CancerNetwork: I see. We also saw the results of an interdisciplinary trial which showed that paclitaxel(Drug information on paclitaxel), in combination with bevacizumab(Drug information on bevacizumab) was more efficacious and less toxic to either of the two newer chemotherapy agents when combined with bevacizumab. Paclitaxel is the current standard of care as first-line treatment for women with breast cancer. What is your interpretation of these results?
Dr. Blackwell: The study that you are describing, the lead group presented very finely by Dr. Hope Rugo from UCSF. It is one of these, "Is the glass half full, or is it half empty?" I was excited to see that our old friend paclitaxel, which we have been using for the treatment of both metastatic and early-stage breast cancer, remains highly active in first-line metastatic breast cancer. In fact, the control arm of paclitaxel plus bevacizumab really mirrored that which was seen in ECOG2100 in terms of progression-free survival. I guess the glass is kind of half empty because we were all hoping that we had made improvements both in the use of traditional taxane therapy such as nanoparticle bound paclitaxel or ixabepilone, which is not a taxane but has a similar mechanism of a microtubule disruption but a different binding site. In fact, the two experimental arms when combined with bevacizumab really didn’t seem to make a significant improvements in outcomes for these patients with first-line metastatic breast cancer. There was some strong evidence that the dosing, the doses that were prescribed, at 150 mg/m2 3 weeks on, 1 week off for nab-paclitaxel, and ixabepilone at 16 mg/m2 3 weeks on, 1 week off, appear to not be very well tolerated and resulted in a fair amount of dose reductions and I think we will continue to hear some discussion about whether or not it was the dose reduction that impaired the ability to improve the outcomes in these patients. But at the end of the day, the toxicity really drove the inability to give the newer chemotherapy agents at the doses that were meant to be given in the context of this trial. So, it is good to know that paclitaxel continues to be a standard and effective option for the treatment of metastatic breast cancer. It is a little disappointing to know that we haven’t made improvements with some of the newer drugs that have become available.
CancerNetwork: So you mentioned the dosing that was used with these newer chemotherapies. Are the doses that were used in this trial, are those the doses that were approved?
Dr. Blackwell: So none of the two taxanes and ixabepilone are approved in the dosings that were used in the context of Dr. Rugo’s study. We have known since Andy Seidman’s study, old-fashioned paclitaxel (cremophor-solubilized paclitaxel)—there is an improved outcome—when cremophor-solubilized paclitaxel is given weekly compared to every 3 weeks at a 175 mg/m2. We do not have an extensive database in terms of efficacy for either weekly ixabepilone or weekly nab-paclitaxel and again, that certainly could have affected the ability to see these drugs improving outcomes. They are both approved as monotherapies given every 3 weeks.
CancerNetwork: Are there any other ASCO result you would like to highlight?
Dr. Blackwell: There was some interesting data in the neoadjuvant setting regarding Herceptin (trastuzumab) vs lapatinib vs the combination of the two. And although in general it looked as though lapatinib and Herceptin resulted in a slightly higher complete pathological response rate we didn’t really see the tremendous improvement in complete pathologic response that we saw with NeoALTTO in favor of the combination of lapatinib and Herceptin, so I think the NSABP neoadjuvant HER2 study kind of toned down, at least a little bit for me the enthusiasm I had about the combination of lapatinib and Herceptin in the neoadjuvant setting. I will continue to use it, especially for locally advanced breast cancer based on the NeoALTTO results.
I think Karen Gelmon’s study looking at first-line taxane, Herceptin vs taxane and lapatinib showing a survival detriment for the use of lapatinib in the first-line setting. This was a very late, late breaking abstract that certainly implies, at least in that setting when combined with a taxane, trastuzumab(Drug information on trastuzumab) remains superior to lapatinib as a single agent in combination with a taxane.
And then I think in a very practical, but less exciting way, the results presented by Dr. Swain of NSABP38 (National Surgical Adjuvant Breast and Bowel Project) which was a much-awaited study looking at six cycles of docetaxel(Drug information on docetaxel)/doxorubicin/cyclophosphamide (TAC) vs dose-dense doxorubicin and cyclophosphamide(Drug information on cyclophosphamide) (AC) followed by paclitaxel or a third arm which was dose-dense AC followed by gemcitabine(Drug information on gemcitabine)-paclitaxel. This study showed basically no difference between the three arms of the study. And so I think for those of us who used to sit around in the old days and debate dose-dense vs TAC it provided very strong rationale both in terms of disease-free survival and overall survival that there really is no difference between the three arms in the adjuvant breast cancer setting. I think most of us would have predicted a higher hematologic and probably all-grade toxicity for the TAC arm—what was surprising in the study was there was actually a higher cumulative incidence of significant adverse events in the dose-dense arm compared to the TAC arm and that is not something probably most of us would have predicted. So at the end of the day, it looks like three arms were about equivalent in a pair-wise comparison model, and the adverse events were pretty similar with not one arm looking a lot worse or a lot better in terms of toxicity. So those are the three studies, besides EMILIA that I will take home with me, and although they are not exciting they are very important studies that really define our continued use of chemotherapy and first-line Herceptin and taxane-based therapy.
CancerNetwork: And just as a last question, briefly, what do you see as among the biggest unmet needs in the treatment of breast cancer patients in general?
Dr. Blackwell: Well, I can tell you it's triple-negative breast cancer. I think chemotherapy works in triple-negative breast cancer in preventing it from coming back and also in treating the disease, but it appears as though in both the metastatic setting where resistance is common and in an adjuvant setting, where unfortunately a high percentage of triple-negative breast cancers come back, I think we need to the HER2 domain and say, "Why don’t we have drugs like this for triple-negative breast cancer?" and really work with our pharma colleagues and basic science colleagues and say we need to do better in the treatment of triple-negative breast cancer.
CancerNetwork: Thank you so much for joining us, Dr. Blackwell!
Dr. Blackwell: Thanks for having me!