Standard of Care for Metastatic TNBC

Joyce A. O’Shaughnessy, MD: Let’s transition to metastatic breast cancer because in triple negative there were new data that came out at ESMO [the European Society for Medical Oncology Virtual Congress], some of them very important, potentially practice changing. Let’s turn to Kevin, and he could give us an overview of the general strategies we have in metastatic triple negative breast cancer. Could you discuss overall outcomes and prognosis because we will get into how do we all sequence things in our own practice, but just from a general standpoint, Kevin?

Kevin M. Kalinsky, MD: Sure. I think that if there is 1 subtype of breast cancer for which we really need additional therapeutics, it’s this subtype of breast cancer. Thankfully, we have had recent approvals of new drugs. In the frontline setting, for those patients who have PD-L1 positive tumors right now, there is the approval of giving atezolizumab, the PD-L1 inhibitor, in combination with nab-paclitaxel. We’ll talk about other studies that were recently reported with checkpoint inhibition in the metastatic setting. Also, for patients who have germline BRCA mutations, we have PARP inhibitors that are approved for patients with HER2-negative disease.

Then we’ll also talk about the approval of sacituzumab govitecan, which is an antibody-drug conjugate, targeting Trop-2, that’s linked to SN-38. For a long time, all we really had for these patients were chemotherapies, and now with the advent of a new antibody-drug conjugate as well as PARP inhibitors and checkpoint inhibitors, that’s really changed and is improving the outcomes of some of our patients.

Joyce A. O'Shaughnessy, MD: Thank you. There’s been some progress, but unfortunately, median overall survival is still in the 16-month range. In France, Suzette Delaloge, MD, MSc, showed at ESMO this lovely real-world evidence database from across academic centers in France going back to 2008 through 2016/2017, that the median overall survival in metastatic triple negative disease is about 14 months. It hadn’t changed. It is very sad, so we definitely need improvement in this group of patients.

Now, that did not take into account any of the new checkpoint inhibitor data that we’ve seen with atezolizumab, the new approval, of course. That is hopefully going to make an impact. But let’s talk about checkpoint inhibitor therapy in the metastatic setting. Adam, could you update us on what we’ve learned from IMpassion130, IMpassion131, and how do you today use the checkpoint inhibitors in your metastatic practice?

Adam M. Brufsky, MD, PhD: Suzette Delaloge’s real-world analysis is really cool, and it says that we made huge progress in HER2-positive disease. We’re getting there. Actually, those data were accumulated before CDK4, so we’re going to get there with ER positive, and it will look pretty good. I think the stuff we’re going to present and talk about in the next half hour is going to tell us where we’re going to go, at least in the first stage with this, and probably help it. The first one was IMpassion130 that everybody’s familiar with. It was 902 patients with first-line metastatic advanced triple negative breast cancer with a treatment-free interval greater than 12 months.

This is really important, and I think it is the biggest difference between this trial and KEYNOTE-355 that we’re going to talk about. The patients in this trial all got nab-paclitaxel with or without atezolizumab and were treated until progression. The bottom line is that in the overall data, in the initial cut of this data, in survival and in PFS [progression-free survival], there really didn’t seem to be significant differences. They only appeared to occur when you looked at the PD-L1 subtype. You had to have, again by the SP142 assay, you had to be 1%. Basically, this is now the final analysis of these data, looking at it, actually the overall survival, overall as well as in the PD-L1 positive population.

In this trial again, I think the median follow-up was fairly long. There was a small increase in overall survival, in the intent-to-treat population, it was about 21 months with the checkpoint inhibitor vs 18.7 months. It was not statistically significant. The hazard ratio was about 0.87. When you look at the PD-L1 population, the difference was quite substantial. It was 25.4 months, which is pretty much what it had been in the past with some of the other cuts of the data, vs 17.9, about 18 months overall survival in the PD-L1 negative population. That was a hazard ratio of 0.67, which was statistically significant.

It was interesting. It was really the only group across all of the 4 subgroups. You had to have atezolizumab, nanoparticle paclitaxel, and be PD-L1 positive, and basically you had the benefit. The other 3 sub arms of the trial didn’t really. When you look at the hazard ratio for overall survival, the big groups had no prior taxane treatment and people who were PD-L1 positive. This shows us thatthe long-term survival is maintained in the study. That was IMpassion130, and I’m really curious to hear what my colleagues would have thought going into ESMO or before we heard the press release. We had seen the KEYNOTE-355 data with paclitaxel that looked like it was going to work, and we figured it was just like a throwaway trial. They just did paclitaxel and it was going to work, and it would be the same, and we’ll go on and move on.

The surprise, and David Miles, MD, presented this, it was pretty surprising in IMpassion131. The IMpassion131 was also a fairly substantial trial that randomized people to paclitaxel with or without atezolizumab, very similar design. There was really nothing different in this study, and it was basically a dead negative. I looked over these data, I pored over it, as I’m sure we all did, trying to find a subgroup. It was a little smaller. It was a 2:1 randomization for atezolizumab to placebo, but nonetheless there was no difference. The hazard ratio was 0.82. You look at these curves, maybe after 6 months there may have been a tiny separation for atezolizumab, but really not much.

It’s crazy that the forest plot was dead negative. There was little bit of response rate benefit. The overall investigator-assessed response rate in the PD-L1 positive population was 64% vs 55%. But really in the overall survival analysis, it was flat negative and if anything, the hazard ratio trended to touch toward the other group. Although when you really look at the data, the hazard ratio crossed 1, but there was a numerical difference. It was 28 months vs 22 with the paclitaxel. Is it simply play of chance? I don’t know, but there is no separation of these curves whatsoever. That’s the big mystery, and I’m really curious to hear what my colleagues have to say. With atezolizumab at least, we have benefit for survival in the PD-1/PD-L1 population in the first line with nanoparticle paclitaxel. But with non-nano, with standard paclitaxel, we don’t.

Joyce A. O'Shaughnessy, MD: Yes, no question. Amazing. I think we were all taken aback, including in the PD-L1 positive population, in the intent to treat as well as PD-L1 positive, no benefit from atezolizumab in combination with regular paclitaxel.

Transcript Edited for Clarity