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Jose Baselga, MD, PhD, and Michael Untch, MD, shared results from the NeoALLTO and GeparQuinto trials, respectively. NeoALLTO is a phase III, randomized, open-label, neoadjuvant study of lapatinib (Tykerb), trastuzumab (Herceptin), and their combination plus paclitaxel in women with HER2-positive primary breast cancer. GeparQuinto (GBG 44) is evaluating lapatinib vs trastuzumab in combination with neoadjuvant anthracycline- and taxane-based chemotherapy.
SAN ANTONIO-No one can deny that adding a new drug to an established treatment regimen means an increase in costs. But if the new agent can improve response rates to the point where a patient may bypass additional therapy, then the benefits, and additional upfront costs, should make for a lower treatment price-tag overall, not to mention a better quality of life. Investigators with multiple trials, including NeoALLTO, suggested that the success they’ve found to date with neoadjuvant HER2 blockade will eventually translate into less therapy and more cost-efficient treatments.
Jose Baselga, MD, PhD, and Michael Untch, MD, shared results from the NeoALLTO and GeparQuinto trials, respectively. NeoALLTO is a phase III, randomized, open-label neoadjuvant study of lapatinib (Tykerb), a dual HER2/EGFR tyrosine kinase inhibitor; trastuzumab (Herceptin); and their combination plus paclitaxel in women with HER2-positive primary breast cancer. GeparQuinto (GBG 44) is evaluating lapatinib vs trastuzumab in combination with neoadjuvant anthracycline- and taxane-based chemotherapy.
In the NeoALLTO trial, patients were randomized to six weeks of anti-HER2 therapy alone, either with lapatanib (1,500 mg/day), trastuzumab (4 mg/kg intravenous dose followed by 2 mg/kg IV weekly dose), or a combination of the two (1,000 mg/day of lapatanib). Paclitaxel was then added to all three regimens for a total of 18 weeks of therapy at which time patients underwent surgery. After surgery, conventional chemotherapy was administered for three weeks and the patients then continued on with the previously assigned anti-HER2 therapy to complete one year of anti-HER2 therapy.
“Please note that this [study] had a unique biological therapy window and that we conducted tumor biopsies at two weeks on everybody. The fact that we started chemotherapy six weeks [after anti-HER2 therapy] allowed us to address the true clinical response rate to anti-HER2 therapies by themselves in the first-line setting,” said Dr. Baselga, previously of the Vall d’Hebron Institute of Oncology in Barcelona, and now chief of the division of hematology/oncology and associate director of Boston’s Massachusetts General Hospital Cancer Center.
The study’s primary endpoint was pathological complete response (pCR) as defined by the NSABP*: No invasive cancer in the breast or only noninvasive in-situ cancer in the breast specimen. According to the results, pCR came in at 24.7% for the lapatinib arm, 29.5% for the trastuzumab arm, and 51.3% for the lapatinib plus trastuzumab arm (P < .0001 for trastuzumab alone vs the combination). For women with hormone-receptor (HR)-positive disease, the pCR in the combination arm was 41.6%; in those with HR-negative disease, the pCR was 61.3% in the combination arm.
The objective clinical response rate at six weeks (the biological window) was 67.1% for lapatinib, 30.2% for trastuzumab, and 52.6% for the combination. At surgery, the response rate was 80.3%, 70.5%, and 74%, respectively (SABCS abstract 2010 S3-3 ).
With regard to safety, 23% of the women in the lapatinib arm experienced grade 3 or higher diarrhea vs 2% in the trastuzumab arm and 21% in the combination arm. Overall, adverse events were common in the lapatinib arm, Dr. Baselga reported. “There were two patients with serious hepatic dysfunction, but no serious cardiac dysfunction,” he said.
“The take-home message is that dual anti-HER2 blockade is a valid concept in HER2-positive breast cancer,” Dr Baselga said. “The complete response rate at six weeks was higher in the lapatanib-containing arms. We did see an increased toxicity but manageable toxicity in the lapatanib arm.”
The NeoALLTO trial will continue to accrue patients to a planned total of 8,400 patients. As the research moves forward, the trial will include a sequential arm of trastuzumab followed by lapatanib.
For the GeparQuinto study, 597 HER2-positive patients were randomized to receive either trastuzumab (loading dose 8 mg/kg, then 6 mg/kg every three weeks) or lapatinib (1,250-1,000 mg/day) throughout four cycles of ECT* (90/600 mg/m² EC followed by 100 mg/m² T in three-week cycles). As with NeoALLTO, patients went on to surgery and then received trastuzumab for six more months if they received the agent to begin with. Lapatinib patients had 12 months of trastuzumab therapy.
According to the results, the pCR (no invasive or noninvasive residual disease in the breast and nodes) was 31.1% in the chemotherapy plus trastuzumab arm and 21.7% in the chemotherapy plus lapatanib arm (P < .05). Using no invasive residual disease in the breast and lymph nodes as criteria, chemotherapy plus trastuzumab turned in a pCR of 45% while chemotherapy plus lapatanib came in at 29.9% (P < .05). Using no invasive residual disease in the breast as the criteria, pCR was 50.4% for trastuzumab and 35.2% for lapatanib (P < .05). At surgery, the breast-conservation rate was 65.6% for the trastuzumab arm and 56% for the lapatanib arm (SABCS 2010 abstract S3-1).
Dr. Untch reported that patients in the lapatanib arm did have a higher discontinuation rate. The discontinuation rate of chemotherapy and targeted therapy was 10% in the trastuzumab arm and 16% in the lapatinib arm. “The discontinuation was because of [lapatanib] side effects, mainly diarrhea. We then lowered the lapatanib dose and gave patients loperamide,” he said.
“Anthracycline-taxane based chemotherapy and trastuzumab achieved a pCR rate of 50% in HER2-positive patients, confirming our previous findings,” said Dr. Untch, head of the multidisciplinary breast cancer section at Helios Clinic in Berlin, referring to results from the GeparQuattro study (J Clin Oncol 28:2015-2023, 2010) and the TECHNO study (SABCS 2010 abstract P1-11_03).
Asked why patients still needed surgery after turning in such promising response rates, Dr. Untch explained that surgery is the current standard of care. However, after undergoing HER2 blockade, many patients in GeparQuinto were eligible for breast-conservation surgery rather than mastectomy. In the future, treatment with HER2 blockade could eradicate the need for surgery.
“We have to [surgically] take out tumor bed to give the pathologist a sample to see if there is ductal carcinoma in-situ,” he said. “But when we see that 50% of the patients do not have invasive tumor cells, perhaps they can avoid surgery.”
Addressing the issue of the higher cost associated with adding targeted therapy, Dr. Untch pointed out that “if, within 12 weeks of very effective therapy, we achieve a 50% or more complete remission [and] the eradication of tumor cells, do we really need to treat these patients for an additional 12 months? That is going to save some costs and that is [a question for] the next generation of trials.”
*NSABP = National Surgical Adjuvant Breast and Bowel Project
*ECT = epirubicin, cyclophosphamide, and docetaxel