Recent advancements in sequencing targeted therapies are reshaping the management of hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, underscoring the critical role of next-generation sequencing (NGS) in personalizing treatment decisions, according to Francisco J. Esteva, MD, PhD.

“[It is important to ensure that] all patients in the metastatic setting are tested not only for estrogen and progesterone receptors [ER; PR] or HER2 [status, but they also must undergo] NGS,” he explained in an interview with 

In the interview, Esteva discussed key factors to consider when treating patients with HR-positive, HER2-negative breast cancer, as well as highlighted data from several key trials across breast cancer treatment landscape and their clinical impact.

Esteva currently serves as the interim chief of the Division of Hematology and Oncology and the chief of Breast Medical Oncology at Lenox Hill Hospital where he is the director of Breast Medical Oncology for Northwell Health, in New York, New York.

Check out additional insights that Esteva provided on the 

: What are the key factors to consider when sequencing CDK 4/6 inhibitors for metastatic breast cancer treatment and how may biomarker assessment inform treatment decisions in this setting?

: The landscape is changing because of the recent approvals of 

 In patients who develop metastatic breast cancer, it's recommended to do a biopsy to [confirm the presence of] metastatic disease to start with, and then request NGS to look for specific mutations in the tumor.

The most relevant [mutations] for this group of patients are genetic alterations in the PIK3CA kinase pathway, which could include a 

. We also look for ER mutations, [but those] would not be used in the front line setting right now. For patients with no [actionable] mutations, we would use a CDK 4/6 inhibitor like palbociclib [Ibrance], ribociclib [Kisqali[, or abemaciclib [Verznio]. It can be in combination with an aromatase inhibitor [AI], possibly fulvestrant [Faslodex], if the patient is progressing. But for patients with 

 mutations, this is where we have now these new therapies. [This] would be for the first-line [setting, to observe] how this affects the treatment, [before] we move [to] the second-line [setting] with 

 mutations [where] selective estrogen receptor degraders and subsequent therapies [might be more appropriate].

Looking to the phase 3 SOLAR-1 trial (NCT02437318), what key findings were observed here?

SOLAR-1 was a study that looked at alpelisib [Piqray], a 

 inhibitor, compared with placebo, in combination with fulvestrant in postmenopausal women with HR- positive, HER2-negative metastatic breast cancer, who progressed on an AI or had prior AI therapy.

The interesting thing is that they looked at 2 different cohorts: the 

 mutation cohort, and the non-mutant wild type 

 kinase cohort. However, in this study, [particularly in patients] with 

 mutations or alterations, these patients had an improved PFS compared [with] placebo. The main complications in these patients were the high incidence of hyperglycemia, rash and other adverse effects that limited the use of this therapy widely.

Another notable trial is the phase 3 INAVO120 trial (NCT04191499). What would you like your colleagues to know about the outcomes of this study?

-mutated HR- positive, HER2-negative, locally, advanced or metastatic breast cancer. The biomarkers were measured either by circulating tumor DNA [ctDNA], by tissue, or ctDNA testing locally. Basically, [patients] were randomized 1:1 to palbociclib and fulvestrant and placebo vs inavolisib, which is a 

The study showed a significant improvement in progression-free survival. This [data] was presented at 

, and [most recently], has been published in the 

. [This treatment approach] prolonged PFS and delayed the initiation of chemotherapy, which is the most important finding in this group of patients.

You can't compare different drugs and different trials, but, for example, the hyperglycemia reported was mostly grade 1 or 2. The same thing for diarrhea, rash, and stomatitis. But [thus far] it seems like it's a tolerable treatment and quite effective for this population in the frontline setting.

Finally, where do the results from the phase 3 CAPItello-291 (NCT04305496) trial fit into the treatment space?

[Patients in the] CAPItello-291 trial, were [in a] similar situation. [These patients had] HR-positive, HER2-negative metastatic disease and were progressing or had received a prior CDK 4/6 inhibitor. [Patients] were randomized to [receive] capivasertib and fulvestrant or fulvestrant and placebo, and they looked at the overall population, as well as patients with 

 pathway alterations, as capivasertib is an inhibitor of AKT.

This study [showed that], patients treated with capivasertib and fulvestrant had a longer PFS, and particularly in the patients with 

 alterations. Again, the AEs seemed acceptable, most of them being grade 1 or grade 2. The quality of later life was maintained. The blood sugar was not extremely high in patients treated with capivasertib compared [with] placebo. Again, [this] sounds like a tolerable treatment.

How should antibody-drug conjugates be sequenced to maximize benefit in HER2-low breast cancer?

Another area that is of high interest is the use of antibody drug conjugates and how we can sequence them. In patients with low levels of HER2 that we used to consider triple-negative breast cancer now have HER 2-low breast cancer, and those patients can be treated with [fam-trastuzumab deruxtecan-nxki; Enhertu] or [sacituzumab govitecan-hziy; Trodelvy]. It was interesting to see the data on trials, and we need to figure out how to sequence these therapies to get the maximum benefit for these patients.

What is your primary takeaway for your colleagues regarding the role of NGS?

My takeaway is that we need to do NGS, whether it's tissue or blood liquid biopsy, looking at ctDNA in all patients, in particular [those with] HR-positive, HER2-negative metastatic breast cancer to identify patients with 

mutations. This will determine [which agent] patients will receive in the front line setting and which [they will get] in the second line setting. However, after AI therapy, there are studies also looking at frontline therapy with capivasertib.

