Eli Lilly arrived at the American Society of Clinical Oncology meeting in Chicago this morning armed with early data for a new drug that could, if all goes right, challenge the dominance of Pfizer and Astellas’ Padcev in bladder cancer.
For now, the bulk of Lilly’s phase 1 trial of LY4052031 is focused on safety and proving that the antibody-drug conjugate (ADC)—which, like Padcev, targets Nectin-4—could show some signs of shrinking tumors in patients with advanced or metastatic urothelial cancer.
Padcev, in combination with Merck & Co.’s Keytruda, has quickly become standard-of-care in the field, but patients can still relapse and often face tough outcomes when they do, Jake Van Naarden, Lilly’s president of oncology and head of corporate business development, told Fierce Biotech in an interview.
“At the time of relapse, Nectin-4 remains overexpressed on the cancer cells,” Van Naarden explained. This led Lilly to hypothesize that cancer evolves to resist Padcev’s chemotherapy payload, called monomethyl auristatin E (MMAE), meaning Nectin-4 is still a viable target if a different chemical is used.
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LY4052031 instead uses a topoisomerase I inhibitor as a payload, which is not yet featured in any approved bladder cancer medicines, Van Naarden said.
For the 48 patients in the Nexus-01 trial who could already be evaluated, 42% saw their tumors shrink after treatment with LY4052031. That includes 12 of 36 patients who had previously been given Padcev and Keytruda, and eight of 12 who were never given Padcev.
It’s those eight patients who hint at LY4052031’s true potential. While going up against Padcev directly would require many more patients and a head-to-head trial, “there’s no reason to believe theoretically” that Lilly’s new ADC couldn’t compete directly with Padcev in first-line treatment, Van Naarden said.
“We have to enroll more and get more comfortable around that,” he told Fierce. “But the preliminary data in that population do look strong, admittedly.”
The most common side effects in the study have been low-grade alopecia and nausea, Lilly reported in the presentation. But some patients experienced significantly worse adverse effects than others, all because of their genes.
“There’s a small but important minority of patients who have a genetic predisposition for slowly metabolizing or poorly metabolizing the payload itself,” Van Naarden explained. “That can lead to some pretty extreme toxicity.”
Three such patients in the study died—one of pneumonia and two of sepsis. Such “outlier toxicities,” Van Naarden said, have always happened when using chemotherapy, but they are typically so rare that they aren’t studied meticulously.
“It wouldn’t surprise me if this is a more common thing than we’ve realized across drug programs,” the oncology leader said. In fact, Lilly only realized this issue in the Nexus-01 study because multiple patients predisposed to respond poorly were enrolled by chance.
When these patients are set aside, LY4052031 is a generally well-tolerated ADC, Van Naarden argued.
Lilly is now moving the trial into a phase 1b dose expansion stage, and if the ADC passes muster the drugmaker would consider heading straight into phase 3, Van Naarden said.
LY4052031 is just one of two next-gen Nectin-4 ADCs Lilly originally envisioned, with the pharma also set to present data for the other candidate at ASCO. But that other program, dubbed LY4101174, won’t be moving forward, Van Naarden said, because the data didn’t cut it.
“It didn’t pan out, and that’s okay,” he said. “We put these two things in the clinic simultaneously in order to figure this out, so our expectation was to pick one.”
