSPER was ascertained by conventional imaging, advent of new, more sensitive imaging modalities, such as fluciclovine and prostate-specific membrane antigen PET, are unlikely to change the calculus, according to Dr. Hussain. “These patients have micrometastatic disease. The fact that we have imaging criteria right now that are not very sensitive does not mean we don’t think the patients have micromets. With the newer technologies, certainly, a good chunk of these patients could have physical metastatic disease,” she elaborated. And cancer treatments often achieve greater benefits when moved earlier in the disease course.

Approved indications aside, oncologists will likely take a tailored approach when deciding to treat nonmetastatic castration-resistant prostate cancer with enzalutamide or a similar agent, Dr. Hussain said. “Like anything else, the issue is going to boil down to a shared decision with the patient, pros and cons, and then making a decision together.”

The findings with enzalutamide in the PROSPER trial are also noteworthy in that they largely mirror those obtained with apalutamide in the SPARTAN trial, which were reported in the same session at the symposium.

 

Weighing the evidence

The 2-year prolongation of metastasis-free survival with apalutamide and enzalutamide is “very impressive,” said invited discussant Philip Kantoff, MD, a medical oncologist and chair of the department of medicine, Memorial Sloan Kettering Cancer Center in New York. “These drugs are very biologically active. This potentially gives us options for men with M0 castration-resistant prostate cancer. It’s something I would like to see as a clinician, but we have to be a little bit cautious. Treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk.”

Clinical benefit of a drug in this patient population could be shown in three ways, he said: curing disease (which is unlikely), prolonging survival (which is as yet unproven), and improving quality of life by, for example, reducing anxiety over rising PSA levels and preventing skeletal-related adverse events (which is hinted at by SPARTAN data showing that enzalutamide delayed time to symptomatic progression).

“Clinical benefit, to me, is not fully demonstrated in these two studies, and there are some untoward effects that need to be better defined,” Dr. Kantoff maintained. In particular, apalutamide was associated with higher (albeit still low) rates of grade 3 or worse falls, fractures, and rash, and enzalutamide with more deaths in the absence of radiographic progression, for unclear reasons.

Susan London/Frontline Medical News

“My confidence in declaring victory would be greater with further scrutiny of the toxicities and understanding how the care patterns in these studies compare with actual practice, specifically, the timing of initiation of alternative therapies in these trials as opposed to what’s going on in the community,” he said.

It is too early to determine whether one drug is superior, according to Dr. Kantoff. “These were not comparative trials, so we don’t have enough information to say one versus the other. There’s a hint of different toxicity profiles. It isn’t clear that the efficacy is different.” And when it comes to adoption by community oncology, the FDA will have a role, sifting through the data for both drugs and rendering decisions, he said.
 

Study details

Median metastasis-free survival in PROSPER was 36.6 months with enzalutamide and 14.7 months with placebo (hazard ratio, 0.29; P less than .0001), Dr. Hussain reported. Benefit was similar across a range of patient subgroups, including patients with PSA doubling times of less than and greater than 6 months.

Patients in the enzalutamide group had half the rate of progression events when compared with peers in the placebo group (23% vs. 49%). Among those with a metastasis-free survival event, the rate of deaths without documented radiographic progression after stopping study treatment was higher with enzalutamide (15% vs. 2%); there were somewhat more cardiovascular deaths with the drug within this subset, but no single cause was clearly predominant, she said.

Median time to PSA progression was 37.2 months with enzalutamide and merely 3.9 months with placebo (HR, 0.07; P less than .0001). Median time to first use of new antineoplastic therapy was 39.6 months and 17.7 months, respectively (HR, 0.21; P less than .0001).

Median overall survival was not yet reached in either group, but tended to be longer with enzalutamide (HR, 0.80).

“Therapy overall was well tolerated. Adverse events were generally consistent with those reported in prior clinical trials in men with castration-resistant disease,” Dr. Hussain said. The rate of grade 3 or worse events was 31% with enzalutamide and 23% with placebo. The enzalutamide group more commonly experienced grade 3 or worse hypertension (5% vs. 2%) and fatigue (3% vs. 1%).

