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© Oxford University Press 2006.
NEWS |
Trastuzumab Faces Trials, Clinical and Otherwise
Last spring's eagerly anticipated interim results from three clinical trials of trastuzumab (Herceptin) showed that the use of the drug in the adjuvant setting cut the risk of relapse in half in early breast cancer patients. As the data continue to accumulate and mature, the benefit appears consistent and real, according to work presented at the San Antonio Breast Cancer Symposium in December. However, questions remain about how best to use trastuzumab, how to manage the cardiotoxicity that comes with its use, and how to make up for the fact that all the trials have been halted early, ruling out the possibility of gathering long-term survival data from a randomized setting.
Adding to the interim results from three other trials presented last year, Dennis Slamon, M.D., Ph.D., professor of hematology and oncology at the University of California Medical School in Los Angeles, presented the results from the first planned interim analysis of the Breast Cancer International Research Group (BCIRG) 006 trial. The trial compared the efficacy of an anthracycline-based regimen both with and without trastuzumab. A third arm of the trial was designed to tease apart the cardiotoxicity often seen with both trastuzumab and anthracyclines such as doxorubicin. These women received docetaxel and carboplatin with concurrent trastuzumab.
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A total of 3,222 women with HER-2–expressing node-positive or high-risk, node-negative operable breast cancer enrolled in the study. As in the other trials, women treated with chemotherapy plus trastuzumab did better than did those treated with chemotherapy alone.
Specifically, after a median follow-up of 23 months, 147 (13.7%) of women treated with doxorubicin and cyclophosphamide followed by docetaxel suffered recurrence or death, compared with 77 (7.2%) of the patients who were treated with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab. In the non-anthracycline arm, 98 (9.1%) had a recurrence or died.
Although both of the trastuzumab arms showed statistically significant improvement relative to the control arm for disease-free survival, there was no statistical difference between the two trastuzumab arms, said Slamon.
There was, however, a statistically significant difference in the frequency of cardiac events between the two experimental arms. In the doxorubicin–trastuzumab arm, 17% of patients lost 10% or more of their left ventricular ejection fraction (LVEF), compared with 9% in the doxorubicin control arm and 8% in the carboplatin–trastuzumab arm.
"This phenomenon is real and not short term, despite what we have been previously told," said Slamon. His team has not seen a complete recovery in all the patients who had a decrease in LVEF in the doxorubicin–trastuzumab arm, even after therapy has been completed and with the use of cardiac medication. The lingering drop in LVEF tended to be in the subclinical range, which could reflect variability in the test itself or could reflect real changes in the women's physiology. It is not clear whether these decreases will develop into something more serious over time. "Is a subclinical decline important? No one knows but we are treating these women in the adjuvant setting and they could go on to live 30, 40, 50 years," said Slamon.
Because the other trastuzumab trials included only paclitaxel-based combinations (see News, Vol. 97, No. 12, p. 870, "Trastuzumab Trials Steal Show at ASCO Meeting"), the new results provide clinicians and patients with a choice of regimens, said Norman Wolmark, M.D., chairman of the Department of Human Oncology at Allegheny General Hospital and chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) in Pittsburgh, Pa. "I think there are more choices as of this presentation, and I think therapy containing Herceptin can be tailored" for individual patients, Wolmark said.
HERA Trial Update
Final cardiotoxicity data from another trastuzumab trial, the Herceptin Adjuvant Trial (HERA), run by the Breast International Group, were presented by Richard Gelber, Ph.D., professor of biostatistics at Harvard and the Dana-Farber Cancer Institute in Boston. After completing standard surgery and chemotherapy, women were randomly assigned to either observation, or to 1 or 2 years of trastuzumab. Thus trastuzumab was given after chemotherapy, not in conjunction with it.
