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San Antonio Breast Cancer Symposium

Updated findings of the phase III SOPHIA trial showed that margetuximab plus chemotherapy led to an increase in progression-free survival (PFS) and an overall survival (OS) compared with trastuzumab (Herceptin) plus chemotherapy in patients with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapies, explained Hope S. Rugo, MD, FASCO.

The second interim OS analysis was based off of 270 OS events and showed that, at a median follow-up of 15.6 months, the median OS in the intent-to-treat population was 21.6 months (95% CI, 18.86-24.05) with margetuximab plus chemotherapy versus 19.8 months (95% CI, 17.54-22.28) with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69-1.13; 

 = .326). The final prespecified OS analysis is planned after 385 events have occurred, which will likely occur in late 2020.

The investigator-assessed PFS showed a 29% reduction in the risk of disease progression or death with margetuximab compared with the trastuzumab arm. The median PFS for margetuximab/chemotherapy was 5.7 months (95% CI, 5.22-6.97) versus 4.4 months (95% CI, 4.14-5.45) for trastuzumab/chemotherapy (HR, 0.71; 95% CI, 0.58-0.86; 

“Overall, the SOPHIA trial showed that margetuximab is safe and similar to trastuzumab and can be given [to patients with HER2-positive breast cancer],” said Rugo, a professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Based on these data, MacroGenics, Inc, the developer of margetuximab, submitted a biologics license application to the FDA for margetuximab for use in combination with chemotherapy as a treatment for patients with metastatic HER2-positive breast cancer.

 at the 2019 San Antonio Breast Cancer Symposium (SABCS), Rugo discussed the updated findings of the SOPHIA trial in HER2-positive metastatic breast cancer.

: Could you give an overview of the structure of the SOPHIA trial?

: SOPHIA is a randomized, phase III, blinded trial evaluating the novel HER2-targeted antibody margetuximab compared with trastuzumab combined with different chemotherapy agents in patients with heavily pretreated HER2-positive metastatic breast cancer. Patients who were enrolled on this trial had received trastuzumab and pertuzumab (Perjeta), and more than 90% had received ado-trastuzumab emtansine (T-DM1; Kadcyla). The primary end points of the trial included PFS by central blinded analysis and OS. Secondary end points included PFS by investigator assessment, safety, and response rate. A really interesting part of the preplanned secondary exploratory end point was to look at variants in the immunoglobulin G (IgG) Fc receptor to see whether there was a differential benefit with margetuximab.

What is the rationale supporting the investigation of margetuximab?

Margetuximab has the same F(ab) fragment as trastuzumab but, as an antibody, the Fc fragment has been altered to enhance immunity. Specifically, margetuximab’s Fc fragment has been engineered to increase affinity for the activating CD16A receptor and decrease affinity for the inhibitory CD32B receptor.

What do the latest findings of the SOPHIA trial show?

At the 2019 SABCS, we presented about 1 year of additional follow-up with PFS by investigator assessment— the central blinded analysis hasn’t happened yet. Margetuximab resulted in a significant improvement in PFS compared with trastuzumab, with a 

 value that has improved to .0006. It was highly significant and a very good hazard ratio, with a 24% relative improvement. The absolute difference was 1.3 months, which is small, but the P value and hazard ratio are very important in terms of assessing the benefit of margetuximab over trastuzumab. We looked at response and clinical benefit rate, which were significantly increased with margetuximab, and showed a clinically important difference in response.

Then, we looked at a second interim analysis of OS. Now, we have 70% of the planned events and, at this analysis, we see a nonsignificant trend toward improved survival with margetuximab.

We also looked at safety, which was very good with margetuximab. We saw more infusion reactions, but these can be managed. We evaluated a shorter infusion [of the drug] after the first dose and that is very well tolerated.

Then we looked at the impact of the IgG Fc gamma receptor differences on the activity of margetuximab. The CD16A Fc receptor has 2 variants: the F allele and the V allele. The F allele has lower affinity and the V allele has higher affinity. Data have already been shown in which the patients who had the high-affinity allele benefited the most from trastuzumab when trastuzumab was added to chemotherapy—and benefit decreased if you had FV or FF. It’s very interesting.

We hypothesized that patients who carried the F allele would have a better response to margetuximab. In fact, when we looked at OS based on patients who had the F allele, FF or FV, we found a bigger difference in OS. The absolute difference was 4.3 months, which was not yet statistically significant with a P value of .08, but it is very intriguing.

In contrast, when we looked at the patients who are homozygous for V, there were only 69 patients. It turned out that the patients randomized to margetuximab in that group had much worse disease, including more brain metastases, more visceral metastasis, and other poor prognosis features. We found that patients with trastuzumab did better than margetuximab because they were a better-risk group. We concluded that margetuximab has the ability to cause an enhanced immune response through this engineered Fc receptor. We learned that the benefit may be greater in patients who carry the CD16A Fc F allele. No evidence at present suggests that patients who have the V allele benefit from receiving margetuximab over trastuzumab.

