Patients with HER2-positive breast cancer have been treated with Tykerb (lapatinib) both in combination with herceptin (trastuzumab), and as an alternative single-agent therapy for pre-surgery (neo-adjuvant) chemotherapy. Two new studies on these drugs, one published in The Lancet Oncology and one in The Lancet, have demonstrated that lapatinib appears to be less beneficial than trastuzumab as a single-agent therapy, whilst The Lancet publication reveals that a combination of both drugs seems to be nearly twice as effective as single-agent therapy, even though lapatinib causes more side effects.
(HER2), The Human Epidermal growth factor Receptor 2, is a powerful mediator of cellular growth and proliferation. In approximately 15% of breast tumors, the HER2 gene is amplified with a corresponding over-expression of the HER2 receptor, which is linked to a poor outcome.
The Lancet Oncology study was conducted by Professor Gunter von Minckwitz at the German Breast Group in Neu-Isenburg, Germany) and Prof. Michael Untch at the AGO-Breast Study Group in Berlin, Germany and their team. The researchers conducted a randomized trial of comparing lapatinib with trastuzumab, in 620 German patients, who all received a standard chemotherapy regimen, with 309 patients receiving combined treatment with trastuzumab, and 311 patients with lapatinib.
The study’s primary outcome was defined as the proportion of patients achieving pathological complete response (pCR), which means the absence of any residual invasive cancer in the breast and absence of any metastatic cells in the regional lymph nodes. They discovered that 30% of patients in the trastuzumab group achieved a pathological complete response, compared with 23% of patients in the lapatinib group.
The researchers observed common side effects in both groups:
39% of patients in the trastuzumab group experienced more swelling of legs, compared with 29% in the lapatinib group, with 30% in the trastuzumab group experiencing shortness of breath, compared with 21% in the lapatinib group. However 75% of those in the lapatinib group reported to have had more diarrhea, compared with 47% in the trastuzumab group, whilst 55% of patients in the lapatinib group experienced skin rash, those in the trastuzumab group reported 32%. Many more patients in the lapatinib group (33%) discontinued the therapy because of toxic effects, compared with 14% in the trastuzumab group, who also reported 70 serious adverse events, in comparison with 87 in the lapatinib group:
|Trastuzumab group||Lapatinib group|
|Swelling of legs:||39%||29%|
|Shortness of breath:||30%||21%|
|Discontinuation of Therapy:||14%||33%|
|Serious adverse events:||70||87|
In a concluding statement the researchers say: “This direct comparison of trastuzumab and lapatinib showed that pathological complete response rate with chemotherapy and lapatinib was significantly lower than that with chemotherapy and trastuzumab. Unless long-term outcome data show different results, lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in combination with neoadjuvant chemotherapy.”
Dr Stephen K Chia of the Division of Medical Oncology at the British Columbia Cancer Agency in Vancouver, BC, Canada stated in a comment related to The Lancet Oncology paper, that:
“Moving forward into the future, no adjuvant (post-surgery) trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials.”
The Lancet study reports on Dr José Baselga at Massachusetts General Hospital Cancer Center at the Harvard Medical School in Boston, MA, USA) and his team from the SOLTI group and Breast International Group, randomized trial of over 400 women from 23 countries who were diagnosed with HER2-postive breast cancer and tumors larger than 2 cm in diameter.
The researchers categorized the women into three groups, with 154 women receiving lapatinib, 149 receiving trastuzumab, and 152 women receiving a combination of both treatments. All drugs were administered pre-surgery, with standard paclitaxel therapy added to each of these anti-HER2 regimens after 6 weeks. After a further 12 weeks of treatment, patients underwent surgery and afterwards continued for 1 year with the same anti-HER2 therapy. The new factor in this study is that patients received the same anti-HER2 therapy pre- and post-surgery, which means that data will eventually be available to assess the relationship between pCR, the primary study endpoint, as well as disease free survival and overall survival.
The researchers explain: “Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models.”
The findings revealed a difference of 21% in the pCR rate between the combination group (51%), which was substantially higher compared with the trastuzumab group alone (30%). The researchers noted no statistically important difference in pCR between the lapatinib (25%) and the trastuzumab (30%) groups, and even though anti-HER2 therapy can cause cardiac toxicity, they observed no major cardiac dysfunctions amongst the treatment groups. Whilst the frequency of grade 3 diarrhea was far higher in the lapatinib group with 23%, the combination group of lapatinib and trastuzumab had a frequency of 21%, whilst the trastuzumab group had only 2%. Likewise, the researchers noted more frequent grade 3 liver-enzyme alterations with lapatinib (18%) compared with the combination group of lapatinib plus trastuzumab (10%) and the trastuzumab group (7%).
The researchers summarize:
“Overall, dual HER2 blockade could be an improved approach to treatment of patients with HER2-positive tumors. Our study shows that dual inhibition of HER2 by lapatinib and trastuzumab in combination with paclitaxel is better than single-agent targeting of HER2 in the neoadjuvant (pre-surgical) setting. Dual HER2 blockade might be a valid approach in patients with early HER2-positive disease. Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant (pre-surgical) setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest.”
Professor Michael Gnant and Dr Guenther G. Steger from the Medical University of Vienna in Austria write in a comment linked to The Lancet article, that trials like this are sufficiently convincing to consider different approaches of evaluating drugs from a both a scientific and regulatory perspective, saying that: “Trials in the neoadjuvant setting based on research-based hypotheses (after establishment of drug safety) could lead to a saving of enormous sums in drug development costs, and promising new drugs for treatment of early breast cancer could become available much more quickly than at present.”
Written by Petra Rattue