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Can TOOKAD Earn ODAC Support in Early Prostate Cancer?

SILVER SPRING, Md. — A novel focal therapy that uses a laser-activated agent for treating early prostate cancer will face scrutiny from an FDA advisory committee on Wednesday, as will an add-on targeted agent for the first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC).

TOOKAD in Early Prostate Cancer

In a morning session, the Oncologic Drugs Advisory Committee (ODAC) will decide on whether padeliporfin di-potassium (TOOKAD) as an alternative to active surveillance constitutes a benefit for men with localized, low-risk prostate cancer.

According to briefing documents from FDA staff, TOOKAD “is a derivative of bacteriochlorophyll, a photosynthetic pigment of aquatic bacteria.” Developed by Steba Oncology, the treatment is administered in a 4 mg/kg dose over a single 10-minute infusion, and then activated by “laser illumination” with fibers placed in the patient’s prostate.

Primary support for the treatment derives from the randomized phase III PCM301 study, which evaluated TOOKAD versus active surveillance in 413 men with low-risk localized prostate cancer — most had very-low-risk disease (62%), T1c tumors (85%), and the average prostate-specific antigen (PSA) level was 6.1 ng/mL (maximum of 10 ng/mL for inclusion). Co-primary endpoints of the trial were rates of definite-cancer at 24 months and time to disease progression.

The FDA had rejected these endpoints in 2011, as it was unclear they represented a clinical benefit, and Steba ultimately conducted PCM301 exclusively in Europe, where it is now approved based on the study’s positive results.

At 2 years, 49% of patients in the investigational arm were free of definite cancer, as compared with 13.5% in the active surveillance arm. And far fewer patients required definitive therapy in the group that received TOOKAD (5.8% vs 26.6% in the surveillance group).

Median time to progression was 28.3 months with TOOKAD versus 14 months with surveillance (HR 0.34, 95% CI 0.25-0.48, P<0.0001), and all subgroups appeared to benefit. However, more toxicity was observed in the treatment arm.

In 2018, the FDA conducted a workshop where experts suggested that decreased rates of pathologic upgrade could be clinically meaningful in localized prostate cancer, if accompanied by a drop in need for definitive therapy due to cancer progression. But they added that this should not be at the expense of long-term cancer control or increased toxicity, as measured by physicians and patient-reported outcomes (PROs).

PRO data will be presented on Wednesday, and ODAC will be asked to discuss whether the overall findings “represent a favorable benefit/risk profile for TOOKAD” in this patient population.

Cyramza in First-Line Lung Cancer

During an afternoon session, ODAC will review data from the international phase III RELAY trial and discuss whether use of ramucirumab (Cyramza) as a first-line add-on treatment in EGFR-mutant NSCLC represents a clinically meaningful benefit.

While the drug significantly slowed disease progression when added to erlotinib (Tarceva), a first-generation EGFR tyrosine kinase inhibitor (TKI), updated interim overall survival (OS) analyses — a secondary endpoint — presented by manufacturer Eli Lilly demonstrated no additional benefit with ramucirumab.

In nearly 450 stage IV EGFR-positive patients with exon 19 deletions or L858R mutations, median progression-free survival reached 19.4 months with erlotinib plus the VEGFR2 inhibitor ramucirumab compared with 12.4 months with erlotinib and placebo (HR 0.59, 95% CI 0.46-0.76, P<0.0001).

At a December 2019 data cutoff, 59 patients (26%) in the investigational arm had died compared with 66 patients (29%) in the control arm (HR 0.92, 95% CI 0.65-1.32).

“Given the upper limit of the confidence interval of 1.3, the results suggest a possible detrimental effect on survival for patients treated with the combination of ramucirumab and erlotinib,” FDA staff wrote in briefing documents ahead of the meeting. “In the context of an add-on therapy associated with increased toxicity, FDA considers this a safety concern.”

Grade ≥3 treatment-emergent adverse events (AEs) occurred in 72% of the ramucirumab arm versus 54% of the placebo arm. Serious AEs were reported in 29% and 21%, respectively. Grade ≥3 toxicities more frequent in the ramucirumab versus placebo arm included hypertension (24% vs 5%), dermatitis acneiform (15% vs 9%), diarrhea (7% vs 1.3%), and others.

“While the first-line treatment of patients with EGFR-positive NSCLC remains an unmet medical need, there are therapies currently approved for which an improvement in OS has been observed when compared to first generation EGFR TKI,” said FDA staff.

Since the RELAY trial started enrollment, first-line treatment of EGFR-mutated NSCLC has evolved. In the U.S., patients are now treated with osimertinib (Tagrisso) alone based on findings from the FLAURA trial, which most recently reported a nearly 7-month OS advantage against physician’s choice of erlotinib or gefitinib (Iressa).

Along with indications in gastric/gastroesophageal junction, liver, and colorectal cancers, ramucirumab is approved in NSCLC as a second-line option for metastatic patients who progress on or after platinum chemotherapy or after an appropriate targeted therapy for those with EGFR– or ALK-positive disease.

Last Updated February 24, 2020