User login
Approximately half of all patients with locally advanced or metastatic urothelial cancer (la/mUC) are ineligible to receive cisplatin-based chemotherapy. They face poor outlooks and extremely limited treatment options.
A new study indicates that enfortumab vedotin (EV) can cause major, prolonged responses in most patients in that unfortunate setting.
EV is an antibody-drug conjugate directed against nectin-4, an immunoglobulin-like cell adhesion molecule that is highly expressed in UC, obviating the need for testing prior to treatment. It is internalized in malignant cells, with release of the active moiety (monomethyl auristatin E; MMAE). MMAE causes microtubule disruption, with resultant cell-cycle arrest and apoptosis.
EV received accelerated approval from the Food and Drug Administration in December 2019 after publication of the results from cohort 1 of the open-label, single-arm, phase 2 EV-201 study.
Arjun V. Balar, MD, of the Perlmutter Cancer Center at New York University Langone Health, presented results from cohort 2 of EV-201 – the cisplatin-ineligible cohort – at the 2021 Genitourinary Cancer Symposium (Abstract 394).
EV in patients ineligible for platinum-based therapy
Patients in cohort 2 of EV-201 had received immune checkpoint inhibitor therapy for la/mUC. They received EV in the FDA-approved dose for cohort 1: 1.25 mg/kg EV on days 1, 8, and 15 of a 28-day cycle.
Patients experienced disease progression during or following their most recent treatment. Patients with more than two neuropathies, active central nervous system metastases, and uncontrolled diabetes mellitus were excluded.
“Platinum ineligible” was defined as a creatinine clearance between 30-59 cm3/min, Eastern Cooperative Oncology Group performance status (ECOG PS) 2, or hearing loss of grade 2 or greater.
The primary endpoint for cohort 2 was confirmed overall response rate (ORR) per RECIST 1.1 by blinded independent central review. Secondary endpoints were duration of response, progression-free survival, overall survival, and safety.
There were 91 patients enrolled. Two patients never received EV treatment because of deterioration after registration. The median treatment duration among the remaining 89 patients was 6.0 months (range, 0.3-24.6).
Impressive results in poor-risk patients
The patients in EV-201 cohort 2 were elderly (median age, 75 years; range, 49-90) with comorbidities. The primary reasons for platinum-ineligibility were creatinine clearance less than 60 mL/min (66%), grade 2 or greater hearing loss (15%), and ECOG PS 2 (7%); 12% of patients met more than one criterion for platinum ineligibility.
The primary tumor site was in the upper urinary tract in 43% of patients, and 79% had visceral metastases, including 24% with liver involvement.
The confirmed ORR was 52% (95% confidence interval, 40.8-62.4), with 20% complete responses. There were responses in all subgroups, including patients with primary tumor sites in the upper tract (ORR, 61%), those with liver metastasis (ORR, 48%), and patients who had not responded to immune checkpoint inhibitors (ORR, 48%).
A total of 88% of patients had some decrease in measurable tumor diameters, generally within a few weeks of treatment initiation (median time to response, 1.8 months). The rapid response to treatment was especially important to patients having cancer-associated pain.
The median progression-free and overall survival durations were 5.8 months (95% CI, 5.0-8.3) and 14.7 months (95% CI, 10.5-18.2), respectively. The median response duration was 10.9 months (95% CI, 5.78-NR). More than 25% of responses extended beyond 12 months.
About 82% of patients in cohort 2 discontinued treatment, most commonly because of disease progression (51%). The second most common reason was the development of treatment-related adverse events (TRAE; 24%).
Drilling down on treatment-related adverse events
As might be expected for cisplatin-ineligible patients, adverse events were higher for patients in cohort 2 than for cohort 1 and led to treatment discontinuation in 16% of patients overall.
TRAEs over grade 3 occurred in 55% of patients. TRAEs of special interest included rash (61% overall; 17% ≥ grade 3), peripheral neuropathy (54% overall; 8% ≥ grade 3), and hyperglycemia (10% overall; 6% ≥ grade 3). Dose reductions, interruptions, and physical therapy were helpful.
Twenty percent of patients with TRAE hyperglycemia had hyperglycemia at baseline, and 30% of TRAEs were in patients with high body mass index (BMI).
There were four treatment-related deaths, all in patients 75 years or older with multiple comorbidities. Three of the four deaths occurred within 30 days of first EV dose in patients with BMI of 30 or greater (acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome). The remaining death occurred more than 30 days after the last dose (pneumonitis).
Context and caution
The authors concluded that EV produced durable responses in platinum-ineligible patients with la/mUC, including 20% complete responses. Safety was felt to be as expected, given the known toxicities of the agent and the compromised medical condition of the patients studied.
