 In the first-line setting, the only trials that have shown survival so far is MONALEESA-7, as Denise said, in the premenopausal population with an AI [aromatase inhibitor] and a more aggressive disease, and then MONALEESA-3 with the fulvestrant; first and second line was a combined trial. The overall study was positive for survival, for the first and second line, there was a trend. They weren’t powered enough, but those are really important survival data.

There were survival data in the second line with both abemaciclib and with palbociclib; we're waiting the data. How do these survival data emerging impact what you do in the first-line setting? Given the MONALEESA-3, are you sometimes using fulvestrant in the first-line setting? What is your take on that?

 It's such a great question, Joyce. I think that there are many considerations. First we saw these really impressive survival data, and it occurs with subsets. I think we also learned from PALOMA-3 that if either your tumor needs chemotherapy or you get chemotherapy because that's what the physician does, we can't separate that, your PFS [progression-free survival] with next-line fulvestrant is shorter. Regardless of the use of a CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitor, you don't do as well.

I think that we all believe that hormone therapy, even in combination, is generally much better tolerated than chemotherapy, with a few exceptions of very toxic targeted agents. I think that it is really important, and Denise's data really make this point, that we should be using CDK4/6 inhibitors in combination with endocrine therapy rather than chemotherapy, except in very limited situations. So how do we decide on the endocrine partner in the first-line setting?

We had data from the previous trials that suggested that you might, if you had never had prior endocrine therapy in any setting, from FALCON, and you had soft tissue disease or bone disease, that you might have a better PFS with fulvestrant than with an AI. Anastrozol was used in that study. But of course the PFS data even in the best situation weren’t as long as we've seen in first-line settings with an AI and CDK4/6 inhibitor.

I always wonder, with this being such a unique group of patients, how do we decide which endocrine partner to use? We saw the data from the PARSIFAL trial at ASCO [the American Society of Clinical Oncology annual meeting] this year, which is helpful. It was trial done by the SOLTI network. They randomized patients to receive fulvestrant or letrozole with the CDK4/6 inhibitor palbociclib in the first-line setting. It's more of a real-life population, almost 500 patients. You had to have relapsed at 12 months or longer from the end of endocrine therapy or be endocrine naïve.

What was interesting was there was absolutely no difference in progression-free survival. Progression-free survival was quite nice. It was 32.8 months for letrozole and 28 months for fulvestrant. They were great data for our patients, at a median follow-up of 32 months. It didn't make a difference whether you had seen the aromatase inhibitor in the adjuvant setting either, which I think was incredibly encouraging for all of us to see. It also didn't make a difference whether you'd had visceral disease or nonvisceral disease.

There was some difference in numbers, but it was not statistically significant. All of these data together from PARSIFAL help me in that most of my patients would prefer to take an all oral regimen. I don't believe that you would only see a survival benefit with fulvestrant and you wouldn't see it with an AI in postmenopausal women, but you're going to see it in the patients with aggressive disease who are premenopausal. That just doesn't make sense from what we know.

So I would still favor the use of an AI with the CDK4/6 inhibitor if a patient has relapsed more than 12 months from an AI or has de novo metastatic disease. I would then use fulvestrant with the multitude of other partners that we are evaluating in the second- and greater-line setting. Maybe we'll be using oral SERDS [selective estrogen receptor degraders] in that setting in the future as well. I think that will make a big difference for us. In terms of toxicity and how we select CDK4/6 inhibitors, I try to rotate. I had done that with the AIs years ago and still do it.

We do sequence between them. I think that there are going to be fascinating data, and we'll talk about whether sequencing matters. I also think that we often try to use the trials themselves to decide how we use agents in a premenopausal patient. In the first-line metastatic setting, I tend to use ribociclib. In patients who have a lot of GI [gastrointestinal] problems, I might not jump to abemaciclib. But for people who have trouble coming in for blood counts, maybe abemaciclib is a better choice. Then palbociclib, of course we use a lot because it was the first agent to be approved.

Videos

CDK4/6 Clinical Trial Survival Data Impact

 Now let's move onto metastatic breast cancer, hormone receptor positive, HER2 negative. We'll turn to Denise because Denise had some interesting data from the MONALESSA-3 and 7 trials at ASCO [the American Society of Clinical Oncology annual meeting], which I'd like to hear her summarize. In the context of what's going on, are we getting some survival advantages with the CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors?

 Thanks Joyce. It continues to be such an exciting time in hormone receptor-positive metastatic breast cancer again. It's been such a welcomed addition of the CDK 4/6 inhibitors in first-, second-, and later-line settings in the hormone receptor-positive patients. We were all excited when we had the initial look at the data from the PALOMA trial back in 2015, and then in 2017 we saw 3 CDK4/6 inhibitors get FDA approval.

I think we've learned how to embrace them in the practice. They have become a standard of care in the first-line setting for the hormone receptor-positive patients. I think when we look at the data from palbociclib, ribociclib, and abemaciclib, we continue to try to look at subgroups in the hormone receptor-positive patients, looking at patients with visceral disease, time of relapse, and what their prior adjuvant therapy consists of.

