Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial)

Reporter: Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2011

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English

Presenter: V. Guarneri
Presenter's Institution: Modena University Hospital, Modena, Italy

Background

  • The treatment of patients with breast cancer continues to evolve, with cytotoxic chemotherapy, endocrine therapy, and molecular targeted therapies as the backbone of systemic therapy. As we continue to better our understanding of the biology of breast cancer cells, therapies to target specific pathways continue to be developed with the goal of expanding available effective therapy in specific populations. Several drugs targeting different molecular pathways have been approved to treat metastatic breast cancer, but for early breast cancer trastuzumab (Herceptin) is the only available targeted agent; it is currently approved in combination with chemotherapy for adjuvant or neoadjuvant treatment in women with HER2-positive breast cancer. Lapatanib (Tykerb) is a dual HER2/EGFR tyrosine kinase inhibitor approved for use in combination with capecitabine (Xeloda) for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received previous therapy that included an anthracycline, a taxane, or trastuzumab. Unlike trastuzumab, lapatinib has infrequent adverse effects on cardiac function.
  • Chemo + trastuzumab is the standard of care for HER2+ disease. P95Her2 is a truncated form of HER2 that lacks the trastuzumab binding site and is expressed in 30% of HER2 positive breast cancers. Pre-clinical and clinical evidence suggests the presence of P95Her2 confers resistance to trastuzumab. The combination of lapatinib and trastuzumab, which together block the inner (lapatanib) and outer (trastuzumab) domains of the HER2 receptor therefore has potential to enhance antitumor activity.
  • The study described here is a randomized phase II trial of preoperative taxane-anthracycline chemotherapy in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. The primary aim of the study was to compare pathological complete response (pCR) in breast and axillary nodes for the three different treatment regimens.

Methods

  • For all arms, chemotherapy (CT) consisted of weekly paclitaxel x 12 followed by 5-FU, epirubicin, cyclophosphamide (FEC) x 4. Pts randomized to arm A received CT plus weekly trastuzumab; in arm B pts received CT plus lapatinib 1250 mg po daily; in arm C pts received CT plus weekly trastuzumab and lapatinib 750 mg po daily. Surgery was performed within 5 weeks of the last FEC administration.
  • Study inclusion criteria: women with stage 1-3, HER2+ breast cancer. The study sample size was calculated using the two-step Simon's design with a planned accrual of 120 pts.
  • Biomarker anaylsis was also performed; P95HER2 expression was measured to explore the potentially clinically relevant difference in the pCR rate according to P95 status. P95 was evaluated using immunohistochemistry with a score of 0-3+.
  • The primary study aim was assessment of pCR in breast and axilla, and secondary aims were to assess the safety of the treatments, rate of breast conservation surgery (BCS), and biomarker anaylsis.
  • The expected pCRwith chemo + a single anti-Her 2 agent is 40%. For chemo plus both lapatanib and trastuzumab to be of clinical value, according to the presenter, there would need to be at least a 50% pCR rate.

Results

  • 121 pts from 12 institutions were randomized.
    • The median age was 49 yrs (26-68 yrs);
    • Division according to stage was as follows: stage IIA 32%, IIB 50%; IIIA 18%; there was no major differences in stage distribution across the study arms ; most were stage IIB or IIIA.
    • 59% of patients were ER and/or PR positive.
    • Eighty pts completed surgery and were evaluable for response:
  • 50 pts (62.5%) received breast conservation (BCS). By arm, the rates of BCS were 68% for arm A, 58% for arm B, and 78% for arm C. A conversion from mastectomy to BCS was observed in 23/44 patients (conversion rate: 52%).
  • The overall pCR rate was 36.2% (28% in arm A, 32% in arm B, and 48% in arm C). There was a lower than expected pCR rate in arm B. pCR rates in the axilla were: arm A- 74%, arm B -69%, and arm C- 84%.
  • P95 was expressed in 30.7% of the study patients. There was 97% concordance between central review and local lab testing for P95 positivity. There was no difference in path CR rates according to P95 expression.
  • The mean left ventricular ejection fraction (range) at baseline was 62% (52%-77%), 61% (44%-78%) after 12-13 weeks, and 61% (44%-74%) at the end of therapy. No patient had symptomatic cardiac events, including CHF.
  • At the initial dose of 1500 mg/day, grade 3 diarrhea was observed in 20%. The dose of lapatanib was later changed to 750 mg due to grade 3 diarrhea. 39 patients in arm A, 23 pts in arm B ,and 23 in arm C required a dose reduction in lapatanib. Diarrhea, skin disorders (rash), and hepatic disorders were higher in those receiving lapatanib.

Author's Conclusions

  • There was a > 50% increase in the path CR rate for P-FEC-trastuzumab-lapatanib, which was superior to P-FEC-trastuzumab or P-FEC lapatanib. P95 does not predict pCR rate with any of the three arms.
  • Preliminary activity data are promising, and cardiac safety data are reassuring. P-FEC and anti Her-2 therapies can be given with good cardiac tolerability in patients. Diarrhea is the significant toxicity which causes dose reductions and treatment interruptions in the majority of pts.

Clinical Implications

  • One of the advantages of lapatinib is that patients may be able to take it more conveniently for a longer period of time, without significant detriment in quality of life compared to conventional chemotherapy.
  • Dual blockade of the Her-2 receptor with trastuzumab-lapatanib appears to better than single blockade with respect to path CR, but it is not certain how best to use lapatinib and trastuzumab together in early breast cancer patients, specifically with respect to how soon to initiate and how long to continue therapy.
  • While enthusiasm for lapatinib is based on pCR rates, which may be good surrogates for long-term outcome, some argue that drug approval or practice change should not be based on pCR, as it is not always correlated with improved disease-free and overall survival. As the data matures we will need to see if the pCR translates into improved survival.
  • Analysis of local control rates for patients converted from mastectomy to BCS would also be of interest, as some groups have demonstrated increased risk of local recurrence in patients undergoing BCS rather than planned mastectomy after neoadjuvant chemotherapy.
  • Cost-benefit analysis will also be important given the high costs of both drugs.

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