The study discussant, Arlene O. Siefker-Radtke, MD, of the University of Texas MD Anderson Cancer Center, Houston, agreed that EV fills an unmet need, showing impressive responses in patients with visceral, liver, and bone metastases. She agreed that EV should be investigated across the spectrum of urothelial cancer.
Dr. Siefker-Radtke reminded attendees that the FDA package insert for EV described a 48% increase in the area under the concentration-time curve concentration of the MMAE active moiety in patients with mild hepatic impairment and that EV use should be avoided entirely in patients with moderate to severe liver disease.
She speculated whether augmented toxicity in patients with a high BMI could be attributable to clinically occult impaired hepatic function from fatty liver infiltration.
She indicated that clinicians should monitor closely patients with higher BMI and grade 3-4 hyperglycemia or elevated hemoglobin A1c levels and advised holding EV in patients who develop:
- Glucose levels above 250 mg/dL
- Peeling skin or bullous skin lesions. These lesions can be heralded by a diffuse erythematous or papillary rash in the preceding weeks.
- Grade 3 diarrhea or mucosal membrane toxicity of other types.
Notwithstanding concerns about toxicity and the need for monitoring, EV merits continued study in combination with other agents and in additional settings in the clinical spectrum of urothelial cancer. It is an important new option for oncologists caring for patients with urothelial cancer.
The EV-201 study was funded by Seagen. Dr. Balar and Dr. Siefker-Radtke disclosed relationships with Seagen and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Approximately half of all patients with locally advanced or metastatic urothelial cancer (la/mUC) are ineligible to receive cisplatin-based chemotherapy. They face poor outlooks and extremely limited treatment options.
A new study indicates that enfortumab vedotin (EV) can cause major, prolonged responses in most patients in that unfortunate setting.
EV is an antibody-drug conjugate directed against nectin-4, an immunoglobulin-like cell adhesion molecule that is highly expressed in UC, obviating the need for testing prior to treatment. It is internalized in malignant cells, with release of the active moiety (monomethyl auristatin E; MMAE). MMAE causes microtubule disruption, with resultant cell-cycle arrest and apoptosis.
EV received accelerated approval from the Food and Drug Administration in December 2019 after publication of the results from cohort 1 of the open-label, single-arm, phase 2 EV-201 study.
Arjun V. Balar, MD, of the Perlmutter Cancer Center at New York University Langone Health, presented results from cohort 2 of EV-201 – the cisplatin-ineligible cohort – at the 2021 Genitourinary Cancer Symposium (Abstract 394).
EV in patients ineligible for platinum-based therapy
Patients in cohort 2 of EV-201 had received immune checkpoint inhibitor therapy for la/mUC. They received EV in the FDA-approved dose for cohort 1: 1.25 mg/kg EV on days 1, 8, and 15 of a 28-day cycle.
Patients experienced disease progression during or following their most recent treatment. Patients with more than two neuropathies, active central nervous system metastases, and uncontrolled diabetes mellitus were excluded.
“Platinum ineligible” was defined as a creatinine clearance between 30-59 cm3/min, Eastern Cooperative Oncology Group performance status (ECOG PS) 2, or hearing loss of grade 2 or greater.
The primary endpoint for cohort 2 was confirmed overall response rate (ORR) per RECIST 1.1 by blinded independent central review. Secondary endpoints were duration of response, progression-free survival, overall survival, and safety.
There were 91 patients enrolled. Two patients never received EV treatment because of deterioration after registration. The median treatment duration among the remaining 89 patients was 6.0 months (range, 0.3-24.6).
Impressive results in poor-risk patients
The patients in EV-201 cohort 2 were elderly (median age, 75 years; range, 49-90) with comorbidities. The primary reasons for platinum-ineligibility were creatinine clearance less than 60 mL/min (66%), grade 2 or greater hearing loss (15%), and ECOG PS 2 (7%); 12% of patients met more than one criterion for platinum ineligibility.
The primary tumor site was in the upper urinary tract in 43% of patients, and 79% had visceral metastases, including 24% with liver involvement.
The confirmed ORR was 52% (95% confidence interval, 40.8-62.4), with 20% complete responses. There were responses in all subgroups, including patients with primary tumor sites in the upper tract (ORR, 61%), those with liver metastasis (ORR, 48%), and patients who had not responded to immune checkpoint inhibitors (ORR, 48%).
A total of 88% of patients had some decrease in measurable tumor diameters, generally within a few weeks of treatment initiation (median time to response, 1.8 months). The rapid response to treatment was especially important to patients having cancer-associated pain.
