CDK46 Inhibitors for Newly Diagnosed ER Positive HER2 Negative Metastatic Breast Cancer

Drs. Allison Zibelli and Arielle Heeke discuss the NATALEE trial's novel approach to high-risk HR+ breast cancer, the potential of delaying CDK4/6 inhibitors in HR+, HER2-negative mBC to decrease toxicities and costs in the SONIA trial, and de-escalation strategies in HER2+ early-stage breast cancer.

TRANSCRIPT

Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your guest host for the ASCO Daily News Podcast today. I'm an associate professor of medicine and a breast medical oncologist at the Sidney Kimmel Cancer Center at Jefferson Health in Philadelphia. My guest today is Dr. Arielle Heeke, a breast medical oncologist at the Levine Cancer Institute at Atrium Health in North Carolina.

Today, we'll be discussing practice-changing studies and other key advances in breast cancer that were featured at the 2023 ASCO Annual Meeting.

Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.

Arielle, it's great to speak with you today.

Dr. Arielle Heeke: Thank you so much for having me.

Dr. Allison Zibelli: Let's start with LBA500. This was the NATALEE trial of ribociclib and endocrine therapy as adjuvant treatment in patients with hormone receptor-positive HER2-negative early breast cancer. What are your key takeaways from the study, and how do you think this changes our approach to high-risk ER-positive breast cancer?

Dr. Arielle Heeke: Yeah, this was definitely the study for which many of us were waiting to see the results. It was exciting to see the results come through so quickly. As you mentioned, the NATALEE trial was a phase 3 study that evaluated three years of adjuvant ribociclib at a dose of 400 milligrams, which is a little different than what we're used to in the metastatic space at 600 milligrams. But essentially, it randomized patients to receive this 400-milligram dose with their adjuvant aromatase inhibitor therapy versus just the standard of care adjuvant endocrine therapy in patients that are high risk with early-stage breast cancer.

What made NATALEE somewhat unique is they defined high risk a little bit more broadly than we've seen in previous studies, such as monarchE. So, what I mean by that is NATALEE enrolled patients with stage 2 and 3 early-stage breast cancer. And notably, they allowed for patients that were lymph node-negative but had some other high-risk features, such as a grade 3 tumor or a grade 2 tumor with high-risk genomics, such as oncotype or a high Ki-67. So, by broadening who was eligible, NATALEE captured more patients at risk for recurrence. Of course, we know that recurrence is not specific for patients with lymph node-positive disease. We can see recurrence even with stage 1, but certainly, we start to see more recurrence risk as patients drift into stage 2 and stage 3.

In the NATALEE study, the majority of these patients did receive prior chemotherapy, which I also think is interesting. We've kind of seen in the metastatic space that sometimes chemotherapy can augment patients' responsiveness to CDK4/6 inhibitors. But specifically in NATALEE, 88% of patients had received prior chemotherapy, and ultimately, about a third of the patients were lymph node-negative.

So, diving into some of the results with this first analysis that we saw at ASCO, with the median follow-up for invasive disease-free survival of just 27.7 months, they were able to show that the risk for invasive disease was reduced by 25.2% with the addition of ribociclib plus endocrine therapy compared to endocrine therapy alone. And this three-year invasive disease-free survival rate was 90.4% for the combination therapy compared to 87.1% for endocrine therapy alone, which is an absolute difference of 3.3%. Additionally, patients treated with ribociclib and endocrine therapy had a 26.1% reduced risk for distant disease-free survival compared with endocrine therapy alone, and this was a rate of 90.8% for ribociclib with endocrine therapy compared to 88.6% with endocrine therapy alone, which correlates to an absolute benefit of 2.2%.

They did show results for overall survival as well, but again, follow-up was just a median of 27.7 months. So, data was essentially immature to show any true overall survival benefit from this approach. And in fact, only 20% of patients had completed three years of ribociclib at this data cutoff. And as a reminder, again, NATALEE involved ribociclib for three years compared to two years, which we've seen with other studies in this space.

