Lapatinib/Trastuzumab Stops Trastuzumab Resistance in Breast Cancer
San Antonio, TX – The combination of trastuzumab (Herceptin) and lapatinib (Tykerb) achieved a significant overall survival (OS) benefit compared to lapatinib alone in heavily pretreated women with metastatic HER2-positive breast cancer. These updated survival results of the phase IIII EGF 104900 trials suggest that lapatinib can overcome resistance to trastuzumab in this population.
“The clinical benefit of the lapatinib/trastuzumab combination are quite compelling and lead me to believe that the agents may be acting together to form a sort of ‘dual blockade’ to obstruct the HER2 pathway necessary for the tumor to thrive,” said Kimberly Blackwell, MD, Duke University Medical Center, Durham, NC, lead investigator of the trial.
The study included 296 women with HER 2 breast cancer, one of the most aggressive types of breast cancer. All patients had recurrences after a median of 3 prior trastuzumab-containing regimens. Study participants were randomized to receive either lapatinib 1500 mg/day or lapatinib 1000 mg/day combined with trastuzumab 2 mg/kg after a 4 mg/kg loading dose. Crossover to the combination arm was permitted for disease progression on the lapatinib monotherapy arm.
Both treatment arms were well balanced. Median age was about 51 years; median number of prior chemotherapy regimes was 4 in the monotherapy arm and 5 in the combination therapy arm. Fifty percent had estrogen receptor– and progesterone receptor–negative disease. About one-third of the women had 6 or more prior metastatic regimens. More than 70% had visceral involvement. About 18% had known brain metastasis.
Median OS was 9.5 months on lapatinib alone versus 14 months on the combination of the two drugs (HR, 0.74; P = .0026). One-year survival was 41% versus 56%, respectively. Dr Blackwell said a more than 10% difference has been maintained with longer follow-up. The benefit of the combination therapy remained significant even after adjusting for baseline prognostic factors, Dr Blackwell said (HR, 0.71; P = 012).
The high percentage of women who crossed over to the lapatinib/trastuzumab arm (52%) may have underestimated the actual survival difference between the two arms, Dr Blackwell noted. After adjusting for crossover, a trend was seen for a clinically relevant 25% reduction in death on the combination therapy.
Adverse events were similar in the two arms, with the exception of grade 1-2 diarrhea, which was significantly higher in the combination arm (P = .03). The incidence of adverse events ≥grade 3 was 7% in both groups. Adverse events that occurred in 10% or greater included diarrhea, nausea, rash, fatigue, and vomiting. Grade 3-4 cardiac adverse events were reported in 1 patient on monotherapy and 3 patents in the combination arm. One patient in the combination arm had cardiac failure and subsequently died of pulmonary embolism that could have been disease-related or treatment-related, said Dr Blackwell. “As a practicing clinician, I think it is amazing that there has been no safety signal for this combination. It is remarkable,” Dr Blackwell stated.
At an official Press Conference, moderator Edith Perez, MD, called this study “provocative” and said, “This is the first time that a study validates continuous trastuzumab in the metastatic setting.”
Dr Blackwell commented that physicians outside the United States do not use continuous trastuzumab but that physicians in the United States are moving toward this practice. Two large studies are planned—one in early stage breast cancer and one in the neoadjuvant setting—to compare lapatinib plus trastuzumab versus sequential therapy with both drugs versus either drug alone. SABCS Abstract 61.