A combination of drugs appears to be more effective than monotherapy as neoadjuvant treatment for patients with HER2-positive breast cancer, according to clinical trials reported at the CTRC-AACR San Antonio Breast Cancer Symposium.
The strongest proof that combination therapy may be better in the neoadjuvant setting came from the Phase III Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (Neo-ALTTO) trial, which showed a pathological complete response rate (pCR) of 51.3% in women given trastuzumab and lapatinib in addition to neoadjuvant chemotherapy.
In contrast, the rate was 29.5% with the addition of trastuzumab alone and 24.7% with the addition of lapatinib alone to chemotherapy, reported José Baselga, MD, PhD, Chief of the Division of Hematology and Oncology and Associate Director of Massachusetts General Hospital Cancer Center.
Pathologic complete response was defined according to National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines, as having no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen.
A Valid Concept
For the secondary endpoint of total pCR, dual anti-HER2 therapy again fared better, with a rate of 46.9% vs 27.6% for trastuzumab alone and 20.0% for lapatinib alone.
“Dual blockade of HER2 is a valid concept,” said Dr. Baselga. “It's a new concept, and if you put it in context with the other studies here, I think it does imply a sea change in the way we explore these therapies.”
In the study, which was funded by GlaxoSmithKline, 455 women with invasive, operable, nonmetastatic HER2-positive breast cancer and adequate cardiac function were randomized to receive lapatinib (initially 1,500 mg then amended to 750 mg daily mid-trial), trastuzumab (4 mg/kg and then 2 mg/kg), or a combination of the two for 18 weeks prior to surgery. All women also received paclitaxel (80 mg/m2) starting at Week 6.
In the six weeks before chemotherapy was started, lapatinib was associated with a higher overall clinical response rate: 52.6% vs 30.2% for trastuzumab.
Toxicities, primarily diarrhea and liver enzyme alterations, were increased but manageable in the lapatinib arms, Dr. Baselga said.
Specifically, the rate of Grade 3-4 diarrhea was 23% in the lapatinib arm, 21% in the combination arm, and 2% in the trastuzumab arm. Liver enzyme alterations were observed in 13% of women in the lapatinib arm, 9% in the combination arm, and 1% in the trastuzumab arm.
One woman taking the combination treatment died, but the cause is not yet known, he said.
Trastuzumab Outperforms Lapatinib
In a second presentation, German researchers reported that when given with chemotherapy, neoadjuvant trastuzumab was associated with a pCR rate of 31.3% vs 21.7% for lapatinib alone, a significant difference.
Pathologic complete response was defined using the “most stringent” standards, as having no invasive or non-invasive tumor residuals in the breast or nodes, explained lead investigator Michael Untch, MD, Head of the Multidisciplinary Breast Cancer Department at the Helios Clinic in Berlin.
The Phase III study, known as GeparQuinto, involved about 600 women with HER-2 positive early and locally advanced cancer randomized to receive trastuzumab or lapatinib, plus epirubicin, cyclophosphamide, and docetaxel.
When “the more liberal NSABP definition was applied,” the pCR rates were 50.4% in the trastuzumab arm and 35.2% in the lapatinib arm, Dr. Untch said.
Tumor Samples to be Studied
The efficacy of lapatinib was somewhat clouded by the fact that 23% of women taking the drug dropped out of the trial, mainly due to side effects, chiefly diarrhea.
“But we have learned how to deal with this,” Dr. Untch said, explaining that prophylactic treatment should be started as soon as there are signs of diarrhea.
The researchers plan to examine more than 1,500 tumor samples to find out if certain genetic signatures can predict—“with near 100% accuracy”—which women will be cured by the HER2-targeted drugs alone and won't even need surgery, he said.
The study was funded by Sanofi, Roche, Novartis, and GlaxoSmithKline.
A third, Phase II study showed that neoadjuvant use of a trastuzumab and pertuzumab doublet plus docetaxel chemotherapy is associated with a pCR rate of 45.8%, using the NSABP definition.
