CHICAGO – Dual HER2 blockade with lapatinib and trastuzumab provides no additional benefit in the adjuvant treatment of HER2-positive breast cancer, according to the long-awaited, first results from the phase III ALTTO trial.
At 4 years, the primary outcome of disease-free survival was 86% with trastuzumab alone, compared with 88% with concurrent lapatinib (Tykerb) and trastuzumab (Herceptin) (hazard ratio, 0.84; P = .048), and 87% with trastuzumab followed by lapatinib (HR, 0.96; P = .610), Dr. Martine Piccart-Gebhart reported during the plenary session at the annual meeting of the American Society of Clinical Oncology.
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Dr. Clifford Hudis
Median overall survival rates were 94%, 95%, and 95%, respectively.
ALTTO’s sister trial, NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization), demonstrated that neoadjuvant treatment with combination trastuzumab and lapatinib doubled the number of pathological complete responses (pCRs), compared with each single agent, and reduced the overall risk of death by two-thirds in women with a pCR.
"The doubling in pCR observed in NeoALTTO did not translate into improved survival outcomes in ALTTO at 4.5 years," said Dr. Piccart-Gebhart, head of the medicine department, Jules Bordet Institute, Brussels.
Invited discussant and past ASCO president Dr. George Sledge Jr., professor of medicine and chief of oncology at Stanford University Medical Center, Palo Alto, Calif., pointed out that ALTTO called for a stringent P value of .025 or less to demonstrate statistical significance, but that no one should be "fooled" by the disease-free survival P value of .048 into thinking this was a positive trial.
"This is a negative trial," he said.
He also noted that the 555 disease-free events seen in ALTTO fell far short of the 850 events planned for, and thus the trial was underpowered.
"Might this trial, with more events and further follow-up, turn statistically positive? Perhaps, but not very positive given the results we’ve seen today," Dr. Sledge commented. "HER2 has reverted to the incrementalism that we see so commonly in the adjuvant field. This is not, alas, 2005. This is not a great leap forward. This is a serious disappointment not just for investigators, but for the entire field."
Several previous trials (B-31, N9831, and HERA) presented at the same meeting in 2005 showed a striking disease-free survival advantage from the addition of 1 year of trastuzumab to adjuvant chemotherapy in women with HER2-positive breast cancer.
During a press briefing, ALTTO study cochair Dr. Edith Perez cast the low event rate of ALTTO in a slightly more positive light, saying that the "patients overall did pretty well."
Ripple effects
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Dr. Edith Perez
Had the results of ALTTO been positive, it would have changed the design of future breast cancer trials by eliminating the need for large adjuvant trials, suggested Dr. Perez, deputy director at large, Mayo Clinic Cancer Center, Jacksonville, Fla. Novel targeted agents could have been reliably evaluated in the neoadjuvant setting if pCR had correlated with the findings in adjuvant trials.
As it stands now, the data call into question whether an improvement in pCR can be routinely used as a reliable surrogate for disease-free and overall survival, ASCO president Dr. Clifford Hudis, chief of breast cancer at Memorial Sloan Kettering Cancer Center, New York, said at the briefing.
"The answer from ALTTO right now is maybe not, and this, I think, is going to cause a tremendous amount of high-level technical scientific discussion in terms of drug development," he told reporters.
Dr. Hudis pointed out that last fall, the Food and Drug Administration for the first time ever approved a drug, pertuzumab (Perjeta), for use in the preoperative breast cancer setting based on an increased pCR rate alone. The hope is that this will ultimately save lives, although this question won’t be answered until 2016, when results from the APHINITY trial are expected, he said.
Based on the ALTTO data, "the simple link that improving the rate of shrinkage of the cancer will necessarily reduce the rate of distant recurrence is not established," Dr. Hudis said. "So our ability to go from big studies taking many years to small studies taking months is not established. That’s a fundamental observation, and it may have implications well beyond breast cancer."
ALTTO design
The open-label, multicenter ALTTO study randomized 8,381 women after surgery to concurrent trastuzumab and lapatinib, trastuzumab followed by lapatinib, or trastuzumab alone for 1 year. Patients received anti-HER2 therapy after completing all chemotherapy (design 1), concurrently with a taxane following anthracycline (design 2), or concurrently with a non-anthracycline, platinum-containing regimen (design 2B).