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Preoperative Anti-HER2 Agents Yield Benefits

Web Exclusives - Drug Resistance

SAN ANTONIO—For women with human epidermal growth factor receptor type 2 (HER2)-overexpressing breast cancer, preoperative treatment with agents that block HER2 leads to high rates of pathological complete response (pCR), according to the results of three studies presented at the 33rd annual San Antonio Breast Cancer Symposium. 

The studies used various combinations of trastuzumab, lapatinib, and pertuzumab (a novel monoclonal antibody) in the neoadjuvant setting. 

Neil Spector, MD, director of translational research in oncology at the Duke Cancer Institute in North Carolina, moderated a press conference where the results were announced where he commented, “This is a very exciting area. We have gone from HER2-overexpressing disease being the most lethal type of breast cancer to a subtype that we are talking about curing.” 

Two of the studies evaluated the tyrosine kinase inhibitor lapatinib, but this agent proved second-best to trastuzumab. In the phase 3 Neo ALTTO trial, 455 women were randomized to lapatinib, trastuzumab, or lapatinib plus trastuzumab, all with paclitaxel. Patients received 6 weeks of the biologic, with weekly paclitaxel added to the regimen for 12 more weeks, yielding a total of 18 weeks of neoadjuvant treatment. 

The pCR rate by National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines (absence of invasive cancer cells in the breast at surgery or only noninvasive in situ cancer in the breast) was 51.3% with lapatinib plus trastuzumab versus 24.7% for lapatinib, and 29.5% for trastuzumab (P = .0001). In the breast plus lymph nodes, pCR rates were 47% with lapatinib plus trastuzumab, 20% with lapatinib, and 28% with trastuzumab, reported Jose Baselga, MD, of Massachusetts General Hospital Cancer Center, Boston. 

In the phase 3 GeparQuinto study, 620 patients were randomized to epirubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles plus trastuzumab or lapatinib initiated with chemotherapy. The trastuzumab arm achieved a significantly higher pCR rate than the lapatinib arm according to the NSABP definition—50.4% and 35.2%, respectively (P <.05)—and also by the investigators’ more stringent definition of no microscopic evidence of residual tumor cells in the breast or nodes: 31.3% versus 21.7%, respectively (P <.05), reported Michael Untch, MD, of the Multidisciplinary Breast Cancer Center at the Helios Clinic, Berlin. 

Pertuzumab/trastuzumab led to high responses

In the phase 2, four-arm NeoSphere trial of 417 women, triple therapy with pertuzumab, trastuzumab, and docetaxel produced 50% more pCRs than were achieved with trastuzumab and docetaxel, reported Luca Gianni, MD, of the Fondazione IRCCS Istituto Nazionale Tumori in Milan, Italy. 

“In addition, this combination without chemotherapy was capable of eradicating the tumor in a remarkable number of cases (17%), therefore avoiding the toxicities seen with chemotherapy,” Gianni noted. 

The pCR rate (by NSABP definition) was 45.8% with trastuzumab/pertuzumab/docetaxel, compared with 24.0% with pertuzumab/docetaxel (P = .003), 29.0% with trastuzumab/docetaxel, and 16.8% with trastuzumab/pertuzumab (P = .0198). 

This effective three-drug regimen was quite well tolerated, although “strikingly low toxicity” was seen when the docetaxel was omitted in the trastuzumab/pertuzumab arm. Grade 3/4 toxicity was seen in less than 4% of these patients, compared with approximately 50% of the chemotherapy arms, Gianni said. 

Unexpectedly in Neo ALLTO and GeparQuinto, pCR rates were higher in the estrogen receptor (ER)-negative patients than in the ER-positive ones. Although both hormone subgroups benefited from the HER2 blockade, pCR rates climbed to more than 60% in the ER-negative subgroup.

 All regimens were well tolerated in general; however, those containing lapatinib had much higher rates of diarrhea, the investigators noted. In Neo ALLTO, grade 3 diarrhea was observed in more than 20% of patients on lapatinib compared with 2% with single-agent trastuzumab. In Neo ALLTO and GeparQuinto, approximately 35% of patients on the lapatinib arms were unable to receive the full planned doses of this agent and, in GeparQuinto, there were 10% more treatment discontinuations with lapatinib than with trastuzumab (23% vs 13%), largely due to side effects, Uncht said.

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