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Francisco J. Esteva, MD, PhD, discusses how NGS sequencing, PIK3CA-targeted therapies, and ADCs are reshaping treatment in HR+/HER2– breast cancer.

NGS and Novel Therapies Lends to Prolonged Survival Outcomes in HR+/ HER2– Breast Cancer 

Data surrounding perioperative treatment approaches for patients with early-stage HER2-positive breast cancer have helped establish standards of care in this setting, and ongoing clinical trials are looking at ways to de-escalate or escalate therapy in the neoadjuvant and adjuvant settings based on individual patient and disease characteristics, according to Francisco J. Esteva, MD, PhD.

“HER2[-targeted] therapy in patients with stage II/III [HER2-positive] breast cancer is the standard of care. We can deliver the [HER2] antibodies trastuzumab [Herceptin] and pertuzumab [Perjeta] either intravenously [IV] or subcutaneously, and they're both equally effective,” Esteva explained in an interview with 

 State of the Science Summit™ (SOSS) on breast cancer, which he chaired, Esteva highlighted data from several key trials across the early-stage HER2-positive breast cancer landscape and their clinical impact. He also discussed the importance of evaluating the de-escalation of therapy in this population.

Esteva is the interim chief of the Division of Hematology and Oncology and the chief of Breast Medical Oncology at Lenox Hill Hospital, and he serves as the director of Breast Medical Oncology for Northwell Health, in New York, New York.

: What is the current treatment landscape for early HER2-positive breast cancer?

: The landscape of early-stage HER2-positive breast cancer has evolved over the last few years. Nowadays, unless a patient has a small tumor with negative lymph nodes, we generally prefer to use neoadjuvant HER2-targeted therapy. When [patients] achieve a pathologic complete response [pCR] to neoadjuvant therapy in HER2-positive early breast cancer, those patients have the best outcomes in terms of event-free survival and overall survival [OS].

Pivotal studies [evaluated neoadjuvant] trastuzumab and pertuzumab plus a taxane with or without carboplatin. The phase 2 NeoSphere trial [NCT00545688] evaluated docetaxel, trastuzumab, and pertuzumab, and the phase 2 TRYPHAENA trial [NCT00976989] added carboplatin to docetaxel, trastuzumab, and pertuzumab. [At the SOSS], I discussed the different backbones of chemotherapy that are generally used, including docetaxel or weekly paclitaxel, [which] can also be used in this setting with similar results.

We also discussed how to deliver the [anti-HER2] antibodies, whether it's IV or subcutaneous. We also [explored] the role of ado-trastuzumab emtansine [T-DM1; Kadcyla] in patients who have residual disease after neoadjuvant therapy.

[With the current treatment options], the results are quite good [in early-stage HER2-positive breast cancer], and the pCRs are high in general. For patients at lower risk [of recurrence], there are clinical trials trying to de-escalate the amount of chemotherapy given to these patients. For example, this could meaning giving the [anti-HER2] antibodies by themselves without chemotherapy with close monitoring, or in combination with hormone therapy in the estrogen receptor [ER]–positive [population]; these are the types of clinical trials that we're trying to do to de-escalate the chemotherapy that we give prior to surgery.

After surgery, if a patient achieves a pCR, we generally continue the antibody therapy by itself; however, in patients with residual disease, we may have to escalate the treatment, which does not mean only considering T-DM1. We are also doing clinical trials and adding new drugs, like tucatinib [Tukysa] fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd].

What was the clinical impact of the NeoSphere trial?

NeoSphere was the pivotal FDA registration trial for pertuzumab. This was 

the first time that any medication, any drug, was approved in the neoadjuvant setting

 using pCR as the primary end point. Prior to that, the FDA always required [an improvement in] disease-free survival [DFS] or OS for approval. In this study, [417] patients were [randomly assigned] to 4 different groups: docetaxel and trastuzumab for 4 cycles prior to surgery; docetaxel, trastuzumab, and pertuzumab for 4 cycles prior to surgery; trastuzumab and pertuzumab without chemotherapy; and docetaxel and pertuzumab.

The pCR [rate] was higher in the group treated with docetaxel, trastuzumab, and pertuzumab. Post-operatively, patients received chemotherapy with an anthracycline, so the long-term effects may also be influenced by that; however, the pCR rate at the time of surgery was based only on those 4 cycles of docetaxel, trastuzumab, and pertuzumab.

How did the TRYPHAENAtrial help inform clinical practice?

TRYPHAENA was a supportive study, and the primary end point was to look at cardiac safety in patients receiving anthracycline, trastuzumab, and pertuzumab. Two of the arms included FEC [fluorouracil, epirubicin, and cyclophosphamide] in sequence with the triplet combination, and the third arm was docetaxel, carboplatin, trastuzumab, and pertuzumab for 6 cycles. They also collected the pCR rate, which was also high in this population.

What was the clinical impact of results from the phase 3 FeDeriCa trial (NCT03493854)?

The FeDeriCa trial [randomly assigned] patients to the standard of care at the time of IV trastuzumab and pertuzumab given [plus chemotherapy] compared with a subcutaneous formulation of trastuzumab plus pertuzumab [Phesgo]. This was a neoadjuvant trial, so these treatments were given prior to definitive surgery.

The pharmacokinetics in both groups were basically the same, and the pCR rate, which was a secondary end point, was also similar for IV vs subcutaneous therapy. [Data from this study] led to the [FDA] approval of [trastuzumab and pertuzumab] as a subcutaneous formulation, which can be used in the neoadjuvant setting.

