CHICAGO—Drs. Edith A. Perez and Martine Piccart-Gebhart shared the unenviable task of reporting final, negative results from the randomized, Phase III ALTTO trial, in presentations here at the American Society of Clinical Oncology Annual Meeting (Abstract LBA4).
The long-awaited results showed that adding lapatinib to adjuvant trastuzumab, either concurrently or sequentially, does not increase disease-free survival compared with use of trastuzumab alone in women with early-stage HER2-positive breast cancer.
At 4.5 years, the disease-free survival rate was 86 percent for the group receiving trastuzumab alone, 88 percent for those receiving concurrent treatment of the two drugs, and 87 percent for patients in the sequential-treatment arm.
Beyond the study's impact on the development of lapatinib, the report will have profound long-term implications on drug development and approval in this country, experts said. If the results had been positive, they would have validated the U.S. Food and Drug Administration's Accelerated Approval process, which is based on the assumption that pathological complete response (pCR) after neoadjuvant treatment would translate into an improvement in long-term disease-free survival.
The lapatinib-trastuzumab duo was tested earlier, in the preoperative setting, in the Phase III NeoALTTO trial. The combination therapy resulted in twice as many patients with a pCR compared with use of trastuzumab alone. Further analysis, as reported at the most recent San Antonio Breast Cancer Symposium, showed that the improved pCR rates seen in the hormone receptor-negative/HER2-positive subgroup did translate into improved long-term outcomes (OT 4/10/14 issue).
But women in ALTTO did not have any added benefit with the adjuvant combination.
In an ASCO news conference about the plenary studies, Perez, Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Florida, and senior author on the report, tried to put a positive spin on the results: “We were encouraged to see that most patients in the trial with HER2-positive early breast cancer did well with standard trastuzumab therapy,” she said. “But we were surprised that adding lapatinib did not provide further benefit, since the combination of these drugs was promising in the smaller NeoALTTO trial that preceded this study.”
The target population for both studies was the 20 percent of HER2-positive breast cancer patients who have a relapse, primarily metastatic, within 10 years despite trastuzumab treatment.
ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation, also known as BIG 2-06), supported by GlaxoSmithKline and the National Cancer Institute, included 8,381 women treated at 946 medical centers in 44 countries.
Treatment consisted of lapatinib plus trastuzumab (the concurrent arm), trastuzumab followed by lapatinib (the sequential arm), or trastuzumab alone for one year. The anti-HER2 therapies were given after completion of chemotherapy in 4,613 women, and the rest received it concurrently with chemotherapy and also after.
Adverse Events Higher with Lapatinib
Piccart-Gebhart, the first author of the study, Professor of Oncology at Université Libre de Bruxelles and Director of Medicine at Jules Bordet Institute in Brussels, Belgium, formally presented the ALTTO data in the plenary session.
Besides the disappointment in terms of progression-free survival, she reported, the lapatinib-trastuzumab combination was associated with much higher rates of adverse events than use of trastuzumab alone, including diarrhea (75% for the combination vs. 20% for trastuzumab alone), rash (55% vs. 20%, respectively), and hepatobiliary adverse events (23% vs. 16%).
The good news, she said, was that there was no increase in cardiac adverse events: “The rate of congestive heart failure was less than one percent, even though 95 percent of women received anthracycline chemotherapy.”
Follow-up will continue, she said, and a protocol-specified updated efficiency analysis is planned in two years.
‘Would Have Changed Practice Tomorrow’
ASCO 2013-2014 President Clifford A. Hudis, MD, predicted that the negative report from ALTTO would “throw a monkey wrench into the Food and Drug Administration's Accelerated Approval logic.”
Speaking at the news conference, he said the study results operate on two levels: “On the one hand, from a practical point of view, this study, if positive, would have changed practice tomorrow morning. These drugs are available and the adjuvant setting is one where there is tremendous drive to reduce recurrence and obviously prevent early death.
“But on a second, more technical level, the report has tremendous potential implications, because in 2013, the FDA, for the first time ever, approved a drug, pertuzumab, in the preoperative setting on the basis of increased pathological complete response rate.”
Getting the drug quickly into the market based on pCR, rather than on progression-free survival, would theoretically save lives, he said. “That may turn out to be true for pertuzumab—we're going to have to wait for results of the AFFINITY study. But the question from a societal point of view is whether we can routinely use the improvement in pathological complete response in the preoperative setting as a reliable surrogate for disease-free and overall survival.
“And the answer, at least from ALTTO, is that maybe we cannot.”