The rate of adverse events leading to study discontinuation was 9% with enzalutamide and 6% with placebo, and that of death due to adverse events was 3% and 1%, respectively.

Dr. Hussain disclosed that she receives honoraria from OncLive; has a consulting or advisory role with Abbvie, Bayer, and Genentech/Roche; has patents, royalties, or other intellectual property pertaining to dual inhibition of MET and VEGF for the treatment of castration-resistant prostate cancer; and receives travel, accommodations, or expenses from Abbvie, Bayer, and Genentech. In addition, her institution receives research funding from AstraZeneca, Genentech, PCCTC, and Pfizer. The trial was sponsored by Pfizer, with collaboration of Astellas Pharma Inc. and Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

SOURCE: Hussain M et al. Abstract 3.

SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.

The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.

“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”

Clinical implications

“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”

Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”

“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”

Study details

Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.

Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.

“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”

The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”

As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.

The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.

SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408

SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.

The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.

“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”

Clinical implications

“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”

Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”

“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”

Study details

Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.

Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.

“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”

The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”

As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.

The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.

SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408

SAN FRANCISCO – Two concurrent chemoradiation induction regimens had similar safety and efficacy when used as part of a bladder-sparing strategy in patients with muscle-invasive bladder cancer, suggest primary results of the NRG/RTOG 0712 trial. But one offers better patient convenience.

The selective bladder-preservation paradigm entails maximal transurethral resection of the bladder tumor (TURBT) followed by induction radiation and concomitant chemotherapy, lead author John J. Coen, MD, a radiation oncologist with 21st Century Oncology, Providence, Rhode Island, noted at the 2018 Genitourinary Cancers Symposium. Patients then undergo cystoscopy to assess their response.

“A key component of this therapy is close urologic surveillance,” he noted. “This is trimodality therapy with close urologic surveillance, and cystectomy is prompted at the earliest time it’s indicated.”

Clinical implications

“I would have to see more details about the toxicity data for the chemotherapy, the radiosensitizers,” session co-chair Yair Lotan, MD, a professor of urology at the UT Southwestern Medical Center, Dallas, Texas, commented in an interview. “But in general, if you have two equivalent protocols in terms of effectiveness, and one is less toxic or more convenient, that’s always preferable. From the standpoint of coming once a day rather than twice a day to get radiation, if I were a patient, I would prefer that regimen”

Current practice in this patient population likely hinges on where a patient is treated, he said. “Based on the new nonmetastatic muscle-invasive guidelines, many of them would be recommended surgery or possibly chemoradiation protocols, and then there are a lot of factors such as patient preference and outcomes that would probably impact the decision making.”

“Certainly, this study won’t prove standard of care because standard of care in the global picture for a patient with muscle-invasive disease really will depend on a randomized trial of surgery versus radiation or chemoradiation, multimodal therapies,” Dr. Lotan maintained. “Not every patient is even eligible; some patients with hydronephrosis or unresectable disease may not be the best candidates for multimodal therapy. But more information from these types of trials may help clinicians decide which multimodal therapy approach to use.”

Study details

Patients enrolled in NRG/RTOG 0712, a multicenter randomized phase 2 trial supported by the National Cancer Institute, had clinical T2 or T3-4a bladder cancer. Hydronephrosis and obvious lymph node involvement were exclusion criteria.

Like the rate of freedom from metastasis, the rate of complete response after induction therapy was similar for the two arms: 87.9% with twice-daily radiation plus 5-flourouracil-cisplatin and 75.8% with daily radiation plus gemcitabine.

“These rates exceed historical complete response rates, and this is likely a result of improved selection over time and more thorough TURBTs performed over time,” Dr. Coen proposed. “Over the course of multiple successive RTOG trials, our selection criteria have been refined. One excellent example would be that hydronephrosis has been excluded on more contemporary trials, but if you look at older trials, those patients were included.”

The 3-year rate of bladder-intact distant metastasis–free survival was 66.7% and 69%, respectively. “This is a very important endpoint. These results are excellent,” he commented. “And there is really no appreciable difference between the two arms on the actuarial analysis.”

As far as specific treatment failure events in the trial overall, three patients died, eight underwent cystectomy, and eight developed distant metastases. Although numbers were small, these events appeared fairly evenly distributed across arms.