Moving on to the phase 2 PHranceSCa trial (NCT03674112), what were the key findings and their impact?

PHranceSCa randomly assigned patients initially to receive subcutaneous vs IV trastuzumab and pertuzumab. Patients then crossed over to the other approach, and they were asked to choose which one they preferred after being exposed to both. The majority of patients chose the subcutaneous formulation. There was also an update [from the trial presented] at the 

 showing that long-term effects were very similar between both approaches.

What did data from the phase 3 KATHERINE trial (NCT01772472) evaluating T-DM1 for patients with HER2-positive residual breast cancer?

The KATHERINE study was conducted in patients with residual disease following neoadjuvant HER2-targeted therapy. Patients were [randomly assigned] to T-DM1 or continuation of trastuzumab, and patients who received T-DM1 had a higher DFS and OS.

An update at the 2023 San Antonio Breast Cancer Symposium showed an improvement in 7-year invasive DFS for patients receiving T-DM1 compared with trastuzumab in the adjuvant setting, and the OS was improved in patients receiving T-DM1 compared with trastuzumab. Long-term cardiac effects were rare in both groups.

T-DM1, as of today, is the standard of care for patients with residual, invasive disease after neoadjuvant HER2-targeted therapy.

How have the trials and data regarding perioperative treatment approaches in HER2-positive breast cancer helped shape the treatment paradigm?

The choice of taxane, even though most clinical trials were done with docetaxel, is [not critical], [as] evidenced by studies producing similar results [between each backbone]. The way monoclonal antibodies are delivered is not as important in terms of efficacy. There are patient preferences and time savings if you use the subcutaneous formulation, but that's a personal choice by the physicians and the patients. It is something that we have available. It's also important to consider clinical trials to de-escalate or escalate therapy, depending on the situation, to move the field forward.

Francisco J. Esteva, MD, PhD, highlights various pivotal studies for the treatment of HER2-positive early-stage breast cancer.

Long-Term Findings Solidify Role of HER2-Targeted Therapy in Early HER2+ Breast Cancer

 State of the Science Summits™ on breast cancer, one of which she chaired, Lubna Naaz Chaudhary, MD, MS, highlighted the clinical implications of data from both the phase 2 PARSIFAL (NCT02491983) and Young-PEARL (NCT02592746) clinical trials.

The PARSIFAL trial was a randomized, open-label investigation of palbociclib (Ibrance) in combination with either fulvestrant (Faslodex) or letrozole in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer. Young-PEARL enrolled premenopausal patients with ER-positive, HER2-negative metastatic breast cancer following progression on prior tamoxifen; these patients were randomly assigned to receive palbociclib plus exemestane (Aromasin) with a GnRH agonist vs capecitabine.

Want to read more on upcoming and ongoing treatment in metastatic breast cancer? Chaudhary, who serves as an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, shared her thoughts on treatment with CDK4/6 inhibitors 

: What were the key findings from the PARSIFAL trial?

: This is an important study. The question of PARSIFAL was whether there would be benefit or a difference in efficacy when [using different endocrine therapies with] a palbociclib backbone. [This trial investigated] palbociclib plus a nonsteroidal aromatase inhibitor [AI], which we commonly use, vs palbociclib plus fulvestrant. Many years ago, studies in patients with stage IV disease showed that a selective ER degrader [SERD] mechanism is more effective than an AI mechanism. The question [of PARSIFAL] was, when we have CDK4/6 inhibitor present, would we see a difference between a SERD vs a nonsteroidal AI?

The study showed no difference in efficacy between [the combinations]. With no difference in efficacy seen, and us having options of using PIK3CA/AKT pathway–targetable drugs with fulvestrant, we should keep our practice the way it is, using a CDK4/6 inhibitor with an AI first, and then reserving fulvestrant for later combinations.

How do data from Young-PEARL inform your practice?

Young-PEARL was in premenopausal patients who progressed on prior endocrine therapy and were treated with either palbociclib plus an AI and ovarian suppression or capecitabine. The question was: In these young patients, would it be better to treat them with chemotherapy vs ovarian suppression in combination with an AI and a CDK4/6 inhibitor?

The median progression-free survival was [longer] with the palbociclib combination, which reinforces our practice right now that we don’t need to switch these patients to chemotherapy early on. We have a lot of good, targeted therapy combinations, endocrine therapy options, and CDK4/6 inhibitors, as well as other agents [we can use] before we switch to chemotherapy.

Another key point [from] Young-PEARL was that we must pay attention to the adverse effects [AEs], and we have to know where those AEs are coming from. This is because if we just look at the tabular data, the grade 3 AE incidence was much higher in the palbociclib arm, at [approximately] 90% vs approximately 40% with capecitabine. That can look scary, but we must then read in more detail, because most of those grade 3 AEs were asymptomatic neutropenia, and that we are comfortable with [managing]. It’s easy to manage and does not cause symptoms for patients whereas capecitabine causes hand-foot syndrome, diarrhea, and gastrointestinal toxicity. We want to pay attention to the interpretation of the data when we consider the numbers.

What ongoing research initiatives in ER-positive, HER2-negative breast cancer are you involved in?

I am the chair of our breast program [at the Medical College of Wisconsin], so I oversee our whole breast cancer clinical trial portfolio. I currently have 2 ongoing investigator-initiated clinical trials. One that is almost done accruing is a phase 2 trial [NCT04243616] investigating the role of cemiplimab [Libtayo]—which is a PD-1 inhibitor—in the neoadjuvant setting plus standard-of-care anthracycline plus taxane-based chemotherapy. [This combination is being evaluated] in [patients with] triple-negative breast cancer, as well as in ER-positive/HER2-negative disease.

