Targeting programmed cell death protein and its ligand (PD-1/PD-L1) have become the backbone of immunotherapy for cancer. In an era where there are big expectations from various immunotherapies, PD1 and PD-L1 inhibitors have delivered the most; currently there are 10 PD-1/PD-L1 inhibitors approved across a total of 17 different cancer types and for two tissue-agnostic malignancies.
In 2019, PD-1/PD-L1 inhibitors generated nearly $22.5B in combined sales in the eight major markets, including the US, five major European markets (France, Germany, Italy, Spain and UK), Japan, and China. This drug class has dominated oncology drug development in recent years and there has been a noticeable surge in PD-1/PD-L1 targeted combination trials across all major markets.
In light of this surge, certain trends are collectively shaping development efforts for bringing new combination therapies for treating cancer to market.
In the last four consecutive years, the clinical trials investigating PD-1/PD-L1 targeted combination therapies have increased steadily. Also, from 2017 to 2019, the PD-1/PD-L1 targeted combination therapies pipeline has become early-stage heavy with numerous promising new combination partners being disclosed.
In contrast to the combination therapy trials, the number of early-stage clinical trials for PD-1/PD-L1 monotherapies has been shrinking. Despite the current COVID-19 pandemic, the growth in the number of active combination trials continued in 2020, albeit at a significantly slower rate. However, the full scale of the pandemic’s impact on trial efficiencies and recruitment rates, as well as the ripple effects in following years, are still yet to be determined.
The industry’s attention is moving towards PD-1/PD-L1 targeted combination therapies, also highlighting important trends in preferred types of combination therapies. While chemotherapies are becoming less attractive options as combination partners, targeted therapies and other immuno-oncology (IO) agents are becoming more prevalent complimentary options.
Drugs that target the vascular endothelial growth factor (VEGF) pathway represent almost half of all targeted therapies in combination trials. Furthermore, poly-ADP ribose polymerase (PARP) inhibitors form another prominent targeted therapy class, and underscore the efforts to combine biomarker-led treatment options with PD-1/PD-L1 inhibitors to improve patient selection. This could also infer fewer patients being recruited for more targeted clinical trials in the future.
Lastly, IO + IO combinations represent the second most common combination therapy modality. In addition to better utilizing more complex therapies such as cell-based therapies, vaccines, and oncolytic virus therapies, companies are increasingly invested in new checkpoint targets and next-generation immune modulating agents to bypass resistance mechanisms and increase efficacies in immune-silent cancer types. In 2020 to date, the adenosine pathway and lymphocyte activation gene-3 (LAG-3) has been extensively studied.
Oncology drug development is progressing in a new era of PD-1/PD-L1 targeted combination therapies. The clinical trials that are actively running in all major markets reveal important trends that are shaping the future of cancer treatment. In the upcoming years, more stratified treatment algorithms supported by biomarker-led targeted therapies and robust IO + IO combinations addressing key resistance mechanisms in underserved patient segments and cancer types will change the treatment outcomes for cancer patients.