Oncology · 2012
Anti-PD-1 antibody activity across multiple solid tumors
BMS-936558, later nivolumab (also MDX-1106, ONO-4538)
When ipilimumab was approved for melanoma in 2011, immune checkpoint blockade was still largely framed as a melanoma story. The thinking was reasonable: melanoma had a high mutational burden, a long history of occasional spontaneous regression, and a record of responding to interleukin-2. Whether the same approach would work in lung cancer, which most oncologists regarded as immunologically cold, or in kidney cancer, was an open question. The PD-1 pathway offered a different mechanism, one targeting a checkpoint expressed at the interface between T cells and tumor cells rather than during initial activation.
Tasuku Honjo at Kyoto University had discovered PD-1 in 1992, and subsequent work identified its ligands PD-L1 and PD-L2 as proteins expressed by tumors to suppress local immune responses. Bristol-Myers Squibb developed an anti-PD-1 antibody, BMS-936558, also called MDX-1106 and ONO-4538, and began phase 1 testing. The dose-escalation trial enrolled 296 patients across five tumor types: advanced melanoma, non-small cell lung cancer, castration-resistant prostate cancer, renal cell carcinoma, and colorectal cancer.
Suzanne Topalian at Johns Hopkins served as first author and principal investigator. Objective responses were recorded in 28% of melanoma patients, 27% of renal cell carcinoma patients, and 18% of non-small cell lung cancer patients. Several of these responses lasted over a year, which was unusual for a phase 1 trial and suggested durable disease control rather than transient tumor shrinkage. Colorectal and prostate cancer patients showed little response, a finding that later prompted investigation of mismatch repair deficiency as a predictor of benefit.
The lung cancer result received particular attention. Adenocarcinoma and squamous cell lung cancer had resisted immunotherapy for years, and an 18% response rate in unselected patients was higher than most had predicted. F. Stephen Hodi contributed to the melanoma cohort analysis. Publication in the New England Journal of Medicine in 2012 reframed PD-1 blockade not as a specialized niche agent but as a class of drugs relevant to multiple tumor types, which shifted investment and trial design across oncology.
Within a few years, nivolumab received approval in melanoma (2014), non-small cell lung cancer (2015), and renal cell carcinoma (2015), followed by many additional indications. PD-L1 expression testing and, later, tumor mutational burden became biomarkers used in selecting patients. Tasuku Honjo shared the 2018 Nobel Prize in Physiology or Medicine with James Allison. The phase 1 paper's multihistology design became a template for subsequent basket trials testing immunotherapy across tumor types defined by molecular features rather than tissue of origin.
Key People
- Suzanne Topalian — First author and principal investigator of the nivolumab phase 1 trial.
- Tasuku Honjo — Discovered PD-1; 2018 Nobel laureate in Physiology or Medicine.
- F. Stephen Hodi — Co-investigator; contributed to melanoma cohort analysis.
- Mario Sznol — Co-author; contributed to safety and response characterization across tumor types.
N Engl J Med 2012;366:2443-2454
Related landmarks
- 2011 · National Lung Screening Trial (NLST) (Oncology)
- 2010 · Ipilimumab improves survival in metastatic melanoma (Oncology)
- 2017 · Tisagenlecleucel (Kymriah): First FDA-Approved CAR-T Cell Therapy (Oncology)
- 2018 · Nobel Prize in Physiology or Medicine for cancer immune-checkpoint therapy (Oncology)