I think we see that exciting, resonating message of the efficacy of the CDK4/6 inhibitors. We have a challenge of trying to figure out who does not benefit from a CDK4/6 inhibitor in the hormone receptor-positive patients. We have our first-line trials. I think the MONALESSA-7 was an exciting trial, a bit unique in that it really tried to carve-out those premenopausal, perimenopausal patients who had participated in the other CDK4/6 study, but that was a dedicated trial. With that we see the issue in these premenopausal patients of a more aggressive biology. It was a different patient population in the sense of the key entry criteria for those patients.

That trial also looked at tamoxifen in combination with ribociclib, and due to an interaction, that arm was closed. So tamoxifen is not seen in combination with ribociclib. But the nonsteroidal aromatase inhibitors [AIs] have combined nicely with all 3 of the CDK4/6 inhibitors. What we've now tried to look at, and some of the data that I was able to present at ASCO, is that when we see this resounding message for ribociclib and abemaciclib of this overall survival and median progression-free survival advantage, we've looked at some of the hormone receptor positive-patients who present with visceral metastasis.

Are they different from our bone only or soft tissue presentations? I think traditionally that's been a presentation that I know many of my partners with a hormone receptor-positive patient who has had a metastasis in the liver or lung have shied away from an endocrine approach and really thought about chemotherapy for those showing disease in such a life-threatening organ.

The data that I was able to present are looking at both the MONALEESA-3, which was the 2:1 randomization of ribociclib with fulvestrant, and then the MONALEESA-7 with the premenopausal and perimenopausal group, looking at it in combination with an AI. The data looked at carving out those patients who presented with either visceral metastasis, specifically lung and liver, which was about 60% of those patients, and seeing how did they fare. Did they fare as well as patients in the overall population who gained a median progression-free and overall survival advantage?

I think the resounding message was the efficacy of the CDK4/6 inhibitors in combination with endocrine therapy in these presentations with perhaps considered more life-threatening disease in liver and lung, and showed a survival advantage and median progression-free survival advantage for those populations as well, at no increased toxicity. Sometimes we look at the liver in terms of being able to metabolize, or looking at the issues with a bump in the liver function test as a consequence of the CDK4/6 inhibitor.

None of that was exasperated in that patient population. I think there’s a lot of comfort now in not pulling a trigger for cytotoxic chemotherapy in the absence of a patient presenting with visceral crisis. Being able to look at a presentation with liver metastasis, lung metastasis, or both, and seeing that they too achieve a 20% and 30% reduction in the risk of death of starting out with an endocrine therapy in combination with ribociclib for their presentation of hormone receptor-positive metastatic breast cancer.

I know that gives us more confidence that, as we've seen with the overall population, when we really dissect into these subgroups of not just bone-only disease, but visceral metastases, we're seeing that same resounding message of efficacy in those subgroups. I think that gives us a lot of confidence of the role of the cell cycle inhibitors in combination with endocrine therapy as remaining the standard of care, no matter what those presentations are outside of the visceral crisis.

 Super, that’s so important, it's really paradigm changing. You've got survival data for the worst of these patients, unless like you said, they’re a total visceral crisis, which is uncommon. Otherwise, their survival is positively impacted by CDK4/6 inhibitors, through MONALEESA-7 and 3, ribociclib. We should be using much less chemotherapy in the first-line setting. On survival, it is emerging with these CDK4/6 inhibitor trials, and we have 2 endocrine agents, fulvestrant, an aromatase inhibitor in the first-line setting.

CDK4/6 Inhibition in HR+ Metastatic Breast Cancer 

 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?

 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 

 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 

 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.

 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.

 OK, thank you. How about you, Denise, how do you sequence things?

 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 

 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.

 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.

 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.

 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.

Next-Generation Sequencing: Triple Negative Breast Cancer

 We have got 1 more therapeutic option that is pretty new to our practice. I thought we might talk about sacituzumab: what we know from the available phase 2 data, what was said about ASCENT, the phase 3 trial, and a refresh for our memory about the data.

Then we want to finish up the discussion by how we incorporate sacituzumab; we've talked about checkpoint inhibitors, PARP inhibitors, now we'll talk about sacituzumab govitecan. How do we do the first line, second line, third line for our various emerging subtypes of triple negative? Hope, could you summarize for us what you’re thinking about sacituzumab?

 I'm happy to. I think it's been very exciting for us to have another agent approved in the treatment of patients with resistant triple negative breast cancer [TNBC]. Of course, we're very interested to see how this antibody drug conjugate [ADC] fares in earlier-line therapies in different combinations, even in the neoadjuvant setting. Sacituzumab is in the ever-popular group of drugs now called antibody drug conjugates, and it's a fascinating antibody against Trop-2, which appears to be highly expressed in most subsets of breast cancer, if not all. It's linked to a novel toxin, and it's the metabolite of irinotecan SN-38. It has a high drug-to-antibody ratio similar to the current new class of antibody drug conjugates, where it's really double what we saw for T-DM1 [trastuzumab emtansine].

That may have an impact both on efficacy and toxicity, of course, but also on some bystander effect type of response that we may be seeing. Sacituzumab is dosed differently than some of the other ADCs; it's given day 1 and day 8 every 3 weeks, and it was initially tested in a phase 1b expansion, where there were a number of different tumors that were tested in different subtypes. In that initial expansion, there were exciting response rates seen in patients who had received 3 to 5 prior lines of chemotherapy.