The rate of grade 3 or 4 acute toxicity was 57.6% with twice-daily radiation plus 5-flourouracil-cisplatin and 54.6% with daily radiation plus gemcitabine. The large majority of events were blood and bone marrow toxicity. “It’s quite notable that the rates of GU and GI toxicity were very low,” commented Dr. Coen, who disclosed that he had no relevant conflicts of interest.

SOURCE: Coen, J. et al, 2018 Genitourinary Cancers Symposium, Abstract 408

SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.

Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.

“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”

Other viewpoints

“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.

“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”

“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.

“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.

On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”

The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”

Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.

Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.

Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.

Study details

Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.

Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.

In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).

Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).

Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.

The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.

The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.

Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.

In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.

Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.

SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407

SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.

Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.

“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”

Other viewpoints

“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.

“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”

“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.

“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.

On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”

The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”

Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.

Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.

Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.

Study details

Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.

Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.

In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).

Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).

Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.

The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.

The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.

Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.

In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.

Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.

SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407

SAN FRANCISCO – Patients who have undergone nephro-ureterectomy for upper-tract urothelial cancer (UTUC) fare much better if they are given adjuvant chemotherapy, according to the first results of the POUT trial reported at the 2018 Genitourinary Cancers Symposium.

Standard treatment for this rare cancer is radical nephro-ureterectomy followed by surveillance, noted lead author Alison Jane Birtle, MD, MRCP, FRCR, a consultant clinical oncologist at the Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom. Evidence has been insufficient to recommend adjuvant therapy.

“We know that UTUC shares a similar etiology with bladder cancer, where there is strong evidence for chemotherapy,” she said. “Trials of adjuvant chemotherapy in bladder cancer have been challenging because of cystectomy being a much more morbid operation. So adjuvant chemotherapy after nephro-ureterectomy should be much easier to give because of the less morbid procedure.”

Other viewpoints

“It’s fantastic that we finally have data in upper-tract cancer. However, I worry about how this data is going to be interpreted, and I argue that it should not be considered the standard of care,” session attendee Matthew Campbell, MD, of the MD Anderson Cancer Center, Houston, commented during a question and answer period.

“I believe that this is showing that chemotherapy is very important in this disease, and if anything, it should be moved into the neoadjuvant setting, where more patients will be cisplatin candidates. Though there is challenge with staging upper-tract disease, at MD Anderson, we consider patients with high-grade disease or hydronephrosis to be at high enough risk to consider for neoadjuvant chemotherapy, and that’s been our approach.”

“When we looked at developing POUT, there was a big debate about whether it should be a neoadjuvant or adjuvant study,” Dr. Birtle replied. UK oncologists expressed concern that not all patients have histologic confirmation of UTUC preoperatively; therefore, chemotherapy could lead to overtreatment for some.

“We plan to go back and look at the CT urograms and the diagnostic imaging done prior to surgery just to see if we can be 100% confident in our diagnostic accuracy preoperatively, to see if we would be more confident with a neoadjuvant study,” she added. The investigators have also reviewed data from the British Association of Urological Surgeons on the postoperative dip in GFR. “It didn’t really seem from that 2015 data that there was a huge unmet need for patients postoperatively, where we would have missed them had we not treated them preoperatively,” she said.

On a related note, session attendee Surena Matin, MD, also of MD Anderson, asked “How many patients were potentially precluded because of their GFR, and do you have any data regarding response rates in the carboplatin arm?”

The main reason for exclusion was ineligible pathology and not GFR, according to Dr. Birtle. “This goes back to the previous question of can you be certain that a patient has locally advanced disease prior to nephro-ureterectomy? About 60% of patients who were thought to have muscle-invasive disease ultimately on nephro-ureterectomy didn’t.”

Confidence intervals for chemotherapy benefit in the subgroup given carboplatin were wide and overlapped unity, but still favoring benefit and falling within the overall treatment effect, she said.

Session attendee Joaquim Bellmunt, MD, Dana-Farber Cancer Institute, Boston, noted that the chemotherapy benefit was not significant in that subgroup and also in the subgroups with lymph node–positive disease and with positive margins. “I think that saying … chemotherapy is for everybody based on this trial” is incorrect, he asserted. “It may be good just to tone down the message that this is the new standard of care.” He further questioned the trial’s early stopping, noting that continuing would have provided more information in these patients.

