Investigation of Pembrolizumab De-Escalation After pCR Aims to Challenge SOC in Early-Stage TNBC

The ongoing phase 3 OptimICE-pCR trial (NCT05812807) is investigating treatment de-escalation with pembrolizumab (Keytruda) in patients with early-stage triple-negative breast cancer (TNBC) who achieve a pathological complete response (pCR) following neoadjuvant chemotherapy plus pembrolizumab, with the goal of sparing patients from adverse effects (AEs) without increasing the risk of recurrence, according to Yuan Yuan, MD, PhD.

In the study, patients who achieve a pCR following neoadjuvant chemotherapy plus pembrolizumab will be randomly assigned to undergo observation in the experimental arm or continue with single-agent pembrolizumab in the control arm.

“We know that [treatment with] an immune checkpoint inhibitor is a double-edged sword, and there may be delayed-onset immune toxicity for these young women. This is a timely question,” Yuan explained in an interview with OncLive^® following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Yuan, the director of Breast Medical Oncology Medicine and medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center in Los Angeles, California, discussed the OptimICE-pCR trial and other ongoing clinical trials in breast cancer being conducted at Cedars-Sinai, and expanded on the role of CDK4/6 inhibitors and other novel treatment strategies for patients with hormone receptor (HR)–positive breast cancer.

OncLive: Could you expand on key ongoing clinical trials in breast cancer currently being conducted at Cedars-Sinai?

Yuan: I recently joined Cedars-Sinai, and one of my tasks was to expand our clinical trial portfolio to build our next-generation trials. Within that theme, we are introducing some of the cutting-edge, neoadjuvant studies, including investigator-initiated trials and large corporate group trials that are addressing important questions.

For example, when a patient [with TNBC] finishes neoadjuvant chemotherapy [plus pembrolizumab], depending on pathological response, they get the standard of care, which is comprised of continuation of up to one year of [single-agent] pembrolizumab. If the patient achieved a pCR, meaning there’s no residual cancer left at the surgical specimen, they would automatically have to continue one year of pembrolizumab. That practice will be studied in our upcoming Alliance for Clinical Trials in Oncology[–sponsored] OptimICE-pCR trial, giving us an opportunity to see if patients who achieve pCR should continue [pembrolizumab] or stop [treatment] at that point.

Additionally, what if a patient [with TNBC] doesn’t have a pCR [following neoadjuvant chemotherapy plus pembrolizumab]? In high-risk TNBC, what else can we do to lower the risk of future recurrence? Can we bring up some of the effective antibody-drug conjugates from the metastatic setting to the post-neoadjuvant setting? There were 2 trials that we were approached [about], including [the phase 3] ASCENT-05 trial [NCT05633654], which is studying sacituzumab govitecan-hziy [Trodelvy] plus [pembrolizumab] vs [physician’s choice of treatment]. [The phase 3] TROPION-Breast03 trial [NCT05629585] is evaluating datopotamab deruxtecan [(DS-1062a) with or without durvalumab (Imfinzi)] vs [investigator’s choice of treatment] in this space.

These are interesting trials that could address clinical needs, helping us to tailor and perhaps better personalize therapy for these patients.

What are some other areas you hope to see clinical trials at Cedars-Sinai address?

[One topic of interest] is how to turn an immune-cold tumor to immune hot. We know that immune checkpoint inhibitors are wonderful, but not every patient will benefit from them. By nature, many breast cancers are immune cold. It’s difficult for immune checkpoint inhibitors to elicit immune responses [in these patients]. How can we help to change the tumor microenvironment? Fitting into that theme, we have 2 trials.

In the neoadjuvant setting for [patients with] newly diagnosed, early-stage, high-risk [TNBC], we just activated a [phase 2] study [NCT05491226] leveraging pembrolizumab plus a CSF1 receptor inhibitor, in combination with radiation. That study is built upon Cedars-Sinai’s previous experience, [showing] that pembrolizumab plus radiation could increase pCR.

