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Neoadjuvant ado-trastuzumab emtansine, pertuzumab increases pathologic complete response in HER-2–positive breast cancer
NEW ORLEANS — Neoadjuvant treatment with ado-trastuzumab emtansine and pertuzumab appeared more beneficial than standard paclitaxel plus trastuzumab among women with HER-2–positive invasive breast cancer, according to results of the I-SPY 2 trial presented at the American Association for Cancer Research Annual Meeting.
Researchers observed the benefit regardless of hormone receptor status.
Angela DeMichele
“We are encouraged by this and look forward to adding new combinations to [ado-trastuzumab emtansine] as a less toxic backbone, including immunotherapies and other targeted therapies,” Angela DeMichele, MD, MSCE, professor of medicine and epidemiology at Perelman School of Medicine at University of Pennsylvania, said during a press conference. “It gives us an opportunity to start thinking about tailoring therapy, particularly in the neoadjuvant setting. ... It could help us start to give up some of the more toxic chemotherapies like paclitaxel that we have used in the past.”
Women who achieve pathologic complete response (pCR) defined as no residual invasive cancer detected in the breast tissue or lymph nodes at the time of surgery is an excellent surrogate for long-term clinical outcomes among women with HER-2–positive breast cancer. However, not every patient achieves pCR, and researchers hope to identify new trials that increase the pCR rate in this population.
Researchers involved with I-SPY 2 a phase 2, adaptively-randomized trial established to identify specific drugs or combinations that could be advanced to phase 3 assessed whether ado-trastuzumab emtansine (Kadcyla, Genentech) plus pertuzumab (Perjeta, Genentech) could help more women with HER-2–positive invasive breast cancer achieve pCR.
The analysis included 83 patients with invasive HER-2–positive disease at least 2.5 cm in size. All patients had adequate organ function and performance status.
Fifty-two patients received ado-trastuzumab emtansine 3.6 mg/kg, plus pertuzumab administered in an 840-mg loading dose followed by 420 mg every 3 weeks. The 31 patients in the control group received paclitaxel 80 mg/m2, plus trastuzumab administered in a 4-mg/kg loading dose followed by subsequent weekly doses of 2 mg/kg.
Treatment continued for 12 weeks. After that, all patients received standard doxorubicin and cyclophosphamide.
Treatment arms were well balanced with regard to age, race, ethnicity and MRI tumor diameter at the time of diagnosis. Approximately two-thirds of women in each group had hormone receptor-positive disease.
DeMichele and colleagues used Bayesian predictive probabilities to estimate the likelihood that patients would achieve a pCR. They also calculated the probability of success that the investigational arm would be superior to the control arm, as well as the probability that the probability that it would succeed in a subsequent phase 3 trial.
Results showed the combination of ado-trastuzumab emtansine and pertuzumab was associated with a higher estimated pCR rate than the control regimen among all women with HER-2–positive disease (52% vs. 22%). Estimated pCR rates for the investigational regimen were higher among women with hormone receptor-negative disease (64% vs. 33%) and those with hormone receptor-positive disease (46% vs. 17%).
Researchers calculated a 99.5% probability that the investigational regimen would be superior to the control arm for all women with HER-2–positive disease. They calculated superiority probabilities of 98% for women with hormone receptor-negative disease and 99% for those with hormone receptor-positive disease.
The probabilities that the investigational regimen would be successful in a phase 3 trial were 94% for all women with HER-2–positive disease, 90% for those with hormone receptor-negative disease and 93% for those with hormone receptor-positive disease.
During the experimental agent portion of the study, women who received the control regimen experienced higher rates of hypertension (any grade, 45% vs. 17%; grade 3 or higher, 10% vs. 4%), neuropathy (any grade, 45% vs. 17%) and alopecia (any grade, 58% vs. 8%).
“[These] are side effects that really matter to women and can really affect their day-to-day function,” DeMichele said.
Women assigned ado-trastuzumab emtansine plus pertuzumab experienced higher rates of elevated alanine transaminase level (25% vs. 13%) and aspartate transaminase level (25% vs. 13%), but the majority were low grade and not clinically significant, DeMichele said.
Adverse event rates calculated during the entire study period followed a similar pattern.
Several phase 3 trials are ongoing to help establish the role of ado-trastuzumab emtansine with or without pertuzumab in the neoadjuvant setting, and those results are eagerly awaited, DeMichele said.
“What we ultimately want to achieve is to get the greatest proportion of patients to a pathologic complete response,” DeMichele said. “If we can use trials like I-SPY 2 to identify ways to do that without using more toxic chemotherapy, that is going to be a win for patients.” – by Mark Leiser
Reference:
DeMichele, AM. Abstract CT-042. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Di sclosure: DeMichele reports institutional research funding from Calithera, Genentech, Incyte, Johnson & Johnson, Novartis and Pfizer, as well as scientific advisory board roles with Novartis and Pfizer. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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In this case, researchers evaluated ado-trastuzumab emtansine (Kadcyla, Genentech) — or T-DM1, an antibody–drug conjugate of trastuzumab with DM1 — given with pertuzumab (Perjeta, Genentech) compared with paclitaxel and trastuzumab (Herceptin, Genentech), which is a standard treatment.
