2014: Pembrolizumab and Nivolumab: PD-1 Era (2014)

The FDA approvals of pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb)
in 2014—initially for advanced melanoma—inaugurated the PD-1 checkpoint era and rapidly expanded
checkpoint immunotherapy beyond the CTLA-4 mechanism established by ipilimumab. PD-1 (programmed
death-1) is an inhibitory receptor expressed on activated T cells; its ligands PD-L1 and PD-L2
are expressed on tumour cells and stromal cells, enabling cancer to suppress local immune responses
by delivering inhibitory signals directly within the tumour microenvironment.

Tasuku Honjo at Kyoto University discovered PD-1 in 1992 while studying mechanisms of apoptosis
in T cells. The recognition that PD-1 functioned as an immune checkpoint came from Honjo's group
and Gordon Freeman's group at Harvard, who identified PD-L1 as a ligand in 2000 and demonstrated
that the PD-1/PD-L1 axis contributed to tumour immune evasion. Pharmaceutical development proceeded
in parallel at Medarex (nivolumab antibody backbone) and at Merck Research Laboratories (humanised
pembrolizumab, initially MK-3475).

The pivotal trials showed objective response rates of 30–40 % in previously treated metastatic
melanoma—substantially exceeding chemotherapy—and, importantly, demonstrated durable responses:
patients who responded often maintained disease control for years. Pembrolizumab subsequently
received FDA approval in more than 30 distinct indications including non-small-cell lung cancer,
head and neck cancer, urothelial carcinoma, microsatellite instability-high solid tumours (the
first tissue-agnostic approval in oncology), Hodgkin lymphoma, gastric cancer, and many others.
Nivolumab accumulated a similarly broad indication profile.

The PD-1 antibodies became the highest-revenue oncology drugs in pharmaceutical history:
pembrolizumab's global sales exceeded $25 billion in 2023.