Also, what was encouraging from NATALEE were the readouts for toxicities. Neutropenia is definitely a concern with this class of medication, and they were able to show that rates of neutropenia were overall lower than what we've seen in the pooled data in the metastatic space. And also that problematic QTc prolongation for which we have to get EKGs baseline two weeks and four weeks. They also showed that the likelihood of having QTc prolongation on this therapy was significantly less at that 400-milligram dose compared to 600.

I think the key takeaway is yes, this drug is effective as adjuvant therapy, which is perhaps not surprising since we've seen such promising results in the metastatic space, but numerically not as striking as what we have at this point with adjuvant abemaciclib, but of course, this is a newer study. We hope to see that continued separation of the curves as we were fortunate enough to see with the abemaciclib data, but obviously we'll be looking for additional analyses from NATALEE.

And then how this will change practice, of course, we'll have to wait to see if the therapy is approved for use in the adjuvant setting for early-stage hormone receptor-positive breast cancer, but it certainly will be a nice option for patients that struggle with GI toxicity kind of at baseline. But also, if they were previously on abemaciclib and were not able to tolerate due to the GI toxicity, this would be an option for them. Also, as mentioned, it's a broader patient population, so we can consider this perhaps for a patient with lymph node-negative disease.

Although we will have to ask ourselves that just because someone meets eligibility for the NATALEE study, and if the therapy is ultimately approved, is it appropriate to give it to all those patients? Or do we need to still kind of think of this in the setting of the highest-risk patient, not just any patient with stage 2 plus disease? There was a lot of talk at the meeting, certainly about biomarkers and potentially using ctDNA to try to find these predictors of benefit from CDK4/6 inhibitor therapy, but obviously, still a long way to go before we can use that type of technology in this space.

Dr. Allison Zibelli: Thank you. Staying on the topic of CDK4/6 inhibitors, everybody was excited about the SONIA trial, which was LBA1000, and this trial was asking if we can delay using CDK4/6 inhibitors for newly diagnosed ER-positive HER2-negative metastatic breast cancer as a way to decrease both toxicity and cost. Tell us about this study.

Dr. Arielle Heeke: The SONIA trial was such a cool study to see, and the presenter reported findings in such a thought-provoking way. Really great to see this sort of work being done because I think we all wonder deep down in our gut, if more is more, or if we do need to kind of be a little bit more thoughtful about how we introduce these therapies certainly from a patient perspective. Patients that participate at ASCO [meetings] have been saying for years how important it is to consider the toxicities in terms of side effects, but also, of course, financial toxicities. So, it was great to see the SONIA trial at center stage.

Essentially, as you mentioned, it was a study that randomized patients in the first-line setting with metastatic hormone receptor-positive breast cancer to receive either first-line CDK4/6 inhibitor therapy or second-line CDK4/6 inhibitor therapy. So basically, there was a mandated crossover, so patients that received the CDK4/6 inhibitor first-line did not receive a second line and vice versa. Patients that were randomized to receive their endocrine therapy as monotherapy first line went on to receive CDK4/6 inhibitor at second-line. And the second-line endocrine therapy was fulvestrant in both of those situations.

We kind of run into this problem with patients now where we have so many therapies available to us that we don't typically run out of treatment options, but rather we run up against treatment toxicity or ultimate failure of the human body to keep up with the demands of ongoing therapy. So, again, while it's maybe somewhat attractive to start treatments earlier using things first-line rather than second-line or longer, just kind of post-CDK4/6 inhibitor progression, you know using this CDK4/6 inhibitor again with a different endocrine therapy backbone is probably not offering a meaningful benefit to that many patients. So this type of study is so necessary to really try to help us frame who needs those therapies sooner and longer or perhaps is there a substantial portion of patients that we don't need to put them through that sort of toxicity.

