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“The NIH/CTSU studies — and this is not just my opinion — are not funded adequately to allow community oncologists to participate. It costs more to treat patients on clinical trials than is provided, so it’s like docs are forced to subsidize the study. This is a major issue and one that is deeply frustrating.”
— F Anthony Greco, MD
Lung Cancer Update
The enclosed reference piece highlights twenty ongoing studies attempting to move the field forward by evaluating the impact of a variety of targeted biologic agents in the management of early and advanced breast cancer. These trials test the clinical value of a number of new strategies and, like most current research efforts in oncology, include critical translational evaluations that will hopefully allow us to better understand the molecular basis for these interventions.
There is no shortage of ideas to pursue in this regard, but as noted by Dr Greco, there certainly is a dearth of resources that prevents these concepts from being executed. Tony’s frustration as a US-based practitioner is easy to understand because clinical trial participation often puts investigators in the impossible position of wishing to be part of the solution but having to do so without adequate reimbursement for the services they provide.
The result was clearly evident during this year’s ASCO plenary session, in which all four of the papers presented were research reports from Europe. The real travesty here is that somehow we found 700 billion dollars to bail us out of a financial mess that few of us actually understand, while we ignore a disease that each day strikes our patients without mercy.
The ideas being put forth in the studies profiled in this monograph represent a potential path to progress worthy of our focus and resources. It is time we increased our commitment to getting these studies done and new ones launched so that we can continue to dream up new ideas that will eliminate the personal catastrophes that are a daily part of oncology practice.
— Neil Love, MD
DrNeilLove@ResearchToPractice.com
“NSABP-B-40 is a neoadjuvant study to follow up NSABPB-27, which added docetaxel in sequence to AC and resulted in the still intriguing and somewhat inexplicable doubling of the pCR rate but no advantage in terms of disease-free survival, recurrence-free survival, et cetera. NSABP-B-40 started out as a trial to assess the addition of capecitabine or gemcitabine to docetaxel, a straightforward three-arm trial. We decided to add a wrinkle by reversing the order and putting the taxane ahead of AC. We were close to activating NSABP-B-40 but decided that the bevacizumab data in metastatic disease were compelling and took it from a three-arm trial to a highly complicated study. It’s now a three-by-two study of neoadjuvant therapy with a secondary randomization to bevacizumab or not.”
— Charles E Geyer Jr, MD
Adjuvant Therapy for Breast Cancer:
Where We Are, Where We’re Headed, 2008
“The novelty of NSABP-B-40 is that we’re using pCR as an endpoint with an emphasis on developing a molecular taxonomy to determine whether we can characterize patients who obtain a pCR as a surrogate marker to measure outcome.
Disease-free and overall survival are not primary endpoints for NSABP-B-40. We view it as a new mechanism to test promising agents in the neoadjuvant setting, and we believe it is an appropriate direction to pursue, particularly with the number of agents that are available and the limited resources, both from a support standpoint and a population standpoint.”
— Norman Wolmark, MD
Breast Cancer Update Issue 1, 2007
“NSABP-B-45 will evaluate patients considered to be at high risk based on the observation that they did not achieve a pathologic complete response, either in the primary breast or in the axillary nodes, after preoperative therapy. Patients will be randomly assigned to one year of sunitinib or to placebo. This is an exciting setting in which to determine the value of a biologic agent for this patient population. Currently we do not have an algorithm to predict patient benefit in this particular subset, so robust tissue collection will be a prerequisite as we evaluate possible predictive markers for likelihood of benefit from sunitinib therapy.”
— Norman Wolmark, MD
Breast Cancer Update Issue 5, 2008
“We are launching the BEATRICE trial globally, which is for patients with triple-negative early breast cancer. This is a pragmatic trial that we designed together with a global team of investigators to explore the value of adding bevacizumab to chemotherapy in the adjuvant setting.
In the design of this trial basically any chemotherapy backbone is acceptable, because it’s not addressing a chemotherapy question. It’s a bevacizumab question. We believe, at least in the absence of administering concurrent trastuzumab, that you can safely administer bevacizumab with most of the chemotherapeutic cocktails we might use.
If the patient has a node-negative or a node-positive tumor and doesn’t have distant metastases or rip-roaring cardiovascular disease or hypertension, then she will be randomly assigned on a one-to-one basis to bevacizumab or not. The one-year duration of the bevacizumab is purely arbitrary, and it begins with day one of chemotherapy.