That is hard because patients with very resistant triple negative disease don't get to 5 lines of therapy, unfortunately, due to poor responses and organ dysfunction. In these patients who were heavily pretreated, there did seem to be good and durable responses. This trial was expanded to include 108 patients, which was the number that was used for the FDA accelerated approval. This is a single-arm trial, and it's similar to what we just saw for trastuzumab deruxtecan; you can have a single-arm phase 2 study that meets an unmet need, like heavily pretreated patients who received most prior treatment.

If you have good efficacy data and reasonable toxicity, you get accelerated approval, but you have to show that it's better than a standard in a randomized phase 3 trial to get final approval. The overall response rate in those 108 patients who were heavily pretreated was 33%, and almost all were partial responses, but about 3% had complete responses. The median response duration was almost 8 months, going out to 11 months, which is certainly better than we see with anything else that we treat patients with in the third-line or greater setting.

The range actually went out for some patients who are on drug for more than 2 years, and we don't really know who those are, which was really amazing. There were about 17% of patients who stayed on treatment for more than 12 months, which was amazing. The drug itself is reasonably well tolerated. It's interesting, going into these studies we thought the biggest issue would be diarrhea, based on irinotecan. Diarrhea occurs, but it's pretty easily managed with education and using antidiarrheal medications as needed.

 polymorphisms that had been looked at in irinotecan because it really hasn't been associated with more diarrhea at the moment. I think it just has to do with the amount of exposure to free drug. You must educate patients, but it's usually pretty well managed. Neutropenia, however, is very common. About 65% of patients had at least some grade of neutropenia, and 43% had grade 3 to 4 neutropenia. Thrombocytopenia was rare; anemia is the usual problem we run into.

For the neutropenia, I think that what they did in the trials and in the ASCENT trial, is require an ANC [absolute neutrophil count] of 1.5 going into each new day 1 of a cycle. In clinical practice, we’re much less likely to use that. We use an ANC of 1. I think that we have to have a low threshold for using growth factors in patients, and in fact, my approach has been since the approval is that if a patient needed growth factors for gem/carbo [gemcitabine/carboplatin], or eribulin, they’re going to need growth factors for sacituzumab, so you might as well start out using something; you can always back off.

It works pretty well. Some people have even used pegfilgrastim after the day 8 because you have 2 weeks, although that certainly is by investigator decision. Then the final trial that will lead to approval is ASCENT. The ASCENT trial had a press release just before the approval that demonstrated that they reached their primary end point with a progression-free survival benefit comparing sacituzumab govitecan to chemotherapy of physician choice in the third line or greater. These are very exciting data. We look forward to seeing it sometime later this year, but it hasn't yet been presented. There just aren’t data yet.

The other thing to briefly mention is that alopecia is seen with many of these new antibody drug conjugates; 38% of patients had grade 1 or 2 alopecia. You do have to warn patients that they can lose their hair, and we don't yet know if scalp cooling works. Alopecia is also seen with the other ADC that recently had accelerated approval, trastuzumab deruxtecan. A lot of people can keep most of their hair, but you have to warn patients because it's a big issue in the metastatic setting.

Phase 3 ASCENT Regimen Accelerated Approval

 The SWOG S1416 is really the first data in triple-negative breast cancer that has shown benefit from the addition of a poly [ADP-ribose] polymerase [PARP] inhibitor, which makes it really exciting. I think the genius of that trial was the definition of the breast cancer gene-[

] like population. It needs a prospective follow-up trial of course, but it is a very nice attempt to define this group that may have homologous recombination deficiency beyond the germline 

The group is not ready for prime time. We do not have veliparib available, but it is a very nice hypothesis generating trial. The lack of benefit from veliparib in the germline 

 patients stands in contradistinction to the BROCADE 3 where patients received paclitaxel carboplatin with or without veliparib, and the curves were on top of each other for the first 6 to 8, 9 months, and then they split because the patients had the opportunity to stop the chemotherapy and continue veliparib versus placebo as maintenance therapy at their physician's discretion. There was this nice tail on the curve with the veliparib with maintenance strategy, and in the SWOG 1416, there really was not much.

They are waiting still for the data to be fully analyzed, but they really don't think there was very much in the way of a maintenance strategy. We will have to wait and see those data, but that is probably going to explain the difference there. It looks like we may be able to eventually go to a maintenance strategy for veliparib, hopefully based on the Brocades 3 data.

Those are really hypothesis generating for the future, but for our practice, I really want to see what Denise thinks about the TBCRC 048. Is this ready for our practice on Monday morning? The 2 findings were pretty clear from that trial, I thought. What do you think?

 I agree. I think you know we have been struggling a bit about how to incorporate the PARP inhibitors into practice and for which patients. I think it's an easy thought to think about just our 

 patients, but now that we have so much profiling and we're looking at now what do we do when we have a somatic 

 mutation? I think as we step back, this is a great segue into trying to figure out, the approaches to triple negative breast cancer. I think it brings in the role of genetic testing to identify the 

for the patients that never received genetic testing in the adjuvant setting.