“That's nearly 50% higher than achieved with docetaxel and trastuzumab, the standard therapy,” noted Luca Gianni, MD, Director of Medical Oncology at the Fondazione IRCCS Istituto Tumori di Milan.
In the study, known as NeoSphere, trastuzumab plus docetaxel was associated with a pCR rate of 29.0%, pertuzumab and docetaxel had a pCR rate of 24.0%, and the trastuzumab and pertuzumab doublet was associated with a pCR rate of 16.8%.
Most importantly,” Dr. Gianni said, the study showed that “a proportion of HER2-positive tumors can be eradicated without the need for chemotherapy.”
Cost an Issue
Neil L. Spector, MD, Professor of Medicine at Duke University Medical Center, said the next logical step is to test a combination of all three HER-targeted drugs “and get away from chemotherapy.”
HER2-positive breast cancer was the most lethal type of breast cancer a decade ago, he noted, and “now we are talking about a cure.”
Cost, however, can be an issue. Dr. Spector showed a slide that listed the three targeted therapies—lapatinib (L), trastuzumab (T), and pertuzumab (P)—with icons to reflect approximate costs:
T + L $$
T + P $$$
T + P + L (A piggy bank being smashed)
Dr. Untch noted that if neoadjuvant therapy eradicates 50% or more of tumor cells, patients may not need to be treated with 12 more months of adjuvant trastuzumab, thereby lowering costs.
pCR as Predicting Survival
The big question is whether pCR rates will translate into better clinical outcomes with longer follow-up.
Dr. Baselga expressed confidence that they will, pointing out that neoadjuvant trials such as the Neoadjuvant Herceptin (NOAH) trial support pCR rate as a reliable surrogate for progression-free survival rates.
That study, presented at the 2008 San Antonio Breast Cancer Symposium, showed that the event-free survival rate at a median of three years was 70.1% in patients given trastuzumab plus chemotherapy, compared with 53.3% for those who received chemotherapy alone, a significant difference.
The pathologic complete response rate, a secondary endpoint, was 43% in the trastuzumab arm versus 23% in the chemotherapy-alone arm, again a significant difference.
Neoadjuvant therapy with dual HER2 blockade holds the possibility of improving overall survival rates as well, Dr. Baselga said.
“With new therapies, we could easily go to curing over 90% of patients at five years, and trastuzumab alone is associated with a five-year survival rate of about 87%.
pCR as Non-Predictive of Survival
But study discussant Eric P. Winer, MD, Director of the Breast Oncology Center and Thompson Senior Investigator in Breast Cancer Research at the Dana-Farber Cancer Institute, said that pCR is “not ready for prime time—we'd all like to say it is, but it just isn't.”
“Improvements in pathologic complete response have not always been associated with better disease-free survival and overall survival,” he said.
Whether the additional 20% of patients with a pCR on dual HER2 blockade ultimately leads to better disease-free survival rates will depend on whether those were patients who would have previously relapsed, Dr. Winer said.
Also, failure to achieve a complete response does not mean that patients will not be cured after surgery, Dr. Winer said.
The bottom line: Pathological complete response rates should not be used to change clinical practice or for drug approval, he concluded.
What's Up, What's Down
Eric Winer, MD, in his Discussant's talk, offered attendees a score card on ‘What's Up and What's Down?’ in the treatment of HER2-positive breast cancer:
* Up: Trastuzumab plus lapatinib with paclitaxel: Not ready for adjuvant or neoadjuvant use yet, but the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) study results are being awaited. That trial is comparing lapatinib, trastuzumab, the sequence of the two, and their combination in the adjuvant setting.
* Up: Trastuzumab plus pertuzumab with docetaxel: Ready for an adjuvant trial, and non-chemotherapy-containing doublets should move forward.
* Down: Lapatinib alone plus chemotherapy: Appears a little less active and more toxic. The jury is out until the ALTTO results are in.
* Down: Pertuzumab alone plus chemotherapy: Hard to get excited about it, he said.