These are really very interesting data that suggest that the individual aspects of the patient play a role in how they respond to treatment. We know it’s true for toxicity, and it appears, at least in this situation, that there may be an association with efficacy. The next plan is to wait for the final OS analysis, which we expect at the end of 2020. Also, a neoadjuvant trial is planned that will focus on patients who carry the F variant of the CD16A receptor and that will help us understand whether that group of patients, who have more intact immune systems, benefit more from margetuximab.

Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-02. bit.ly/2N0wKZn.

Hope S. Rugo, MD, FASCO, discusses the updated findings of the SOPHIA trial in HER2-positive metastatic breast cancer.

Margetuximab Plus Chemo Reveals Intriguing Benefit in HER2+ Breast Cancer

Results of the phase II HER2CLIMB trial demonstrated that the addition of tucatinib to trastuzumab (Herceptin) and capecitabine (Xeloda) reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

In findings presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), the tucatinib triplet showed a median overall survival (OS) of 21.9 months (95% CI, 18.3-31.0) versus 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88; 

 = .0048). Furthermore, the 1-year OS rate was 76% in the tucatinib arm versus 62% in the control arm. The 2-year OS rates were 45% versus 27% in the tucatinib and control arms, respectively.

The addition of tucatinib to trastuzumab/capecitabine also resulted in a 46% reduction in the risk of disease progression or death compared with trastuzumab and capecitabine alone (HR, 0.54; 95% CI, 0.42-0.71; 

 <.00001). The median progression-free survival (PFS) was 7.8 months (95% CI, 7.5-9.6) for the triplet arm versus 5.6 months (95% CI, 4.2-7.1) in the control arm. Moreover, the 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively.

The HER2CLIMB trial (NCT02614794) permitted enrollment of patients with brain metastases; in this subgroup, the addition of tucatinib reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69; 

 <.00001). Here, the median PFS was 7.6 months with tucatinib versus 5.4 months with trastuzumab/capecitabine alone. Additionally, the 1-year PFS rates were 25% versus 0%, respectively, and a subgroup analysis also showed an OS benefit with tucatinib in this subgroup (HR, 0.58; 95% CI, 0.40-0.85).

“Tucatinib in combination with trastuzumab and capecitabine was effective for patients with and without brain metastases,” said lead study author Rashmi K. Murthy, MD, MBE. “Furthermore, this was a very welltolerated regimen with mainly low-grade toxicities. This [approach] allows for continued treatment for patients beyond progression.”

In December 2019, the FDA granted tucatinib a breakthrough therapy designation for use in combination with trastuzumab and capecitabine to treat patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, who had prior trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Just a few days later, Seattle Genetics, Inc, submitted a new drug application (NDA) for tucatinib for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive disease, including those with brain metastases, following at least 3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant, or metastatic setting. The NDA was based on the HER2CLIMB data.

 during the 2019 San Antonio Breast Cancer Symposium, Murthy, an assistant professor in the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the findings of the HER2CLIMB trial in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

: Could you provide an overview of the HER2CLIMB trial?

: HER2CLIMB was a pivotal study that evaluated tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2-positive metastatic breast cancer, including those with and without brain metastases. The background for this study is that [this disease] remains incurable, and we have limited treatment options after progression with the standard systemic treatments: trastuzumab, pertuzumab, and T-DM1. Additionally, up to half of patients will develop brain metastases during their disease course.

Tucatinib is an investigational oral tyrosine kinase inhibitor that is highly selective for HER2 with minimal inhibition of EGFR, so it may provide a more favorable toxicity profile. Also, in a phase Ib study, we saw that tucatinib in combination with trastuzumab and capecitabine has a safe profile with encouraging antitumor activity in heavily pretreated patients, including those with brain metastases. The efficacy in brain metastases is also supported by preclinical work.

In this study, we saw that when tucatinib was added to standard therapy of trastuzumab and capecitabine, it improved PFS in patients with and without brain metastases. Moreover, there was a significant OS benefit, notably in this heavily pretreated patient population that included patients with brain metastases. This represents a major advance in the treatment of patients with advanced HER2-positive breast cancer.

What impact will these data have on the field?

These data will support a change in the standard of care. Hopefully, this treatment will be made available to patients soon following progression on trastuzumab, pertuzumab, and T-DM1.

What factors were considered when enrolling patients for the HER2CLIMB trial?

