5:33 PM
Jun 16, 2017
 |  BioCentury  |  Product Development

I-SPY adapts

Veliparib data provide lessons on combos in platform trials like I-SPY-2

The Phase III failure of the first targeted therapy to graduate from I-SPY 2 does not mean the platform trial wasn’t able to predict the correct outcome. What it does mean is that I-SPY 2 cannot distinguish the relative contributions of the components of a novel combination regimen -- which isn’t what it was designed to do anyway.

According to I-SPY 2, adding the combination of veliparib from AbbVie Inc. and carboplatin to standard of care had an 88% chance of significantly increasing pathologic complete response (pCR) over SOC alone in a Phase III trial in neoadjuvant triple-negative breast cancer (TNBC).

Detailed results of a subsequent Phase III study from AbbVie that were presented at the American Society of Clinical Oncology (ASCO) meeting on June 4 showed the combination did improve pCR over SOC -- it’s just that all the benefit came from carboplatin, while veliparib made no contribution at all.

“They saw a signal, but it wasn’t from the drug we had hoped it would be from,” Laura Esserman told BioCentury.

Esserman is lead PI on I-SPY 2, director of the UCSF Carol Franc Buck Breast Care Center and the co-leader of the breast oncology program at the UCSF Helen Diller Family Comprehensive Cancer Center.

“They saw a signal, but it wasn’t from the drug we had hoped it would be from.”

Laura Esserman, UCSF

The implications for the current I-SPY study and similar platform trials are that combinations ought to have some clinical evidence of efficacy -- and synergy -- before they are tested in a platform study.

For the future, the I-SPY PIs are working on a new trial protocol that takes a more stepwise approach to untested combinations by allowing patients who don’t respond to monotherapy to be re-randomized to receive an additional component to get them to pCR before surgery.

Veliparib’s vicissitudes

Veliparib entered I-SPY 2 in 2010. Based on preclinical evidence, the hope was the PARP inhibitor could increase the efficacy of DNA damaging chemotherapies such as carboplatin.

PARP inhibitors block the repair of single-strand breaks in DNA. Preventing that repair can cause the death of breast cancer 1 early onset (BRCA)-deficient cells or potentiate the effects of some chemotherapies independent of BRCA status.

In a rat xenograft model of breast cancer, when veliparib was added to carboplatin, tumor burden decreased significantly more than when carboplatin was used alone. Veliparib monotherapy had no effect on tumor volume.

I-SPY 2 is a platform trial that is testing multiple drugs in biomarker-defined subgroups of neoadjuvant breast cancer. All patients receive SOC with paclitaxel.

I-SPY 2 estimated the pCR rate for veliparib plus carboplatin in triple-negative disease at 51% vs. 26% in the control arm, which received paclitaxel alone. Based on the adaptive models, veliparib plus carboplatin was predicted to have an 88% probability of beating paclitaxel on pCR in a 300-patient Phase III study.

AbbVie designed the Phase III trial to confirm the benefit seen in I-SPY 2 while showing the contribution of veliparib. For combination therapies, FDA requires evidence of each component’s contribution of efficacy and safety.

The three-arm study enrolled 634 patients randomized to a triplet of veliparib plus carboplatin and paclitaxel, a doublet of carboplatin and paclitaxel, and paclitaxel by itself.

The primary endpoint was pCR, with pairwise comparisons of the triplet vs. the doublet, and of the triplet vs. paclitaxel alone.

The triplet missed the primary endpoint vs. the doublet (53.2% vs 57.5% p=0.36). However, the triplet was significantly better than paclitaxel alone (53.2% vs 31.0%, p<0.001).

“It actually really verified...

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