For the moment, all that can be said is that this trial provides reassurance that trastuzumab is a safe and potent adjuvant treatment for HER2-positive breast cancer, he said.
‘Failure of Study Design’
Asked for her perspective for this article, Angela DeMichele, MD, Co-Leader of the Breast Cancer Program and Director of Clinical Trials at the University of Pennsylvania, said the ALTTO results are not a failure of neoadjuvant therapy, but rather, a failure of study design and are not necessarily surprising.
DeMichele, who was not involved in ALTTO, said there were some subtleties worth pointing out: “The NeoALTTO trial did show an increase in pathological complete response, but the way the treatment was given was not comparable to that in ALTTO. In NeoALTTO, it was just the anti-HER2 treatment and paclitaxel given before surgery, and the doxorubicin and cyclophosphamide [AC] given after surgery.
“We all know that AC is very active in breast cancer, and giving both arms the AC would have blunted the effect seen with the lapatinib,” she said. “So in many ways NeoALTTO amplified, incorrectly, the benefits of the lapatinib.”
Also, most NeoALTTO patients had tumors over 5 cm or had positive lymph nodes, while in ALTTO most patients had tumors under 5 cm and many under 2 cm, and half of the patients did not have lymph node involvement.
“That's very different,” DeMichele said. “Patients can do only so much better, and there weren't really enough events in ALTTO to drive the analysis that showed lapatinib would have worked.”
That's not to say that more time or more patients would have changed things, she added, because the biology of these early-stage patients is such that they are not going to relapse.
“I think there was very little chance that this trial would show a benefit,” DeMichele said. “There was a lot of wishful thinking going on. We've had a lot of positive trials in the HER2 setting, and we got comfortable with that and thought we were going to continue to have positive trials—but not if we don't design the trials properly.”
The Discussant for ALTTO, George W. Sledge, Jr., MD, Professor of Medicine and Chief of the Division of Oncology at Stanford University, called ALTTO a negative, underpowered trial and said he considered it a serious disappointment—“not just for the investigators but for the entire field.”
“It is [now] difficult to mount any enthusiasm for combined blockade of HER2 in the adjuvant setting, at least with the combination used here.” The trial might eventually turn statistically positive with more follow-up and more events, he said, “but not very positive, given these results we see today.”
Sledge, a former ASCO President and an OT columnist, said the negative adjuvant trial was given a prominent spot in the plenary session because it requires researchers to rethink the approach to the development of drugs for early stage breast cancer: “And the ALTTO results are not a confidence builder for this approach.”
Meanwhile, he said, the breast cancer community holds its collective breaths for results from the AFFINITY trial, the study of pertuzumab in addition to chemotherapy and trastuzumab as adjuvant therapy in patients with HER2-positive primary breast cancer, sponsored by Hoffmann-La Roche.
4 Study Arms, 3 Designs
ALTTO had four study arms:
* Trastuzumab alone (2,097 patients);
* Lapatinib alone (2,100 patients);
* Trastuzumab followed by lapatinib (2,091 patients); and
* Trastuzumab plus lapatinib (2,093 patients).
Anti-HER2 therapy was initiated after completion of all chemotherapy (Design 1), concomitantly with a taxane following anthracycline (Design 2), or concomitantly with a non-anthracycline, platinum-containing regimen (Design 2B).
Dosing in Design 1 was trastuzumab at 8 mg/kg IV loading dose followed by 6 mg/kg IV every three weeks for 52 weeks; or lapatinib at 1,500 mg/d for 52 weeks; or trastuzumab at 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly for a total of 12 weeks followed by a six-week treatment-free interval followed by lapatinib at 1,500 mg/d for a total of 34 weeks; or trastuzumab at 8 mg/kg IV loading dose followed by 6 mg/kg IV every three weeks concomitant with lapatinib at 1,000 mg/d for 52 weeks.
In Design 2, dosing was 80 mg/m2 weekly paclitaxel or 75 mg/m2 three-weekly docetaxel administered concomitantly with the anti-HER2 agents.
In Design 2B, six cycles of docetaxel (75 mg/m2) with carboplatin (AUC 6) were administered concomitantly with the anti-HER2 agents; trastuzumab was administered weekly and lapatinib doses were reduced when combined with chemotherapy.
The lapatinib-alone arm was closed in 2011, following the Independent Data Monitoring Committee's recommendation based on a planned interim analysis showing that lapatinib was unlikely to be non-inferior to trastuzumab alone.
Piccart-Gebhart said data from the lapatinib-alone arm will be presented at a future, unspecified meeting.