The eligibility for the HER2CLIMB study included those who had metastatic disease and centrally confirmed HER2 positivity, and were also previously exposed to treatment with trastuzumab, pertuzumab, and T-DM1. The most unique eligibility criteria were with regard to brain metastases. The trial included patients with brain metastases who had stable disease and a history of brain metastases, but—unique to this trial&mdash;it also allowed those who had occult disease identified at screening, or those who had progressing disease in the brain following prior local therapy. These patients were enrolled as clinically appropriate, as long as they did not require urgent medical intervention and were relatively asymptomatic.

What are the next steps for this research?

Moving forward, we will be taking a deeper look at the patient population with brain metastases in this clinical trial. This presents a unique opportunity to further study this group of patients and to understand key details, such as intracranial response and progression rates, among many other things. Additionally, we have an ongoing investigator-initiated trial through the Translational Breast Cancer Research Consortium (TBCRC) to study this combination in patients with leptomeningeal disease. This trial that became activated earlier this year across multiple different sites through the TBCRC. Finally, an ongoing trial is looking at tucatinib versus placebo in combination with T-DM1. That is being done to potentially bring this drug forward into an earlier-line metastatic setting.

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published online December 11, 2019. Published correction appears in 

, published online December 27, 2019. doi: 10.1056/NEJMx190039]. 

Rashmi K. Murthy, MD, MBE, discusses the findings of the HER2CLIMB trial in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.

Murthy Shares Insight on HER2CLIMB Findings With Tucatinib in HER2+ Breast Cancer

The 6-year follow-up results of the phase III APHINITY trial expressed continued benefit for adding adjuvant pertuzumab (Perjeta) to trastuzumab (Herceptin) and chemotherapy in patients with HER2-positive early breast cancer, explained Martine J. Piccart, MD, PhD.

The APHINITY trial (NCT01358877) examined the adjuvant combination of pertuzumab with trastuzumab plus chemotherapy. Longer follow-up data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) showed a 0.9% absolute improvement in overall survival (OS) rate and also reduced the risk of invasive disease recurrence in patients with HER2-positive early breast cancer.

The OS rate was 94.8% in the pertuzumab arm compared with 93.9% in the placebo arm, leading to a 15% reduction in the risk of death; however, this was not found to be statistically significant as per a predetermined 

 value of .0012 (HR, 0.85; 95% CI, 0.67-1.07; 

 = .170). However, the survival data are still immature, according to Piccart.

Earlier data from the APHINITY trial, which showed an invasive disease-free survival (iDFS) benefit with the addition of adjuvant pertuzumab, led to the December 2017 FDA approval of pertuzumab in combination with trastuzumab and chemotherapy as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence. Researchers are in the process of identifying biomarkers beyond nodal status that will predict which patients will benefit from receiving this regimen.

“Dual HER2 blockade plus chemotherapy is the preferred option in early HER2-positive breast cancer for women at high risk,” said Piccart. “It is not an option right now for women with node-negative disease because we have not seen any treatment effect there. However, we are working hard at finding biomarkers beyond nodal status. We hope to build a risk score that will be based on not only nodal status, but tumor size, age, hormone receptor status, tumor-infiltrating lymphocytes, and number of 

“We want to integrate all of these factors to define a risk,” Piccart added. “Then, we can perform a step analysis. For a certain risk, we can see whether the 2 curves are superimposable or if they are diverging. With this type of analysis, we hope to have a better way of identifying patients who might clearly benefit from pertuzumab.”

 during the 2019 SABCS, Piccart, professor of oncology at the Université Libre de Bruxelles and the director of the Department of Medicine at Jules Bordet Institute, discussed the 6-year follow-up of the APHINITY trial and its impact on the breast cancer field.

: Could you provide an overview of the APHINITY trial?

: We are very happy about the 6-year results of the APHINITY trial. We can say that the clinical benefit of pertuzumab has been observed in patients with early HER2-positive breast cancer and node-positive disease. We now have an estimated absolute benefit at 6 years at 4.5% for the rate of iDFS. At this second interval analysis of OS that we performed, [these data are] still quite immature. We will continue to follow up.

We have not seen new cardiac safety issues, meaning we have a favorable clinical benefit versus harm ratio because the incidence of severe cardiac events with the addition of pertuzumab to standard chemotherapy and trastuzumab is 0.8% versus 0.3% [without pertuzumab].

Another interesting observation is now we can see that the benefit of pertuzumab is independent of the hormone receptor status. When we did the primary analysis 2.5 years ago with a shorter median follow-up, we had the impression that the benefit was confined to the group of women with hormone receptor—negative, HER2-positive disease. Now, we can clearly see a benefit emerging in the hormone receptor–positive population, and that’s probably because events in this population accumulate more slowly over time. We see a little divergence between the curves. Now, at 6 years, the absolute benefit in those with hormone receptor–positive disease is very clear, at about 3%, and that has important clinical implications.

How are the updated data expected to affect clinical practice?