We are expanding the eligibility [criteria of this trial] to not only include PD-L1–positive patients, but also those with PD-L2–positive [disease]. We’ve had a couple of publications already in the PD-L2–positive arena, so we’re excited to see what this study shows.

Lubna Naaz Chaudhary, MD, MS, highlights the PARSIFAL and Young-PEARL trials and discusses ongoing research in ER-positive/HER2-negative breast cancer.

Ongoing and Planned Research Build on Prior Advancements in ER+/HER2– Breast Cancer

Robust phase 3 trial data have led to the integration of CDK4/6 inhibitors into the hormone receptor–positive, HER2-negative breast cancer treatment paradigm, and the continued emergence of data have helped answer selection and sequencing questions about agents such as ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance), according to Lubna Naaz Chaudhary, MD, MS.

“In our first-line setting, we always want to try to use a CDK4/6 inhibitor with an aromatase inhibitor [AI], as supported by [data from] our phase 3 studies,” she explained in an interview with 

 on breast cancer, Chaudhary, who serves as an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, discussed factors she considers when selecting a CDK4/6 inhibitor, expanded sequencing decisions, as well as highlighted what the future looks like for these inhibitors.

: How are you selecting CDK4/6 inhibitors for the treatment of patients with breast cancer?

[In my presentation on CDK4/6 inhibitors], I went over the data on first-line and second-line for all 3 CDK4/6 inhibitors. We talked about the [data from the] phase 3 trials [that helped support the use of these agents], including [the first-line trials] PALOMA-2 [NCT01740427], MONARCH 3 [NCT02246621], and MONALEESA-2 [NCT01958021].

All 3 studies met the primary end point of progression-free survival [PFS]. However, the secondary end point of overall survival [OS], which is an important end point, was only met and statistically significant in the [MONALEESA-2 trial] of ribociclib. Abemaciclib did show an improvement in OS [in MONARCH 3], but it was not statistically significant. The [PALOMA-2 study] of palbociclib did not have a statistically significant OS [improvement]. Currently, unless contraindicated, the first-line therapy approach would be ribociclib [in combination] with an AI.

What other data help support ribociclib as a CDK4/6 inhibitor of choice in the first-line setting?

I went through data for all 3 CDK4/6 inhibitors in breast cancer. In the first-line setting, we want to use a CDK4/6 inhibitor; if not contraindicated, we use ribociclib. However, for an individual patient, abemaciclib and palbociclib are very good options. I feel comfortable with using any of those.

In the second-line setting, we have strong data on PFS and OS [for CDK4/6 inhibitors]. If we have a patient who received AI alone as first-line monotherapy, then we definitely want to use any [of the] available [CDK4/6 inhibitors] in the second line in combination with fulvestrant [Faslodex].

What are some of the contraindications to ribociclib that patients may have?

This is where our adverse effect [AE] profile comes in. Palbociclib and ribociclib [are associated with] more myelosuppression, whereas abemaciclib has more gastrointestinal [GI] toxicity and diarrhea concerns. There is also some cardiac and QTc monitoring required with ribociclib, and we have patients [who may be on] other medications that can cause a prolonged QTc interval. If a patient has a baseline cardiac or QTc issue, then that patient may not be a good candidate for ribociclib. [In that case], we are going to choose between abemaciclib and palbociclib.

Palbociclib was very well tolerated, so I would feel comfortable using that. Conversely, if we have a patient who started with abemaciclib, and they're having a lot of diarrhea and [other] AEs from a GI standpoint, then we can go to either ribociclib or palbociclib. [CDK4/6 inhibitor selection] depends on the potential AEs that may develop or baseline cardiac issues.

What are some of the treatment considerations for patients in the post-CDK4/6 inhibitor setting?

We have very good studies at this point in regard to the question of [using another] CDK4/6 inhibitor after [disease progression] on an initial CDK4/6 inhibitor. [During the State of the Science Summit, 3 trials were discussed: the 

 phase 2 MAINTAIN [NCT02632045], and the phase 2 PACE [NCT03147287] trials. With prior palbociclib use, we have strong data for switching [patients] to ribociclib or abemaciclib [after progression], based on the MAINTAIN and postMONARCH trials, respectively. There is a modest improvement in PFS. It's not a huge difference, but there is some improvement, including better tolerability and a delay in starting chemotherapy.

In patients with no targetable mutations [where the treatment] plan would be fulvestrant alone [after progression on an initial CDK4/6 inhibitor], switching the CDK4/6 [in the second-line setting] is a good option.

We always want to check for targetable alterations like an 

 mutation, an AKT pathway mutation, or a 

 mutation. If any of those are present, then we want to combine fulvestrant with targeted agents like alpelisib [(Vijoice) for those with 

 mutations] or capivasertib [(Truqap) for those with AKT pathway mutations]. We can also use elacestrant [Orserdu] for [patients with] an 

What have data shown for adjuvant CDK4/6 inhibitors?

We have 2 approved at this point, and we have been using [adjuvant] abemaciclib for the last couple years, 

based on data from the phase 3 monarchE trial [NCT03155997] 

that showed a reduced risk of recurrence with that addition of 2 years of abemaciclib compared with an AI alone in [patients with] high-risk, node-positive, estrogen receptor–positive breast cancer.

had the approval of adjuvant ribociclib per the phase 3 NATALEE trial [NCT03701334]

; this indication [includes patients with] high-risk stage II or III HR-positive, HER2-negative breast cancer, [including those with node-negative disease]. Three years of treatment of [adjuvant] ribociclib plus an AI also reduced the risk of recurrence.