We are hoping to see that anti-angiogenic therapy will make a difference in this population of patients with triple-negative disease. We do know that if you are to evaluate triple-negative tumors and compare them to all other comers, on average, one tends to see more VEGF production than in the nontriple-negative tumors. The other tumors that pop up with higher VEGF levels are the HER2-positive cancers.”
— John Mackey, MD
Meet the Professors Breast Cancer,
Issue 1, 2008
“The rationale for combining bevacizumab with the nonanthracycline regimen TC in the “TIC-TAC- TOE” trial stems from the hypothesis that a HER2-negative population exists that does not need anthracyclines. Many groups are interested in that hypothesis, including US Oncology, Sarah Cannon, TORI and the NSABP. If indeed that is the case, then we want to see what bevacizumab contributes to a nonanthracycline regimen. This is similar to the BETH trial approach examining TCH and bevacizumab.
I want to add a cautionary note that I don’t believe we are ready to drop anthracyclines without a prospective trial. We have decades of efficacy data with anthracyclines, so although I love the TC regimen, for patients with node-positive disease I believe that one of the proven three- or four-drug regimens — TAC, dose-dense AC/paclitaxel or FEC followed by docetaxel — is still the standard.”
— Joyce O’Shaughnessy, MD
Breast Cancer Update Issue 5, 2008
“We have been in serious discussion with US Oncology about their “TIC-TAC” trial. NSABP will take the lead in adding onto that trial an arm called TOE. The trial will evaluate TC versus TAC versus TC and bevacizumab in women with node-positive or high-risk node-negative disease. I believe it’s an important trial that will include bevacizumab without an anthracycline. Only one other study will have any data on that — the BEATRICE trial, which will evaluate seven adjuvant chemotherapy regimens with or without bevacizumab in patients with triple-negative disease.”
— Sandra M Swain, MD
Adjuvant Therapy for Breast Cancer:
Where We Are, Where We’re Headed, 2008
“ECOG-E5103 is a large adjuvant study that encompasses several features. It has a practical element in that we allow patients and their physicians to select administration of AC every two weeks or every three weeks. We’ll stratify for that choice, so it won’t affect our results.
This design builds on the improvements we’ve made in adjuvant therapy in the past. The backbone of the chemotherapy is four cycles of AC followed by weekly paclitaxel. That’s building on the ECOG-E1199 study, the adjuvant trastuzumab studies and the E2100 trial in the metastatic setting.
It’s also incorporating preclinical data on the potential synergy between lower dose but more continuous taxane exposure and bevacizumab. In laboratory studies, at doses much lower than the doses that are required to have any direct cytotoxic effect on the tumor cells, the taxanes have a clearly separate effect on endothelial cells. To obtain that effect, however, you need more prolonged exposure. With weekly schedules, we have a lower dose but more continuous exposure to the drug.”
— Kathy D Miller, MD
Breast Cancer Update Issue 5, 2008
“When we design these trials, we have a responsibility to ask interesting questions. With the ALTTO study, we felt that it was important to compare the relative merits of these anti-HER2 treatments.
The single-agent lapatinib arm has not made everyone comfortable, but we believe that the lapatinib data in metastatic breast cancer are encouraging. It is important to examine what a small molecule administered orally can do, as opposed to an antibody that must be administered in a hospital setting. In some countries in the world, it might be a problem to go to the hospital every three weeks for a full year.
The other arms are exciting. One of them is exploring the sequence of the two drugs — three months of trastuzumab, a short washout period and then lapatinib to complete a year of treatment. The third arm, which could be the winner, is the combination of the two agents.
We wanted this trial to reflect practices around the world. It’s a major collaborative effort of more than 40 countries. Chemotherapy can be introduced in two ways. One is to administer the chemotherapy first, and you have a lot of flexibility in the choice of chemotherapy regimen.
The second option is the concurrent administration of the biologics with paclitaxel. We are probably going to introduce an option for concurrent docetaxel in the near future because we are beginning to have data there.
At present, the ALTTO trial is requiring patients to receive anthracyclines, but this may change also. We don’t want to be in a situation when the trial is finished in which people tell us anthracyclines are no longer needed. We are strongly hoping to be able to allow regimens such as TCH to be used in the trial.”
— Martine J Piccart-Gebhart, MD, PhD
Breast Cancer Update Issue 6, 2008
“ALTTO is a huge, international undertaking between the Breast International Group and the North American Breast Intergroup. The backbone chemotherapy can vary depending on where you live.