It is certainly a dialogue I picked up with patients and say, “We have a therapeutic agent that may benefit.” Some patients had been approached in an adjuvant setting and may not have felt strongly about it, but I think I use that as a way of reintroducing it because there is a therapy tied to it. I think likewise for profiling patients, it is another trigger of maybe we don't always find a target that's actionable.

When we see this data, you think there is a reason to profile these tumors and try to identify them even though they're not a germline but are somatic mutations. I think we are going to continue to evolve with some of the other mutations like the ataxia-Telangiectasia mutated and checkpoint kinase

 to be able to continue to increase the armamentarium for these triple negative breast cancer patients and be able to use these targeted agents as single agents here with the PARP, to look at it, and then again utilizing in our triple-negatives testing for the PD-L1 with SP142 that we've touched on, to embrace that population that's going to be eligible for the consideration of immunotherapy.

I think now the hard part may be in how do we sequence someone that has a somatic or germline mutation and may be PD-L1 positive? It kind of opens a Pandora's box in a nice way. I think looking at survival data is important, so that may be a segue of looking at how to use or sequence if you have a PD-L positive and a 

positive somatic or germline patient. I think it just broadens the horizons of how we think of triple negative, and we have kind of learned that in itself is a very heterogeneity population.

It merits an investigation and to tease out the subpopulations in triple-negative breast cancer because I think we have exciting targets in agents to improve the outcomes from these patients and to continue offering therapeutic choices that could keep these patients and quality of life and with stable disease.

Thank you. The time for next generation sequencing is here, and reintroducing it to the clinic, reintroducing the idea of germline testing now even more with the 

 data. How about you Hope. Are you thinking about the germline PALB2s as a somatic 

? Would you consider using olaparib for those patients?

I already have. We participated in that trial, and I enrolled our only patient at our institution, who had 

 mutation and did have a prothrombin ratio, but then it rapidly progressed in brain. I'm really interested in trying to get these drugs earlier in the course of therapy, and a lot of these patients with mutated 

 have hormone or are hormone receptor positive. I think the OlympiAD trial would be really helpful for us in the adjuvant setting to try and better understand if we can take patients with high-risk disease and change their outcome by giving these agents earlier.

 mutations. I think, to Denise's point, looking at the somatic BRCA-mutant patients and other mutations that cause DNA repair defects is going to be interesting. This trial underneath Nadine Tung's leadership through our consortium will expand and include additional patients and expand to various groups, so that we'll have even more data.

I think it's really important and having these agents is important as well. I think for the SWOG is interesting to me because the hazard ratio for this 

-like group was 0.53, but the difference actually in progression-free survival was very small. It was just about 1.7 months, and they did suggest this survival difference although it wasn't statistically significant; I think their numbers are really small.

I wonder how many of these patients might have had somatic mutations in

 versus those who had the HRD [homologous recombination deficiency] defect alone without somatic mutations. You know it's going to be interesting over time to see that. I also wonder if some of the differences seen here versus the Brocades trial have to do with the poor tolerance of cisplatin. Having seen patients who enrolled on that trial who were miserable on the cisplatin, you wonder whether or not the choice of the DNA damaging chemotherapy is important here as well.

SWOG S1416 and TBCRC 048 Phase 2 Trial Overviews

 Another really important topic in the very rapidly evolving landscape in triple-negative breast cancer germline breast cancer gene [BRCA] patients is the topic of poly [ADP-ribose] polymerase [PARP] inhibitors. There were interesting data sets at American Society of Clinical Oncology [ASCO]. Some may be perhaps immediately practice-changing, and then another one that I think is real forward looking. Tiffany, why don't you give us a summary of where we are with PARP inhibitors and your take on some of the new data.

I'm happy to. I think we've all had some time to digest the data from OlympiAD and from EMBRACA that led to the FDA approvals of both olaparib and talazoparib for patients who carry germline 

 mutations. Just as a reminder, the OlympiAD study was a randomized trial of olaparib versus treatment of physician's choice. This was for patients with known pathogenic germline

In that study where the primary end point was progression-free survival, the single agent PARP inhibitor actually was associated with about a 3-month improvement in median progression free survival [PFS] over the cytotoxic chemotherapy. Actually, a lot of the quality of life and toxicity measures really favored the PARP inhibitor over cytotoxic chemotherapy. An interesting follow up in the OlympiAD data was a subset analysis of those patients treated in the first-line setting, and olaparib was associated with about a 50% improvement in median overall survival over chemotherapy of physician's choice.

If we look at the EMBRACA data that led to the talazoparib approval, EMBRACA was also a randomized phase 3 study of a single agent PARP inhibitor up against treatment of physician's choice. Very reasonable control arm chemotherapies such as capecitabine, gemcitabine, vinorelbine, and, similarly, talazoparib was associated with a significant improvement in median PFS: about a 3-month absolute difference there, and about a 40% to 50 % improvement in PFS.

We have some interesting new data; Jennifer Litton presented at American College of Radiology about the overall survival data from the EMBRACA study and there after a follow up of almost 4 years. There really was no apparent significant difference in overall survival in the overall study population for talazoparib versus standard-of-care chemotherapy, and median overall survival was about a year and a half or about 19 months. There are no overall survival data that was proven with the talazoparib agent, and we do have some data in a subset analysis for overall survival benefit from olaparib.

