Meeting NewsPerspective

Enfortumab vedotin induces responses in advanced urothelial cancer

Daniel P. Petrylak, MD
Daniel P. Petrylak

CHICAGO — The investigational therapy enfortumab vedotin demonstrated an objective response rate of 44% among a cohort of patients with locally advanced or metastatic urothelial cancer whose disease progressed after two previous lines of therapy, according to results from the single-arm, phase 2 EV-201 study presented at ASCO Annual Meeting.

Further, the study’s lead author told HemOnc Today that 84% of patients who received the novel agent, which exhibited a manageable safety profile, experienced some form of tumor shrinkage.

Most patients with advanced urothelial cancer will experience disease progression after first-line platinum-based chemotherapy and then receive one of five FDA-approved checkpoint inhibitors as second-line therapy, according to Daniel P. Petrylak, MD, professor of medicine and urology and co-director of the Signal Transduction Research Program at Yale Cancer Center, and a HemOnc Today Editorial Board Member.

“There is an unmet medical need for new therapies for the treatment of metastatic urothelial carcinoma. For example, only approximately 20% of patients will respond to checkpoint inhibition therapy, and there is no FDA-approved agent for the treatment of these patients,” Petrylak added. “Unfortunately, there is no standard therapy for patients who have progressed after platinum-based chemotherapy and PD-L1 or PD-1 inhibitors.”

Enfortumab vedotin (ASG-22ME; Seattle Genetics, Astellas) is an investigational antibody-drug conjugate that consists of an anti-nectin-4 monoclonal antibody attached to a synthetic cell-killing agent, monomethyl auristatin E — a microtubule-disrupting agent — using proprietary linker technology.

Petrylak explained that nectin-4 is a cellular adhesion molecule that is expressed in approximately 97% of urothelial cancer specimens.

“Enfortumab vedotin is a monoclonal antibody to nectin, which is linked to an anti-tubulin agent, MMAE, and thus can deliver this agent directly to bladder cancer cells,” he added.

Petrylak and colleagues presented data from cohort 1 of the phase 2, single-arm trial that evaluated enfortumab vedotin among patients with locally advanced or metastatic urothelial carcinoma. Cohort 1 included 125 patients (median age, 69 years; range, 40-84; 70% men) enrolled between October 2017 and July 2018 who received previous platinum chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor (median prior systemic therapies, 3; range, 1-6). Enrollment continues for cohort 2, which includes patients with no prior chemotherapy.

About one-third of patients (35%) in cohort 1 had upper-tract primary tumors, and 65% had a PD-L1 status by combined positive score of less than 10. Researchers observed nectin-4 expression among all 120 patients with adequate tissue for testing.

Patients received 1.25 mg/kg IV enfortumab vedotin on days 1, 8 and 15 of each 28-day treatment cycle.

ORR per RECIST version 1.1 criteria as measured by blinded independent central review served as the primary endpoint. Secondary endpoints included duration of response, PFS, OS and safety.

Results showed an ORR of 44% (95% CI. 35.1, 53.2), including 15 complete responses (12%) and 40 partial responses (32%). Thirty-five patients (28%) had stable disease, whereas 23 patients (18%) had disease progression.

The ORR among patients with liver metastases was 38% (95% CI, 24.7, 52.8).

Median time to response was 1.8 months (range, 1.2-9.2), with responses lasting a median 7.6 months (range, 0.95-11.30 +).

Survival analyses showed median PFS of 5.8 months (95% CI, 4.9-7.5) and median OS of 11.7 months (95% CI, 9.1 to not reached).

Twelve percent of patients discontinued treatment due to treatment-related adverse events. The most common treatment related adverse events included fatigue (50%), alopecia (49%) and decreased appetite (44%). Grade 3 or higher treatment-related adverse events included rash (12%), hyperglycemia (6%) and peripheral neuropathy (3%).

“I was impressed with the consistency of the data between our phase 1 and 2 trials,” Petrylak said. “The response rates are similar in both studies, both for all patients as well as those patients with hepatic metastases.”

Petrylak said that the response rate among patients with hepatic metastases needs further study because they are a known poor prognostic factor for urothelial cancer.

“If approved by the FDA, enfortumab vedotin is an option for treatment of patients who have been treated with chemotherapy as well as checkpoint inhibition therapy,” he said.

“A phase 3 trial is ongoing comparing enfortumab vedotin to dealer’s-choice chemotherapy in patients with metastatic disease who have failed chemotherapy and checkpoint inhibition therapy.” – by Drew Amorosi

Reference:

Petrylak DP, et al. Abstract. LBA4505. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Petrylak reports consultant/advisory roles with Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Eli Lilly and Dendreon; providing expert testimony for Celgene and Sanofi; stock and other ownership interests in Bellicum Pharmaceuticals and Tyme; and research funding from Agensys, Astellas Medivation, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Eli Lilly, Endocyte, Genentech, Innocrin Pharma, Johnson & Johnson, Merck, MedImmune, Millennium, Novartis, Pfizer, Progenics, Roche, Sanofi, Seattle Genetics and Sotio. Please see the abstract for all other authors’ relevant financial disclosures.

Daniel P. Petrylak, MD
Daniel P. Petrylak

CHICAGO — The investigational therapy enfortumab vedotin demonstrated an objective response rate of 44% among a cohort of patients with locally advanced or metastatic urothelial cancer whose disease progressed after two previous lines of therapy, according to results from the single-arm, phase 2 EV-201 study presented at ASCO Annual Meeting.