Those subgroups were small, so analyses were underpowered to definitively rule out chemotherapy benefit, according to Dr. Birtle. The investigators had intensive discussion about the recommendation to stop early, because of a goal to determine overall survival impact. Ultimately, “when we saw the data in terms of disease-free survival and metastasis-free survival, the magnitude of the effect was so big that we felt it was uncomfortable and unethical not to offer patients treatment,” she said.

Study details

Patients in POUT’s chemotherapy arm received four cycles of chemotherapy—gemcitabine-cisplatin if their GFR was 50 mL/min or higher, or gemcitabine-carboplatin if their GFR was 30-49 mL/min—starting within 90 days of nephro-ureterectomy.

Of note, approximately 40% of all patients in the trial were aged 70 years or older, including the 5% who were aged 80 years or older. “This is very reassuring for a study of adjuvant platinum-based chemotherapy,” Dr. Birtle commented. Fully 71.2% of the chemotherapy patients received all four planned cycles.

In an intention-to-treat analysis, risk of disease-free survival events (death from any cause, metastasis, or any ureteric or renal bed recurrence) was sharply reduced with chemotherapy versus surveillance (hazard ratio, 0.49; P=.001). The proportion of patients event free at 2 years was 71% in the chemotherapy group and 54% in the surveillance group. Benefit was generally similar across subgroups, and findings were much the same after adjustment for nodal involvement, microscopic margin status, and planned chemotherapy regimen (hazard ratio, 0.47; P=.001).

Risk of metastasis-free survival events was also sharply lower with chemotherapy (hazard ratio, 0.49; P=.002), with a proportion event free at 2 years of 74% in the chemotherapy group and 60% in the surveillance group. These findings were also much the same after adjustment for the above factors (hazard ratio, 0.47; P=.002).

Overall survival tended to be better with chemotherapy than with surveillance (hazard ratio, 0.55), but data are still immature for this endpoint.

The rate of grade 3 or worse adverse events during the treatment period was 53.2% with chemotherapy and 13.5% with surveillance; events with chemotherapy were as expected, with neutropenia, thrombocytopenia, and gastrointestinal events predominating. The rate of febrile neutropenia was 5.7% with gemcitabine-cisplatin and 7.8% with gemcitabine-carboplatin, but there were no neutropenic deaths.

The rate of grade 3 or worse adverse events for the entire trial period was 62.1% with chemotherapy and 24.8% with surveillance.

Data on nephrotoxicity are still being evaluated, according to Dr. Birtle. Only seven patients who started on gemcitabine-cisplatin had to switch to gemcitabine-carboplatin because their GFR fell.

In a related translational study, the investigators are evaluating both the baseline CT urograms and the resected tumors to identify prognostic and predictive markers, she said.

Dr. Birtle disclosed that she receives honoraria from Roche, Janssen, Astellas, and Bayer, and is a consultant to Sanofi-Aventis. The trial was funded by the UK Clinical Trials Awards and Advisory Committee.

SOURCE: Birtle A et al. Genitourinary Cancers Symposium. Abstract 407

SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.

Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

Clinical implications

“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”

Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”

“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
 

Study details

The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.

Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.

Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.

“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.

“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”

In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group

Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).

Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.

When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.

Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.

[email protected]

SOURCE: James ND et al. GUCS Abstract 162.

SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.

Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

Clinical implications

“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”

Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”

“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
 

Study details

The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.

Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.

Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.

“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.

“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”

In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group

Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).

Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.

When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.

Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.

[email protected]

SOURCE: James ND et al. GUCS Abstract 162.

SAN FRANCISCO – Adding docetaxel to first-line long-term hormone therapy for advanced prostate cancer, whether metastatic or not, improves quality of life, reduces need for subsequent therapy, and is cost effective, suggests a new analysis of data from the STAMPEDE trial.