That's where we've been until ASCO where we had 2 really interesting presentations, both looking at the potential advantage of PARP inhibitors beyond just germline 

 mutations. I think that the first study that I'd like to spend some time looking at was the SWOG trial that was presented; this was a SWOG S1416. This was a randomized phase 2 trial in patients with triple negative breast cancer or known germline 

 mutations, treated in the first or second line. Patients were randomized to either cisplatin monotherapy or cisplatin in combination with veliparib.

I'm making a note because we do have some other trials that have previously reported on veliparib. In this particular trial veliparib was dosed at 300 mg twice a day for a 14-day continuous regimen. This is a much higher dose than what we have seen in previous studies such as BrighTNess and BROCADE. In this trial of cisplatin versus cisplatin plus veliparib, the primary end point was PFS but in some unique subsets or specified subsets. One subset of interest was those patients with germline 

A second subset of interest was those patients who had 

-like triple-negative breast cancer. That was defined in a number of different ways. You could have a homologous recombination deficiency [HRD] assay with a cut point of greater than 42 suggesting you have a BRCA-like cancer. You could have a somatic 

 mutation in the tumor to be classified in this way. You could have 

 promoter methylation, and you can have germline mutations in other genes besides 

 that are known to have HRD deficiency regulation. That class of tumors were considered 

Then the last subset to be looked at were those that were non­–

-like tumors. These patients in the study had no prior exposure to cisplatin or PARP inhibitors. More than 300 patients were randomized in the phase 2 study. The majority of them were really first-line patients, almost three-quarters of the patients were treated first line as opposed to second line, and when you look at the characteristics of these patients only about 13% carried a germline 

About half of the patients were classified as 

-like. I think that the really big, exciting take-home message from all of these analyses of the SWOG study was that in the patients that were reclassified as 

-like triple-negative breast cancer, there was about a 50% improvement in PFS in those patients. The PFS increased from about 4.2 months to almost 6 months, and that was also associated with an improvement in response rate from about 30% to 45%.

This met statistical significance. They looked at overall survival for this 

like subset and there was a trend towards the addition of veliparib associated with OS, but that did not meet statistical significance. When they looked at the germline 

 mutation patients, remember that a very small subset, only 13% of the overall study population, did not appear to have an advantage to adding veliparib in that small subset.

-like population, there did not appear to be an advantage to veliparib over cisplatin as a single agent. It is worth noting that the addition of the PARP inhibitor to cisplatin was associated with significantly more grade 3 or 4 toxicity. This is not surprising; we’ve seen this when other PARP inhibitors have attempted to combine with platinum and other cytotoxics.

I do, however, think that this was interesting data to start to see perhaps a broader application for PARP inhibitors in triple negative breast cancer beyond the indication of just germline 

 mutations. There was some other interesting data. We can talk about another trial that is similar in some ways; it was the TBCRC 048 study, and Nadine Tung , MD, presented this at ASCO as well. This was a single arm olaparib monotherapy trial and a phase 2 study of about 54 patients.

The eligibility for the study were patients who had somatic 

2 mutations, germline mutations, or other cinematic mutations that are also known to be associated with HRD. This could include mutations like ataxia-Telangiectasia mutated, checkpoint kinase 2, 

 There was an extensive list of potential candidate mutations that are either somatic or germline to be eligible for the single agent olaparib arm. I will say that this was a first-, second-, or third-line study, and when the analysis was performed, the primary end point was response rate. The data was divided to look at cohort 1 based on germline mutations or cohort 2 based on the somatic mutations.

What was really compelling and exciting to see was that overall response rate was about 30% to 33%, both for cohort 1 and cohort 2. When you dive into the data a little bit more carefully and you look at those patients who had germline mutations other than 

, all the responses were associated with germline 

 mutation. When you looked at the cohort of somatic mutations, again, where the response rate was about 30%, all those partial responses were attributed to somatic 

mutation. This is exciting; we are starting to find other potential candidate biomarkers to suggest benefit from PARP inhibition.

The TBCRC 048 study is now expanding recruitment, and there will be additional slots available for patients with germline 

 mutations to allow for continued exploration of single agent olaparib in that space.

ASCO New Data: PARP Inhibitors 

 One other point I want to bring out about the KEYNOTE-355 trial was that when you look at the forest plot, and I think, Hope, you alluded to this, the 2 taxane options, the nab-paclitaxel and the paclitaxel, the hazard ratio with the addition of the pembrolizumab was in the 0.5 ballpark. It was quite robust with regard to PFS , very impressive. The point estimate with gemcitabine and carboplatin with the addition of pembrolizumab was not as striking, it was 0.7, 0.74, or something like that.

It is because the patients who recurred quickly were allowed on the trial. As Hope described, as long as they had made 6 months, they were still allowed, and that's a very poor prognosis subgroup. By protocol, they were required to get the gemcitabine, carboplatin. The gemcitabine, carboplatin were the patients who had the poorest prognosis. I think that the choice of gemcitabine, carboplatin and pembrolizumab would be a very reasonable choice. In other words, I'm not deterred at all by those data, and I want to hear from you guys.