In the US, we will predominately use an anthracycline and then weekly paclitaxel, with four different ways of administering the HER2- targeted therapy: trastuzumab alone, lapatinib alone, both agents together or a sequence of the two agents with a washout period. Everyone receives one year of the HER2-targeted therapy. We will carefully examine the efficacy and toxicity with respect to the heart.
Much debate goes on about the single-agent lapatinib arm and whether it is ethical.
It’s standard in this country to use trastuzumab in that setting: Are we omitting an effective therapy in favor of an as-yet unproven therapy? In the metastatic setting, the data with lapatinib are impressive. I’ve been increasingly reassured that there’s activity, especially in combination with paclitaxel, as Angelo Di Leo presented at ASCO 2007.”
— Julie R Gralow, MD
Breast Cancer Update Issue 3, 2008
“The BETH trial is a collaboration between the CIRG and NSABP examining a nonanthracycline-containing regimen combined with trastuzumab with or without bevacizumab. We feel strongly in the NSABP, as does Dr Slamon, about using nonanthracycline regimens. We chose TCH from BCIRG 006. The second interim analysis from that trial showed a significant benefit with TCH compared to AC-docetaxel. But, this is a large international collaboration with many investigators in Europe who don’t belong to the CIRG or NSABP, and they wanted to include an anthracycline-containing regimen. So a cohort will receive docetaxel/trastuzumab-FEC with or without bevacizumab.
We hope the study will accrue quickly, because many physicians aren’t comfortable with using anthracyclines anymore. I believe the data are convincing, especially if you consider BCIRG 006 and the Gennari meta-analysis showing that patients with HER2-negative disease don’t benefit from anthracyclines and those with HER2-positive disease do. If you put all this together, you either need an anthracycline or trastuzumab for a patient with a HER2-positive tumor. Of course, we have chosen trastuzumab, not the anthracycline.”
— Sandra M Swain, MD
Adjuvant Therapy for Breast Cancer:
Where We Are, Where We’re Headed, 2008
“The most exciting trial that we’re conducting is the BETH trial, a collaborative effort between the NSABP and CIRG that is evaluating bevacizumab in combination with trastuzumab in the adjuvant setting for HER2-positive breast cancer. We proposed the idea because Dennis Slamon’s laboratory found evidence of a profound synergistic interaction between those two drugs. In Phase I and then Phase II trials, they demonstrated tremendous efficacy with the two agents in advanced breast cancer. It was only logical to move it into the adjuvant setting. In the BETH trial design, we require that all tumors be submitted for central analysis prior to randomization to ensure true HER2 positivity. We will also examine a number of molecular markers, and we hope to tease out the subpopulation of patients who particularly benefit from the combination of trastuzumab and bevacizumab.”
— John Mackey, MD
Breast Cancer Update Issue 1, 2008
“In relation to the issue of the timing of the introduction of bevacizumab for the treatment of metastatic breast cancer, we have the negative study of capecitabine with versus without bevacizumab in patients with previously treated metastatic disease and the positive ECOG-E2100 study of first-line paclitaxel with or without bevacizumab, which demonstrated improvements in response rate and progression-free survival. At this point, we don’t have any solid data to justify routinely introducing bevacizumab in the second-line setting. However, RIBBON 2 is an important ongoing trial that plans to randomly assign 650 patients who have already received first-line chemotherapy to chemotherapy with or without bevacizumab.”
— Edith A Perez, MD
Breast Cancer Update Issue 3, 2008
“The CLEOPATRA trial is evaluating docetaxel with trastuzumab with or without pertuzumab in patients with previously untreated, HER2-positive metastatic breast cancer. Pertuzumab is an anti- HER monoclonal antibody, which prevents the dimerization of HER2 and HER3. We conducted a small study with pertuzumab and observed an 18 percent response rate in patients who were previously treated with trastuzumab. José Baselga’s group also presented an update of their study, and the response rate was approximately 26 percent with the use of pertuzumab alone.”
— Sandra M Swain, MD
Adjuvant Therapy for Breast Cancer:
Where We Are, Where We’re Headed, 2008
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EDITOR'S NOTE
Bail Us Out
Neil Love, MD
CLINICAL TRIALS
Neoadjuvant Therapy
Adjuvant Therapy
Metastatic Disease
Breast Cancer
Clinical Trials Guide:
A CME Audio Series and Activity
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