The concept of complete HER2 blockade with biologic agents gained steam at the 33rd Annual San Antonio Breast Cancer Symposium upon the results of several phase III studies in the neoadjuvant setting. High rates of pathologic complete responses (pCR) were observed with various regimens of trastuzumab (Herceptin), lapatinib (Tykerb), and the investigational agent pertuzumab (Omnitarg), leading one scientist in the field to predict that chemotherapy might be eliminated altogether for some patients.

Neil Spector, MD, Director of Translational Oncology Research at the Duke Cancer Institute in North Carolina, delivered a plenary lecture on anti-HER2 therapies at the San Antonio meeting, which was held December 8-12, 2010. He commented at a press briefing, "I have always believed total HER2 blockade is optimal. Since we have three targeted therapies, each acting differently but aimed at the same target, I can envision future trials of these agents in combination, perhaps moving away from chemotherapy in a subset of patients."

He added, "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."

But Eric Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, tempered the enthusiasm with a note of caution as the invited discussant of the studies. Although pCR is consistently associated with excellent clinical outcomes, he said improvements in pCR have not always been associated with statistically significant improvements in disease-free and overall survival. Therefore, he maintained, pCR (regardless of the agent used) should not yet be used as an "endpoint for drug approval or practice change."

NeoALLTO and GeparQuinto

Lapatinib came up short in two phase III studies that examined its effect. NeoALTTO, conducted by the Breast International group (BIG), compared lapatinib, trastuzumab, and lapatinib/trastuzumab combination therapy, all with paclitaxel, in 455 patients.¹ Patients received 6 weeks of the biologic(s), with weekly paclitaxel added to the regimen for 12 more weeks, yielding a total of 18 weeks of neoadjuvant treatment.

Jose Baselga, MD, Associate Director of the Massachusetts General Hospital Cancer Center, Boston, reported that 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/trastuzumab vs 24.7% for lapatinib and 29.5% for trastuzumab (P = .0001). Pathologic CR rates in the breast and lymph nodes were 47% with lapatinib/trastuzumab, 20% with lapatinib, and 28% with trastuzumab, Dr. Baselga reported. Thus, with regard to the primary objective of the NeoALLTO trial (pCR), the combination proved superior, and the investigators concluded that dual blockade of the HER2 pathway is a valid concept.

Overall clinical responses at 6 weeks (before paclitaxel was given) were highest in both arms with lapatinib (67.1% with lapatinib/trastuzumab and 52.6% with lapatinib), but at the time of surgery response rates were fairly similar among the arms: 80.3% with the combination, 74.0% with lapatinib, and 70.5% with trastuzumab.

Rates of breast-conserving surgery were similar among the three arms (around 40%), and in the node-negative subsets, rates were highest with lapatinib/trastuzumab (69% vs 48% with lapatinib and 56.6% with trastuzumab, respectively [P = .03]).

In the 85-center GeparQuinto study, 620 patients were randomly assigned to receive epirubicin/cyclophosphamide for four cycles followed by docetaxel for four cycles plus trastuzumab or lapatinib initiated with chemotherapy.² After surgery, trastuzumab was given for 6 more months in the trastuzumab arm and for 12 months to patients initially receiving lapatinib.

The trastuzumab arm achieved a significantly higher pCR rate according to the NSABP definition-50.4% and 35.2%, respectively (P < .05)-and also by the investigators' more stringent definition of pCR (no microscopic evidence of residual tumor cells, invasive or noninvasive, in the breast or nodes): 31.3% vs 21.7% with lapatinib (P < .05), reported Michael Untch, MD, head of the Multidisciplinary Breast Cancer at the Helios Clinic, Berlin.

In another component of the GeparQuinto trial reported at the meeting, bevacizumab (Avastin) added no benefit to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel.³

Impressive Outcomes with Pertuzumab/Trastuzumab

In the 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, Director of Medical Oncology at the Fondazione IRCCS Istituto Tumori in Milan.⁴

"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," Dr. 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).

The triplet was well tolerated, with no significant differences in grade 3/4 adverse events over the other arms. Strikingly low toxicity was noted for trastuzumab/pertuzumab, which was associated with grade 3/4 toxicity in less than 3% of patients, in sharp contrast to 45% to 57% for the docetaxel-containing arms. There was no meaningful increase in cardiac risk with the addition of pertuzumab over the short four-cycle course of neoadjuvant treatment.

