Claudine J. Isaacs, MD, discusses significant advances that have been made across all different breast cancer subtypes in recent years, as well as ongoing research efforts.
Significant advances have been made across all different breast cancer subtypes in recent years, and to continue to propel progress forward, efforts have been focused on accelerating the research and development of novel agents to provide patients with more personalized treatment approaches that will ultimately prolong survival, according to Claudine J. Isaacs, MD.
For example, the ongoing, phase 2 I-SPY and I-SPY2 trials are evaluating the efficacy of multiple agents via numerous investigational arms with a neoadjuvant chemotherapy backbone. The studies include more than 20 different arms and have enrolled patients with several disease subtypes, including hormone receptor (HR)–positive/ERBB2-negative (previously HER2 or HER2/neu), HER2-positive, and triple-negative breast cancer (TNBC).1,2 The novel design allows for the quick adaptation and incorporation of novel drugs into the treatment paradigm, explained Issacs.
“Notably, the I-SPY2 trial allows us to much more rapidly evaluate the potential role of a new agent because it is so biomarker heavy. In medicine, we all recognize that some drugs will work for some patients but not for others. This trial allows us to see some early signals of where a particular drug might have its greatest role,” said Isaacs. “[We can] start off with potentially a broader group. Then, if we're seeing benefit only in a certain subset, we can continue enrollment to that cohort. [This will] gradually phase out the groups in whom we don't believe there's a benefit. In terms of its design itself, it really has been revolutionary.”
In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Breast Cancer, Isaacs, a professor of medicine and oncology at Georgetown University, medical director of the Fisher Center for Familial Cancer Research, and co-director of the Breast Cancer Program at Lombardi Comprehensive Cancer Center, discussed novel research efforts being made to personalize treatment in breast cancer.
OncLive®: What are some of the latest developments that have been made in breast cancer treatment?
Isaacs: We’ve made tremendous advances in breast cancer over the past several years in all of the different subtypes [of the disease]. If we think about the advances in HER2-positive disease, we've had tremendous change in the past 9 to 12 months with the approval of 3 new drugs for metastatic disease.
[For example,] we saw the approval of tucatinib [Tukysa] given in combination with capecitabine and trastuzumab [Herceptin]. What the HER2CLIMB study showed was prolongation, not only in progression-free survival [PFS], but even in overall survival [OS], as well. We also saw the accelerated approval of [fam-trastuzumab deruxtecan-nxki (Enhertu)], an anti-HER2 drug that has also been shown to have tremendous activity. We also have some exciting phase 3 trials and we’re waiting on the data to really confirm the efficacy of this drug, as well as for us to be able to tease out some of the adverse effects. We also have neratinib (Nerlynx), which was approved for use in metastatic disease.
Up until 1 year ago, we really had clear guidelines for what to do [in the] first- and second-line [setting], but beyond, we didn't really have anything. Now, we have a land of riches where we have many options for our patients. It's a matter of choosing what we think is the next best option, but with the notion that we have newer and newer drugs that can prolong survival in this group of patients.
If we think about the triple-negative space, we have a series of trials that have looked at and confirmed the role of immunotherapy, particularly in the first-line setting. Given the results of the IMpassion trials, we really think that nab-paclitaxel (Abraxane) is probably the best chemotherapy partner. Most of our data really reinforce this notion of immunotherapy being most beneficial in a subset of patients who have PD-L1–positive disease; the first-line setting is really where we get that benefit.
We also have the exciting data from the ASCENT trial regarding sacituzumab govitecan in patients who have received between 2 to 5 lines of chemotherapy for metastatic TNBC. The exciting data that were presented from the analysis of that trial during the 2020 ESMO Virtual Congress showed not only a benefit in terms of response rate and PFS, but also most meaningfully, a real benefit in terms of OS. We finally have some tangible gains that we're making in the triple-negative metastatic space, as well as some increasing data [regarding] the role of immunotherapy in the neoadjuvant space for TNBC.
The final area of major developments [includes] data on CDK4/6 inhibitors in the adjuvant space. Data from the monarchE trial show that our very highest-risk patients—[those who have 4 or more positive nodes or those who have 1 to 3 positive nodes with other more aggressive features—benefitted from the addition of abemaciclib (Verzenio) to a standard endocrine backbone for the first 2 years of therapy. We also have data on alpelisib (Piqray); we saw some of the more mature findings presented during [the 2020] ESMO Virtual Congress.
It's really a land of plenty right now in breast cancer where we're trying to figure out how we should integrate all these new therapies. The great news with this is that we keep on making additional advances for our patients.
What is the rationale for the I-SPY2 trial? What makes this research unique?
I-SPY is a platform trial; this means that the backbone of the trial is the same, but it gets to cycle in new drugs as they come up. The trial allows for rapid integration of new drugs, new developments, and it keeps on building on itself; it keeps on pushing and adjusting to the new current standard of care. [The trial] allows us to have a more rapid way to assess promising new drugs, looking at them potentially in certain subtypes of breast cancer.
The trial is open for all [patients with] high-risk stage II and stage III [breast cancers], including those with TNBC, HR-positive, and HER2-positive [disease]. Some drugs only make sense for some of the subtypes, while others make sense for all of them. The trial allows new drugs to be integrated quickly into use; it allows us to just add on a new drug instead of writing a whole new phase 2 trial. Obviously, there's a lot of discussion and a lot of thought [that goes into this]. Many people are involved in the choice of which drugs make sense and which ones we should bring forward.
