Thursday, January 19, 2012

One-Two Punch: Curbing HER-2 Positive Breast Cancer with Herceptin-Tykerb Combo

Using Tykerb (lapatinib; GlaxoSmithKline, U.K.) and Herceptin (trastuzumab; Genentech, South San Francisco, Calif.) anti-HER-2 drugs together doubles the odds of recovery compared to either drug alone in HER-2 positive early breast cancer patients, reports NeoALTTO trial investigators in the January 17th online publication at Lancet Oncology journal homepage.  This study provides a proof-of-concept that dual HER-2 block is better than using a single agent HER-2 blocker.

What was done

NeoALTTO (NeoAdjuvent Lapatinib and/or Trastuzumab Treatment Optimization Study) was a multicenter, randomized, phase 3, neoadjuvent (i.e., preoperative) trial conducted at 23 centers that spanned five continents (except Australia).  In this study 455 women with more than 2 cm diameter HER-2 positive tumors with invasive breast cancer were given either oral lapatinib (1500 mg daily) or trastuzumab (4 mg/kg loading dose and 2 mg/kg weekly thereafter) alone, or lapatinib (1000 mg) and trastuzumab in combination. 

The average age of patients was 50 (range 42-59); nearly 80% had tumor-free axillary lymph nodes; and, approximately 70% of these women were not candidates for conservative breast surgery.  This trial was open-label but patients and the investigators involved in data collection or analyses were blinded.

The treatment schedule was 6 weeks of assigned anti-HER2 (lapatinib or trastuzumab or  lapatinib/trastuzumab combination) followed by 12 weeks of trastuzumab plus paclitaxel.  The paclitaxel daily dose was 80 mg/m[sq.].  Breast surgery was done within 4 weeks of the last paclitaxel dose.  The first six weeks with no chemotherapy is called the "biological window"; this window was the key design which allowed comparison between various groups by acquiring biopsy samples at critical times and study early responses.

The major endpoint of this study was pathological clinical cure (pCR) at the time of surgery.  pCR is defined as disappearance of clinical evidence of disease in biopsy samples; it doesn't mean cure (see definition here or here or here).  Since pCR is known to correlate with improved survival (e.g., in trastuzumab plus chemotherapy clinical trial), it was used here as a surrogate marker of clinical benefit.  Locoregional  total  pCR (lpCR) was defined by the absence of invasive cancer cells in the axillary lymph nodes.

The investigators also looked at objective tumor response rate (also called disease response or objective response) during the paclitaxel dosing period before surgery.  These objective measurements were made by physical examinations (caliper measurements) or imaging techniques, such as mammography, MRI or echography.

What was the outcome

Significantly higher pCR was observed in lapatinib/trastuzumab combination group (51.3%) compared to lapatinib (24.7%) or trastuzumab (29.5%).

Locoregional total pCR (lpCR) was two-fold higher in  lapatinib/trastuzumab combination group compared to trastuzumab (odds ratio: 2.39) with no difference between trastuzumab alone and lapatinib alone.  And, 73% of the patients on combination HER-2 therapy had no evidence of tumor cells' spread to the lymph nodes at the time of surgery.

Estrogen receptor (ER) status has no effect on the pCR outcome within a therapy group.  For example, there was no difference in pCR in estrogen ER-positive or negative tumor containing patients who were all assigned to  lapatinib/trastuzumab combination group

Objective response 6 weeks after the completion of biological window was higher in lapatinib alone (52.6%) or  lapatinib/trastuzumab combination (67.1%) groups compared to trastuzumab alone (30.2%) -- as was expected.  This is because trastuzumab requires longer time to reach therapeutic steady-state levels in serum.  Thus, objective responses were similar (70-80%) across all groups just prior to surgery (after 12 weeks of trastuzumab plus paclitaxel) when trastuzumab would have reached steady-state levels in serum.

More patients completed therapy if they were on trastuzumab alone.  More patients discontinued therapy due to drug toxicities when lapitanib was one the drugs: 29 patients out 151 (who received drug) discontinued in lapitanib alone group; Similarly, the drop-out rate was 32/149 in lapitanib/trastuzumab combination group, but only 2/147 in trastuzumab alone group.

