Dr. Leisha Emens is professor of medicine in hematology/oncology at the University of Pittsburgh Hillman Cancer Center. She is also co-leader of the Hillman Cancer Immunology and Immunotherapy Program and director of translational immunotherapy for the Women’s Cancer Research Center. She is internationally recognized for her research on using immunotherapy to treat breast cancer.
At the European Society for Medical Oncology Virtual Congress 2020, Dr. Emens presented final overall survival results from the IMpassion130 study, showing that the combination of Tecentriq, which has the chemical name atezolizumab, and Abraxane, which has the chemical name nab-paclitaxel, improved overall survival by 7.5 months compared to Abraxane alone for people diagnosed with metastatic PD-L1-positive, triple-negative breast cancer. But another trial — the IMpassion131 study — found that combining Tecentriq with Taxol, a different form of paclitaxel, was no better than Taxol alone in treating the same type of breast cancer — metastatic triple-negative disease.
Listen to the podcast to hear Dr. Emens explain:
- the differences in the designs of the two studies
- how Abraxane is different from Taxol
- possible reasons for the difference in results
- what this means for patients
Running time: 16:58
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Show Full Transcript
This podcast is made possible by the generous support of Lilly Oncology.
Welcome to the Breastcancer.org Podcast, the award-winning podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org's senior editor, Jamie DePolo.
Jamie DePolo: Hello, thanks for listening. Dr. Leisha Emens is professor of medicine in hematology and oncology at the University of Pittsburgh Hillman Cancer Center. She is also co-leader of the Hillman Cancer Immunology and Immunotherapy Program and director of translational immunotherapy for Women's Cancer Research Center. She is internationally recognized for her research on using immunotherapy to treat breast cancer.
At the European Society for Medical Oncology Virtual Congress 2020, Dr. Emens presented final overall survival results from the IMpassion130 study, showing that the combination of the immunotherapy Tecentriq, which has the chemical name atezolizumab, and Abraxane, which has the chemical name nab-paclitaxel, improved overall survival by 7.5 months, compared to Abraxane alone, for people diagnosed with metastatic PD-L1-positive, triple-negative breast cancer.
But another trial, the IMpassion131 study, found that combining Tecentriq with Taxol, which is a different form of paclitaxel, was no better than Taxol alone in treating the same type of breast cancer, metastatic triple-negative disease.
Dr. Emens joins us today to talk about the differences in the results and what they mean for patients.
Dr. Emens, welcome to the podcast.
Dr. Leisha Emens: Hi. Thank you very much for having me. It's a pleasure to be with you today.
Jamie DePolo: We're delighted to have you back. So, first I'd like to talk about the results that you presented from the IMpassion130 study, and while the improvement in overall survival wasn’t statistically significant, it was a meaningful improvement with 7.5 months. So, could you talk a little bit about what the results mean for people who've been diagnosed with metastatic triple-negative disease that's PD-L1 positive?
Dr. Leisha Emens: Yes. Sure. Of the breast cancer subtypes, triple-negative breast cancer has the worst prognosis, and it's also the most likely to contain immune cells and be PD-L1-positive. Because triple-negative breast cancer has also, historically, only been treated with chemotherapy and it's a very aggressive disease, it really represents an unmet clinical need, and the fact that it tends to be immune activated also identifies it as the best place to begin to develop immunotherapy for breast cancer patients.
So, IMpassion130 is the first trial to rigorously show that adding immunotherapy to standard chemotherapy can benefit, at least to some set of patients. It was a global randomized, double-blind phase 3 clinical trial that studied the addition of atezolizumab or placebo to the chemotherapy drug nab-paclitaxel in patients with incurable or advanced triple-negative breast cancer that had not yet been treated in the advanced-disease setting.
The study had endpoints that looked at progression-free survival in all patients, as well as in the subgroup that were PD-L1 immune-cell-positive, as well as overall survival in all patients as well as in the subgroup that were immune-cell-positive.
The study enrolled 902 patients and randomized them equally. So, there were equal number of patients that received immunotherapy, or atezolizumab, with nab-paclitaxel and that received placebo with nab-paclitaxel. The patients enrolled in each of these arms were quite similar, and about 41% expressed PD-L1 on their immune cells.
