Emerging Data are Expanding Treatment Options, Extending Survival Across Breast Cancer Subtypes

Matthew P. Goetz, MD

New developments with CDK4/6 inhibitors, PARP inhibitors, and immune checkpoint inhibitor sequencing are providing patients with breast cancer with more tailored treatment options than ever before, according to Matthew P. Goetz, MD.

“The main message that’s coming out right now, which is not restricted to just breast cancer, but [applies to] oncology in general, is that things are moving at a rapid rate,” ,” said Goetz following an OncLive^® State of the Science Summit™ on breast cancer, which he co-chaired with Judy C. Boughey, MD, of Mayo Clinic. “This is good news for patients. We are clearly making inroads in areas that we haven’t in the past.”

In an interview with OncLive^®, Goetz laid out some key highlights from the meeting, including overall survival (OS) data with ribociclib (Kisqali) and abemaciclib (Verzenio) in estrogen receptor (ER)–positive, HER2-negative disease; the questions that arise when an agent elicits a progression-free survival (PFS) benefit but not an OS benefit; the role of adjuvant pembrolizumab (Keytruda) in patients with triple-negative breast cancer (TNBC) who achieve pathologic complete response (pCR); and the efficacy of PARP inhibitors in earlier settings. He also highlighted exciting research being conducted with selective estrogen receptor modulators (SERMs), which are being revitalized in breast cancer treatment as a potential way to mitigate toxicity in patients, specifically those who are premenopausal.

Goetz is a professor of oncology and pharmacology, as well as a consultant in the Division of Medical Oncology in the Department of Oncology at Mayo Clinic.

OncLive^®: Could you provide an overview of your presentation on new data in the adjuvant and metastatic breast cancer settings with CDK4/6 inhibitors?

Goetz: The focus [of my presentation was] on the treatment of patients with metastatic breast cancer that is ER positive and HER2 negative, as well as high-risk patients with early-stage breast cancer and the role of CDK4/6 inhibitors. [I asked and answered the questions:] What are the updates? What new data should inform how we treat our patients in this setting?

What has the phase 3 PALOMA-2 trial (NCT01740427) shown regarding PFS with palbociclib (Ibrance) in the metastatic setting?

The PALOMA-2 trial was an important clinical trial that randomized patients in the first-line metastatic ER-positive, HER2-negative setting to receive either the standard of care at that time, which was letrozole [Femara] plus placebo, or palbociclib with letrozole. This was 1 of 3 seminal trials done in the first-line setting, the others being the [phase 3] MONALEESA-2 trial [NCT01958021] and the [phase 3] MONARCH 3 trial [NCT02246621]; each [trial tested] different CDK4/6 inhibitors.

What we have known for quite some time is that all these trials look similar on paper. We’re always cautious about doing cross-trial comparisons, but looking at these trials, the addition of a CDK4/6 inhibitor essentially doubled the PFS. What was not clear, however, was: Do these drugs improve OS? Over the past year or 2, these data are becoming mature, and we’re beginning to see OS data.

What is the distinction between the terms disease-free interval and treatment-free interval, and why is this distinction important when evaluating trial findings?

The [phase 1/2] PALOMA-1 trial [NCT00721409] was the first trial to report the benefit of palbociclib, but it was a relatively small, randomized trial. As we look at the PALOMA-2 trial, we need to step back and look at what we’ve learned from all the trials in the metastatic setting. We have now consistent survival data from the MONALEESA-2 trial, the [phase 3] MONALEESA-7 trial [NCT02278120], the [phase 3] MONALEESA-3 trial [NCT02422615], and the [phase 3] MONARCH 2 trial [NCT02107703]. [In MONALEESA 2, MONALEESA-3, and MONALEESA-7,] the addition of ribociclib to standard endocrine therapy consistently improved OS, [in addition to improving] PFS. For MONARCH 3, which investigated the first-line CDK4/6 inhibitor abemaciclib, we don’t have mature survival data yet. That trial was the latest to show PFS data, but we do expect [OS] data to come out from that trial soon.

Findings from the [phase 3] PALOMA-3 study [NCT01942135] have also been reported and showed that the addition of palbociclib to standard endocrine therapy did not improve OS. [That study enrolled] a more heavily pretreated group of patients, so we’ve been eagerly awaiting the OS data.

[At the 2022 ASCO Annual Meeting,] Richard S. Finn, MD, [of the David Geffen School of Medicine at UCLA], presented data [from PALOMA-2]. In the intention-to-treat population, there was no improvement in OS, with a stratified hazard ratio of 0.956 and a P value of .3378. What that told us was that although palbociclib improves PFS, it does not prolong life.

