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I-SPY 2 is a permanent, adaptive trial that tests new breast cancer drugs before surgery, steering each drug towards the tumour subtypes where it is working and graduating the winners in two years instead of ten. Several of its graduates became approved treatments.
I-SPY 2 opened in 2010 as a Bayesian adaptive platform trial, sponsored by the non-profit Quantum Leap Healthcare Collaborative and led by Laura Esserman at UCSF with Don Berry as its statistician. Women with stage 2 or 3 breast cancer at high risk of recurrence (by hormone receptor, HER2 and MammaPrint status) receive standard paclitaxel then anthracycline chemotherapy, with or without an experimental drug, before surgery. The endpoint is pathological complete response, read within months rather than the years a survival endpoint takes. Randomisation is adaptive: as each arm's results accumulate within ten biomarker signatures, new patients are more likely to be assigned to the arm doing best for their subtype.
A drug graduates when the model predicts at least an 85 percent chance of success in a 300-patient phase 3 trial in a given signature; it is dropped for futility when that chance falls below 10 percent. Several arms run at once against a shared control, so each new drug needs far fewer patients than a stand-alone trial.
Graduates and what became of them: veliparib with carboplatin (triple-negative disease, published in the New England Journal of Medicine in 2016, which led to the BrighTNess phase 3 and confirmed the value of carboplatin); neratinib (HER2-positive, hormone receptor-negative disease, NEJM 2016); pembrolizumab (HER2-negative disease, reported at ASCO in 2017), which fed into KEYNOTE-522 and the approval of pembrolizumab for early triple-negative breast cancer; the AKT inhibitor MK-2206; trastuzumab emtansine with pertuzumab (HER2-positive disease, replacing paclitaxel and trastuzumab); durvalumab with olaparib (HER2-negative disease); and the PD-1 and LAG-3 antibody pair cemiplimab and fianlimab (HER2-negative disease, 2022). Other arms, including ganitumab, trebananib, ganetespib and talazoparib with irinotecan, did not graduate, which is also the point: the platform retires drugs early and cheaply.
More than two thousand women have taken part. The trial has also shown that long-term outcomes track pathological complete response across every subtype and treatment, that response-predictive subtypes defined by immune, DNA repair and hormone signatures sort patients better than receptor status alone, and that MRI plus biopsy during treatment can identify women who are responding early. Those findings became I-SPY 2.2, which changes treatment during the trial according to early response.
ctDNA clearance may refine pCR as a surrogate: a patient with residual disease but no ctDNA may not need escalation, the hypothesis behind ctDNA-guided post-neoadjuvant trials.
This is the paper Europe PMC returns for registry id NCT01042379 with the most citations, so it is the natural first reading for anyone following the I-SPY 2 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Shares Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial, Quantum Leap Healthcare Collaborative, Laura J. Esserman, Seamless, adaptive and Bayesian trial designs.
Shares Gene-expression prognostic assays, Laura J. Esserman, Master protocol (platform, basket and umbrella trials), UCSF Helen Diller Family Comprehensive Cancer Center.
Shares PARP inhibitors, Olaparib, Paclitaxel / nab-paclitaxel, Carboplatin.
Shares Olaparib, Durvalumab, Carboplatin, Triple-negative breast cancer (TNBC).
Shares Master protocol (platform, basket and umbrella trials), Trastuzumab emtansine, Pertuzumab, PARP inhibitors.
Shares Fianlimab, Cemiplimab, Paclitaxel / nab-paclitaxel, Carboplatin.
Shares Fianlimab, Cemiplimab, Paclitaxel / nab-paclitaxel, Carboplatin.
Shares PARP inhibitors, Olaparib, Paclitaxel / nab-paclitaxel, Carboplatin.