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INVESTIGATORS

The I-SPY 2.2 Trial

I-SPY 2.2 is the latest evolution in the I-SPY family of trials for early breast cancer, introducing a number of critical innovations that permit the optimization of treatment for each patient in the context of a phase II signal-finding trial.

Efficiency Bred From Innovation

The success of the I-SPY 2 trial is not simply the result of a single innovation in trial design. It is the result of a pain-staking deconstruction and re-engineering of the entire clinical trial enterprise, from protocol development through registration.

Platform Design

The adaptive platform approach permits parallel evaluation of multiple experimental treatments. A master protocol means treatments can come and go as they finish testing.

Response Monitoring

Serial MRIs are used to closely monitor the impact of treatment on the tumor at multiple points before, during and after treatment. MRI non-invasively predicts whether complete response has been achieved.

Biological Targeting

I-SPY 2.2 uses molecular ‘response-predictive subtypes’ to characterize each participant’s tumor in order to guide treatment assignments and assess subtype-specific efficacy of treatment.

Treatment Re-direction

If an experimental therapy does not work, participants are switched to an established, biologically targeted therapy. Participants may receive up to 3 ‘blocks’ of treatment in I-SPY 2.2.

Treatment Sparing

Participants get no more treatment than needed to achieve a complete response in order to limit side effects of unnecessary treatment. A key goal is to eliminate traditional chemotherapy.

Treatment Strategies

In addition to assessing experimental agents, I-SPY 2.2 assesses whole treatment strategies consisting of multiple sequential treatments, more closely reflecting clinical approaches.

How I-SPY 2.2 Works

  • I-SPY 2.2 consists up of to 3 courses (or ‘Blocks’) of treatment; depending on their response to each, patients may not get all three.
  • Block A is a randomized platform design that evaluates up to 4 experimental therapies across multiple subtypes, without the use of paclitaxel
  • Block B consists of multiple subtype-specific ‘best in class’ treatments assigned based on I-SPY’s response-predictive subtypes (RPS)
  • Block C is rescue therapy, consisting of anthracycline chemotherapy at a minimum
  • Serial MRIs assess the tumor’s response to treatment throughout the trial. If MRI shows there is no residual cancer remaining (confirmed by core biopsy) after Block A treatment, participants go directly to surgery, forgoing further treatment (‘de-escalation’); if there is residual cancer, they proceed to additional treatment in Block B.  
  • The same MRI approach is taken in Block B. Participants with no residual cancer after Bloc B treatment go to surgery; those with residual cancer proceed to Block C treatment. 
  • All those receiving Block C treatment go to surgery when it is completed. 
  • In this way, participants receive only the amount of treatment needed to achieve a complete response, to limit potential side effects 
  • I-SPY2.2 also tries to limit side effects by limiting exposure to treatments that are not working. Halfway through treatment in Blocks A and B, if MRI shows very little change in the tumor, participants may forgo the remainder of treatment in that Block and proceed to the next. 
  • 1 in 5 participants will be initially randomized to a control arm in which treatment begins in Block B 
For more information contact Tammy Neseth at t.neseth@quantumleaphealth.org

Key Publications

Shatsky R, Trivedi MS, Yau C, et al. Datopotamab–deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nature Medicine https://www.nature.com/articles/s41591-024-03267-1

Khoury K, Meisel JL, Yau C, et al. Datopotamab deruxtecan in early stage breast cancer: the I-SPY2.2 sequential multiple assignment randomized phase 2 trial. Nature Medicine https://www.nature.com/articles/s41591-024-03266-2

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