The median progression-free and overall survival durations were 5.8 months (95% CI, 5.0-8.3) and 14.7 months (95% CI, 10.5-18.2), respectively. The median response duration was 10.9 months (95% CI, 5.78-NR). More than 25% of responses extended beyond 12 months.
About 82% of patients in cohort 2 discontinued treatment, most commonly because of disease progression (51%). The second most common reason was the development of treatment-related adverse events (TRAE; 24%).
Drilling down on treatment-related adverse events
As might be expected for cisplatin-ineligible patients, adverse events were higher for patients in cohort 2 than for cohort 1 and led to treatment discontinuation in 16% of patients overall.
TRAEs over grade 3 occurred in 55% of patients. TRAEs of special interest included rash (61% overall; 17% ≥ grade 3), peripheral neuropathy (54% overall; 8% ≥ grade 3), and hyperglycemia (10% overall; 6% ≥ grade 3). Dose reductions, interruptions, and physical therapy were helpful.
Twenty percent of patients with TRAE hyperglycemia had hyperglycemia at baseline, and 30% of TRAEs were in patients with high body mass index (BMI).
There were four treatment-related deaths, all in patients 75 years or older with multiple comorbidities. Three of the four deaths occurred within 30 days of first EV dose in patients with BMI of 30 or greater (acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome). The remaining death occurred more than 30 days after the last dose (pneumonitis).
Context and caution
The authors concluded that EV produced durable responses in platinum-ineligible patients with la/mUC, including 20% complete responses. Safety was felt to be as expected, given the known toxicities of the agent and the compromised medical condition of the patients studied.
The study discussant, Arlene O. Siefker-Radtke, MD, of the University of Texas MD Anderson Cancer Center, Houston, agreed that EV fills an unmet need, showing impressive responses in patients with visceral, liver, and bone metastases. She agreed that EV should be investigated across the spectrum of urothelial cancer.
Dr. Siefker-Radtke reminded attendees that the FDA package insert for EV described a 48% increase in the area under the concentration-time curve concentration of the MMAE active moiety in patients with mild hepatic impairment and that EV use should be avoided entirely in patients with moderate to severe liver disease.
She speculated whether augmented toxicity in patients with a high BMI could be attributable to clinically occult impaired hepatic function from fatty liver infiltration.
She indicated that clinicians should monitor closely patients with higher BMI and grade 3-4 hyperglycemia or elevated hemoglobin A1c levels and advised holding EV in patients who develop:
- Glucose levels above 250 mg/dL
- Peeling skin or bullous skin lesions. These lesions can be heralded by a diffuse erythematous or papillary rash in the preceding weeks.
- Grade 3 diarrhea or mucosal membrane toxicity of other types.
Notwithstanding concerns about toxicity and the need for monitoring, EV merits continued study in combination with other agents and in additional settings in the clinical spectrum of urothelial cancer. It is an important new option for oncologists caring for patients with urothelial cancer.
The EV-201 study was funded by Seagen. Dr. Balar and Dr. Siefker-Radtke disclosed relationships with Seagen and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Approximately half of all patients with locally advanced or metastatic urothelial cancer (la/mUC) are ineligible to receive cisplatin-based chemotherapy. They face poor outlooks and extremely limited treatment options.
A new study indicates that enfortumab vedotin (EV) can cause major, prolonged responses in most patients in that unfortunate setting.
EV is an antibody-drug conjugate directed against nectin-4, an immunoglobulin-like cell adhesion molecule that is highly expressed in UC, obviating the need for testing prior to treatment. It is internalized in malignant cells, with release of the active moiety (monomethyl auristatin E; MMAE). MMAE causes microtubule disruption, with resultant cell-cycle arrest and apoptosis.
EV received accelerated approval from the Food and Drug Administration in December 2019 after publication of the results from cohort 1 of the open-label, single-arm, phase 2 EV-201 study.
Arjun V. Balar, MD, of the Perlmutter Cancer Center at New York University Langone Health, presented results from cohort 2 of EV-201 – the cisplatin-ineligible cohort – at the 2021 Genitourinary Cancer Symposium (Abstract 394).
EV in patients ineligible for platinum-based therapy
Patients in cohort 2 of EV-201 had received immune checkpoint inhibitor therapy for la/mUC. They received EV in the FDA-approved dose for cohort 1: 1.25 mg/kg EV on days 1, 8, and 15 of a 28-day cycle.
Patients experienced disease progression during or following their most recent treatment. Patients with more than two neuropathies, active central nervous system metastases, and uncontrolled diabetes mellitus were excluded.