Further, the study’s lead author told HemOnc Today that 84% of patients who received the novel agent, which exhibited a manageable safety profile, experienced some form of tumor shrinkage.

Most patients with advanced urothelial cancer will experience disease progression after first-line platinum-based chemotherapy and then receive one of five FDA-approved checkpoint inhibitors as second-line therapy, according to Daniel P. Petrylak, MD, professor of medicine and urology and co-director of the Signal Transduction Research Program at Yale Cancer Center, and a HemOnc Today Editorial Board Member.

“There is an unmet medical need for new therapies for the treatment of metastatic urothelial carcinoma. For example, only approximately 20% of patients will respond to checkpoint inhibition therapy, and there is no FDA-approved agent for the treatment of these patients,” Petrylak added. “Unfortunately, there is no standard therapy for patients who have progressed after platinum-based chemotherapy and PD-L1 or PD-1 inhibitors.”

Enfortumab vedotin (ASG-22ME; Seattle Genetics, Astellas) is an investigational antibody-drug conjugate that consists of an anti-nectin-4 monoclonal antibody attached to a synthetic cell-killing agent, monomethyl auristatin E — a microtubule-disrupting agent — using proprietary linker technology.

Petrylak explained that nectin-4 is a cellular adhesion molecule that is expressed in approximately 97% of urothelial cancer specimens.

“Enfortumab vedotin is a monoclonal antibody to nectin, which is linked to an anti-tubulin agent, MMAE, and thus can deliver this agent directly to bladder cancer cells,” he added.

Petrylak and colleagues presented data from cohort 1 of the phase 2, single-arm trial that evaluated enfortumab vedotin among patients with locally advanced or metastatic urothelial carcinoma. Cohort 1 included 125 patients (median age, 69 years; range, 40-84; 70% men) enrolled between October 2017 and July 2018 who received previous platinum chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor (median prior systemic therapies, 3; range, 1-6). Enrollment continues for cohort 2, which includes patients with no prior chemotherapy.

About one-third of patients (35%) in cohort 1 had upper-tract primary tumors, and 65% had a PD-L1 status by combined positive score of less than 10. Researchers observed nectin-4 expression among all 120 patients with adequate tissue for testing.

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Patients received 1.25 mg/kg IV enfortumab vedotin on days 1, 8 and 15 of each 28-day treatment cycle.

ORR per RECIST version 1.1 criteria as measured by blinded independent central review served as the primary endpoint. Secondary endpoints included duration of response, PFS, OS and safety.

Results showed an ORR of 44% (95% CI. 35.1, 53.2), including 15 complete responses (12%) and 40 partial responses (32%). Thirty-five patients (28%) had stable disease, whereas 23 patients (18%) had disease progression.

The ORR among patients with liver metastases was 38% (95% CI, 24.7, 52.8).

Median time to response was 1.8 months (range, 1.2-9.2), with responses lasting a median 7.6 months (range, 0.95-11.30 +).

Survival analyses showed median PFS of 5.8 months (95% CI, 4.9-7.5) and median OS of 11.7 months (95% CI, 9.1 to not reached).

Twelve percent of patients discontinued treatment due to treatment-related adverse events. The most common treatment related adverse events included fatigue (50%), alopecia (49%) and decreased appetite (44%). Grade 3 or higher treatment-related adverse events included rash (12%), hyperglycemia (6%) and peripheral neuropathy (3%).

“I was impressed with the consistency of the data between our phase 1 and 2 trials,” Petrylak said. “The response rates are similar in both studies, both for all patients as well as those patients with hepatic metastases.”

Petrylak said that the response rate among patients with hepatic metastases needs further study because they are a known poor prognostic factor for urothelial cancer.

“If approved by the FDA, enfortumab vedotin is an option for treatment of patients who have been treated with chemotherapy as well as checkpoint inhibition therapy,” he said.

“A phase 3 trial is ongoing comparing enfortumab vedotin to dealer’s-choice chemotherapy in patients with metastatic disease who have failed chemotherapy and checkpoint inhibition therapy.” – by Drew Amorosi

Reference:

Petrylak DP, et al. Abstract. LBA4505. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosures: Petrylak reports consultant/advisory roles with Astellas Pharma, AstraZeneca, Bayer, Bellicum Pharmaceuticals, Eli Lilly and Dendreon; providing expert testimony for Celgene and Sanofi; stock and other ownership interests in Bellicum Pharmaceuticals and Tyme; and research funding from Agensys, Astellas Medivation, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Eli Lilly, Endocyte, Genentech, Innocrin Pharma, Johnson & Johnson, Merck, MedImmune, Millennium, Novartis, Pfizer, Progenics, Roche, Sanofi, Seattle Genetics and Sotio. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Scott Tagawa

    Scott Tagawa

    This trial enrolled patients with metastatic urothelial carcinoma with progression despite previous treatment with platinum chemotherapy and a checkpoint inhibitor. The typical survival for patients in this trial would normally be measured in months.

    The drug being examined had a very interesting 40%-plus response rate in phase 1 testing and has apparently been confirmed now in a phase 2 trial for a disease state for which there are not many treatment options.

    This trial essentially confirms the response rate as being quite favorable in all of the disease subsets and with an acceptable toxicity profile.

    • Scott Tagawa, MD, MS
    • Weill Cornell Medicine and NewYork-Presbyterian

    Disclosures: Tagawa reports a consultant role with and institutional funding (to Weill Cornell) from Seattle Genetics.

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