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Data from the 2-year trastuzumab arm are not available yet, but, as reported at ASCO in May, with a median follow-up of 1 year, 127 (7.5%) women experienced disease relapse or death in the trastuzumab arm, whereas 220 (13%) did in the observation arm. The 2-year disease-free survival rate was 77.4% for patients in the observation arm and 85.8% in the trastuzumab arm.
According to the final cardiotoxicity data, 7.4% of patients on trastuzumab had a decrease in LVEF of more than 10 points compared with 2.3% of patients in the control arm. The decrease in LVEF function was confirmed in 3.19% and 0.58% of cases, respectively. Severe congestive heart failure occurred in 10 (0.6%) patients in the trastuzumab arm but in none of those on observation. All the differences were statistically significant. One patient died of cardiac problems in the observation group. The cardiac advisory board concluded that cardiac toxicity has been "manageable and reversible," said Gelber.
Early Stoppage
Following the release of the first interim analysis of the HERA trial, patients in the observation arm were offered trastuzumab. Fifteen percent chose to remain on observation, 25% chose to take the drug for 1 year, and 60% opted to be randomly assigned to take either 1 or 2 years of trastuzumab. All patients will continue to be monitored, said Gelber.
"Questions have been raised in some quarters suggesting that the results from this study and from others are much too early to use for clinical decision-making," said Gelber. "So what happens if further follow-up shows no benefit for trastuzumab? We did a quick calculation of that. Even if beyond this point there is no benefit for trastuzumab and the two arms have the same rate of relapse and we continue to follow the women for 4 more years, there is less than a 20% chance that the statistical significance in the HERA trial would disappear. So at least in terms of reducing the risk of early events, these results are solid."
But what is lost from the early unblinding and crossovers? The problem, said Larry Norton, M.D., deputy physician in chief for Breast Cancer Programs at Memorial Sloan-Kettering Cancer Center in New York, is that not only are there questions that these trials can no longer answer, such as long-term toxicity associated with the addition of trastuzumab, but also that "we are never going to know" the answers to those questions.
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"There is no question that this is a very important result, and that this is a very big effect, and has a survival benefit," Norton continued. "But I think we are going to have to follow the patients who have been treated with adjuvant Herceptin very, very carefully. In terms of long-term effects and sites of metastasis, the story is not closed. There are still many unanswered questions."
Correlates of Response
One major question for trastuzumab research is what molecular changes correlate with response to the drug. The BCIRG includes a prospective analysis of molecular correlates of response, and the first biomarker the team examined is the coamplification of the topoisomerase II gene in the HER-2 amplicon. Researchers know that the size of the chromosomal region around HER-2 that gets replicated varies substantially among individuals. The large fragments contain up to 40 genes, including topoisomerase II. Given that topoisomerase II is a known target of doxorubicin and other anthracyclines, the researchers predicted that patients whose HER-2 amplicon included the topoisomerase II gene, and who would therefore overexpress both genes, would respond better to anthracycline-based trastuzumab combinations, relative to patients whose HER-2 amplicon did not include topoisomerase II.
Thus far, the researchers have analyzed the molecular data and clinical outcomes from 2,120 patients. Of those, 744 (35%) have both HER-2 and topoisomerase II coamplified. Overall these patients have better disease-free survival compared to those whose HER-2 amplicons lack topoisomerase II, regardless of chemotherapy regimen. However, when Slamon and colleagues looked at just the patients with the HER-2–topoisomerase II amplicon, they found that patients treated with the doxorubicin–trastuzumab regimen did better than those treated with either the carboplatin–trastuzumab combination or anthracycline without trastuzumab. In fact, there was no difference between the carboplatin–trastuzumab combination or control arms in terms of disease-free survival for these patients.
Moreover, when the team then looked at only those patients who lacked the topoisomerase II amplification by treatment arm, they found that the trastuzumab regimens were equally effective. The team concludes that the benefit seen in the anthracycline–trastuzumab combination in the total study population is due almost exclusively to the extra benefit derived from anthracyclines by patients with the HER-2–topoisomerase coamplification.
