Doubling Down on Human Epidermal Growth Factor Receptor 2

Of the major molecular subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2) –positive disease undoubtedly would win the “most improved” award. The introduction of the HER2-targeted therapies trastuzumab and lapatinib has had a dramatic impact on the clinical outcomes of patients. The use of trastuzumab, in particular, has led to significant improvements in survival in both the adjuvant and metastatic settings. Despite this progress, there is clearly room for additional improvement. A small but significant percentage of women with early-stage disease still relapse after receiving trastuzumab-based adjuvant chemotherapy regimens. In the metastatic setting, virtually all women eventually progress on trastuzumaband lapatinib-based therapies. Novel therapeutic approaches are therefore needed to overcome de novo and acquired resistance to HER2-targeted therapy. There is also a need to reduce the toxicities of therapy and ultimately do away with chemotherapy all together. The possibility that these goals can be accomplished is strengthened by recent clinical data demonstrating that HER2 remains a valid therapeutic target, even after cancers have progressed on multiple HER2-directed therapies. Thus, for some, most, or all HER2-positive tumors, HER2 itself continues to represent a major vulnerability. The challenge is determining the optimal method to capitalize on this vulnerability. One approach to overcoming resistance in these cancers is to combine distinct HER2-targeted agents that have complementary mechanisms of action. This concept is supported by preclinical studies demonstrating synergistic or at least additive activity when combining agents. These results prompted several clinical studies evaluating combinations of HER2-directed agents. In patients with HER2positive metastatic breast cancer who had progressed on trastuzumabbased therapy, trastuzumab added to lapatinib improved disease control and survival compared with lapatinib alone. Similarly, in patients treated with preoperative therapy, the combination of trastuzumab and lapatinib plus paclitaxel led to higher rates of pathologic complete response (pCR) than either targeted agent alone administered with paclitaxel. Combining two HER2-directed antibodies, pertuzumab and trastuzumab, has also shown promise. An initial phase II trial of the combination in patients with HER2-positive metastatic breast cancer who had progressed on prior trastuzumab-based therapy demonstrated that the combination was active. The combination has been further studied in two randomized trials. In the first-line metastatic setting, the phase III Cleopatra study compared docetaxel, trastuzumab, and pertuzumab with docetaxel, trastuzumab, and placebo. Recently released data indicate that the addition of pertuzumab to the treatment program was associated with a significant improvement in progression-free survival compared with placebo. In the preoperative setting, the phase II NeoSphere study demonstrated that patients who received pertuzumab and trastuzumab along with docetaxel had higher pCR rates than those who received either single antibody with docetaxel. Interestingly, another arm of that study evaluated the efficacy of pertuzumab and trastuzumab in the absence of chemotherapy and found that 17% of patients on this regimen achieved a pCR. In the article that accompanies this editorial, Cortes et al report on a study that was designed to further evaluate whether the promising activity observed with the combination of pertuzumab and trastuzumab actually required the presence of trastuzumab. In their initial study of the pertuzumab and trastuzumab combination in 66 patients whose cancer had progressed on trastuzumab, they demonstrated an objective response rate of 24% and clinical benefit rate (CBR; defined as objective response rate plus stable disease 6 months) of 50%. To assess the relative contributions of each antibody, they enrolled an additional cohort of 29 patients and treated them with pertuzumab monotherapy. At the time of progression, patients were offered continuation of the pertuzumab with the addition of trastuzumab. The eligibility criteria of this cohort were the same as the previous cohorts, except that patients on the new cohort had to have received their last dose of trastuzumab at least 4 weeks before starting study therapy. This stipulation was included to minimize the chance that residual trastuzumab from a patient’s previous therapy could influence the results of this study. Among the 29 patients treated with pertuzumab monotherapy, only one had an objective response (3%), and the CBR was 10%. At the time of progression, 17 of the patients continued pertuzumab and had trastuzumab added to their regimen. In this cohort, three patients had objective responses (18%), and the CBR was 41%. Progressionfree survival was numerically longer for those patients on combination therapy compared with the patients in the monotherapy cohort (17.4 v 7.1 weeks). These results are consistent with the hypothesis that the two antibodies together are more effective than pertuzumab monotherapy. However, on their own, these data are not definitive. The study is limited by the extremely small sample size and the possibility that selection bias influenced which of the patients went on to receive the combination therapy. Although demographic data indicate that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 14 MAY 1