OncoLink has the unique pleasure and honor to present our readers with insight into an eagerly awaited trial that will cause much stir at the 2004 meeting of American Society of Clinical Oncology in New Orleans this week. Data will be presented that has lead the U.S. Food and Drug Administration to grant approval for the combination of gemcitabine hydrochloride (Gemzar, Ely Lilly) and paclitaxel (Taxol, Bristol-Myers Squibb) for the first line treatment of anthracycline refractory metastatic breast cancer. This is an enormous coup in the breast oncology world where up to now there has not been a standard of care first line therapy for metastatic breast cancer. The treatment choice was often left up to the individual practitioner and was often motivated by patient performance status, other co-morbid conditions, prior adjuvant therapy, and patient motivating for therapy. This phase III trial has established a new standard of care that would be difficult to dispute if the presented data is as touted.
OncoLink secured an exclusive interview with Dr. Paolo Paoletti, Vice President of Clinical Research, Oncology, at Eli Lilly and company. The primary data will be presented on Saturday June 5th, 2004 from at 3:00pm in Hall H, by Dr. Kathy Albain from Loyola University Medical Center, Maywood IL. (Abstract number 510). In his supervisory role, Dr. Paoletti oversaw coordinated efforts from this multi-center, multi-national, randomized, clinical trial.
The trial consisted of 529 patients with metastatic breast cancer after failure of prior anthracycline containing adjuvant chemotherapy, (unless anthracyclines were clinically contraindicated). The study compared gemcitabine and paclitaxel combination given every three weeks to paclitaxel alone administered on the same schedule. The primary end points of the study were overall survival and time to documented progressive disease. The response rate seen with the combination therapy was around 40% as opposed to single agent paclitaxel of 22%. Time to documented disease progression with the combination therapy was 5.2 months as opposed to 2.9 months for paclitaxel alone. The survival data and toxicity profile will be disclosed only at ASCO and prevented Dr. Paoletti from discussing it in detail with OncoLink at this time. The most common grade 3 and 4 toxicities were said to be hematologic: neutropenia, anemia, and thrombocytopenia, elevated liver enzymes, as well as fatigue, and neuropathy. None of these adverse reactions are surprising to any practicing oncologist who has experience administering these chemotherapeutics. It are these data that convinced the FDA to approve this regimen for the first line treatment of metastatic breast cancer following anthracycline adjuvant treatment.
Below is an exclusive interview with Dr. Paoletti who provided us with an understanding to the rationale of the trial and the future of this regimen.
OncoLink: Thank you, Dr. Paoletti for your time and insight and congratulations on gaining approval for something for which there was no standard of care. First I must ask you, there has been much debate about the use of sequential single agents versus combination therapy for metastatic breast cancer. The idea being that in the setting of metastatic disease you are treating for the goal of symptom palliation and life prolongation, so subjecting a woman to toxic chemotherapy is unjustified. Many oncologists feel that if the gain were cure then difficult treatment is well worth it, but when cure is not an option, we cannot impose such toxicities on our patients. What is your feeling about this?
Dr. Paoletti: This is a good question and there is much debate on how to best treat metastatic breast cancer. Europeans tend to favor the multi-drug therapy approach and the Americans prefer single agent. Of course, Joyce O'Shaughnessy's trial that compared capcitabine (Xeloda) and docetaxel (Taxotere) to docetaxel alone showed a significant survival advantage to the combination arm. A two to three months survival advantage may be very important to the individual patient and for breast cancer patients taken as a whole, certainly represents a tremendous improvement. This, in my view, sends an important message that two drugs maybe better than one. Dr. O'Shaughnessy's trial did prove to be very toxic and the trick is to find a combination therapy that is effective and prolongs survival while is tolerable and safe.
The European philosophy is that there is a tendency to achieve a higher response rate, a longer disease free survival, and a longer period of time with no symptoms with more aggressive therapy. Bonadonna's studies would support this thinking. In Europe they often give a combination of gemcitabine, epirubicin, and paclitaxel. With this regimen, by the way, the response rates are in the 90 percent range. We think that this achieves a better palliation as well.
You will see at this years ASCO meeting, that this is an important message to take away on the treatment of metastatic breast cancer. We need to change the modality of treatment by all practitioners to combination therapy.
OncoLink: There is such panoply of chemotherapeutics available for metastatic breast cancer, all of whom have respectable response rates. What was the rationale for picking these two particular agents?
Dr. Paoletti: We have reason to believe that gemcitabine, due to its mechanism of action is a nice drug to work in combination with any effective drug. There are good phase II data to support its use with either paclitaxel or docetaxel. We believe that this is an effective and safe combination.
OncoLink: Why did you chose paclitaxel and not docetaxel as the Tax 311 trial would imply that the latter has more activity in terms of response rate.
Dr. Paoletti: Very good question. You must remember we must begin these trials many years before the data are known. This trial was started before docetaxel was the leading drug so to speak. Gemcitabine is the right drug to be combined with any taxane. We also have encouraging phase II data on gemcitabine and docetaxel.
OncoLink: Who are the best candidates for this treatment? Or are there patients who would not be appropriate for this regimen?
Dr. Paoletti: Most of the patients will benefit from this combination. At the end of the game, the final judgment is by the physician treating the patient. We must remember that combination therapy is more toxic than single agent. The approval that we received was not gained on a selective patient population, rather on all patients who failed anthracyclines as adjuvant therapy.
OncoLink: What about women who received paclitaxel as adjuvant therapy? Now more and more women are receiving this.
Dr. Paoletti: You bring up a good point. It is best to try in women who have had a longer disease free interval, In other words, those who are furthest away from the time of receiving paclitaxel as adjuvant treatment.
OncoLink: Have you seen anyone become resistant to these agents where use of these two drugs in the future is precluded? Or is this more of a theoretical risk?
Dr. Paoletti: I have not seen it personally, but I was not directly responsible for the patients. Nothing like this was reported.
OncoLink: Since hematologic toxicity was the most common grade 3/4 toxicity, were growth factors used in the study?
Dr. Paoletti: No, growth factors were not part of the protocol.
OncoLink: Do you think it would have changed outcome had they been used.
Dr. Paoletti: No, but again, please wait for full details at the upcoming ASCO meeting.
OncoLink: Have you any data or insight on the use of proteomics and genomics to identify patients who would most benefit from this regimen?
Dr. Paoletti: This is certainly the future and we are heavily engaged with this question. Analysis of gene profiling is still ongoing and Lilly is engaged 100% in doing clinical trials and development of tailored therapy. This will be part of the new generation of oncology.
OncoLink: Finally, gaining approval is a huge stepping-stone, but do you see this combination being used by American oncologists?
Dr. Paoletti: It is our duty to make all practicing oncologists understand that this is a very important contribution to the treatment of metastatic breast cancer. Two drug regiments have a higher response rate than single agents. Even the NSABP will use this regimen in one of its upcoming trials. Certainly the NSABP would not pick this treatment if it were too toxic or ineffective. The final jury is still out.
OncoLink would like to thank Dr. Paolo Paoletti for his time and insight.