Hope, how are you going to decide? Let's say pembrolizumab is fully approved; we don't have OS yet, but where might you think about using gemcitabine, carboplatin, plus pembrolizumab, for example?

 To comment on the approval, I do think it is likely that we'll need an overall survival, but of course we don’t know. I hope that we’ll see that in the not too distant future. But I think that we would use the same criteria that I used when I enrolled patients on KEYNOTE-355. It's patients who did not respond to neoadjuvant taxanes and progressed at 6 months or greater; I would choose gemcitabine, carboplatin. We do have a difficult situation in those patients.

I think we're interested to see if we can capture more of those patients by treating them in the neoadjuvant setting, for example, or post-neoadjuvant setting. I doubt it because if you think about it, if you had residual disease, I don't think post-neoadjuvant treatment will work because you're going to give them capecitabine for 6 months. By then, those people will have started to recur, so you're not going to capture them by giving them a checkpoint inhibitor after that.

That's where our differentials are in clinical practice when we don't use checkpoint inhibitors, and I would use the same. I tend to use nab-paclitaxel if a patient has already seen paclitaxel in that setting at 100 mg per meter squared. Certainly that's the dose we used in IMpassion130. There are some data in the neoadjuvant setting and others that suggest that higher doses are more effective, but it's never been definitive, and you get so much neuropathy, you're limited on duration.

 Thank you. Denise or Tiffany, any other comments about the gemcitabine, carboplatin in KEYNOTE-355?

 I would echo what Hope has said, and I think that our neoadjuvant and adjuvant approaches are rapidly changing with emerging data about the use of checkpoint inhibitors. Interestingly, we have the I-SPY data of pembrolizumab in the preoperative setting. We have neoadjuvant data there suggesting benefit. It'll be interesting to see what happens if that is really moving into the earlier space, how we're treating our patients who recur, whether it's 6 months or later in that first-line setting, who remain PD-L1 positive.

 Exactly. How about you Denise, any final thoughts on KEYNOTE-355?

 I echo the practice comments that both Hope and Tiffany have made. It's a nice ability to welcome and embrace another chemotherapy combination with immunotherapy in triple negative breast cancer. I think a lot of those patients have been taxane-exposed and have toxicities, and there are limitations in being able to deliver that. Being able to have gemcitabine, carboplatin and feeling good about that combination and the results of those combinations, although we're still waiting on the survival, will be a welcome addition. Because there are many patients who either have toxicities with the taxanes or aren't good candidates, from neuropathy, from other medical conditions like diabetes, that now gives us a way to continue to deliver what we think is going to be our standard of care with immunotherapy in that population.

 Right, well said. More options to decrease toxicity and increase efficacy for patients. Real nice data.

KEYNOTE-355 Regimen’s Role in Treatment Paradigm

 I want to hear from everybody about what you are doing about testing for PD-L1 now in your practice. It almost seems like, the CPS [combined positive score] of 10 or more was seen in 38% of the population, and the SP142 was 40%, 41% in the IMpassion130. The first question is, although they're different antibodies and though the SP142 was just immune cells, the CPS is both tumor cells and immune cells, still it's interesting that they're coming in around 40% of the patients.

First of all, are they the same patients? And secondly, from a practical standpoint, is it going to be where if I get any test that is PD-L1 positive by the definition for that antibody, that I'm going to say I can use whatever checkpoint inhibitor I want?

Hope, is there a real overlap between the 40% in the 2 trials?

 It's interesting, and they'll have to go back on the available tumor samples and use the other testing methods. This is something we did in IMpassion130 and data we presented at ESMO [the European Society for Medical Oncology annual meeting] last year, when we had in-person meetings. What we did was we looked at the biomarker-evaluable population, where about 46% of patients were SP142 positive. This is an antibody where 1% or more of the immune cells need to test positive for PD-L1. We compared it to 22C3 and another antibody, and 22C3 uses the CPS scoring system where you make a ratio that includes both tumor cells and immune cells. In that, 80% of patients were positive.

If you use a score of 1 for CPS, you're measuring most tumors, and that is almost identical to what was seen in the neoadjuvant KEYNOTE-522 trial. Seventy-five percent of patients had a CPS score of 1 or greater. When we looked at the overlap, almost all except for 1% of patients who were positive by SP142, were positive by the CPS score. It does appear that it encompasses the same group of patients. When you do modeling, it's a little bit different, but in this patient group, more patients were positive with CPS.

If you used SP142, you basically got the population that was also CPS positive, so it makes me think by leading in…. And then when they looked at the benefits by progression-free survival and overall survival in IMpassion130, the double positives got the benefit. It was the SP142 that stood out, so you could have a hypothesis that this 39% or so in KEYNOTE-355 are almost a similar group of patients who are positive by SP142, even though we don't know for sure. It does suggest that, it is very unfortunate, but about 40% of our patients can benefit; the rest we need to do more for.

 Thanks, that helps us in practice a little bit. It kind of simplifies things. Tiffany, what are you guys doing at Memorial Sloan Kettering Cancer Center in terms of testing? And how do you think you’ll interpret, now that we have 2 different antibodies, and soon we will have pembrolizumab available to us in practice. What antibody are you guys going to use, do you know yet?