There are many questions about why that might be. Dr Finn presented [the observation that] when looking at the disease-free interval, comparing, for example, PALOMA-2 vs MONALEESA-2, MONALEESA-7, and MONALEESA-3, the number of patients enrolled with a short disease-free interval, less than 12 months, was upward of 22% in PALOMA-2, whereas it appeared there was a smaller number of patients [with this short disease-free interval] in MONALEESA-2, MONALEESA-7, and MONALEESA-3. The implication here is that the PALOMA-2 trial enrolled a population of patients who had more aggressive disease and recurred quickly, and that the MONALEESA-2, MONALEESA-7, and MONALEESA-3 studies all showed a survival advantage because they enrolled a group of patients who had a better prognosis, so that’s maybe why there are survival differences.

However, as it turns out, PALOMA-2 used the term disease-free interval to define the time from the end of neoadjuvant treatment to disease recurrence. The MONALEESA trials used a different term, treatment-free interval, to define the same thing. Look, then, at the populations while using this idea of disease-free interval, or simply get rid of those terminologies, and ask the question: How many patients presented with a treatment-free interval or disease-free interval of less than 12 months? [These numbers are] almost identical between MONALEESA-2 and PALOMA-2. We can confidently say that this [term discrepancy] is not a reason why PALOMA-2 did not show a survival difference and the MONALEESA trials did.

There were some other concerns, as well. Missing data was laid out as a possible explanation, but if you look at the experimental arms in MONALEESA and PALOMA-2, they have identical percentages of patients with missing survival data. Where things stand at this point, we can look at the total data and say that in PALOMA-1, PALOMA-2, and PALOMA-3, there’s no survival data, and [palbociclib] did not improve invasive disease-free survival [DFS] in the adjuvant setting [either].

This is an interesting observation, [to ask the question:] Why [can a drug] improve PFS, but not OS? Certainly, there needs to be more work on that. However, I always tell my patients in the clinic that I have 2 different drugs, 1 that improves survival and 1 that doesn’t, and it’s not much of a conversation. The patients are generally going to choose the drug that lengthens their life. That’s why we are here, to prolong life.

[This is hard work] that, over time, involves large databases such as the SEER database, to answer the question: Do [these drugs] improve survival? We will probably see, over time, a change in the preference for the use of these drugs, and a switch toward the drugs that improve survival.

What do studies such as the phase 3 PALLAS trial (NCT02513394) and the phase 3 PENELOPE-B trial (NCT01864746)show about the potential role for CDK4/6 inhibition in early-stage hormone receptor–positive disease?

CDK4/6 inhibitors have moved into the adjuvant setting. We have data from PALLAS, PENELOPE-B, and the [phase 3] monarchE trial [NCT03155997], which is testing abemaciclib. In the trials testing palbociclib, there was no improvement in invasive DFS with the addition of palbociclib to standard endocrine therapy, whereas we did see an improvement in invasive DFS with the addition of abemaciclib to standard endocrine therapy.

The other trial for which we’re eagerly awaiting the readout is the [phase 3] NATALEE trial [NCT03701334]. This trial is testing the addition of ribociclib, at a lower dose, to standard anticoagulant therapy. This trial is a bit different in that the investigational arm is using ribociclib for a total of 3 years, as opposed to 1 or 2 years, as has been tested in the other CDK4/6 inhibitor trials. We’re interested to see what the results of the NATALEE trial show, but for right now, we have only 1 option to utilize in the adjuvant space, and that’s abemaciclib.

Your colleague, Roberto Leon-Ferre, MD, of Mayo Clinic, presented on new strategies in the adjuvant and metastatic settings for TNBC. How do findings from the phase 3 KEYNOTE-522 study (NCT03036488) raise questions regarding the need for pembrolizumab after pCR?

This is an important question, and it relates to the fact that traditionally, when we treat patients with neoadjuvant chemotherapy and they achieve a pCR, they do extremely well long-term, and we don’t continue chemotherapy after surgery. What’s quite interesting in the trials that have tested pembrolizumab in the adjuvant setting is that those trials not only utilized pembrolizumab in the neoadjuvant setting, but, in [trials such as] KEYNOTE-522, pembrolizumab was continued after surgery. Not all the trials did this. For example, the [phase 2] GeparNUEVO trial [NCT02685059], which investigated the immune checkpoint inhibitor durvalumab [Imfinzi], only administered the drug during the neoadjuvant phase.

