I-SPY 2 graduates two neoadjuvant treatments to phase III trials

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pCR ‘not a clinically meaningful endpoint’

These two multicenter trials may ultimately lead to changes in treatment in the years ahead. The investigators created a collaborative culture around these studies, and the work that appears in the Journal would not have been possible absent that spirit of cooperation and collective creativity. However, these trials were not designed to predict the ultimate success of either neratinib or carboplatin-veliparib in improving disease-free or overall survival. Instead, they predict a positive result with the use of pathological complete response rate as an endpoint in a definitive neoadjuvant study.

Clinicians should remember that pathological complete response rate itself is not a clinically meaningful endpoint; its value is as a surrogate for outcome. Although pathological complete response rate is consistently associated with a decreased risk of relapse and death for individual patients, even substantial improvements in pathological complete response rate in neoadjuvant trials have not consistently translated into improvement in long-term outcomes. The reasons for this are myriad, including the molecular heterogeneity of breast cancer and the possible effect of postsurgical interventions. Most importantly, pathological complete response rate will correlate with survival outcomes only if the neoadjuvant agents leading to the improvement in pathological complete response also eradicate resistant tumor clones.

At this time, improvements in pathological complete response rates as reported in neoadjuvant studies – whether the studies are exploratory, such as I-SPY 2, or more definitive – should not change clinical practice; rather, we should wait for the definitive clinical trials that result from them. Nonetheless, standard neoadjuvant therapy remains a sound clinical approach with the potential to individualize therapy. It also remains a valuable research tool that has the potential to help us develop hypotheses and explore mechanisms of drug resistance.

Lisa A. Carey, MD., is with the UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, and Eric P. Winer, MD, is with the Breast Oncology Program, Dana-Farber Cancer Center, Boston. These comments are excerpted from an editorial (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMe1603691).




Taking a step toward the goal of personalized medicine, investigators in the multicenter, adaptive I-SPY 2 trial report that tailoring neoadjuvant therapy combinations to specific cancer subtypes in women with high-risk breast cancer will likely result in higher rates of pathological complete responses for at least two subtypes, including patients with triple-negative disease.

Among women with triple-negative breast cancer (tumors lacking human epidermal growth factor receptor 2 [HER2], estrogen, and progesterone receptors) in the phase II trial, a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and carboplatin added to paclitaxel was associated with an estimated 51% pathological complete response (pCR) rate, compared with 26% for patients treated with weekly paclitaxel alone. The predicted probability of success in a phase III trial with the combination was 88%, reported Hope S. Rugo, MD, director of the Breast Oncology Clinical Trials Program at the University of California San Francisco, and her colleagues in I-SPY 2.

Dr. Hope S. Rugo

Dr. Hope S. Rugo

“The experience with veliparib-carboplatin in our trial shows the advantage of an adaptively randomized phase II platform trial for matching therapies with biomarker subsets to better inform the design of phase III trials so that they can be more focused, smaller, and faster. Future patients stand to benefit, but trial participants benefit as well in that exposure to ineffective therapy is minimized,” the investigators wrote (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513749).

Partial results from this trial were reported at the 2013 San Antonio Breast Cancer Symposium.

On the basis of these phase II data, an ongoing phase III neoadjuvant trial is comparing standard chemotherapy alone, with carboplatin, or with veliparib plus carboplatin as treatment for triple-negative breast cancer, Dr. Rugo and her associates said.

In another arm of I-SPY 2 involving a subset of patients with HER2-positive, hormone receptor–negative cancers, the mean estimated pCR rate was 56% for patients treated with the investigational tyrosine-kinase inhibitor (TKI) neratinib, compared with an estimated 33% among patients treated with anti-HER2 agent trastuzumab (Herceptin). All the participants received standard neoadjuvant therapy, which consisted of 12 cycles of paclitaxel, followed by 4 cycles of doxorubicin and cyclophosphamide. The estimated probability of success in phase III with neratinib was 79%, reported John W. Park, MD, of University of California San Francisco, and his coauthors on behalf of I-SPY 2 investigators (N Engl J Med. 2016 July 7. doi: 10.1056/NEJMoa1513750).

On the basis of this phase II study, and to reflect the current standard of dual HER-targeting, the investigators are proceeding with a phase III trial comparing neratinib as neoadjuvant therapy added to pertuzumab (Perjeta), trastuzumab, and a taxane vs. the three latter drugs, and against a combination of neratinib, trastuzumab, and taxane, all followed by doxorubicin and cyclophosphamide.

Partial results of the phase II trial were reported at the 2013 annual meeting of the American Association for Cancer Research.

Nimble trial, tailored therapies

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response through Imaging and Molecular Analysis 2) is an ongoing “platform” trial exploring the use of new drugs combined with a standard neoadjuvant therapy backbone for the treatment of high-risk cancers.

Women with stage II or III breast cancers with tumors 2.5 cm or larger are assessed for one of eight biomarker subtypes according to HER2 (human epidermal growth factor receptor 2) status, hormone receptor status, and genetic risk factors based on a 70-gene assay. The patients are then randomized within each biomarker subtype to receive standard therapy with or without an investigational agent.

Each sub-trial has a primary endpoint of an improvement in pathological complete response compared with the standard of care. Changes in tumor volume on MRI are used to predict whether patients will achieve a pCR. Regimens that have a high Bayesian predictive probability of success in a subsequent phase III neoadjuvant trial within the biomarker signature in which they performed well are eligible for moving on to phase III trials.

Triple-negative disease

Among the subgroup of patients with triple-negative disease, 72 were assigned to receive veliparib 50 mg by mouth twice daily for 12 weeks, plus carboplatin at a dose intended to achieve a pharmacologic area under the concentration versus time curve of 6 mg/hour per liter on weeks 1, 4, 7, and 10, plus intravenous paclitaxel at a dose of 80 mg/m2. An additional 44 patients (controls) were randomized to receive paclitaxel alone.

Following paclitaxel alone or with the combination, all patients received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2-3 weeks for four doses, followed by myeloid growth factor support as appropriate. Following treatment, all patients underwent surgery that included axillary node sampling in accordance with National Comprehensive Cancer Network (NCCN) and local practice guidelines. Adjuvant radiation and endocrine therapy were recommended in accordance with standard guidelines.

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