I-SPY 2 Showcases Adaptive Randomised Trial Strategy For Neoadjuvant Breast Cancer Therapy

I-SPY 2 results support adaptively randomised trial design for investigation of biomarker-directed neoadjuvant breast cancer agents

medwireNews: Preliminary results from an adaptively randomised phase II study for patients with high-risk breast cancer demonstrate the benefits of matching patients to neoadjuvant agents using biomarker subsets.

The I-SPY 2 trial recruited patients with a stage II or III tumour at least 2.5 cm in diameter and classified them into eight biomarker subtypes on the basis of tumour HER2 status, hormone receptor (HR) status and a 70-gene profile. Participants were then assigned to receive experimental treatment options matched to their cancer subtype using adaptive randomisation.

In the first of two reports published in The New England Journal of Medicine, patients with HER2-positive tumours were assigned to receive 12 cycles of paclitaxel with either trastuzumab or the tyrosine kinase inhibitor (TKI) neratinib , while patients with HER2-negative disease were given paclitaxel alone or alongside neratinib. All patients then received a further four cycles of doxorubicin and cyclophosphamide before surgery.

Neratinib reached the prespecified threshold for efficacy in patients with HER2-positive, HR-negative tumours, with an average estimated rate of pathological complete response of 56% in the 115 patients assigned to receive the TKI versus 33% for the 78 patients given standard treatment.

Indeed, neratinib was shown to have a 95% probability of being superior to standard therapy and was calculated to have a 79% likelihood of being successful in a phase III trial of 300 patients.

Neoadjuvant neratinib is now moving forward into phase III testing within the I-SPY 3 programme aimed at achieving accelerated approval from the US Food and Drug Administration, say Laura Esserman, from the University of California, San Francisco in the USA, and co-investigators.

This study will reflect the now standard use of dual HER2 targeted therapy in breast cancer and test combinations of neratinib, pertuzumab , trastuzumab and taxanes, focusing on HER2-positive, HR-negative patients, they add. 

The I-SPY 2 investigators also adaptively randomised treatment so that HER2-negative patients were assigned to receive the poly(ADP-ribose) polymerase inhibitor veliparib plus carboplatin and paclitaxel or to receive standard care with paclitaxel alone. These regimens were all followed by four cycles of doxorubicin and cyclophosphamide before patients underwent surgery.

The estimated rate of pathological complete response in the patients with HER2-negative tumours given veliparib–carboplatin was 33% versus 22% for those given control treatment. And the researchers say the benefit of veliparib–carboplatin was concentrated in the subgroup of patients with a triple-negative HR signature, with an estimated rate of 51% versus 26% for controls.

However, for the subgroup of patients with HR-positive tumours, the estimated rate of pathological complete response was just 14% with veliparib–carboplatin versus 19% for controls.

Thus, the probability of veliparib–carboplatin being superior to control treatment was 91% for any HER2-negative patients and 99% for triple-negative patients, but just 28% in the HR-positive group. The corresponding probability of success in a phase III trial of 300 patients was 53%, 88% and 8%.

Veliparib–carboplatin was associated with a higher rate of grade 3 or 4 haematological side effects than standard treatment, although the investigators are unable to say which of the two agents was responsible for the greater toxicity.

“The experience with veliparib–carboplatin in our trial shows the advantage of an adaptively randomized phase 2 platform trial for matching therapies with biomarker subsets to better inform the design of phase 3 trials so that they can be more focused, smaller, and faster”, Laura Esserman et al conclude.

“Future patients stand to benefit, but trial participants benefit, as well, in that exposure to ineffective therapy is minimized.” 


Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med 2016; 375: 11–22. DOI: 10.1056/NEJMoa1513750

Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib–carboplatin treatment in breast cancer. N Engl J Med 2016; 375: 23–34. DOI: 10.1056/NEJMoa1513749

medwireNews (www.medwireNews.com ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016