 Great question. We have been using the SP142 antibody, given the atezolizumab indication and the data that we have from IMpassion130 already. I think Hope raises some interesting points about the degree of overlap, and maybe we are looking at the same population when you use the CPS of greater than 10 and the Ventana SP142. It'll be interesting to see what ultimately the indications are and where positivity is set for CPS score.

Honestly, of the hazard ratios and the potential benefit seem so close, even for CPS greater than 1, although that didn't meet statistical significance. I think for now we are still using SP142 as our antibody of choice. Another point that hasn't really been raised is what tissue is used for testing and some of the limitations there. With using SP142 as the antibody of the choice, we know we are unable to do that assay on cytology. We're unable to do that on bone. We tend to prefer using this assay on, say, the breast primary when trying to distinguish what the PD-L1 status is, and I'm curious if perhaps the CPS score may allow for some different testing. I don't know if anyone's experienced that in using the CPS assay.

 Yes, I want to clarify what you just said there, Tiffany. You said for the SP142, it’s not advisable to use it for bone. Was there another tissue that wasn't advisable?

 Yes. You cannot do it on cytology on FNA  you need core tissue for that.

 That's interesting. I think that what has happened, not just in IMpassion130, we don't have the data from KEYNOTE-355 yet, but also from other studies that Sherene Loi, MD, and others have done from the earlier trials with single-agent checkpoint inhibitors, is that the PD-L1 positivity varies by site of disease. People thought that LDH might be a marker of resistance when your LDH is high, and liver metastases were. It's fascinating that that was the lowest percentage of positivity we saw in IMpassion130.

It was a small number of patients, but still, fit into all the other spectrum of data where breast, much more likely to be positive, lung, and soft tissue. In fact, the 1 long-term survivor I have on pembrolizumab from the KEYNOTE trial in the second-line cohort is somebody who had lung metastases. It's fascinating that maybe it's more immune sensitive.

 Interesting. Denise, what about you guys? What are you doing right now with testing around the atezolizumab selection of patients? Do you think that the new KEYNOTE data will make any difference in your testing?

 I think so. Traditionally, based on the FDA approval, we've been using the SP142, but we do a lot of other molecular testing and profiling where we get signals of positivity. That doesn't correspond to the tests that the FDA requires for approval. Now with the exciting data with pembrolizumab, we're having to rethink the strategy of how we're going to incorporate selecting which tests for which patient population. And then moving forward with health care providers, how they are going to look at these 2 immunotherapies as they hit the market for triple negatives.

I think that will be giving us some direction as well, but for the most part we've gotten comfortable with the SP142, and now we're going to have to rethink the algorithms as we have all these diagnostic companion tests that are required by the FDA to be able to utilize those agents based on the exciting data.

 Yes, and it is reassuring to me that if…it happens to be that not all the laboratories carry all of the antibodies, etc, if we get an SP142, 1 or more, it's likely that that's going to be a CPS of 10 or more. It's not 100% overlap perhaps, but it's likely, and vice versa. Personally, I'll feel comfortable, because not all the labs are going to have all of the assays. I take a little bit of comfort as well that the CPS of 1 or more was very close to statistical significance. Even if you were off a hair, give or take, giving the patient the benefit of the doubt of the checkpoint inhibitor doesn't seem to be out of the ballpark.

PD-L1 Testing Standard of Practice

 Let's turn to some new data. I'm going to turn us over to Hope Rugo, who is going to take us through the KEYNOTE-355 study, and also very importantly, how we find these patients who are PD-L1 positive.

 Thanks very much, Joyce. This was a very interesting presentation at ASCO [the American Society of Clinical Oncology annual meeting] this year. We've been waiting for additional data after the striking and practice-changing data from IMpassion130. KEYNOTE-355 differed in a couple of ways. One was that patients were included who had developed metastatic disease, 6 months or greater, so greater than 6 months after they had received their last treatment with curative intent chemotherapy. For example, neoadjuvant or adjuvant taxane or anthracycline. The second difference is that in addition to nab-paclitaxel as a chemotherapy partner, patients were also allowed to receive paclitaxel, and gemcitabine and carboplatin.

Those 2 key differences in design are important for us clinically because we do see quite a number of patients who relapse within that 6- to 12-month period where we believe they have relative taxane resistance. I think we've all been interested to find out whether checkpoint inhibitors can be combined with different agents because essentially all of the data with the exception of a small trial with eribulin has been with nab-paclitaxel, or in some cases paclitaxel. If we think about the single-agent data, I think it's clear to us all that we did need more information about combinations with chemotherapy. The monotherapy data showed response rates in the mid-20%, low-20% range for patients in the first-line setting, but in the second- or greater-line setting, response rates were very low, even when PD-L1 positivity was selected for. Like IMpassion130, the KEYNOTE-355 trial was designed to include all-intent-to treat patients.