So that's the SONIA trial. Some things to note about the patient population, these patients were a bit older than what we've seen in some of our metastatic CDK4/6 inhibitor trials. There was a median age of 64 and 87% were postmenopausal. Additionally, just 40% had received prior chemotherapy. And as is true for most of our studies, 91% have received palbociclib on study with just 8% receiving ribociclib. And the choice of the CDK4/6 inhibitor was per the treating provider, and at the time of the of study globally, palbociclib was the more commonly prescribed CDK4/6 inhibitor. But over the last year or so, data has certainly emerged favoring ribociclib in the metastatic setting.

On the SONIA trial, patients were monitored for a median of 37.3 months. And looking at the primary endpoint of the second progression-free survival, which is defined as the time for random assignment to the second objective disease progression or death, for those patients who received first-line CDK4/6 inhibition, had a PFS2 of 31 months compared to 26.8 months with second-line CDK4/6 inhibitor use. And this slight difference was non-statistically significant. So the conclusion was that time to second progression was not impacted by whether or not a patient received first-line CDK4/6 inhibition or second-line CDK4/6 inhibition. Additionally, there were no differences in overall survival between the 2 arms with a median overall survival of 45.9 months with first-line CDK4/6 inhibitor use versus 53.7 months in second-line CDK4/6 inhibitor use.

And that actually equates to significant differences in time on drug. The median duration of CDK4/6 inhibitor use with first-line therapy was 24.6 months compared to 8.1 months with second-line use. And by being on therapy for an additional 16.5 months if you use CDK4/6 inhibitor first-line, this, of course, leads to increased toxicity and certainly increased financial burden. And it was estimated that for each patient that receives this therapy first-line, there is an additional $200,000 spent on getting them the CDK4/6 inhibitor first-line, whereas the results from SONIA suggested that whether you use it first-line or second-line, the outcomes are essentially exactly the same.

And then specific for the SONIA trial, by conducting the study, they saved approximately €25 million on drug expenditure during the conduct of the trial. It's just amazing when you take it to that scale. And then lastly just to mention, they looked at quality of life assessments as well and there were no differences in the two arms whether they got first-line or second-line CDK4/6 inhibition.

Dr. Allison Zibelli: I thought this study was remarkable, and it got a long ovation when it was presented at the meeting. I'm certainly going to use this strategy and prioritize who needs upfront CDK4/6 inhibitor therapy.

I think that we have to think of not just drug toxicity for our patients, but financial toxicity. A lot of these drugs have very high copays and the number one cause of bankruptcy in the United States is medical costs. So that's something we really have to keep in mind. I also thought it was very interesting that the study was designed in cooperation with the patient advocacy group and patients themselves were very enthusiastic about this study and helped design it and helped recruit to it. So all in all, I thought this was a remarkable study.

So moving on, LBA1013 was the TORCHLIGHT study of toripalimab versus placebo in combination with nab-paclitaxel for patients with metastatic or recurrent triple-negative breast cancer. Many of us are not familiar with toripalimab. Can you tell us about the drug and how it was used in this study?

Dr. Arielle Heeke: Yes, toripalimab is essentially an immunotherapy agent. It's an IgG4K monoclonal antibody that targets PD-1. In this study, TORCHLIGHT, patients were randomized to receive toripalimab versus placebo in combination with nab-paclitaxel in newly metastatic triple-negative breast cancer. The patients on study were randomized two to one to receive drug or placebo. The drug is given on day 1 of a 3-week cycle at 240 milligrams and then patients of course also receive nab-paclitaxel on a day 1 and day 8 schedule of a 21-day cycle. They did look at outcomes on the study based on PD-L1 positivity status and they assessed for PD-L1 with an IHC assay JS311 antibody that ultimately generated a combined positive score. And PD-L1 positivity was defined as a CPS of greater than or equal to one based off of this assay. In the study population, about a third of patients were- patients' tumors were CPS negative, a third had a CPS of 1 to 10 and about a quarter had a CPS of greater than or equal to 10. And then approximately 7% of the tumors had an unknown status.

