Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer
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.
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.
- 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.
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.
- 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.
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not linked directly; found by shared links- Key paperIwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack
Shares Drew M. Pardoll, Atezolizumab, PD-1 / PD-L1 immune checkpoint & T-cell activation, No one can predict who responds to immunotherapy.
- Key paperASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors
Shares Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma, Atezolizumab, Immune-related adverse events (irAEs), Nivolumab.
- Key paperCheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanoma
Shares F. Stephen Hodi, Immune-related adverse events (irAEs), Bristol Myers Squibb, No one can predict who responds to immunotherapy.
- PersonTasuku Honjo
Shares No one can predict who responds to immunotherapy, Nivolumab, PD-1, Pembrolizumab.
- IdeaExtended-interval immunotherapy: give checkpoint inhibitors every 8-12 weeks once stable
Shares Atezolizumab, Nivolumab, PD-1, Pembrolizumab.
- Key paperCheckMate 067 at ten years: half of melanoma patients treated with nivolumab plus ipilimumab were alive a decade later
Shares F. Stephen Hodi, Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma, Immune-related adverse events (irAEs), Bristol Myers Squibb.
- IdeaWatch the immune system's response in the blood three weeks in
Shares Objective response rate (ORR), Immune-related adverse events (irAEs), No one can predict who responds to immunotherapy, Biomarkers are not validated or standardised.
- InstitutionSociety for Immunotherapy of Cancer
Shares Drew M. Pardoll, Suzanne L. Topalian, F. Stephen Hodi, Immune-related adverse events (irAEs).