ASCO: Merck KGaA, Pfizer's Bavencio combo misses survival mark in crowded kidney cancer space

Five years after scoring an FDA approval to treat newly diagnosed advanced kidney cancer, the combination of Merck KGaA’s Bavencio and Pfizer’s Inlyta has failed on the overall survival endpoint of a phase 3 trial.

The Bavencio-Inlyta combo showed a favorable trend, reducing the risk of death by 14% compared with Pfizer’s Sutent as a first-line treatment in renal cell carcinoma with PD-L1 expression, the final overall survival (OS) analysis from the JAVELIN Renal 101 trial showed.

But the number, gleaned after a median follow-up of more than six years, missed statistical significance. The study has therefore missed one of its two independent primary endpoints. In the overall trial population, the death-risk reduction was smaller at 12%.

The results were shared in an abstract Thursday and will be presented in detail at the upcoming American Society of Clinical Oncology 2024 annual meeting.

The Bavencio regimen won’t lose its FDA approval, and the trial is still considered positive because the PD-L1/TKI combo previously showed it can significantly stall tumor progression or death versus Sutent. But missing the overall survival mark won’t be helpful to Bavencio in its competition with PD-1/TKI rivals from Merck & Co. and Bristol Myers Squibb.

Longer trial follow-ups are typically unfavorable for OS readouts for immunotherapy-based regimens in first-line kidney cancer, a spokesperson for Merck KGaA’s EMD Serono biopharma arm told Fierce Pharma, citing external factors that can affect the analyses.

Previously, in the phase 3 CheckMate-9ER trial, BMS’ Opdivo and Exelixis’ Cabometyx significantly reduced the risk of death by 30% compared with Sutent in the preplanned final OS analysis after a median follow-up of about 33 months. But the showing shrank to 23% during a longer follow-up of about 56 months.

Similarly, in its own combination with Inlyta, Merck’s Keytruda significantly slashed the risk of death by 47% against Sutent in the KEYNOTE-426 trial after a short follow-up of nearly 13 months. Then, after about 30 months of median follow-up, the figure decreased to 32%.

While the Bavencio combo missed the OS mark in the overall population, EMD Serono pointed to a subgroup of patients who had a favorable risk profile under the International Metastatic RCC Database Consortium. In these roughly 200 patients of the nearly 900-strong trial, Bavencio and Inlyta showed a 27% reduction in the risk of death, which is the biggest benefit seen so far among existing therapies.

The regimen also boasts a low discontinuation rate: Only 4.8% of patients permanently stopped both Bavencio and Inlyta due to treatment-related adverse events versus 9.3% for Sutent.

“We continue to believe in the value of Bavencio + [Inlyta] as the data, both clinical and real-world, clearly show the benefit of this treatment combination by balancing efficacy and [quality of life] for patients in the [first-line kidney cancer] setting, especially in favorable-risk group and older patients where maintained QoL is a key goal,” the company spokesperson said in a statement.

Nevertheless, as the combo has failed to register a significant OS benefit since its approval, the Bavencio-Inlyta regimen has largely come to be viewed as inferior to PD-1/TKI combos, including Keytruda’s Lenvima pairing.

Merck KGaA, recognizing the competition, only has had a “limited focus” in kidney cancer, according to the spokesperson. Instead, the company is directing its Bavencio efforts toward first-line maintenance use in advanced bladder cancer, which represents the drug’s largest indication in the U.S.

But it faces a new threat in that indication in the form of Keytruda’s combination with Pfizer and Astellas’ antibody-drug conjugate Padcev, which entered first-line bladder cancer treatment last year to much fanfare.

Earlier this month, Peter Guenter, who leads Merck KGaA’s pharma business, said the company had not yet seen a significant effect from the Keytruda-Padcev launch in the U.S. But he noted a decrease of platinum-based chemotherapy in the first three months of 2024. That means Bavencio might see a bigger impact starting in the second quarter, because the PD-L1 drug is approved as a maintenance therapy in patients who’ve responded to a round of chemo.

In the first quarter, Bavencio’s sales increased 14% year over year at constant exchange rate to 186 million euros. Because only about 30% of the drug’s sales come from the U.S., Merck KGaA still expects the drug to continue to grow in 2024.

Merck KGaA had previously shared Bavencio rights with Pfizer until the New York pharma returned its stake last year to win antitrust clearance for its $43 billion acquisition of Seagen, which co-developed Padcev.