And then getting right into the results, we were provided results in the PD-L1 positive subgroup as well as the whole patient population. Looking at the primary endpoint of PFS, there were significant improvements seen in median PFS with the addition of toripalimab to nab-paclitaxel, again in the first line setting with a median PFS of 8.4 months with the addition of the immunotherapy agent versus 5.6 months with placebo. And this was statistically significant. And then in the intent to treat population, there were some numeric improvements, in median, progression-free survival at 8.4 months with the addition of toripalimab versus 6.9 months with placebo.

We also got some results with overall survival that were quite intriguing, although this initial analysis was not designed to necessarily prove statistically significant differences in overall survival. But again, there were some promising trends. Looking first at the PD-L1 positive subgroup, the median overall survival was 32.8 months with the addition of toripalimab versus 19.5 months with placebo. Breaking it down a little bit further based on CPS values, for a CPS of 1 to 10, median overall survival was 32.8 months versus 19.5 months. And then for those very high CPS or greater than or equal to ten, median overall survival was not reached in this group versus 18.3 months with placebo. Also, looking in the intent-to-treat population, there were also improvements in overall survival with the addition of toripalimab with a median overall survival of 33.1 months with the addition of immunotherapy versus 23.5 months with nab-paclitaxel alone. So potentially, depending on next steps of this study, we would potentially have an option to add immunotherapy that is not biomarker specific, meaning we can potentially provide toripalimab to all patients regardless of their PD-L1 status.

Dr. Allison Zibelli: Very interesting new drug to look forward to. So, one of the major themes of this year's meeting was de-escalation strategies. For example, LBA506 reported the three-year invasive disease-free survival of the PHERGain trial, which looked at eliminating chemotherapy for HER2-positive patients getting neoadjuvant therapy. Tell us about the design of this study and how will it impact the care of these patients?

Dr. Arielle Heeke: The design was very complicated. I had to look at it a few times to really make sure I got my head around it. But I think once you do figure it out, you can see how there might be a path forward in clinical practice. Although I think for all of this work, it's maybe not ready yet for primetime, but certainly thought-provoking. But the PHERGain clinical trial, I feel like we've heard about this study for a little while and this concept of de-escalation really kind of started in the HER2-positive space. But this study was a randomized study of chemotherapy de-escalation and early HER2-positive breast cancer using PET/CT as a marker of response to therapies that don't involve chemotherapy.

Patients were eligible for the study if they had stage 1 to 3a HER2-positive breast cancer with no prior therapy for breast cancer, and ultimately 356 patients were enrolled in a 1 to 4 randomization scheme with the majority of patients ultimately enrolled into the experimental group, which is called Group B. So, to break down Group A and Group B, Group A essentially were patients that receive typical standard of care, which at this point is TCHP for six cycles, neoadjuvantly or prior to surgery. Once they complete those cycles they move into surgery and then Herceptin-PERJETA adjuvantly for additional twelve cycles.

I should also note that this study was conducted prior to results of the KATHERINE trial that showed benefit of switching to adjuvant T-DM1 if there's residual disease. So, patients in Group A as well as Group B did not receive T-DM1 at any point. So, again, Group A is kind of your standard of care. Group B was the "experimental arm." And so, what they did in this arm to assess potential de-escalation strategies, patients first received Herceptin-PERJETA alone for two cycles with or without endocrine therapy, if they were also hormone receptor-positive. But after those two cycles, they underwent a PET/CT, and then if a response was garnered, they would continue with Herceptin-PERJETA and again plus or minus endocrine therapy to complete six cycles total before proceeding on with surgery. Then if they were fortunate enough to achieve complete response at the time of surgery, then they just continued with Herceptin-PERJETA maintenance, whereas if they did not achieve a complete response at the time of surgery, then they actually received TCHP 6 times adjuvantly. So, the chemotherapy was introduced after surgery.

