Merck's Keytruda Plus Chemotherapy Fails to Meet Primary Endpoints in Phase III KEYNOTE-361 Trial for Advanced Bladder Cancer

News Event

Today, MSD announced that its PD-1 antibody Keytruda failed to outperform chemotherapy in improving overall survival (OS) and progression-free survival (PFS) in patients with advanced bladder cancer when added to standard chemotherapy. The KEYNOTE-361 trial enrolled 1,010 patients with advanced bladder cancer, who were treated with Keytruda monotherapy, platinum-based standard chemotherapy, or combination therapy, with OS and PFS as the primary endpoints. Although the combination therapy showed improvement in both endpoints, the differences did not reach statistical significance. Due to the failure of the combination therapy, no formal statistical analysis was conducted for Keytruda monotherapy.

Drug Source Analysis

Bladder cancer was one of the earliest approved indications for PD-1 inhibitors. Most major PD-1 agents received second-line approval for advanced bladder cancer due to their high response rates. However, despite these high response rates, the durability of responses was limited. Consequently, in head-to-head trials, only Keytruda demonstrated a survival benefit over chemotherapy in study KN045; other agents have not yet shown superior efficacy. Both Keytruda and Tecentriq have entered the first-line setting, primarily for patients with high PD-L1 expression or those intolerant to platinum-based therapy. In March this year, although the DANUBE trial of the PD-L1 inhibitor Imfinzi combined with the CTLA-4 antibody tremelimumab enrolled patients with high PD-L1 expression, it failed to demonstrate superiority over chemotherapy, highlighting the limitations of PD-1/PD-L1 inhibitors in this population. In the IMvigor130 trial, while the combination of Tecentriq and chemotherapy improved progression-free survival (PFS) compared with chemotherapy alone, the difference in overall survival (OS) did not reach statistical significance. With the widespread adoption of PD-1 inhibitors, crossover treatment upon disease progression may have increased the likelihood of trial failures. Nevertheless, based solely on current efficacy data, PD-1 inhibitors cannot replace chemotherapy in the treatment of advanced bladder cancer.

Although chemotherapy has well-established efficacy, its severe side effects often significantly impair patients’ quality of life. While PD-1 inhibitors may not necessarily surpass chemotherapy in terms of efficacy, they have a considerably more favorable safety profile. Therefore, selecting the optimal initial treatment when efficacy is comparable remains a critical clinical question. Although targeted therapies and immunotherapies demonstrate remarkable effectiveness in certain patient subsets, chemotherapy continues to serve as the first-line treatment for many cancers and is unlikely to be phased out in the near future. The therapeutic window of chemotherapy arises from its selective killing of rapidly dividing tumor cells. However, unlike tumor cells cultured in laboratories, those in real-world patients proliferate much more slowly; for instance, breast cancer cells grow hundreds of times slower in vivo than in vitro. Meanwhile, some normal human cells, such as bone marrow cells, typically divide faster than solid tumor cells, thereby becoming a bottleneck that limits therapeutic efficacy. Fortunately, many chemotherapeutic agents possess additional, yet poorly understood, mechanisms of tumor cell killing, including immune-oncology (IO)-related mechanisms. The contribution of these elusive mechanisms has helped several ultimately approved oncology drugs achieve an adequate therapeutic window. Nevertheless, the limited understanding of these mechanisms comes at a cost: candidates must be selected through clinical trials with high failure rates.

Although PD-1 inhibitors have a relatively well-defined mechanism of action, their true working mechanisms may be more complex. The observation in clinical practice that these drugs induce deep and durable responses in a subset of patients, with relatively mild side effects, has further stimulated strategies to screen for drug combinations in clinical settings. The astonishing number of clinical trials involving PD-1 inhibitors stands in stark contrast to the relatively weak preclinical data supporting them. The success of Keytruda (pembrolizumab) combined with chemotherapy as a first-line treatment for lung cancer has provided empirical validation for such combinations in other solid tumors. However, knowledge gaps regarding the mechanisms of both components make it difficult to predict which indications are more likely to succeed. The evidence I have seen suggests primarily that chemotherapy reduces immunosuppressive cells and increases cytotoxic T cells within the tumor microenvironment in animal models. Yet, we are still in the exploratory stage of determining which specific changes within this highly complex “marketplace” of factors can predict clinical efficacy. Although PD-1 inhibitors have significantly improved the treatment of solid tumors, even such a cornerstone therapy may not be sufficient to support a nearly random strategy for developing combination therapies. Balancing the probability of success against the potential returns is a nuanced endeavor.