I believe we have enough CDK4/6 inhibitor data in the adjuvant setting. More options here are to [emerge here with] ongoing studies looking at selective estrogen receptor degraders in the adjuvant setting. We will see how that turns out.

Lubna Naaz Chaudhary, MD, MS, discusses selecting a CDK4/6 inhibitor in hormone receptor–positive breast cancer.

Data Continue to Help Shape CDK4/6 Inhibitor Selection, Sequencing in HR+ Breast Cancer

Along with helping select a preferred chemotherapy regimen for a select group of patients, molecular testing has helped shape treatment decisions in advanced pancreatic cancer, according to Tanios S. Bekaii-Saab, MD, who added that the continued development of RAS inhibitors could increase the importance of genetic testing for this patient population.

“The future for pancreatic cancer is looking much brighter than the past. Five to 7 years ago, pancreatic cancer was considered a desert for targeting,” Bekaii-Saab said in an interview with 

. “Today, it's more target-rich. [This testing has given us] a better understanding of how to use some of the chemotherapy [strategies], some strategies to target 

 and other alterations, and how to take advantage of the small proportion of patients who could be candidates for immune-oncology [IO]–based therapy."

In the interview, Bekaii-Saab outlined factors for selecting a chemotherapy regimen in the frontline setting for patients with advanced pancreatic cancer, underscored the importance of molecular testing for this patient population, and explained how targeted therapies could play a bigger role in this paradigm.

Bekaii-Saab currently serves as the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research, chair and consultant in the Division of Hematology and Medical Oncology at Mayo Clinic, and co-leader of Advanced Clinical and Translational Science at Mayo Clinic Cancer Center in Phoenix, Arizona.

: What are the current treatment considerations in the first line for advanced pancreatic cancer?

: The landscape for treating pancreatic cancer in the first-line [setting] has become a bit more complicated. We're still limited by options—primarily cytotoxic therapy—except for [patients with] microsatellite instability–high tumors, where pembrolizumab [Keytruda] or another IO-based therapy would be the standard, and that's only approximately 4.5% of the patients or less. For all other patients, the only deciding factor on what [other treatment options] to use [outside of chemotherapy] is the presence of 

 mutations, which are present in approximately 2% to 3% [of patients] at the germline level and approximately another 2% [of patients] at the somatic level.

When we think about the landscape of genetic alterations in the first-line [setting], we do favor a platinum-based regimen when there are 

 mutations, and that [regimen] can be FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin]; however, [data from a phase 2 trial (NCT01585805)] from Eileen O'Reilly, MD, [of Memorial Sloan Kettering Cancer Center], [showed that] gemcitabine plus cisplatin is a preferred regimen to go with [for patients harboring 

For the other 95% [of patients], we're currently looking at 3 options: NALIRIFOX [irinotecan liposome (Onivyde), oxaliplatin, 5-fluorouracil (5-FU), and leucovorin], FOLFIRINOX, and gemcitabine plus nab-paclitaxel [Abraxane].

Have triplet regimens proven to be more effective than doublets?

We have 2 triplet [chemotherapy regimens with NALIRIFOX and FOLFIRINOX] and then a doublet [regimen with] gemcitabine plus nab-paclitaxel. The answer for the longest time was that it's better to use a triplet because it's more aggressive, and this is an aggressive cancer. However, we have data from 2 studies—one from Japan called [the phase 2] JCOG1407 trial [jRCTs031180085], and another one called [the phase 2] PASS-01 trial [NCT04469556]—that suggest that gemcitabine plus nab-paclitaxel may do just as well or out-perform FOLFIRINOX, which was surprising. 

In Japan, gemcitabine plus nab-paclitaxel is now the standard over FOLFIRINOX. PASS-01 was interesting because it excluded patients with 

mutations. Therefore, those patients who were highly sensitive to platinum were excluded, and it showed that gemcitabine plus nab-paclitaxel is at least as good, maybe a little bit better [than FOLFIRINOX]. [Those results] complicated the landscape a little bit, and now the thought is, [these 2 regimens] seem to be about the same.

Then NALIRIFOX entered. The [phase 3] NAPOLI 3 study [NCT04083235] looked at gemcitabine plus nab-paclitaxel vs NALIRIFOX. NALIRI [refers to] the liposomal formulation of irinotecan used in this combination [along with] a lower dose of oxaliplatin. [Prior data] suggested that it's safer to [decrease the dose of oxaliplatin] and not sacrifice outcomes.

[In NAPOLI 3, NALIRIFOX] was better than gemcitabine plus nab-paclitaxel, and that threw a wrench into the whole thinking that [these chemotherapy regimens] are similar. Now we have a study that shows a triplet is better than gemcitabine plus nab-paclitaxel.

A lot of folks will say there shouldn't be much of a difference [between] NALIRIFOX and FOLFIRINOX. The problem is that we've never compared them, and I suspect they'll never be compared head-to-head. At the same time, we have 2 studies with FOLFIRINOX and gemcitabine plus nab-paclitaxel that were negative in the sense that they didn't show superiority [for one of the regimens], and now we have another study with NALIRIFOX that did show superiority vs gemcitabine plus nab-paclitaxel.

In your eyes, have data from NAPOLI 3 made NALIRIFOX a preferred regimen?