In the metastatic setting, my investigator-initiated phase 1/2 trial [NCT05318469] is also looking at a drug [that is] perhaps already well known after the [COVID-19] pandemic, but the research [informing this study] started before the pandemic. My colleague, Peter P. Lee, MD, of City of Hope, had studied which drugs could be used to turn an immune-cold tumor to immune hot. After an aggressive, rigorous screening process, they identified ivermectin, which is an oral antiparasitic pill. In mouse models of TNBC, they were able to turn immune-cold tumors to immune hot [with ivermectin] and further enhance the efficacy of immune checkpoint inhibitors.

Based on these exciting data, we were able to launch the investigator-initiated trial combining ivermectin with a next-generation immune checkpoint inhibitor balstilimab [AGEN2034]. That [trial] is active now.

What are some of the challenges researchers currently face regarding enrollment for clinical trials?

Despite the dissemination of knowledge among patients, the research community, and investigators, enrolling patients to clinical trials remains challenging for many reasons. Through the [COVID-19] pandemic, we took a hard hit because of patient access and lack of personnel.

From the patient perspective, modern clinical trials are driven by precision medicine. For example, we considered a trial targeting the mutation, NF1. We looked at our Cedars-Sinai database, and out of the thousands of patients that we sequenced, only 15 patients had NF1 mutations. These are mutation-driven, precision medicine–driven trials. Not every patient will fit into the [inclusion] criteria. Therefore, trials are no longer broad, and that fractionizes the population [eligible for enrollment].

Moreover, lack of access to clinical trials [remains a concern]. For underserved populations, insurance may limit patients’ access to a large system. Cedars-Sinai is trying to disseminate our trial information [to] these underserved populations. We are continuing to work hard to get our trial information to the right patients to help them go through trial enrollment.

Turning to HR-positive breast cancer, how could novel agents fit in with the currently approved CDK4/6 inhibitors?

Since the initial approval of [palbociclib (Ibrance) in 2015], we have 3 CDK4/6 inhibitors as metastatic treatment options. With the recent FDA approval of abemaciclib [Verzenio], [we now have] the first CDK4/6 inhibitor [available for use as adjuvant treatment] for [patients with] high-risk, estrogen receptor [ER]–positive breast cancer.

At the 2023 ASCO Annual Meeting, we heard more about the [phase 3] NATALEE trial [NCT03701334], which was a large, randomized study looking at 3 years of adjuvant ribociclib [(Kisqali)] plus endocrine therapy] in the same setting. [After the study met its invasive disease-free survival end point], we are anticipating multiple drugs [being available] in the [adjuvant setting for patients with ER-positive breast cancer]. Therefore, [understanding] how to utilize them and how to select patients to get appropriate treatment is important. It is a shifting landscape.

Moreover, once a high-risk patient receives a CDK4/6 inhibitor [in the adjuvant setting], what if they relapse in the future? Are we going to still treat them with the same strategy? What else can be offered? These are moving targets that oncologists and patients are interested in learning [more about].

We also discussed oral selective estrogen receptor degraders [SERDs], which are very important new [agents]. I can’t recall how many patients have shared with me that they don’t like needles. Fulvestrant [Faslodex] injection is effective, but the modality is not well received. Giving patients the option of oral SERDs [would be] a huge improvement. However, the FDA approval [for elacestrant (Orserdu)] is limited to the patients who have an ESR1 mutation. That calls for more research in the non-ESR1–mutated population to see how we can expand beyond that [indication]. There is a lot of ongoing research, and I anticipate that in next couple of years, we will have a plethora of options for [patients with] ER-positive disease beyond just CDK4/6 inhibitors, which is a great thing.

Cathie Chung, MD, of Cedars-Sinai, led a deeper discussion on CDK4/6 inhibitors in HR-positive breast cancer. What are some of the questions that still need to be addressed regarding the use of these agents in this patient population?

Among the 3 [FDA-approved] CDK4/6 inhibitors [palbociclib, abemaciclib, and ribociclib], we know that cross-trial comparisons are not ideal. However, we can generate some consensus. The first question that oncologists and patients were facing with the drugs is: which one should we pick when facing a frontline decision? Some of the data Dr Chung presented helped us to understand which drug had the best efficacy and overall survival [OS] benefit.

