Next-Generation Sequencing: Triple Negative Breast Cancer

Joyce O’Shaughnessy, MD: I want to just finish this segment by talking about how we sequence things for our patients. One thing I’d mention to pick up on what Hope said, is that in the approval for the sacituzumab govitecan, patients are required to have 2 prior cytotoxic therapies in the metastatic setting, unless they had recurred within a year of their adjuvant, neoadjuvant chemotherapy.

Within a year counts as 1 line of metastatic therapy, and then they only have to have 1 line of cytotoxic therapy. It's kind of second line in metastatic because those are pretty resistant type patients. Tiffany, how do you sequence things for the various subsets of our triple negative population?

Tiffany A. Traina, MD: It is nice that we have so many agents to choose from now. I think as we've heard already in the discussions, when I hear triple negative breast cancer, I reflexively need to know what is this patient’s PD-L1 status for the tumor, and what is their germline BRCA status? Increasingly, I'd like to have next-generation sequencing to understand some of their somatic chartable mutations.

For those patients who test PD-L1 positive, if they're more than 6 months from their adjuvant therapy, I would be considering using a first-line checkpoint inhibitor in combination with chemotherapy. For those who also may be germline BRCA positive, this is trickier, as Denise already alluded to, but we do have that overall survival data from IMpassion, and I think that's quite compelling. I probably would err on the side of incorporating that checkpoint inhibitor in the first-line setting and then considering PARP inhibition for those patients next.

Soon, my hope is that we won't have to choose either/or, but there are studies going on right now looking at combinations of PARP inhibitors and checkpoint inhibitors. Maybe for those patients who are fortunate enough to have 2 biomarkers, we'll have a little bit better direction. For those patients who are PD-L1 negative and lack a germline mutation, I still will strongly consider clinical trials in the first-line setting. We have a lot of work to still be done here.

Looking at things like AKT mutations or PI3 kinase mutations, TNBC [triple negative breast cancer] may allow for some targeted therapies in the first-line setting. Some trials going on right now are the IPATunity and trials with capivasertib and other AKT inhibitors. Sacituzumab is a great new agent, and having participated in ASCENT and some of the earlier phase 2 studies, it has great activity. We all struggle with those patients who potentially have seen 5 drugs in the early stage setting for their really high-risk TNBC, and unfortunately, recur rather quickly.

I think in this space, if they lack PD-L1, I see the moving up sacituzumab to perhaps the second line as you alluded to already. Eribulin is also very much a standard-of-care chemotherapy with activity in TNBC that I in practice tend to move up earlier if a trial isn't available for my patient.

Joyce O’Shaughnessy, MD: OK, thank you. How about you, Denise, how do you sequence things?

Denise Yardley, MD: Like Tiffany, I think in the first-line setting we were really looking at testing for the PD-L1 presence to give that opportunity of atezolizumab in combination with nab-paclitaxel to give those patients that overall survival advantage that we've seen. In addition, we look for the germline BRCA mutation, and I go for the overall survival and would sequence with a PARP afterward. I think we increasingly do these metastatic tumor biopsies to do the next-generation sequencing to identify any other actionable targets, largely to get patients on clinical trials.

That is where the targets are outside of the PD-L1. Outside of that, I think I'm back to looking at sequential chemotherapy agents and selecting them based on what the patient was on. I'm a big fan of eribulin in this setting. Most of the patients have seen an anthracycline and taxane, so we look at that if they haven't utilized a platinum like the gem-carbo [gemcitabine/carboplatin] combination in these patients.

I think continuing sometimes to use time with chemotherapy and then look back at what opportunities are coming forth with the clinical trials and trying to sequence them. Some patients require 2 priors, so I get my standard-of-care chemotherapies, and then get them on these clinical trials. Some are first-line PD-L1 negatives, and that's where I channel those patient populations. I think always trying to look at what we have standard of care and what we have with the ability to integrate a clinical trial at any point in the course of that patient's disease.

Joyce O’Shaughnessy, MD: Super. Why don't you have the last word here Hope about other combinations, but also anything you want to add with regard to sequencing.

Hope S. Rugo, MD, FASCO: I agree with the sequencing issues. I'm really intrigued to see whether the addition of agents that target the PIK3CA pathway may make a difference and with immunotherapy enhancing the immune response. I think that's a really interesting area, but we've seen a lot of very intriguing single-arm data that don't pan out in the randomized trial setting, so I don't think we should be doing this outside of trials.

I think one of the interesting things about these agents, these antibody drug conjugates, as a class is that may be beneficial across different disease groups regardless of the antibody. For sacituzumab govitecan, I had mentioned this basket trial where they looked at different diseases and different subsets, and they also looked at hormone receptor-positive breast cancer in the metastatic setting heavily pretreated, and patients showed an impressive response rate that was quite durable.

The ongoing TROPICS trial is the phase 3 trial design, very similar to ASCENT, that's looking at sacituzumab govitecan versus chemotherapy of physician choice. It briefly held enrollment due to the COVID-19 [coronavirus disease 2019] pandemic and has opened up again. I'm hopeful that we could rapidly accrue to this trial and allow additional treatment options for our patients with metastatic hormone receptor-positive disease that represents such a big group that we treat.

Interestingly, trastuzumab deruxtecan is also being tested in this HER2 low population, of which a subset have triple negative disease. We may see some data from this; it's odd to use trastuzumab, but maybe it's through this hypothesized bystander effect, which it must be drug leaking out all around. It also has a really high drug-to-antibody ratio, so that's going to be interesting to see as well because that's a randomized phase 3 trial that's ongoing.

In terms of other sequencing, how we use checkpoint inhibitors, I mentioned that it's relatively tragic only 40% of patients can benefit from checkpoint inhibitors from what we know now in the metastatic setting. We will always see de novo metastatic disease, and we know these rapidly progressing tumors don't benefit very much either. One of the ideas is to try to enhance the effect.

Tiffany mentioned this, there is a trial going on called KEYLYNK-009, which has an induction with pembrolizumab, gemcitabine, carboplatin, and then randomizes patients after induction to either receive a PARP inhibitor and pembrolizumab versus continued chemotherapy and pembrolizumab. I think that's going to be fascinating as well based on the data that PARP inhibitors may enhance the host immune reaction to tumor through the STING pathway and interferon. That will be very interesting.

Joyce O’Shaughnessy, MD: Yes, super interesting, there's lot going on—AKT inhibition ipatasertib, capivasertib, immune-oncology, PARP inhibitor combinations, etc. I’ll finish by saying that with sacituzumab, I find that it's pretty much of a go-to agent now, and I think the more drug resistant the patient has shown herself to be, unfortunately, the earlier we're going to be trying to use it. I'm basically using it as soon as I can in the metastatic setting. Because irinotecan has a long history of being noncross-resistant with the agents we have available, we just don't go after that target. It's a new target; it can be quite helpful to patients with some very durable responses, as everybody has said.

Transcript edited for clarity.