That's a tough question. I have moved more and more toward considering NALIRIFOX; however, I haven't universally moved to it because it does have its own [unique] toxicities. It is better regarding neuropathy, but it is a little bit worse in terms of gastrointestinal toxicities, which can be tough on some older patients and even some younger patients.

In my practice, I universally use biweekly gemcitabine plus nab-paclitaxel instead of the weekly regimen. [Based on] at least most published experience, the biweekly regimen performs historically as well as the weekly regimen.

In the first-line landscape, [where] we do germline testing and somatic human profiling on everyone, if there is evidence of 

 [mutation], I'm moving to gemcitabine plus cisplatin [with] the biweekly regimen. At some point, I may consider a PARP inhibitor for maintenance; however, for many patients, I have been shying away from that strategy. With biweekly gemcitabine plus cisplatin, you can extend their life, and for the complete responders, I have [seen] some good responses where I have been able to give them a holiday from any treatment.

For the rest of the patients, [frontline treatment] decisions are more] individualized. A good number of patients are still receiving biweekly gemcitabine plus nab-paclitaxel; for others, I'm starting to use more and more NALIRIFOX, and a few [still receive] FOLFIRINOX.

What roles do germline testing and somatic tumor profiling play in the treatment-selection process?

Universally, every patient [with advanced-stage pancreatic cancer] who comes to our clinic now undergoes both germline testing and somatic tumor profiling. [This testing] is important because there are a number of targets identified as important to assess in pancreatic cancer and others.

One of those [mutations] that had been considered undruggable for the longest time is 

mutations [are] omnipresent in pancreatic cancer, where approximately 90% to 93% of patients have 

 mutations. The remaining 7% of patients are also are target rich, [where they could have alterations such as] 

 mutations. [There are] other fusions, like 

 fusions, that are relevant for other targeted strategies.

It's incredibly important to have this genetic profile when we think about 

 G12Cmutations and have a couple of agents that were approved for other indications, but [are also included] in the NCCN Guidelines for pancreatic cancer. I worked very closely with an agent called adagrasib [Krazati]. There's also another agent called sotorasib [Lumakras], and we've seen, at least in my experience with adagrasib and from the published data, some interesting responses for many patients. However, 

 G12Cends up being mutated in less than 1% of all patients. Most patients will have either a 

There are agents being developed [specifically] targeting KRAS G12D or G12V

 There are also agents being developed that target all

 [mutations] instead of targeting only one and are making their way into the second-line [setting]. There's [

the phase 1 RMC-6236-001 trial (NCT05379985)

] that's looking at a compound called RMC-6236, which is a pan-RASagent.

[There are other] strategies that are looking at moving KRAS G12D–targeted agents and pan–RAS

targeted agents even further into the first-line [setting], along with exploratory studies [looking at] combinations with chemotherapy.

Tanios S. Bekaii-Saab, MD, discusses the evolution of frontline treatment in advanced pancreatic cancer.

Molecular Testing Helps First-Line Treatment Landscape Evolve in Pancreatic Cancer

The treatment paradigm for platinum-resistant ovarian cancer has advanced with the integration of therapies like mirvetuximab soravtansine-gynx (Elahere); however, improved definitions for platinum resistance and the development of other antibody-drug conjugates (ADCs) could also create more shifts in this treatment paradigm in the future, according to Kathleen N. Moore, MD, MS.

“With additional data, we're about to change a lot of these paradigms for the betterment of patients [by providing a] better selection of drugs,” Moore said in an interview with 

In the interview, Moore discussed how mirvetuximab soravtansine has altered the ovarian cancer treatment paradigm, expanded on the evolving definition of platinum resistance, and highlighted other ADCs currently under development.

Moore is a professor in the Section of Gynecologic Oncology, associate director of Clinical Research at Stephenson Cancer Center, and director of the Oklahoma TSET Phase I Program at the University of Oklahoma College of Medicine in Oklahoma City.

: How has the treatment landscape evolved for patients with platinum-resistant ovarian cancer?

Moore: The treatment paradigm for patients whose tumors are no longer expected to respond to platinum has changed somewhat. However, it is about to change much more with [various] trials that are expected to read out.

[First], the definition for [which] patients are [considered platinum-resistant] is under some evolution. [The definition] used to be very strict, and it still is from a regulatory standpoint, referring to patients whose tumors progress within 6 months of their last platinum[-based treatment]. That's still a regulatory requirement, but I do think that there's an increasing understanding; that is not the absolute definition of tumors that are probably inappropriate for platinum. It also includes patients who received platinum, and the tumor didn't shrink at all. Maybe they were on some kind of maintenance therapy, [such as] bevacizumab [Avastin], and [the tumor] didn't grow for eight months. That tumor is not platinum-sensitive, as it did never respond to platinum.

There's an increasing understanding of these nuances, [and ineligibility also includes] patients who have allergies to platinum and can't receive platinum anymore. There is also a group of tumors that have progressed during PARP inhibitor maintenance and are still considered platinum-sensitive because of the length of time from their prior platinum, but we are starting to understand that some of these tumors respond less robustly to platinum. They're not entirely resistant, but they're not as sensitive as we might otherwise think, and we may be looking at differently at those tumors, as well. The definitions are shifting as we get more definitive data in those spaces.

What have been some of the other key updates in the advanced ovarian cancer space?

We have had 2 important [developments] in the past year to 2 years. The first is mirvetuximab soravtansine, which is 

 and is pending global approvals for patients whose tumors are platinum-resistant and are folate receptor–alpha [FRα] high.

