ESMO: New Trodelvy breast, bladder cancer data show why Gilead's going big for Immunomedics

Compared with the spate of multibillion-dollar buyouts last year, biopharma M&A has been relatively quiet in 2020—until last week, when Gilead Sciences surprised the market with its $21 billion purchase of Immunomedics.

Now, two sets of new cancer data from Immunomedics’ first-in-class antibody-drug conjugate (ADC) Trodelvy offer a glimpse into why Gilead paid such big money for the biotech—even as they illuminate the potential competition ahead.

In Trodelvy’s FDA-approved indication of metastatic triple-negative breast cancer (TNBC), the anti-TROP-2 drug cut the risk of disease progression by 59% over chemotherapy in patients who had previously failed on at least two chemo regimens.

More importantly, the phase 3 Ascent trial presented Saturday at the European Society of Medical Oncology's virtual congress showed Trodelvy also helped patients live longer, cutting the risk of death by a whopping 52%. Those on Trodelvy lived a median 12.1 months, compared with just 6.7 months for chemo patients.

As Ascent trial investigators pointed out, Trodelvy is the first ADC to show significant survival improvement over standard chemo in this heavily pretreated TNBC population. The data will likely help Immunomedics turn its conditional FDA nod, earned in April, into a full one.

“[W]e expect broad adoption of Trodelvy in the 3L TNBC patient population, and likely some usage in the 2L setting as well since many metastatic TNBC patients have already received chemotherapy in the neoadjuvant or adjuvant setting,” SVB Leerink analyst Geoffrey Porges wrote in a Monday note to clients. “This positions Trodelvy positively compared to competitors in the TNBC indication.”

But while Trodelvy holds the ADC lead in TNBC, bladder cancer is a different story.

Data from the first cohort of the phase 2 Trophy-U-01 trial showed Trodelvy shrank tumors in 27% of 113 metastatic urothelial cancer patients who had progressed after platinum chemo and checkpoint inhibitors. The response Trodelvy triggered lasted a median 5.9 months—and the drug completely eradicated signs of cancer in six (5%) of the treated patients.

RELATED: Astellas, Seattle Genetics' Padcev bladder cancer trial stops early with 30% death risk reduction

However, that showing fell short of the 44% overall response rate—including 12% complete responses—that Seattle Genetics and Astellas’ anti-Nectin-4 ADC Padcev posted in its own phase 2 trial. In that study, dubbed EV-201, Padcev’s median duration of response also lasted longer, stretching into 7.6 months.

To put more pressure on Trodelvy, Padcev’s phase 3 EV-301 trial just stopped early after an interim analysis showed the drug cut the risk of death by an impressive 30% versus chemotherapy in the same third-line setting.

Although cross-trial comparisons can be problematic, industry watchers do it anyway to assess the competition. And, after the Padcev trial halt this week, analysts pointed up the challenge for Immunomedics.

“We also believe Padcev’s overall survival benefit will raise the bar for its competitor Trodelvy,” SVB Leerink analyst Andrew Berens wrote in a Friday note to clients.

But Immunomedics Chief Financial Officer and Chief Business Officer Usama Malik played down the competition by pointing to potential sequential use between the two drugs. Investigators of the Trophy-U-01 said about 10 patients in the study were pretreated with Padcev, and three had a response, potentially indicating at least Trodelvy use after Padcev. Trodelvy and Padcev target different markers on tumors cells, and they use different toxins to kill off tumor cells as well. 

“The way I frame it is that the market here grows—it’s not necessarily competitive—what it does is that it broadens and allows patients more options,” Malik said in an interview.

Malik also said Trodelvy’s safety profile is better than Padcev’s, but Porges disagreed. In his note, Porges argued that Trodelvy's neutropenia side effects, with 34% at grade 3 or 4 in the Trophy-U-01 trial, will limit its use. Padcev in its trial showed a total of 73% of grade 3 or 4 adverse events, mostly rash, diarrhea and fatigue. “This suggests to us that in the smaller UC indication, Trodelvy is likely to get less adoption than Padcev, or to be used as an even later line treatment,” Porges wrote in the Monday note.

RELATED: Gilead needs 'heroic' Immunomedics revenues to get a return on $21B deal: analyst

The Gilead deal definitely put Trodelvy on a larger commercial platform. “As a small biotech, while I think we certainly punched above our weight class for a long time, the ability to provide much larger access to this product around the world and to hyper-accelerate the development of the pipeline, including Trodelvy, the capabilities and the ambition that Gilead brings to the table is going to be phenomenal,” Malik said.

For Gilead, the Immunomedics deal marks CEO Daniel O’Day’s latest effort to turn the Big Biotech into an oncology force to be reckoned with. But even before the latest Padcev news, industry watchers were questioning whether Gilead overpaid.

For example, Bernstein analyst Ronny Gal figured third-line TNBC and bladder cancer only together represent about $1.5 billion in peak sales for Trodelvy. For Gilead to break even on the deal, Trodelvy needs to reach at least $4 billion at peak, meaning it'll need to gin up an additional $2.5 billion in earlier lines of therapy and other tumor types, he said.

Immunomedics has been trying to improve Trodelvy’s prospects by pairing it up with other drugs, too. When Gilead unveiled the $21 billion deal, Chief Medical Officer Merdad Parsey, M.D., Ph.D., highlighted checkpoint inhibitors and PARP inhibitors as two promising combo options.

In a trial collaboration with Clovis Oncology, Trodelvy’s being tested in tandem with Rubraca in a phase 1/2 trial spanning multiple solid tumors, including TNBC, bladder cancer and ovarian cancer.

Plus, Roche is running a multiarm, phase 1/2 TNBC trial combining Tecentriq—currently the only PD-1/L1 inhibitor approved in TNBC—with different drugs, including Trodelvy in newly diagnosed PD-L1-positive patients. Interestingly, that study also includes Seattle Genetics’ experimental ADC ladiratuzumab vedotin (SGN-LIV1A), which Merck just splashed out $1.6 billion to license for pairing with Keytruda.

Trodelvy has its own Keytruda combo trials going, too. In bladder cancer, Immunomedics recently expanded Trophy-U-01 to include a Keytruda combo. In breast cancer, it plans to pit Trodelvy-plus-Keytruda against solo Trodelvy in a phase 2 test in previously untreated, metastatic TNBC. Another phase 2 will evaluate the same cocktail in HR-positive, HER2-negative disease.

As Trodelvy looks to new indications and geographies, building out a global commercial infrastructure will “remain a high priority for Gilead,” Malik said. “You would expect that those investments will be there.”

Editor's Note: The story has been updated with additional comments from Immunomedics CFO and CBO Usama Malik and SVB Leerink's Geoffrey Porges.