“Platinum ineligible” was defined as a creatinine clearance between 30-59 cm3/min, Eastern Cooperative Oncology Group performance status (ECOG PS) 2, or hearing loss of grade 2 or greater.
The primary endpoint for cohort 2 was confirmed overall response rate (ORR) per RECIST 1.1 by blinded independent central review. Secondary endpoints were duration of response, progression-free survival, overall survival, and safety.
There were 91 patients enrolled. Two patients never received EV treatment because of deterioration after registration. The median treatment duration among the remaining 89 patients was 6.0 months (range, 0.3-24.6).
Impressive results in poor-risk patients
The patients in EV-201 cohort 2 were elderly (median age, 75 years; range, 49-90) with comorbidities. The primary reasons for platinum-ineligibility were creatinine clearance less than 60 mL/min (66%), grade 2 or greater hearing loss (15%), and ECOG PS 2 (7%); 12% of patients met more than one criterion for platinum ineligibility.
The primary tumor site was in the upper urinary tract in 43% of patients, and 79% had visceral metastases, including 24% with liver involvement.
The confirmed ORR was 52% (95% confidence interval, 40.8-62.4), with 20% complete responses. There were responses in all subgroups, including patients with primary tumor sites in the upper tract (ORR, 61%), those with liver metastasis (ORR, 48%), and patients who had not responded to immune checkpoint inhibitors (ORR, 48%).
A total of 88% of patients had some decrease in measurable tumor diameters, generally within a few weeks of treatment initiation (median time to response, 1.8 months). The rapid response to treatment was especially important to patients having cancer-associated pain.
The median progression-free and overall survival durations were 5.8 months (95% CI, 5.0-8.3) and 14.7 months (95% CI, 10.5-18.2), respectively. The median response duration was 10.9 months (95% CI, 5.78-NR). More than 25% of responses extended beyond 12 months.
About 82% of patients in cohort 2 discontinued treatment, most commonly because of disease progression (51%). The second most common reason was the development of treatment-related adverse events (TRAE; 24%).
Drilling down on treatment-related adverse events
As might be expected for cisplatin-ineligible patients, adverse events were higher for patients in cohort 2 than for cohort 1 and led to treatment discontinuation in 16% of patients overall.
TRAEs over grade 3 occurred in 55% of patients. TRAEs of special interest included rash (61% overall; 17% ≥ grade 3), peripheral neuropathy (54% overall; 8% ≥ grade 3), and hyperglycemia (10% overall; 6% ≥ grade 3). Dose reductions, interruptions, and physical therapy were helpful.
Twenty percent of patients with TRAE hyperglycemia had hyperglycemia at baseline, and 30% of TRAEs were in patients with high body mass index (BMI).
There were four treatment-related deaths, all in patients 75 years or older with multiple comorbidities. Three of the four deaths occurred within 30 days of first EV dose in patients with BMI of 30 or greater (acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome). The remaining death occurred more than 30 days after the last dose (pneumonitis).
Context and caution
The authors concluded that EV produced durable responses in platinum-ineligible patients with la/mUC, including 20% complete responses. Safety was felt to be as expected, given the known toxicities of the agent and the compromised medical condition of the patients studied.
The study discussant, Arlene O. Siefker-Radtke, MD, of the University of Texas MD Anderson Cancer Center, Houston, agreed that EV fills an unmet need, showing impressive responses in patients with visceral, liver, and bone metastases. She agreed that EV should be investigated across the spectrum of urothelial cancer.
Dr. Siefker-Radtke reminded attendees that the FDA package insert for EV described a 48% increase in the area under the concentration-time curve concentration of the MMAE active moiety in patients with mild hepatic impairment and that EV use should be avoided entirely in patients with moderate to severe liver disease.
She speculated whether augmented toxicity in patients with a high BMI could be attributable to clinically occult impaired hepatic function from fatty liver infiltration.
She indicated that clinicians should monitor closely patients with higher BMI and grade 3-4 hyperglycemia or elevated hemoglobin A1c levels and advised holding EV in patients who develop:
- Glucose levels above 250 mg/dL
- Peeling skin or bullous skin lesions. These lesions can be heralded by a diffuse erythematous or papillary rash in the preceding weeks.
- Grade 3 diarrhea or mucosal membrane toxicity of other types.
Notwithstanding concerns about toxicity and the need for monitoring, EV merits continued study in combination with other agents and in additional settings in the clinical spectrum of urothelial cancer. It is an important new option for oncologists caring for patients with urothelial cancer.
The EV-201 study was funded by Seagen. Dr. Balar and Dr. Siefker-Radtke disclosed relationships with Seagen and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
FROM GUCS 2021