1. Carlson, Robert H.

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NEW ORLEANS-I-SPY 2, a clinical trial in stage 2 breast cancer using an adaptive design format to test the antibody-drug conjugate trastuzumab emtanzine (T-DM1) and pertuzumab, showed superior pathologic complete response (pCR) rates for the combination compared with standard neoadjuvant therapy of paclitaxel plus trastuzumab.

T-DM1-Pertuzumab. T-... - Click to enlarge in new windowT-DM1-Pertuzumab. T-DM1-Pertuzumab

In the terminology of adaptive design, T-DM1-pertuzumab has "graduated" from the standing platform trial and is ready for phase III testing.


Significantly, this standing platform trial needed only 83 HER2-positive patients randomly assigned to T-DM1 and pertuzumab or to the combination of paclitaxel and trastuzumab to show estimated outcomes.


The estimated pCR rate (based on a statistical Bayesian probability) was 52 percent in the patients assigned to T-DM1-pertuzumab, and an estimated 22 percent in the control group.


"I-SPY 2 accelerates the process of identifying drugs effective for breast cancer subtypes and reduces cost, time, and numbers of patients needed to get effective drugs to market," said first author Angela DeMichele, MD, Professor of Medicine and Epidemiology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia.


"An adaptive randomization design minimizes the number of patients needed to determine efficacy," she continued. "When a drug or combination reaches the goal of showing efficacy, we call that 'graduation,' meaning it reaches the threshold of the predictive probability of the success of that new drug in a subsequent phase II trial."


Principal investigators are Don Berry, MD, MD Anderson Cancer Center, Houston, and Laura Esserman, MD, University of California San Francisco.


Trial's Novel Nature Applauded

AACR President Nancy E. Davidson, MD, Professor of Medicine and Oncology and Director of the University of Pittsburgh Cancer Institute, talked with Oncology Times after the meeting about the study.


"Everybody appreciates the novel nature of the design of the I-SPY 2 trial and the hope that it will allow us to get useful information early, to 'graduate' agents and allow them to go on to larger scale trials that hopefully would be done with a smaller number of patients because they are so enriched for the right people."


Davidson said she was happy to see that happen in this case with HER-2-targeted therapy, "which has been a very rich area of investigation over the last several years."


Breast Cancer Results

I-SPY 2 currently has numerous simultaneously-running experimental arms. In this part of the trial, the study therapies were matched with different breast cancer subtypes based on hormone receptors and the MammaPrint 70-gene signature.


The data presented were on patients with HER2-positive stage 2 breast cancer and tumor size of a least 2.5 cm considered at high risk for early recurrence.


Patients were randomly assigned to a control regimen of paclitaxel 80 mg/m2 plus trastuzumab 4 mg/kg followed by 2 mg/kg, both given weekly for 12 doses; or T-DM1 3.6 mg/kg plus pertuzumab 840 mg load followed by 420 mg, given every 3 weeks for four doses.


Upon completion, patients in each arm proceeded to chemotherapy with doxorubicin and cyclophosphamide followed by surgery.


A total of 1,540 patients were screened for the I-SPY 2 trial overall. For this portion of the trial, 52 patients, who were HER2-positive, were assigned to T-DM1-pertuzumab while 31 HER2-positive patients were assigned to paclitaxel-trastuzumab.


Median patient age was 48 years for the T-DM1-pertuzumab group and 50 years for paclitaxel-trastuzumab. Median tumor diameter was 3.5 cm for both groups.


DeMichele reported that, for all HER2-positive patients, the estimated pCR rate (based on a statistical Bayesian probability) was 52 percent in the patients assigned to T-DM1-pertuzumab, and an estimated 22 percent in the control group.


"That meant the probability T-DM1-pertuzumab being superior to paclitaxel-trastuzumab was 99.5 percent, and our probability that it would be successful in a subsequent phase III trial was 94 percent," DeMichele explained.


Analyzed by subtype, the estimated pCR rate for HER2-positive/HR-negative patients in the T-DM1-pertuzumab arm was estimated at 64 percent, compared with an estimated 33 percent in the control arm, with a 98 percent probability that T-DM1-pertuzumab was superior to control, and a 90 percent probability it would be successful in this subtype in a phase III trial.


For HER2-positive/HR-positive patients, pCR rates were estimated at 46 percent for T-DM1 versus an estimated 17 percent for controls, with a 99 percent probability T-DM1/pertuzumab was superior to control in this subgroup, and a 93 percent probability of success in phase III.


Adverse Events

The toxicity profile of T-DM1-pertuzumab is very different from paclitaxel-trastuzumab: neuropathy, alopecia, and hypertension were much less common with the antibody-drug conjugate, according to DeMichele.


There were very few grade 3 or 4 adverse events in either arm, but women assigned to paclitaxel-trastuzumab had much greater rates of hypertension (45% versus 4%), neuropathy (45% versus 0%), and alopecia (58% versus 0%) when compared with T-DM1 plus pertuzumab.


DeMichele noted that part of the reason for alopecia rates lower than expected was the widespread use of cold caps (scalp hypothermia) in these patients. "I would argue that these are side effects of treatment that really matter to women and affect their activities of daily living," she said.


Additional Research

There are numerous phase III trials going on now to help establish the role of T-DM1 with or without pertuzumab in the neoadjuvant setting, including trials with the PARP inhibitor veliforib (plus carboplatin), the pan-TKI antibody neratinib, and the AKT inhibitor AMG 386.


DeMichele expects the first few phase III results to be published soon. "That's not to say every drug in I-SPY 2 graduates, and in fact some never reach the 85 percent threshold required," she said.


For example, the trial of AMG 386, a selective anti-angiopoietin peptibody, did well in several subsets of cancer patients, but did not reach the threshold and did not "graduate" to phase III.


Other combination trials with the T-DM1-pertuzumab that have been successful in various phenotypes of breast cancer include the KRISTINE trial of T-DM1-pertuzumab versus docetaxel-carboplatin; the KATHERINE trial of T-DM1-pertuzumab post neoadjuvant for patients who have received a Herceptin regimen and have residual disease; and the very large KAITLIN trial of adjuvant T-DM1-pertuzumab.


Additionally, the ADAPT trial tests T-DM1 monotherapy for an entire year. "It will be interesting to see what toxicities there are after a year," DeMichele concluded.


Robert H. Carlson is a contributing writer.