The interesting thing about this study is that it demonstrates a higher pathologic complete response rate with the experimental combination. I think this is going to engender a lot of conversation in two ways. First, it suggests promise for this combination, which is interesting because in some other settings, especially the metastatic setting, the combination has not been as clearly superior to traditional approaches.
The second issue to consider is what it means to achieve a higher pathologic complete response in breast cancer in general, and specifically in HER-2–positive disease. We saw a near doubling of pathologic complete response with lapatinib (Tykerb, Novartis) in the neoALTTO study, but we did not get a meaningful improvement in long-term outcomes in the adjuvant setting for that combination. We currently also have an open question regarding pertuzumab and trastuzumab, because the NeoSphere study showed a big bump in pathologic complete response, but we do not yet have the adjuvant results.
As we evaluate the results of I-SPY 2 and we see a higher pathologic complete response rate for this combination, we are still left needing more data to assess the long-term benefits and impact of this approach.
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In this abstract researchers report results from the I-SPY 2 trial in a cohort of patients with HER-2–positive breast cancer receiving neoadjuvant therapy. Specifically, a nontaxane-containing investigational regimen consisting of ado-trastuzumab emtansine (Kadcyla, Genentech), or T-DM1, plus pertuzumab (Perjeta, Genentech) was compared with a control regimen consisting of paclitaxel plus trastuzumab (Herceptin, Genentech). Both regimens were followed by treatment with doxorubicin plus cyclophosphamide and surgery, and the primary efficacy endpoint was pathological complete response (pCR).
Overall, the estimated pCR rate for the T-DM1 plus pertuzumab arm was 52% (n = 52) compared with 22% for the control arm (n = 31). The estimated pCR rates in the hormone receptor-positive subgroup were 46% compared with 17%. In the hormone receptor-negative subgroup, pCR rates were 64% compared with 33% for the T-DM1 plus pertuzumab and control arms. The posterior probability of superiority to control was at least 98% in all three populations.
The I-SPY 2 trial is a flexible trial that allows for regimens to be seamlessly included or excluded over time. As long as new regimens are entered, the trial apparently can run over an indefinite period of time. Importantly, however, there are prespecified criteria that determine when specific regimens are removed from the trial. Bayesian methods are used to calculate the predicted probability of success in a subsequent phase 3 trial (with pCR as the primary endpoint), and the predicted probability is continuously updated as efficacy results are observed over time. If the predicted probability reaches at least 85%, the regimen can be removed due to efficacy, and it is considered to have “graduated” from the study. If the predicted probability falls below 10%, the regimen is removed from the study due to futility. For the HER-2–positive cohort, if the predicted probability remains between 10% and 85%, a regimen is removed from the study after a maximum accrual of 75 patients is reached.
The appeal of this platform trial is that it can be used to quickly and efficiently evaluate multiple neoadjuvant agents over time without the need for developing a separate study for each investigational regimen. However, the flexibility of this study introduces its own complexities. For example, randomization to the paclitaxel and trastuzumab control arm began at a period of time prior to the introduction of the T-DM1 plus pertuzumab arm, and the control arm was removed from the trial prior to the graduation of the investigational arm. This creates a time-related confounder when comparing the two arms. Of course, describing the details behind the time-adjusted analyses and the calculations of the posterior predicted probabilities (and the associated subjective assumptions) are beyond the scope of this abstract.
Nonetheless, these details would support the interpretation of the promising results. The researchers appropriately conclude that the T-DM1 plus pertuzumab regimen warrants further testing in a trial designed with survival endpoints.
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The T-DM1 and pertuzumab arm had a higher pathologic complete response (pCR) rate than the trastuzumab–paclitaxel arm (52% vs. 22%). The researchers also confirmed that ER–positive cancers have lower pCR rates than ER–negative cancers even among HER-2–positive tumors.
The importance of this trial is that it broadens the repertoire of neoadjuvant trial options for patients with HER-2–positive disease. T-DM1 plus pertuzumab was a very tolerable, nontoxic option with less neuropathy and alopecia.
It should be noted that the reported pCR rates are not the highest, and many different combinations of HER-2–targeted therapies and various chemotherapies induce substantial double-digit pCR rates in the HER-2–positive patient population.
The challenge for the clinical community will be how to select between the number of different options that are now available for patients with HER-2–positive breast cancer to achieve pathologic complete response. The overall message is very clear: The more drugs we add, the higher the pathologic complete response rates are but, generally, the toxicity also increases.
An important question to study will be whether starting with a simple, minimally toxic neoadjuvant regimen could lead to an optimized therapeutic strategy in which those with pCR could be spared from further adjuvant therapy, and those with residual cancer after the neoadjuvant therapy can be “salvaged” by using additional postoperative adjuvant therapy with a combination of agents that were not used as neoadjuvant treatment.