AMSTERDAM – An unexpectedly dramatic benefit from combining trastuzumab and lapatinib when briefly treating women scheduled for breast cancer surgery has researchers focused on the best follow-up study to this promising but preliminary finding from 66 patients.
Among 66 patients with newly diagnosed HER2-positive breast cancer and scheduled for surgery, an average 11 days of treatment with a combination of trastuzumab (Herceptin) and lapatinib (Tykerb) during the period before surgery resulted in a pathologic complete response (pCR) in seven patients (11%) and 11 patients (17%) with minimal residual disease (MRD), Dr. Nigel Bundred reported at the European Breast Cancer Conference.
Mitchel L. Zoler/Frontline Medical News
Dr. Nigel Bundred
These patients had breast cancer tumors at baseline with a median diameter of 2 cm that with treatment for not quite 2 weeks resulted in either complete tumor disappearance or shrinkage to less than 5 mm in diameter in 18 (27%) of the patients on dual therapy, said Dr. Bundred, a professor of surgical oncology at the University Hospital of South Manchester (England).
“No cancer has ever disappeared that fast. It was flabbergasting,” Dr. Bundred said in an interview. “We need to confirm the results, and get larger numbers of patients.”
“This was a really surprising finding,” said Judith M. Bliss, professor and director of the Clinical Trials & Statistics unit of the Institute of Cancer Research in London and a co-investigator. “We knew that trastuzumab and lapatinib are effective treatments, but we had not expected to see such a dramatic effect on the structure and size of the tumor in such a short period of time,” Prof. Bliss said in a video interview.
The finding came as part of the Effect of Perioperative Anti-HER2 Therapy on Overall Survival–Biologic Phase (EPHOS-B) trial, designed to assess changes in a marker of cell proliferation (Ki67) and in a marker of cell apoptosis in relation to treatment with trastuzumab, lapatinib, or both when administered during the 10-12 days from the time patients entered the study until their scheduled surgery.
Judith M. Bliss
During the first phase of EPHOS-B, when 130 patients received trastuzumab monotherapy, lapatinib monotherapy, or neither, one of the 57 patients on trastuzumab (2%) had a pathologic complete response and one patient (2%) had minimal residual disease. No patients on lapatinib alone or in the control arm with no anti-HER2 drug had this sort of response.
During the second phase, 127 patients received trastuzumab alone, trastuzumab plus lapatinib in combination, or controls who received no anti-HER2 treatment. The substantial number of complete or partial responders in the 66 patients who received combined treatment with trastuzumab and lapatinib contrasted with one minimal residual disease among 32 patients (3%) who received trastuzumab alone and no responders among the 29 controls.
Patients receiving trastuzumab, alone or in the combined regimen, received a standard intravenous loading dosage of 6 mg/kg on days 1 and 8 after entry into the protocol, followed by a third dose after surgery on days 15-19; those also receiving lapatinib received 1 g/day orally for 28 days starting on entry.
“A quarter of the patients seem exquisitely sensitive to the combination of trastuzumab and lapatinib,” said Dr. David Cameron, another collaborator on the EPHOS-B study. “It’s pretty unusual to treat for 10-12 days and have 10% of the tumors disappear.”
Follow-up studies will be needed to determine whether patients with a pathologic complete response or minimal residual disease can forgo some or all of the chemotherapy that would usually follow surgery and still have good long-term disease-free survival. “We will focus on optimizing the short-term effect, and then modulate subsequent treatments,” said Dr. Cameron, professor and clinical director of oncology at the University of Edinburgh.
“We think these are patients who don’t need chemotherapy and are particularly sensitive to anti-HER2 drugs,” but so far that hasn’t been proven, cautioned Ms. Bliss.
Dr. David Cameron
The striking efficacy of trastuzumab combined with lapatinib in these 66 patients contrasts with the previously reported results from the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study, which failed to show an advantage in disease-free survival with trastuzumab plus lapatinib, compared with either of these two agents used individually during 1 year of adjuvant treatment in more than 8,000 randomized patients (J Clin Oncol. 2015 Nov 23. doi: 10.1200/JCO.2015.62.1797), But the EPHOS-B results did agree with results from the much smaller NeoALTTO study, which showed in a randomized, multicenter, phase III study with 455 patients a significant incremental increase in pathologic complete response rate in patients on combined trastuzumab plus lapatinib, compared with patients on either drug alone (Lancet. 2012;379 [9816]:633-40).