Patients were randomized 2:1 to receive pembrolizumab or placebo with a chemotherapy partner of choice, but you basically broke down the study like Impassion, into the intent to treat and then the patients who had PD-L1 positivity. Here's where we get into another major difference, which for the clinician is complex in terms of clinical decision-making. There are a number of different antibodies that are commonly used and different mechanisms of scoring to determine PD-L1 positivity. For pembrolizumab, 22C3 is the antibody, compared to SP142 with IMpassion130, and they used a scoring system called CPS [combined positive score].

A score of 1 or greater has been positive, and in the entire population of KEYNOTE-355, 75% of patients had a score of 1 or greater. When the trial had finished accrual, and before the analysis was done and there was any unblinding, they got the results from KEYNOTE-119 with single-agent pembrolizumab and IMpassion130 and thought, “Well we should really analyze the group of patients who have stronger PD-L1 positivity.” They chose a CPS score of 10 or greater.

That was a little under 40%, almost identical to the number of patients who are PD-L1 positive in the immune cells for IMpassion130. When they looked at the patients who were at a CPS score of 10 or greater, they saw a significant difference in progression-free survival [PFS], with an absolute difference of 4.1 months. It went from 5.6 to 9.7 months, and a significant number of patients met their threshold boundary that they set up.

In CPS of 1 or greater, it was still what we would think significant, 0.0012, but their boundary had been 0.00411. They met that for a CPS 10 or greater, but for a score of 1, the boundary was actually point 0.0011 and the 

 value was .0014. I think for the clinician it's frustrating because we don't totally understand that, but the absolute difference in PFS was clearly shorter at 2 months.

It's interesting, it didn't matter what the chemotherapy partner was either, which is really helpful. When you look at the forest plot, and I'm interested in people's thoughts about this, although we don't have a good mechanism for choosing patients other than PD-L1 positivity, and now we have 2 potential ways of testing that. The interesting thing is if you looked at patients who had not received any prior chemotherapy and those who presented in the de novo setting, it looked in the forest plot like those patients benefited the most, and that's interesting. Presumably you haven't split out the people who already have chemotherapy resistance.

There was no differential toxicity to consider, and I think that what we're really waiting for, and as Joyce explained, we have this 7-month survival difference in IMpassion130, and we don't yet have survival data for KEYNOTE-355. I think these are fascinating data that add to our understanding of how we can use checkpoint inhibitors in the metastatic setting and potentially the early stage setting.

Phase 3 KEYNOTE-355 Overview

® entitled, “Advanced Breast Cancer, Expert Perspectives on Recent Progress.” I'm Joyce O'Shaughnessy from Baylor University Medical Center, Texas Oncology, and US Oncology in Dallas, Texas. Joining me today on this virtual discussion are my colleagues, Dr Hope Rugo from the University of California San Francisco, Dr Tiffany Traina from Memorial Sloan Kettering Cancer Center in New York, and Dr Denise Yardley from Tennessee Oncology in Nashville, Tennessee.

Today we're going to highlight a number of topics pertaining to systemic treatment for advanced triple negative breast cancer and metastatic hormone receptor-positive breast cancers, and we're going to talk about the impact of recent clinical trial data on our clinical decision-making. In this discussion we're going to focus on some of the key data from ASCO 2020 [the American Society of Clinical Oncology annual meeting], the virtual meeting, and we're going to have a robust discussion of all the new data and how to apply it to our practice.

Let's go ahead and get started. We're going to look at triple negative breast cancer first, and I'm going to start us off setting the stage. Where are we today? For patients diagnosed with metastatic triple negative breast cancer, we need to know 2 markers right off the bat. We’ve got to know the PD-L1 status, which we'll talk about in depth with regard to the diagnostics, and we need to know their germline 

We have robust data that we’ll go over with regard to PARP inhibitors for patients with germline 

, and we'll talk about how to incorporate the PARP inhibitors. And of course, we now have FDA-approved treatment for patients with PD-L1–positive, first-line metastatic triple negative breast cancer from the IMpassion130 data. We're going to talk quite a bit about the diagnostics of PD-L1, but suffice it to say that there is a survival advantage of 7 months in favor of adding the checkpoint inhibitor, the anti–PD-L1 agent atezolizumab, to nab-paclitaxel in the first-line setting for metastatic triple negative breast cancer.

I dare say that because survival is the most important end point to our patients and to us, that we're going to prioritize the use of a atezolizumab and nab-paclitaxel in the first-line metastatic setting. We will talk about new data that came out at ASCO, the KEYNOTE-355 trial with pembrolizumab and a slate of chemotherapeutic options, but we do have FDA approved the atezolizumab and the nab-paclitaxel. For patients who are not germline 

 and whose breast cancer is PD-L1 negative, we do have data from the TNT trial published by Andrew Tutt, MB, ChB, PhD, a very nice first-line randomized trial of carboplatin, AUC [area under the curve] of 6, versus docetaxel, 100 mg per meter squared, basically showing equivalence of those 2 strategies.

The only subset that really benefited from one agent more than another were the patients with germline 

 who definitely had a higher response rate and median PFS [progression-free survival] with the carboplatin. But otherwise whether we start with a platinum-based regimen or we start with docetaxel, it seems to be equivalent in terms of overall outcomes. We really do have that choice right now for our PD-L1–negative, germline wild-type patients.

Joyce A. O'Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center

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