Those observations have substantial implications for clinical treatment choices, said Slamon. Patients who have the coamplification do better on anthracyclines and thus should be given this regimen. Second, patients who lack the topoisomerase II amplification do not benefit from the anthracyclines and can be treated just as effectively with the less toxic nonanthracycline combination.
Are these conclusions ready for prime time? "The numbers we are talking about are not small, 2,120 patients, and the differences are real and statistically significant," said Slamon. "But I think we still need to get out to the full cohort and have a little longer follow-up.
"The mechanics of the [fluorescent in situ hybridization] test are exactly the same test with one reagent added into the mix. So from a patient's perspective you will get both answers at the same time. I think that is where things will head, but I think other groups will need to confirm it."
Meanwhile, researchers running the NSABP's trastuzumab trial, which compared chemotherapy with or without trastuzumab, are also looking for molecular correlates of response. When the team compared the time to first recurrence in 471 patients who had a c-myc amplification versus 1078 who did not, they found that those who had the amplification benefited more from the addition of trastuzumab. The biology that underlies this benefit is not clear.
Duration of Therapy
Another key outstanding question is the optimal duration of therapy with trastuzumab. "There are no biological or clinical data that argue for or against 1 year" of trastuzumab therapy, said Slamon, so the 1-year duration was chosen empirically, meaning the optimal duration could be longer or shorter. The HERA trial is designed to test whether 1 or 2 years of trastuzumab is better. But what if a short duration is adequate?
A hint of an answer may come from a randomized Finnish study led by Heikki Joensuu, M.D., head of the division of Oncology at the Helsinki University Hospital in Finland, which tested a short 9-week course of trastuzumab administered concurrently with either vinorelbine or docetaxel, followed by three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide.
The trastuzumab study was a subset of a larger study comparing chemotherapy regimens, with 1,010 women randomly assigned to vinorelbine and docetaxel. Women who had HER-2–positive breast cancer were randomly assigned a second time to receive trastuzumab or not.
A total of 232 (23%) women in the trial had HER-2–positive cancers. At a planned interim analysis, with a median follow-up of 3 years, 89.3% of patients were recurrence-free in the trastuzumab arm compared with 77.6% in the control arm, with 12 (10.4%) events versus 27 (23.2%).
"Herceptin is not chemotherapy or used in the traditional way chemotherapy is used, but the Finnish data are provocative," said Slamon. "But they certainly will require testing in a large trial before it is something you can bet the farm on."
Norton noted that it seems that trastuzumab has the biggest effect when it is given with chemotherapy. "If you give it with chemo, do you really have to give it beyond the chemotherapy? The Finnish trial suggests that the biggest impact is seen when you give it with chemotherapy and that you don't have to give it beyond that."
Notably, cardiac toxicity in the Finnish trial does not mimic that seen in the longer trastuzumab trials. No cardiac failure was seen in the trastuzumab arm and only one case (1%) occurred in the control arm. Similarly, 3% of patients in the trastuzumab arm had a greater than 15% drop in LVEF relative to baseline, whereas 6% of those in the control arm did.
"Cardiac toxicity may be limited," with the shorter duration of therapy, said Joensuu. "A randomized comparison between the brief and 1-year regimens appears to be warranted."
If confirmed, the results imply that a short course of trastuzumab, administered with chemotherapy, could provide most of the benefit achieved in a year-long course with less toxicity. And with the drug costing $3,195 per month, roughly $39,000 per year, the savings with a shorter course would be tangible and considerable.
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  B. J. Czerniecki, G. K. Koski, U. Koldovsky, S. Xu, P. A. Cohen, R. Mick, H. Nisenbaum, T. Pasha, M. Xu, K. R. Fox, et al. Targeting HER-2/neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion Cancer Res., February 15, 2007; 67(4): 1842 - 1852. [Abstract] [Full Text] [PDF]
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