There were still lingering questions on patients who present with visceral metastases. Should we jump to chemotherapy, or can we still leverage CDK4/6 inhibitors? Now, we have [data from] the phase 2 [RIGHT Choice] trial [NCT03839823] demonstrating that [ribociclib plus endocrine therapy] in these patients with visceral metastases or in a visceral crisis should be the first option. That provided evidence-based [data] to guide our clinical practice.

What about the second-line setting? When a patient [progresses] on one CDK4/6 inhibitor, what are the next steps? We have seen patients continue with CDK4/6 inhibition with a different endocrine backbone. Data from the [phase 2] MAINTAIN trial [(NCT02632045) of ribociclib plus switch endocrine therapy] have helped guide us in this setting.

Are there any specific biomarkers or patient characteristics that can help identify which of these patients are more likely to benefit from specific therapies?

Notably, alpelisib [Piqray], in combination with fulvestrant, is available for patients with [HR-positive breast cancer harboring] PIK3CA mutations in the second-line setting. Genomic sequencing at the onset of metastatic disease, and perhaps follow-up with a liquid biopsy, [is needed] to understand the tumor evolution and acquired mutations, such as ESR1, to provide more informed decision making. We’re no longer blinded, and these biomarkers can help us select next-generation treatment.

There is [potentially] going to be an AKT inhibitor, capivasertib, available [in the future]. However, in the [phase 3 CAPItello-291] trial [(NCT04305496) of capivasertib plus fulvestrant in patients with advanced HR-positive breast cancer], there was no biomarker selection. [Some treatments] have clear biomarker guidance. Some are lacking [biomarker guidance]. This theme of precision medicine and biomarker selection will stay.

Philomena McAndrew, MD, of Cedars-Sinai, led a case discussion on CDK4/6 inhibitors. What was the key takeaway from the discussion of a 54-year-old patient with ER-positive, HER2-negative breast cancer who progressed following palbociclib plus endocrine therapy in the frontline setting?

The case discussion reinforced [findings from] the MAINTAIN trial, [which showed that] in the second-line setting, you can safely switch from one CDK4/6 inhibitor to another. Moreover, [87%] of patients [in the experimental arm of MAINTAIN] received frontline therapy [with palbociclib plus endocrine therapy] and switched to ribociclib plus fulvestrant. This seems to be a valid approach, and I think her case elegantly depicted that.

Natasha Banerjee, MD, of Cedars-Sinai, discussed oral SERDs and PI3K inhibitors in breast cancer. What other roles could elacestrant have beyond its current indication?

Dr Banerjee had an elegant illustration of ER-targeting strategies, moving from aromatase inhibitors to SERDs, selective estrogen receptor modulators, and oral SERDs. She highlighted the [phase 3] EMERALD trial [NCT03778931], which led to the FDA approval of the oral SERD elacestrant in the second- or third-line setting in ESR1-mutant, ER-positive breast cancer. In those with ESR1 mutations in the trial, elacestrant showcased a much better progression-free survival [than in the all-comer] population.

However, as we hear from patients and clinicians, we believe that the drug will not stop [with this indication]. We are looking forward to hearing more data using elacestrant in combination with targeted therapy, such as the CDK4/6 inhibitors, alpelisib, or everolimus [Afinitor], in the [phase 1/2] ELEVATE trial [NCT05563220].

Arash Asher, MD, of Cedars-Sinai, discussed a roadmap to wellness and survivorship for patients after breast cancer. Why was this an important topic to broach with clinicians?

Medical oncologists spend a lot of time talking about AEs. We all understand that we treat patients, we’re not just treating the disease. We’re treating the whole person. Therefore, their quality of life—not just quantity of life—is important.

In Dr Asher’s presentation, he focused on bone health, because endocrine therapy is being used in over 60% of all patients with breast cancer. Recent data indicate a longer duration of treatment beyond 5 years. These [treatments] can cause unavoidable quality of life and bone-loss issues. This showed timely information beyond managing the disease. We need to focus on survivorship. How can we further help our patients prevent bone loss to improve their bone health?