Hormone therapy alone has historically been standard of care for this disease, lead study author Nicholas D. James, MD, PhD, a professor of clinical oncology at the University of Birmingham, England, noted in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

Clinical implications

“In this analysis of data from the STAMPEDE trial, we see that docetaxel, a chemotherapy drug that has been in our armamentarium for prostate cancer for over a decade, may be applied in earlier and earlier settings in the disease,” commented ASCO expert and moderator of the press briefing, Sumanta K. Pal, MD. “Dr. James has previously reported the survival gains associated with this drug, but today adds the dimension of demonstrating improved quality of life and potentially cost-effectiveness as well.”

Results can be compared against those seen with abiraterone (Zytiga), an oral hormonal therapy that has shown similar benefit in these same patient populations, he said. “Abiraterone may offer the benefit of improved tolerability over a short course versus chemotherapy, but does require a much more extensive duration of use and further mandates concomitant use of prednisone.”

“Understanding the cost and quality of life associated with abiraterone in this setting may help adjudicate between giving this drug or docetaxel for the patients that Dr. James describes,” concluded Dr. Pal, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.
 

Study details

The ongoing multi-arm STAMPEDE randomized trial has thus far enrolled more than 9,000 men with advanced (nonmetastatic and metastatic) prostate cancer and evaluated 10 treatments for the disease. About 60% of enrolled men have metastases.

Dr. James and colleagues developed a state transition model to reflect the natural history of patients entering the trial. Rate of progression and quality of life data (assessed with the EuroQol EQ-5D tool) were ascertained from the trial; costs came from both the trial and the literature.

Results indicated that, despite the adverse quality of life impacts of receiving chemotherapy and of living longer with metastatic disease, adding docetaxel to hormone therapy ultimately increased quality-adjusted life-years, with similar benefit seen in both nonmetastatic and metastatic disease.

“It was very interesting to us that, in the nonmetastatic patients, the quality-adjusted life-year gain was almost of the same magnitude, despite there being no evidence yet in STAMPEDE follow-up of a definite survival benefit in this group,” Dr. James noted. In these patients, chemotherapy has an upfront “quality of life penalty,” but that is offset by the later quality of life gains from delaying relapses (and thus time to further treatment) and, when nonmetastatic disease becomes metastatic, reducing events such as fractures and spinal cord compression.

“These later gains essentially wipe out the quality of life cost, if you like, from docetaxel, giving you a net gain almost as big in magnitude as the gain in metastatic patients,” he summarized. “We think this is a really important new finding.”

In a cost breakdown, adding docetaxel to hormone therapy increased drug costs in patients with both nonmetastatic and metastatic disease. Costs for end of life care, adverse events, and monitoring changed little in either group

Adding docetaxel increased costs for management by about 1,000 pounds sterling in patients with nonmetastatic disease (likely related to the chemotherapy administration) and about 2,000 pounds sterling in patients with metastatic disease (likely related to chemotherapy administration and longer survival).

Of special note, with addition of docetaxel, costs for other life-prolonging therapies – abiraterone, enzalutamide (Xtandi), radium (Xofigo), and similar treatments – fell by about 2,500 pounds sterling in nonmetastatic disease and 1,000 pounds sterling in metastatic disease. These savings are attributable to a shorter period of time spent in the relapsed state for patients who receive docetaxel, Dr. James explained. And savings are much greater for patients with nonmetastatic disease because they spend a much shorter time post relapse, given that the extended failure-free survival with docetaxel does not fully translate to extended overall survival.

When it comes to total lifetime costs, “basically, your downstream savings almost completely wipe out, even in the metastatic patients, the upfront costs,” he summarized.

Dr. James disclosed that he receives honoraria from Sanofi/Aventis, Janssen, Astellas Medivation, Bayer Health, and Merck Sharp & Dohme; has a consulting or advisory role with Janssen, Sanofi/Aventis, Merck Sharp & Dohme, Roche, Astellas Medivation, and Bayer; and is on the speakers’ bureau for Bayer, Janssen, Roche, and Ipsen; in addition, his institution receives research funding from Janssen, Astellas Medivation, Bayer, Sanofi/Aventis, and Roche. The study was funded by Cancer Research UK and the Medical Research Council, United Kingdom.

[email protected]

SOURCE: James ND et al. GUCS Abstract 162.