And then going back to that PET/CT time point, if patients did not achieve a response at that check-in point, after 2 cycles of Herceptin-PERJETA, at that point they were transitioned to chemotherapy with TCHP, again, for six cycles. So, either they could kind of ride all the way through if they got that complete response at the time of surgery with Herceptin-PERJETA only, or if at surgery there was residual disease, they went on to receive TCHP after surgery, or if they did not have a response on that interim PET/CT after 2 cycles of HP then they would go on to receive TCHP neoadjuvantly.

So, looking at the results, they actually had 2 primary endpoints. The first primary endpoint was rates of a complete response at the time of surgery in patients that had a PET response. So, PET responses were actually seen in nearly 80% of all the patients treated with Herceptin-PERJETA without chemotherapy. And in those PET responders, a complete response rate at the time of surgery was seen in approximately 38% of patients. So, 37.9% of PET responders actually achieved a complete response when they went to surgery after receiving Herceptin-PERJETA alone, which is pretty amazing. I mean, we're used to seeing higher complete response rates with neoadjuvant therapy for HER2-positive disease, but again, this is a chemo-free regimen so that is encouraging for that 38% of patients that really didn't need chemotherapy.

And then the second primary endpoint, and this was what we saw basically for the first time with the 2023 ASCO Meeting, was results for the 3-year invasive disease-free survival in Group B or this experimental de-escalation group. And ultimately it was shown that the three-year invasive disease-free survival and the intent to treat group B population was 95.4%, which met its statistical endpoint, or, basically the null hypothesis was rejected. They just needed some sort of outcome that was not worse in terms of the 3-year invasive disease-free survival of 89%.

And then looking actually at the patients that kind of did the best. So, the patients that were PET responders and achieved a complete response at the time of surgery and therefore really only ever received Herceptin-PERJETA, their three-year invasive disease-free survival was 98.8%. So, really very good. Additional endpoints they looked at in Group A and Group B were favorable in terms of three-year invasive disease-free survival in Group A, and then three-year distant disease-free survival and three-year overall survival in both groups, all approximately 98%. So, very favorable.

So, ultimately, these findings reflect a potential role for a chemotherapy-free treatment approach for some patients with early-stage HER2-positive breast cancer. And this particular study, they used PET/CT to influence chemotherapy decision-making, which potentially identified 1 in 3 patients who can omit chemotherapy. With that, 80% of patients receiving the response with a PET/CT, and then of that, 80%, again, 38% actually having that complete response. And ongoing work is also being done to look at other mechanisms to assess for an opportunity to de-escalate with MRI imaging or HER2DX testing to again try to identify patients who can potentially defer chemotherapy in this setting. I did not see from the results what proportion of patients were hormone receptor-positive, which I think is also interesting when thinking about chemotherapy de-escalation, can you lean a little bit more heavily on endocrine therapy? Perhaps we'll get that data in the future.

Dr. Allison Zibelli: That's a very important point. I would like to thank you, Dr. Heeke, for coming on the podcast today and sharing your valuable insights with us. We really appreciate it.

Dr. Arielle Heeke: Absolutely. It was a great meeting to dive into. It's always exciting to see what comes out of ASCO in the breast space. We're usually well represented there, and I hope that these studies will lead to further exploration.

Dr. Allison Zibelli: And thank you to our listeners for joining us today. You'll find links to all abstracts discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Disclosures:

Dr. Allison Zibelli:

None Disclosed

Dr. Arielle Heeke:

Honoraria: Merck

Consulting or Advisory Role: Jazz Pharmaceuticals, Caris Life Sciences, Amgen, Daiichi Sankyo/Astra Zeneca, Pfizer, AstraZeneca, Menarini, Genome Insight

Speakers' Bureau: Daiichi Sankyo/Astra Zeneca