In the United States, the National Comprehensive Cancer Network [NCCN] Guidelines allow for the use of mirvetuximab soravtansine plus bevacizumab in FRα-expressing tumors. That's based on the data from [the phase 1b] FORWARD II trial [NCT02606305]. [Mirvetuximab soravtansine] is the first [ADC] to gain approval and a compendium listing in the NCCN Guidelines for ovarian cancer, and it has been a great addition to the armamentarium, at least in the FRα-high population as a monotherapy, [where we have seen] improvements in progression-free survival, overall survival [OS], and overall response rate [ORR]. We've never seen improvements in OS in this setting, so that's a big accomplishment.

The second is a little less [eye-catching] but it is also important, and that is the fact that we have pulled out weekly paclitaxel with or without bevacizumab as a very different agent for the platinum-resistant setting. It used to be lumped into these investigator choice arms, and you'd have this historical benchmark of expectations of response of about 15%. However, weekly paclitaxel has been looked at alone in 3 big phase 3 studies that have read out.

One trial [NCT03398655] was the VBL gene therapy. Another study [INNOVATE-3 (NCT03940196)] investigated tumor-treating fields, and [the other] one was [the phase 3 AXLerate-OC trial (NCT04729608)] of batiraxcept (AVB-S6-500)]. All of these [studies] added a new drug to weekly paclitaxel vs weekly paclitaxel alone, and all 3 of those studies were negative. All 3 of those studies showed the impressive performance of weekly paclitaxel, with ORRs [ranging from] 30% to 50%.

Mirvetuximab soravtansine and weekly paclitaxel [represent] new drugs into the armamentarium. [Regarding the latter], weekly paclitaxel [may be a preferred regimen] in the eyes of treating physicians as the preferred regimen. I would call it the preferred regimen for anyone who's FRα low or medium. I would use that potentially first, and it would be my go-to after I use mirvetuximab soravtansine. That’s how I would sequence those medications.

That's important for patients and for providers to understand. Weekly paclitaxel and docetaxel are entirely different agents from an efficacy standpoint. There are differences in adverse effects, scheduling, and things that go into shared decision-making, and those are important for patient-centered care. However, purely from an efficacy standpoint, [paclitaxel and docetaxel] are very different agents.

What other ADCs are under development for patients with ovarian cancer?

We're [also] going to see several ADCs with different targets, different payloads, and different linker technology [move into] late-phase clinical trials in ovarian cancer. One is raludotatug deruxtecan [DS-6000], which targets CDH6, and it has a deruxtecan payload. That drug is in phase 2/3 testing right now. The other is rinatabart sesutecan [PRO1184], which is another FRα[-targeted] ADC with an exatecan payload.

These are camptothecin payloads, which are different than microtubule toxin payloads like mirvetuximab soravtansine. These are distinctly different agents, and you could see a patient potentially getting [these agents] in sequence. There are a number of other [ADCs] that are a little bit farther behind [in development]. We just saw readouts in the phase 1 expansion cohorts for several of the TROP2-directed ADCs, and we saw [promising data for] TORL-1-23, which [targets] Claudin-6 with another microtubule toxin [payload]. 

There are a number of [ADCs] that are vying for a spot in the [ovarian cancer treatment] paradigm. We're going to see some big shifts in the sequencing of these medicines in the platinum-resistant space, and we will also see the incorporation of some of these medications into earlier lines of therapy. [The] platinum-sensitive setting is a space I'm interested in putting something head-to-head with platinum to see if platinum really is the best agent in that particular setting. We don't know yet, and that requires a trial. However, that’s a space I'm interested to look at, and many are interested in studying these [ADCs] as maintenance [therapy], which is an exciting opportunity, but it comes with some questions about tolerability of long-term use, potential resistance mechanisms, and how the sequencing of drugs will look [in later lines]. There's a lot of excitement about ADCs moving forward across the treatment paradigm, not just in the resistance setting.

Kathleen N. Moore, MD, MS, discusses the evolving treatment landscape of platinum-resistant ovarian cancer.

Refined Definition of Platinum Resistance, Novel ADCs Could Bring More Changes to Ovarian Cancer Treatment

Treatment individualization is at the core of adjuvant therapy optimization for patients with breast cancer across the spectrum of hormone receptor (HR) positivity and HER2 expression, according to Kari Wisinski, MD.

®, Wisinski highlighted treatment options for patients with node-positive and -negative HR-positive, HER2-negative breast cancer, where chemotherapy fits into the triple-negative breast cancer (TNBC) treatment paradigm, and the evolving role of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for patients with HER2-positive breast cancer with brain metastases.

She shared her insights on the use of CDK4/6 inhibitors in patients with HR-positive metastatic breast cancer 

Wisinski is the Endowed Professor of Hematology and Oncology and chief of the Division of Hematology, Medical Oncology and Palliative Care in the Department of Medicine at the University of Wisconsin (UW) School of Medicine and Public Health in Madison. She is also the associate director of Clinical Research and co-lead of the Breast Cancer Disease Oriented Team at the UW Carbone Cancer Center.

: What is the current treatment strategy regarding the use of adjuvant regimens in patients with premenopausal HR-positive, HER2-negative breast cancer?

: For premenopausal women, the decision about when to add chemotherapy is still an evolving area. For lymph node–negative breast cancer, use of a genomic predictor, such as Oncotype DX or the 21-gene recurrence score, can be a useful tool in making these decisions. There are clear-cut points for where we should recommend chemotherapy and where [a patient] likely does not need it.

