J Clin Oncol. 2010 Feb 1. [Epub ahead of print]
Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer.
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Blackwell KL,
Burstein HJ,
Storniolo AM,
Rugo H,
Sledge G,
Koehler M,
Ellis C,
Casey M,
Vukelja S,
Bischoff J,
Baselga J,
O'Shaughnessy J.
Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA; Texas Oncology, PA, US Oncology, Tyler; Baylor Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas, TX; Otto von Guericke Univeristäte, Madgeburg, Germany; and Vall d'Hebron University Hospital, Barcelona, Spain.
PURPOSE:
Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). PATIENTS AND METHODS:
Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). RESULTS:
In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). CONCLUSION:
Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.
PMID: 20124187 [PubMed - as supplied by publisher]
ASCO: Biologics Work Synergistically Against Metastatic Breast Cancer if Trastuzumab Regimens Fail
2008-06-03T10:36:47-04:00
Crystal Phend
What breastcancer.org says about this article…
ASCO: Biologics Work Synergistically Against Metastatic Breast Cancer if Trastuzumab Regimens Fail
The study reviewed here found that
women diagnosed with HER2-positive metastatic breast cancer that either came back or progressed while getting Herceptin (chemical name: tastuzumab) benefited from adding Tykerb (chemical name: lapatanib) to the treatment plan instead of switching from Herceptin to Tykerb.
Both Herceptin and Tykerb are targeted therapy medicines.
There were almost 300 women in the study. After the HER2-positive metastatic breast cancer came back during Herceptin treatment, about half the women continued to get Herceptin AND had Tykerb added to their treatment plans. The other half stopped getting Herceptin and switched to Tykerb.
Six months later:
- 28% of the cancers treated with both Herceptin and Tykerb didn't grow, compared to 13% of the cancers treated with only Tykerb.
- Nearly 25% of the women who got both Herceptin and Tykerb benefited in some way from the treatment, compared to about 12% of the women who switched to Tykerb. The women were considered to benefit if the cancer didn't grow or went into complete or partial remission.
- 80% of the women who got both Herceptin and Tykerb were alive, compared to 70% of the women who switched to Tykerb.
A year after the change in their treatment plans, 45% of the women treated with both Herceptin and Tykerb were alive, compared to 36% of the women who switched to Tykerb.
Both Herceptin and Tykerb work by blocking the ability of the HER-2/neu protein to make HER2-positive breast cancer cells grow. Herceptin and Tykerb do this in different ways.
Herceptin blocks the protein on the cancer cell's surface. Tykerb blocks the protein inside the cell.
Tykerb, in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine), is approved by the U.S. Food and Drug Administration to treat HER2-positive, metastatic breast cancer that has stopped responding to Herceptin. But
rather than stopping Herceptin and switching to Tykerb when metastatic breast cancer comes back or progresses, many doctors have been adding Tykerb to the treatment plan while continuing Herceptin.
Even though Tykerb isn't approved to be used in combination with Herceptin, the results of this study suggest that this approach might be better than stopping Herceptin and switching to Tykerb. The researchers think that blocking the effect of the HER2/neu protein both outside and inside the cancer cell at the same time might be better than blocking the protein in only one place.
This approach is known as "total HER2 blockade."
Herceptin is given intravenously. Herceptin can cause flu-like side effects such as fever, chills, muscle aches, or nausea. These side effects generally become less severe after the first treatment. Herceptin can sometimes cause heart damage and in some cases the heart damage can be life-threatening.
Tykerb is a pill taken by mouth. Tykerb doesn't seem to cause the serious heart problems associated with Herceptin. The most common side effects from Tykerb when given in combination with Xeloda are diarrhea, redness and tingling in the hands and feet, and a rash. These side effects usually aren't severe. Other side effects can include stomach upset, vomiting, and fatigue.
In this study, the most common side effect was diarrhea. About 48% of the women treated with Tykerb alone had diarrhea; 60% of the women treated with Herceptin and Tykerb had diarrhea. One woman did die from a heart problem, but the heart problem wasn't directly related to the Herceptin or Tykerb treatment.
If you're being treated with Herceptin for HER2-positive metastatic breast cancer, you might want to talk to your doctor about the results of this research. Together you and your doctor can decide whether adding Tykerb to your treatment plan might make sense for you if the cancer stops responding to Herceptin alone.
Visit the Breastcancer.org
Targeted Therapies section to learn more about Herceptin and Tykerb.
Research News on Targeted Therapies
J Cancer Res Clin Oncol. 2009 Apr;135(4):643-7. Epub 2008 Oct 21.
Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.
Camara O,
Jörke C,
Hammer U,
Egbe A,
Rabenstein C,
Runnebaum IB,
Hoeffken K,
Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The CONCLUSIONS:
second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.
PMID: 18936973 [PubMed - indexed for MEDLINE]
J Clin Oncol. 2009 Mar 10;27(8):1191-6. Epub 2009 Feb 2.
Effects of food on the relative bioavailability of lapatinib in cancer patients.
Koch KM,
Reddy NJ,
Cohen RB,
Lewis NL,
Whitehead B,
Mackay K,
Stead A,
Beelen AP,
Lewis LD.
GlaxoSmithKline, Clinical Pharmacology, Research Triangle Park, NC, USA.
Comment in:
PURPOSE: This study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. PATIENTS AND METHODS: A single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. RESULTS: The low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C(max)) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C(max) of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. CONCLUSION: These
large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.
PMID: 19188677 [PubMed - indexed for MEDLINE]
- 1: Clin Transl Oncol. 2009 Jul;11(7):455-9.Links
- mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb(R)).
Vázquez-MartÃ*n A, Oliveras-Ferraros C, Del Barco S, MartÃ*n-Castillo B, Menéndez JA.
The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb(R)) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin(R)). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.