[Looking at the long-term] benefits of those trials, we see fairly similar results between the invasive DFS curves of those 2 trials, even though 1 trial continued pembrolizumab after surgery and the other trial did not continue durvalumab after surgery. A major question is being addressed right now: Is adjuvant pembrolizumab necessary for patients who achieve a pCR? Another potential question is: If a patient hasn’t had a pCR, should they also continue with adjuvant pembrolizumab? However, that’s not going to be addressed right now.

For right now, we want to know whether patients who have achieved a pCR need to continue with the drug. The OptimICE-pCR trial is being done through the National Cancer Institute [NCI] Alliance, led by Sara M. Tolaney, MD, MPH, [of Dana-Farber Cancer Institute]. That trial is asking the question: Do we need to continue an immune checkpoint inhibitor after surgery if pCR is achieved?

Another question we need to address is: Is there a role for immune checkpoint inhibitors after surgery for patients who did not receive an immune checkpoint inhibitor in the neoadjuvant setting? This is [being investigated in] the [phase 3] SWOG S1418 trial [NCT02954874] that’s being led by Lajos Pusztai, MD, of the Yale School of Medicine. We’re hoping that trial will read out. It’s been fully accrued for some time, and we’re hoping to get the results sometime within the next year or 2.

Your colleague, Siddhartha Yadav, MBBS, MD, of Mayo Clinic, spoke about new treatment strategies for patients with germline predisposition gene mutations. What is the best practice for choosing and sequencing PARP inhibitors in metastatic breast cancer?

For the treatment of patients who have BRCA1 or BRCA2 mutations in the metastatic setting, we have data from several trials using different PARP inhibitors showing a clear benefit of those PARP inhibitors. It appears that the benefit of the PARP inhibitors is greater in the earlier settings, meaning in less heavily pretreated patients.

According to emerging data from Jennifer Keating Litton, MD, [of The University of Texas MD Anderson Cancer Center,] and others, bringing PARP inhibitors all the way up front into the neoadjuvant phase, produces some incredible response rates, including pCR rates approaching 50% or higher.

We’re seeing that PARP inhibitors do, indeed, work better in the less heavily pretreated setting. That’s not to say they can’t work later, but this is generally what we see with most targets. For example, with endocrine therapy and CDK4/6 inhibitors, generally, we see better efficacy in the less heavily pretreated setting. That certainly holds with the PARP inhibitors, as well.

What main message from the meeting would you like to give to colleagues?

Thinking about the ER-positive, HER2-negative, metastatic space, we have been stuck at OS rates that have not moved for quite some time in patients who are diagnosed with metastatic disease. The fact that we have seen improvements in OS that are approaching 6 years is remarkable. Many advances are being made that are leading to short-term benefits for patients, as well as long-term survival benefits.

What ongoing or upcoming breast cancer research at Mayo Clinic are you excited about?

Exciting [developments are happening in] ER-positive, HER2-negative breast cancer. We have been stuck for a while with the notion that we need to treat all patients the same way, treating premenopausal or postmenopausal ER-positive, HER2-negative breast cancer with endocrine therapy.

Tamoxifen and aromatase inhibitors have made small improvements in OS. We had hoped selective estrogen receptor degraders [SERDs] would be a major advance, and the SERDs are moving forward. Fulvestrant [Faslodex] is an outstanding drug and having oral versions of it is going to be good.

We’re beginning to see the SERMs revitalized. There are studies with 2 SERMs that I’m excited about. [The first 1] is with endoxifen, which has been studied in the metastatic setting and compared with tamoxifen in endocrine-resistant disease; [this agent] clearly showed benefit in that area. This [was explored in] an NCI Alliance clinical trial. We’re also beginning to see data with another SERM, lasofoxifene, which has clear antitumor activity in ESR1-mutated tumors.

SERMs are of interest because they provide a different toxicity profile that can be helpful for patients. We know about the profile of tamoxifen, and we know the concerns with that drug. Aromatase inhibitors have not been a walk in the park, as we’ve looked at and experienced those toxicities as clinicians and patients. The ability to resurface and go back to the SERMs, perhaps different SERMs, such as lasofoxifene or endoxifen, and try to understand ways that we could bring these back to our patients [is promising].

Ultimately, it’s not about having 1 end-all-be-all drug. We want to have the right drug for the right patient. There shouldn’t be only 1 option per patient, nor should there be only 2 options. We need to have 3 or 4 options, so we get the right drug for the right patient. That’s going to ultimately be a major improvement for both postmenopausal women and premenopausal women.

I have the most concern about premenopausal women. Significant and prolonged ovarian function suppression through aromatase inhibitors is a regimen that is efficacious for breast cancer, but it is poorly tolerated. We need new approaches for premenopausal women. That’s why I’m very excited about the work that is ongoing with the SERMs endoxifen and lasofoxifene.