Although there was not a statistically significant improvement in overall survival in the patient group overall, if you focus in on the 41% of patients that were PD-L1 immune-cell-positive, there was a 7.5-month improvement in median overall survival for those patients who received atezolizumab with nab-paclitaxel. The 3-year overall survival rates for people that got placebo with nab-paclitaxel were 22%, and this increased to 36% for patients who got atezolizumab with nab-paclitaxel.
Jamie DePolo: Okay. I'm curious, too, and I forget the statistic, there's a certain percentage of triple-negative disease that is PD-L1-positive. Is it more than 50%?
Dr. Leisha Emens: So, that’s exactly right. In this particular trial, 41% of the patients enrolled were PD-L1 immune-cell-positive. And that’s an important thing to keep in mind, is that less than half the patients appear to benefit, potentially, from the addition of atezolizumab to nab-paclitaxel. About half the patients in this particular trial had had a taxane agent as part of their chemotherapy for curative intent.
So, about 41% are PD-L1 immune-cell-positive.
Jamie DePolo: Okay. And just to reiterate, really, Tecentriq, the immunotherapy, atezolizumab, only seems to benefit people with cancer that’s PD-L1-positive.
Dr. Leisha Emens: That’s exactly right. Recently, we did the final analysis of overall survival, and in the group of 902 patients in the trial, the half that got atezolizumab with nab-paclitaxel, overall, had a slight improvement in overall survival, but it was only about a couple of months, slightly over a couple months. So, the 3-year overall survival rate for folks that got nab-paclitaxel with placebo was 25% and for folks that got atezolizumab with nab-paclitaxel was 28%. So, not too much of an improvement there.
But if you look specifically at the group of patients that were PD-L1 immune-cell-positive, the addition of atezolizumab to nab-paclitaxel resulted in a 7.5-month improvement in overall survival specifically for that group. And the 3-year overall survival rate for the patients who received placebo with nab-paclitaxel was 22%, and this increased to 36% for the patients with PD-L1 immune-cell-positive disease.
So, that particular biomarker expression of PD-L1 on immune cells identifies the group of patients with potential to benefit.
Not all of the patients who are PD-L1 immune-cell-positive benefit, so we still need better biomarkers to even more effectively select the patients most likely to benefit, but right now, that is the way to pick out the patients who are most likely to derive a clinical benefit from atezolizumab and nab-paclitaxel.
Jamie DePolo: Okay. Thank you. Now there was, I guess, a small controversy at ESMO because the results you presented and the results from the IMpassion131 study seemed to conflict. Now, your results showed the benefit when Tecentriq was added to Abraxane chemotherapy, and the other study showed no benefit, but it was a different chemotherapy. Were there other differences in the designs of the study?
Dr. Leisha Emens: No. On the surface, the trials look quite similar. They enrolled a very similar patient population. Both were first-line studies that enrolled patients that had not had treatment yet for their metastatic disease. They both enrolled patients who had to have had at least 12 months free of disease from their original treatment from their first diagnosis of early-stage disease. Both could have had chemotherapy with a taxane in the past.
Some differences in the way the trials were designed is that the IMpassion131 study enrolled twice as many patients to the combination of atezolizumab and paclitaxel, whereas IMpassion130 enrolled equal numbers of patients into each arm. So, that’s one difference.
A second difference in the way the study was designed is that the IMpassion131 study had a primary endpoint of progression-free survival with secondary endpoints of overall survival, and they looked at each of these both in the patient group overall as well as in the PD-L1 immune-cell-positive patient group. And as you said, for IMpassion131, there was no treatment effect for the addition of atezolizumab to paclitaxel in the patients enrolled on that study. And I think everyone was a little bit surprised by that, actually.
Jamie DePolo: Now, to me, the other thing that was interesting — September 8, which was just before ESMO started, the U.S. Food and Drug Administration issued an alert saying that the combination of Tecentriq and Taxol, which is paclitaxel, wasn’t effective in treating metastatic triple-negative breast cancer, and sort of underscored that the FDA approval of Tecentriq to treat metastatic triple-negative breast cancer says that it should be used with Abraxane, or nab-paclitaxel. So, do you have any inkling as to why the IMpassion131 study used Taxol, and also, if you could explain to us what the difference is between Taxol, or paclitaxel, and Abraxane, or nab-paclitaxel? What is the difference between the two forms of that drug?
Dr. Leisha Emens: No. I think it's important to explore the addition of paclitaxel to immunotherapy as well, and that’s been done in other tumor types. Nab-paclitaxel is not available everywhere, so there are some institutions where it's not on their formulary, and there are some areas of the world where it's not available for patients. So, in that situation, usually the alternative taxane is paclitaxel.