I-SPY is a very multidisciplinary kind of trial; it brings together all the specialties who are involved in the treatment of [patients with] breast cancer. [The trial also] brings together a strong advocate community, a strong drug development community, and a strong biomarker community to really maximize and ensure that we're doing this in the very safest way possible.
It's not designed to be a trial that will definitively prove that a particular drug works in a particular subset of patients with early-stage high-risk breast cancer; rather, it’s designed to give a thumbs up regarding whether a drug is worthy of further evaluation in a particular group of patients. Those are the types of signals we need. These drugs usually take years to make their way forward. The hope is that with something like I-SPY, we'll get evidence that allows us to more rapidly accelerate these discoveries and bring them into the clinic much more quickly.
How does this work address some challenges faced with clinical trials in this space?
One of the things that we struggle with as clinicians who are involved in clinical trials is that it takes a long time not only to get a trial off the ground, but it take a very long time to see whether an approach prolongs survival, and that’s ultimately what we're trying to do. If we wait for that as the end point before we move to the next step, it could take years before we are able to integrate the findings into the clinic.
I-SPY is a trial that had a very recent publication which showed that if a patient achieves a pathologic complete response [pCR] by the time they get to surgery following their neoadjuvant systemic therapy, that's a very good prognostic factor. It doesn't matter what drugs they received to get there; that achievement of a pCR is a very good surrogate end point. It's something that we can obviously discover much more quickly than waiting for years [to see what the survival benefit is] and you also need fewer patients to get that information. Again, that's a really robust way for us to get a signal about the efficacy of a drug and then take it forward to the next step [in the developmental process].
What is some of the progress that has been made with immunotherapy and the role of PD-L1 expression?
The greatest role for immunotherapy in breast cancer has been shown in triple-negative disease, thus far. The first [trial to examine this approach] was IMpassion130, which showed the benefit of adding atezolizumab (Tecentriq) immunotherapy to nab-paclitaxel [Abraxane]. [The regimen] showed a benefit in terms of PFS; however, also, in a subset of patients who had PD-L1–positive disease, it led to a prolongation of OS, which is the most meaningful [measurement] that [we have] for our patients.
Interestingly, there was a trial presented during the 2020 ESMO Virtual Congress which looked at paclitaxel as the backbone with atezolizumab. Results showed no benefit with the addition of atezolizumab. I'm not sure that we would have predicted that; there are many theories for why that might have happened.
Results from the KEYNOTE trials, which used pembrolizumab (Keytruda) and a variety of chemotherapy backbones, [have also been presented]. In addition to the taxanes as the backbone, carboplatin and gemcitabine [also served as] backbones. For the patients who have PD-L1–positive disease, we saw a benefit with adding pembrolizumab to chemotherapy. We now have this very clear indication that if we have a patient with TNBC, at the time of initial diagnosis of metastatic disease, it is now standard of care and critical that we address whether they have PD-L1–positive or –negative disease. These trials, because they use different immunotherapies, they use different [methods to] assess the PD-L1 status of the tumor.
If a patient is PD-L1 positive by one [method] or the other, I want to give them the opportunity to receive immunotherapy in conjunction with chemotherapy. We’re in a fast-moving world, so what I say today might be wrong in 2 months. However, based on what we know at the end of October of 2020, if I had to choose a chemotherapy partner, I would choose nab-paclitaxel. Do I think that's necessarily the only partner? Absolutely not, but that's the [agent] that we have the greatest evidence for right now.
What’s the role of immunotherapy in the neoadjuvant setting?
We have some trials now that have built on the I-SPY2 model. One of their arms had pembrolizumab and showed a tripling of the pCR rate when you added pembrolizumab to a taxane and anthracycline backbone. Very interestingly, [this benefit was true] not only for triple-negative disease but also for HR-positive, HER2-negative disease. We have results from 1 of the KEYNOTE trials as well, that have shown that increase in pCR and have confirmed that [benefit] in a larger phase 3 trial. Another ongoing trial seeks to further build on what I-SPY2 showed in patients with HR-positive, HER2-negative high-risk disease. Right now, the role of immunotherapy is really for [TNBC; this approach is] FDA approved for first-line metastatic [disease]. We have a series of trials that have looked at the addition of immunotherapy for TNBC beyond the frontline and it really doesn't seem to have much benefit. We're confined more to that first-line setting and that’s important for us to assess for our patients.
Where should future research efforts focus?
We need to keep improving outcomes for our patients. We need to examine new drugs and see what we can do to improve long-term outcomes for our patients with metastatic disease and increase the chance of cure for those with early-stage disease. The other thing that we really need to do—and many trials are working to address this—is see who needs what therapy. We need to personalize [care, which] means not only adding drugs but figuring out where we can subtract drugs because everything that we do has toxicity. Both ongoing and planned trials are trying to address that issue of individualization of care. Every time that we find something new, we need to figure out who needs it versus who does not. Maybe we can pull back on something that we were doing by having [a] new drug [available].
One of the areas that we see every day in the clinic is a patient in the early-stage setting [asking], “How long do we continue endocrine therapy?” Several trials are planned to try and help us really drill down who needs more [therapy], who needs that extended adjuvant endocrine therapy, and who does not. It’s a pressing problem that I see in the clinic every day. However, all of the things that we've talked about are areas where we really need to continue to focus. Obviously, a topic that we have not talked about is prevention. I'm a breast medical oncologist but I prefer to see fewer patients. I'd prefer there to be a lower likelihood of developing breast cancer; that's obviously another area that we need to focus on.