Astellas, Seattle plan FDA filing after cancer ADC clears test

Astellas and Seattle Genetics are preparing to file for FDA approval of enfortumab on the strength of phase 2 data. The trial linked the antibody-drug conjugate to a 44% response rate in patients with locally advanced or metastatic urothelial cancer.

Investigators enrolled 128 patients previously treated with platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor in the first cohort of the single-arm trial. The participants received infusions of anti-Nectin-4 ADC enfortumab once a week for a month in the hope that the drug would trigger partial or complete responses. 

With 44% of patients responding to the drug, Astellas and Seattle Genetics think they have the data to get the drug past the FDA. That belief is underpinned by the absence of options for patients in the study population. 

“After progression on platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor, patients with locally advanced or metastatic urothelial cancer are left with no approved standard of care treatment options,” Astellas SVP Steven Benner said in a statement. “These data are very encouraging, and we look forward to discussing the data with relevant health authorities.”

Studies of the leading checkpoint inhibitors show there is ample scope to improve on the treatment of urothelial cancer. Merck’s Keytruda achieved a 21% response rate in a phase 3 trial in the disease. Checkpoint inhibitors from Bristol-Myers Squibb, Roche and others delivered comparable response rates to Keytruda.

Enfortumab could offer another option for patients failed by checkpoint inhibitors but investigators are yet to share a close look at the data. Astellas said duration of response in the phase 2 was in line with an earlier clinical trial, which had an estimated overall survival of 12.5 months as of the end of September. 

The researchers are yet to share details of the split between complete and partial responses. Based on the phase 1, which recorded a response rate of 42%, the vast majority of the responses are likely to be partial.

Analysts at SVB Leerink hailed the trial as a success. 

"We believe that these top-line data meaningfully exceed broad investor expectations, with most looking for an ORR of at least ~30%," the analysts wrote in a note to investors. "We believe that [the trial] has sufficiently cleared the bar needed to obtain accelerated approval, which we view as a 20-25% ORR."

Astellas and Seattle are now working to get the data ready for a filing for approval of the drug, which has breakthrough status from the FDA. The plan is to file a BLA later this year while continuing to run a phase 3 trial to support global registration. 

If Astellas and Seattle successfully execute that plan, they stand a chance of colonizing the emerging post-immune checkpoint inhibitor space. Immunomedics hopes to carve out a piece of that market for its ADC, too.

The ADC, IMMU-132, was knocked back by the FDA in triple-negative breast cancer but is advancing in metastatic urothelial cancer. A pivotal trial started last year, and an early study linked IMMU-132 to a 31% response rate.

Enfortumab and IMMU-132, also known as sacituzumab govitecan, are both ADCs but have different targets. Enfortumab targets cell adhesion molecule Nectin-4 to deliver a microtubule-disrupting drug to cancer cells. IMMU-132 targets cell surface receptor TROP-2 and delivers SN-38, the active metabolite of irinotecan.

The promise shown by the ADCs in urothelial cancer contrasts with setbacks to the broader field. Over the past year, AbbVie terminated a trial of an ADC it acquired in the Stemcentrx takeover. And ADC Therapeutics has canned a study of one of its prospects in HER2-positive cancers.