The two drugs appear to be quite similar on the surface, but they actually have subtle differences in them. Paclitaxel is formulated in a solvent that makes it water soluble, and this could potentially be a difference between the two drugs. In contrast to solvent-bound paclitaxel, nab-paclitaxel is protein bound. So, it is delivered to the tumor enveloped in a protein, and this actually can enhance delivery of the chemotherapy drug within the tumor.
Because paclitaxel is solvent-bound, there can be allergic-type reactions with that. So, paclitaxel, in contrast to nab-paclitaxel, requires steroid pre-treatment to prevent those allergic-type reactions in the patients. So, there's potentially, with regard to the drugs, subtle differences in the way that they're formulated that could impact their effect on the immune system. And then paclitaxel, in contrast to nab-paclitaxel, also requires steroid premedication, which could impact the immune system as well.
Jamie DePolo: Okay. Because, just in case anyone doesn't understand, if you're taking a steroid, that’s really going to suppress your immune system, so it may not be able to react as well when Tecentriq tries to rev it up. Am I understanding it right?
Dr. Leisha Emens: That’s exactly right.
Jamie DePolo: Okay. So, that could be one difference. Do you think that it's really just the difference in chemotherapy that mostly explains the difference in results in the two studies, or do you think there are other things going on?
Dr. Leisha Emens: I mean, there may be other factors as well, and it's probably ultimately going to turn out to be multifactorial. So, you’ve got subtle differences in the chemotherapy agent itself, you’ve got the differential use of steroids, as we've already discussed. There may be unrecognized heterogeneity with regard to the breast tumors and the patient populations. There was difference in geography, where the trials were conducted, so that could also come into play.
And there may be other factors that we have yet to understand. The study design differences that I talked about could play into this as well.
Jamie DePolo: Okay. Thank you. Now, I know some of the other studies are looking at using Tecentriq in combination with other types of chemotherapy besides taxanes. Do we know yet how those are looking? Does it appear that those are effective, too, or is it really more going to be a taxane that it's combined with?
Dr. Leisha Emens: Well, I think each chemotherapy drug has different ways that it can interact with the immune system, and that may be somewhat different depending on the tumor type that’s being treated. So, I think really, the only way to know is to do the clinical trials.
Jamie DePolo: Okay. So, based on all of this, what would your current advice be to someone who's diagnosed with metastatic triple-negative breast cancer? I'm assuming one of the first things you might suggest is that the person get tested to find out if the cancer is PD-L1-positive?
Dr. Leisha Emens: So, for a patient who has been treated with curative intent for triple-negative breast cancer and is unfortunate to have a disease relapse, usually the first step is to biopsy the relapsed disease and determine, again, the profile of the tumor, because sometimes the profile can change. So, a tumor that was formerly triple-negative may begin to express HER2. It may begin to express the estrogen receptor or the progesterone receptor. So, the first step is really to confirm the profile of the tumor again, and as a part of that, we can now add PD-L1 expression on immune cells.
One can test for PD-L1 immune cell expression on that biopsy of metastatic disease. In IMpassion130, we collected tumor samples from the patients that were enrolled. Some of those samples were from the original primary breast cancer and others were from a biopsy of a metastatic site of disease, and it didn’t seem to matter which type of tumor was PD-L1 immune-cell-positive. Provided there was a result that was PD-L1 immune-cell-positive for the patient, that was a patient that could potentially benefit from the addition of atezolizumab to nab-paclitaxel.
Jamie DePolo: Okay. So, that’s interesting. If I'm understanding you correctly, it sounds like the PD-L1 status, perhaps, either doesn’t change, or if the original breast cancer was PD-L1-positive, then maybe it's not necessary to find out if the metastatic site is PD-L1-positive? I don't want to stretch it too far, but I found that interesting.
Dr. Leisha Emens: So, PD-L1 status can also change. If there was a primary tumor that was PD-L1 immune-cell-positive and there was a metastatic biopsy that was PD-L1 immune-cell-negative, I would give that patient the benefit of the doubt and treat with them atezolizumab and nab-paclitaxel.
Jamie DePolo: Okay. Good to know. Thank you so much, Dr. Emens. I really appreciate your insights on this. We always appreciate you joining us.
Dr. Leisha Emens: Thank you very much.
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