# Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer

Source: https://onco.cc/key-papers/paper-topalian-anti-pd1-nejm-2012/  
OnCo record `paper-topalian-anti-pd1-nejm-2012` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Nivolumab shrank tumours in roughly a fifth to a quarter of patients with three different advanced cancers, with responses that lasted more than a year and a hint that PD-L1 on the tumour predicted benefit.

## Summary

This phase 1 dose-escalation and expansion study treated 296 patients with advanced melanoma, non-small-cell lung cancer, renal cell carcinoma, castration-resistant prostate cancer or colorectal cancer with the anti-PD-1 antibody BMS-936558 (nivolumab) at 0.1 to 10 mg/kg every two weeks. Objective responses occurred in 28% of melanoma, 18% of NSCLC and 27% of renal cancer patients, but none in prostate or colorectal cancer; of 31 responders followed for a year or more, 20 had responses lasting at least a year. Grade 3-4 drug-related adverse events occurred in 14%, and there were three deaths from pneumonitis. In 42 patients with tumour PD-L1 staining, 9 of 25 PD-L1-positive tumours responded versus none of 17 PD-L1-negative tumours. A companion paper (Brahmer et al.) reported similar activity for an anti-PD-L1 antibody.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2012
- DOI: 10.1056/NEJMoa1200690
- Authors: Topalian SL, Hodi FS, Brahmer JR, et al.
- Findings: 296 patients across five tumour types; nivolumab 0.1-10 mg/kg every 2 weeks.; Objective response: melanoma 28%, NSCLC 18% (including squamous and non-squamous), renal cell carcinoma 27%; none in prostate or colorectal cancer.; Responses durable: 20 of 31 responders with a year or more of follow-up had responses lasting at least 1 year.; Grade 3-4 drug-related adverse events 14%; 3 deaths from pneumonitis.; PD-L1 expression: 9 of 25 PD-L1-positive tumours responded vs 0 of 17 PD-L1-negative.
- What it means: This study is why PD-1 inhibitors were developed across cancers rather than in melanoma alone: unexpected activity in lung cancer, historically thought immune-resistant, changed drug development priorities industry-wide. It also introduced PD-L1 immunohistochemistry as a candidate biomarker and pneumonitis as a signature toxicity. Within five years PD-1 blockade was approved in more than ten cancers.
- Caveats: Phase 1 with heterogeneous doses and small tumour cohorts; response rates are imprecise.; PD-L1 analysis was on 42 patients with archival tissue; the biomarker later proved imperfect.; No colorectal responses masked the later dMMR story (the one responder in an earlier study was dMMR).; Survival was not assessed.

## Sources

- Full text (DOI): https://doi.org/10.1056/NEJMoa1200690
- Companion anti-PD-L1 paper (Brahmer 2012): https://doi.org/10.1056/NEJMoa1200694

## Connected records

- key papers: [Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC](https://onco.cc/key-papers/paper-herbst-impower110-atezolizumab-pd-l1-nejm-2020/), [Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma](https://onco.cc/key-papers/paper-hodi-ipilimumab-melanoma-nejm-2010/), [Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy](https://onco.cc/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/)
- pathways: [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- cancers: [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Melanoma](https://onco.cc/cancers/melanoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/)
- terms: [Immune-related adverse events (irAEs)](https://onco.cc/terms/irae/), [Objective response rate (ORR)](https://onco.cc/terms/orr/)
- people: [Drew M. Pardoll](https://onco.cc/people/drew-pardoll/), [F. Stephen Hodi](https://onco.cc/people/f-stephen-hodi/), [Gordon J. Freeman](https://onco.cc/people/gordon-freeman/), [Julie R. Brahmer](https://onco.cc/people/julie-brahmer/), [Lieping Chen](https://onco.cc/people/lieping-chen/), [Suzanne L. Topalian](https://onco.cc/people/suzanne-topalian/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [Extended-interval immunotherapy: give checkpoint inhibitors every 8-12 weeks once stable](https://onco.cc/ideas/idea-tr1-extended-interval-checkpoint-dosing/), [Give immunotherapy in the morning](https://onco.cc/ideas/idea-chronotherapy-immunotherapy/), [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/), [Microbiome transplant as a routine immunotherapy adjunct](https://onco.cc/ideas/idea-microbiome-io-fmt/), [Randomised trials of stopping immunotherapy after one year versus continuing](https://onco.cc/ideas/idea-tr1-immunotherapy-stop-trials/)

---
JSON: https://onco.cc/api/v1/entities/paper-topalian-anti-pd1-nejm-2012.json