"Pertuzumab has the ability to enhance the activity of trastuzumab. The combination has good tolerability and remarkable antitumor activity in metastatic breast cancer that has progressed after trastuzumab," Dr. Gianni commented. "The combination has a very favorable therapeutic ratio that justifies its continued use as adjuvant treatment after the end of chemotherapy."

Interesting Responses by Hormonal Status

Unexpectedly in NeoALLTO and GeparQuinto, pCR rates were higher in estrogen receptor (ER)-negative patients than in those with ER-positive disease.

"In NeoALLTO, both hormone subgroups benefited from the lapatinib/trastuzumab combination, although it is worth noting that the ER-negative group did better," Dr. Baselga commented.

Patients with ER-negative tumors had a pCR rate of 61.3% with lapatinib plus trastuzumab, compared with 36.5% for the trastuzumab group and 33.8% for the lapatinib group (P = .005). Rates in the in ER-positive patients, respectively, were 41.6% vs 22.7% and 16.2% (P = .03).

In NeoSphere, the triplet yielded a 63% pCR rate in ER-negative women, compared with 26% in ER-positive patients.

Dr. Winer said the higher pathologic CR rates for ER-negative tumors needs to be "reconciled with" the generally better disease-free survival seen for HER2-positive, ER-positive patients in the adjuvant setting. "The implication is that tumor kinetics vary by ER status," he suggested, "and that ER remains important in HER2-positive patients." Failure to achieve a pCR appears to be less predictive of poor outcome in patients with ER-positive tumors than those with ER-negative tumors, he added.

More Adverse Events with Lapatinib

Dr. Baselga and Dr. Untch both noted the greater toxicity of lapatinib in their studies. In NeoALLTO and GeparQuinto, approximately 35% of patients on the lapatinib arms were unable to receive the full planned doses of this agent. In NeoALLTO, grade 3 diarrhea was observed in more than 20% of patients on lapatinib compared with 2% with single-agent trastuzumab. Additionally, elevated liver enzymes were observed in 22% on both lapatinib-containing arms compared with 1% receiving trastuzumab, Dr. Baselga reported.

In GeparQuinto, the investigators observed 10% more treatment discontinuations with lapatinib than with trastuzumab (23% vs 13%), largely due to side effects, and that may have affected the efficacy seen in this arm, Dr. Untch said. "Compliance of patients receiving lapatinib with epirubicin/cyclophosphamide and docetaxel was lower than with trastuzumab," he noted. "We learned a lesson and lowered the dose of lapatinib. And we gave loperamide for the diarrhea."

Translational Studies Forthcoming

Refinement of these findings will come from a wealth of translational studies within these phase III trials. For NeoALLTO, 10 specimens are collected at each time point (at baseline, week 2, and surgery), which will yield 30 specimens per patient and a total of 11,091 samples. "Our future research is intended to identify predictive markers of sensitivity and resistance. We will also perform PET-CT and assess circulating tumor cells in a subset," Dr. Baselga said.

The companion adjuvant ALLTO trial, which will randomly assign 8,400 patients to various adjuvant regimens using these drugs, will be very informative, he added.

Dr. Gianni similarly said, "We are exploring in our extensive tumor bank the ability to identify biomarkers of benefit from the trastuzumab/pertuzumab combination. One of the main messages from this study is that the neoadjuvant approach allows for rapid testing and ranking of new therapies." ■

References

1. Baselga J, Bradbury I, Eidtmann H, et al: First results of the NeoALTTO trial (BIG 01-06 / EGF 106903): A phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-3. Presented December 10, 2010.

2. Untch M, Loibl S, Bischoff J, et al: Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: Primary efficacy endpoint analysis of the GEPARQUINTO study (GBG 44). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-1. Presented December 10, 2010.

3. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy with or without bevacizumab: Primary efficacy endpoint analysis of the GEPARQUINTO study (GBG 44). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S4-6. Presented December 10, 2010.

4. Gianni L, Pienkowski T, Im Y-H, et al: Neoadjuvant pertuzumab (P) and trastuzumab (H): Antitumor and safety analysis of a randomized phase II study ('NeoSphere'). 33rd Annual San Antonio Breast Cancer Symposium. Abstract S3-2. Presented December 10, 2010.