Lapatinib use has been associated with toxicity, such as, liver dysfunction, diarrhea, which is accentuated once the chemotherapy (paclitaxel) is added to the treatment schedule.  The patients also develop neutropenia when paclitaxel is added to schedule.  These toxicities require pull-back in the daily dose of lapitanib to 750 mg.

Data on disease-free survival and overall survival (OS) will be available once the follow-up period of these patients is complete.  However, there is another ongoing trial ALLTO ( NCT00490139) with similar study protocol but in adjuvent setting in which disease-free survival is the primary endpoint.

What is the significance

Approximately 20% of breast cancer tumors have HER-2/neu gene amplification and HER-2 protein over-expression.  HER-2 positive status generally means poor outcome or the patients.  Trastuzumab is a humanized antibody which binds HER-2 receptor and blocks HER-2 and HER-3 receptor signaling.  Binding of trastuzumab induces ADCC response (antibody-dependent cellular toxicity) and apoptotic cell death.  Lapatinib is a tyrosine kinase inhibitor.  It inhibits kinase activity of the HER-2 receptor, blocks ligand-induced receptor heterodimer formation and signaling.  Lapatinib inhibits tumor cell proliferation.  

Since both drugs target the same signaling pathway but use different mechanisms, together they were expected to deliver a dual HER-2 block and overcome potential resistance to one or the other drug.

Another dual HER-2 blocking strategy (NeoSphere phase 2 trial) was reported last year and published recently:  Adding pertuzumab (OmniTarg; Genentech) to trastuzumab plus docetaxel also doubles pCR and significantly increases progression-free survival in HER-2 positive metastatic breast cancer patients.  Pertuzumab is also an anti-HER-2 monoclonal antibody, but unlike trastuzumab it block receptor dimerization.

Unlike traditional trials, this trial was in neoadjuvent setting and not advanced disease.  clinically, this is precisely the time point where patients need intervention.  It also allows precise determination of tumor biomarkers and personalized approach to therapy.

Other ongoing trials to keep your eyes out include, ALLTO  trial  (NCT00490139)  lapatinib  and  trastuzumab in adjuvent setting, and APHINITY  trial  (NCT01358877) pertuzumab  to  trastuzumab also in adjuvant setting.
  • Baselga, J., Bradbury, I., Eidtmann, H., Di Cosimo, S., de Azambuja, E., Aura, C., Gómez, H., Dinh, P., Fauria, K., Van Dooren, V., Aktan, G., Goldhirsch, A., Chang, T., Horváth, Z., Coccia-Portugal, M., Domont, J., Tseng, L., Kunz, G., Sohn, J., Semiglazov, V., Lerzo, G., Palacova, M., Probachai, V., Pusztai, L., Untch, M., Gelber, R., & Piccart-Gebhart, M. (2012). Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial The Lancet DOI: 10.1016/S0140-6736(11)61847-3
  • Gianni, L., Pienkowski, T., Im, Y., Roman, L., Tseng, L., Liu, M., Lluch, A., Staroslawska, E., de la Haba-Rodriguez, J., Im, S., Pedrini, J., Poirier, B., Morandi, P., Semiglazov, V., Srimuninnimit, V., Bianchi, G., Szado, T., Ratnayake, J., Ross, G., & Valagussa, P. (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial The Lancet Oncology, 13 (1), 25-32 DOI: 10.1016/S1470-2045(11)70336-9 
  • Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, & Valagussa P (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The lancet oncology, 13 (1), 25-32 PMID: 22153890 
  • Gnant, M., & Steger, G. (2012). Dual inhibition of HER2 in breast cancer treatment The Lancet DOI: 10.1016/S0140-6736(12)60068-3

To RE-TWEET this article, click here.

1 comment:

  1. This is a breakthrough in the field of medicine. I hope you can find fast and effective treatment for all kinds of cancers.

    breast reduction surgery