However, then there’s this middle range, between [the Oncotype DX scores of] 16 and 25, where [this decision] becomes more nuanced and difficult. There needs to be a discussion with the patient regarding the other tumor features, the tumor size, the grade, what might be the absolute benefit of chemotherapy for that patient, and whether we know if that’s a chemotherapy benefit vs an ovarian suppression benefit from the chemotherapy. I have those conversations in the clinic and then try to make an individualized decision with each patient about whether to layer in the chemotherapy to their adjuvant endocrine therapy. The National Comprehensive Cancer Network guidelines support that; they [recommend] both options, which gives us the discretion to have these types of conversations and individualize patient decisions.

The second question is: What do we do for premenopausal women who have HR-positive, HER2-negative, node-positive disease, especially if it’s in the range of 1 to 3 positive nodes? At this point, that is also a difficult group to make decisions for. The phase 3 RxPONDER trial [NCT01272037] findings indicate that there’s potentially some chemotherapy benefit in those patients, but there remain questions about whether that is truly chemotherapy benefit vs suppression of the ovaries and effect on endocrine efficacy. The current standard is to consider chemotherapy for premenopausal patients who have node-positive disease. The phase 3 OFSET study [NCT05879926] is an important study that we are doing nationally to address this question, and I’m hopeful that the outcomes of that study comparing chemotherapy plus ovarian function suppression [OFS] and endocrine therapy vs OFS plus endocrine therapy alone will help address this question in the future.

What is the significance of the final overall survival (OS) data from the phase 3 KEYNOTE-522 trial (NCT03036488)?

The KEYNOTE-522 data, when they first came out, demonstrated improvement in pathologic complete response and then event-free survival. This was exciting information for the management of advanced TNBC, and the recent OS data have helped us clearly understand that this treatment is having the effect we had hoped for: that it is preventing recurrences and improving survival for a disease that affects many people, especially at young ages, and can have devastating outcomes. Our next question, because there’s always a next question, is: Do we need all the chemotherapy that is part of the KEYNOTE-522 regimen: anthracyclines, cyclophosphamide, carboplatin, and taxanes? It’s a lot of chemotherapy. There’s good work going on nationally, including the scarlet study, that is trying to evaluate whether [treatment] de-escalation with an anthracycline-free regimen can have the same efficacy as the KEYNOTE-522 regimen.

Lastly, one of the key challenges we face still with immunotherapy is lifelong adverse effects that can happen in the setting of these agents. Developing better predictors for which patients are going to benefit from these agents again, or who might develop toxicities and in whom we might want to avoid [these agents], continues to be a high priority.

How might the data from the phase 3 DESTINY-Breast12 trial (NCT04739761) influence clinical practice for patients with HER2-positive brain metastases?

In HER2-positive breast cancer, brain metastases remain one of our biggest challenges. Although we can often control the systemic disease well elsewhere in the body, brain metastases often develop and become a life-limiting consequence of the disease. At the same time, we’ve also had difficulty identifying newer systemic therapies that can effectively control or shrink brain tumors. Therefore, we’ve relied for many years on radiation and surgery as primary treatments [for these patients].

However, we’ve seen advances in the past few years, with agents like tucatinib [Tukysa], with some central nervous system [CNS] activity. As T-DXd has come into the realm of treatment for [patients with] HER2-positive breast cancer, there have been interesting observations that [this agent could] have activity also in patients who are affected by brain metastases. The results of the DESTINY-Breast12 study are further evidence that T-DXd seems to have CNS activity, and that this agent can be considered as one of our approaches for patients who have HER2-positive breast cancer with brain metastasis.

What is your main message for colleagues about individualized breast cancer management?

Treatment for breast cancer needs to be individualized based on discussions with the patient about their preferences and understanding their underlying other medical issues. The other consideration that is important in this individualization is considering how we use our tools, [such as] molecular testing like Oncotype DX or next-generation sequencing [NGS], to look for tumor mutations to help identify a treatment strategy that makes sense for what’s going on in that patient’s tumor. [We are making] important advances with both circulating tumor DNA and NGS but we also need to understand some of the limitations of those tests when we’re interpreting them and discussing treatment options for patients, making sure we’re putting that all into context.

Kari Wisinski, MD, highlights treatments for HER2– breast cancer, the role of chemotherapy in TNBC, and the benefits of T-DXd for brain metastases.

Genomic Predictors Inform the Evolving Role of Chemotherapy in Breast Cancer Management

Ribociclib (Kisqali) and abemaciclib (Verzenio) are top frontline and adjuvant treatment choices for patients with hormone receptor–positive metastatic breast cancer, although, in the absence of predictive biomarkers, decisions between CDK4/6 inhibitors in these settings often ultimately hinge on patient characteristics and ability to tolerate each agent, according to Kari Wisinski, MD.

“There’s high-level evidence that ribociclib and likely abemaciclib improve overall survival [OS] for first-line metastatic hormone receptor–positive breast cancer,” Wisinski said in an interview with 

 following a State of the Science Summit™ on breast cancer, which she chaired.

In the interview, Wisinski discussed factors that influence her decision between available CDK4/6 inhibitors for patients with previously untreated, hormone receptor–positive metastatic breast cancer, questions regarding the potential role of these agents in the adjuvant setting, and what the future may look like regarding the sequential use of these agents.

Kari Wisinski, MD, discusses factors that influence her decision between CDK4/6 inhibitors for patients with treatment-naive, HR+ metastatic breast cancer.

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