There is a progressive shift from adjuvant treatment to neoadjuvant treatment for all women who have intermediate- or high-risk tumors. The fact is that, in many places around the world, neoadjuvant treatment is not the preferred [approach]; it requires very close collaboration among surgeons, medical oncologists, radiotherapists, radiologists, and pathologists. In many places, adjuvant treatment is still preferred. Hopefully, the APHINITY trial will give women at high risk a better chance to be cured of this disease, because it is an adjuvant trial. The goal, of course, is to cure more patients.

Can any biomarkers be used to choose patients for this treatment?

Last year, we presented a biomarker exploratory analysis of about 1000 patients; one-fourth of those patients had relapsed. Each of the patients who relapsed were matched to those [who did not] relapse. We collected all the tumors, did DNA sequencing and RNA sequencing, evaluated the tumor-infiltrating lymphocytes (TILs), and looked at the 

To make a long story short, there were, at that time, 2 biomarkers that seemed to be linked with the benefit of pertuzumab. We found biomarkers that indicated poor prognosis, but we need biomarkers telling us who needs pertuzumab. The 2 [biomarkers] at that time were TILs and 

 gene copy number. Now, we will have to update this analysis, because we have [identified] more events. Clearly, the biomarker research will be more productive with a longer follow-up.

At this point in time, with the data that we have, the only biomarker that is indicative of a potential benefit of pertuzumab is nodal positivity. Any patient presenting with node-positive disease should be considered for the addition of pertuzumab with a discussion about potential benefits and risk. Hopefully, [in the future], we will be able to do better than that.

What is the safety profile of this regimen?

I have been focusing on cardiac events because these are potentially irreversible, severe adverse events (AEs) from the treatment. A more frequent AE [that is associated with the addition of] pertuzumab to chemotherapy and trastuzumab is diarrhea. Pertuzumab is associated with more diarrhea and with more grade 3 diarrhea, with an incidence of about 10%.

In a curative setting, women will not be too bothered by that. The diarrhea can be controlled, and it is mainly seen when pertuzumab is added to chemotherapy. When the chemotherapy is finished and [treatment] continues with just trastuzumab and pertuzumab, the diarrhea goes away very quickly. It is important to inform patients about that; in talking to them about curative treatments, they want to be mostly aware of the potential irreversible severe AEs. What is transient is less important because they want to get rid of the disease.

What are the next steps of this research?

We need to continue to follow up on our patients. We have a definitive OS analysis that is event-driven and is based on 640 deaths. That is planned and will happen a few years from now; it's going to be important because if we can show a survival benefit, the data become even stronger.

However, I am personally thinking that living without a recurrence, even if your OS is not prolonged, is very important for women. We need to remember that in HER2-positive disease, [patients are] about 10 years younger than [those with] luminal breast cancer. The median age [for HER2-positive breast cancer] is 49. [These patients] are still professionally active and might still have to raise kids. It’s very important to be able to live without the disease and without treatment for several years.

Longer follow-up, repeating the biomarker analysis on more tumor samples with more events, and developing a step analysis that might introduce a composite risk [is necessary]; it can indicate to the physician, with all these parameters integrated, who might benefit from these more expensive treatments.

What does the future treatment of these patients look like?

In Europe in a clinical trial, we plan to closely evaluate a new formulation of pertuzumab and trastuzumab combined as a single subcutaneous injection. We believe that in the future, this could allow women to self-administer the subcutaneous injection at home. That would be fantastic because as soon as the chemotherapy is over, they would not need to come every 3 weeks to the hospital anymore.

Piccart M, Procter M, Fumagalli D, et al. Interim overall survival analysis of APHINITY (BIG 4-11): a randomised multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS1-04.

Martine J. Piccart, MD, PhD, discusses the 6-year follow-up of the APHINITY trial and its impact on the breast cancer field.

Piccart Highlights 6-Year Follow-Up With Adjuvant Pertuzumab Regimen in HER2+ Breast Cancer

In the first 11 months following the FDA approval of the CDK4/6 inhibitor abemaciclib (Verzenio) as a single agent and in combination with endocrine therapy for the treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, it is being used heterogeneously, including in patients with characteristics indicative of worse prognosis.

In a retrospective observational study, real-world use of abemaciclib has resulted in a 12-month real-world progression-free survival (rwPFS) rate of 61.7%, and the median rwPFS has not been reached (95% CI, 9.02-NR), reported Gebra Cuyun Carter, PhD, at the 2019 San Antonio Breast Cancer Symposium.

The Flatiron Health electronic health record-derived database was used to identify 118 female patients with HR-positive, HER2-negative metastatic breast cancer who initiated treatment with abemaciclib between June 30, 2016 and August 31, 2018, and at least 4 months prior to the cutoff date of December 31, 2018. The median follow-up time for this analysis was 6.4 months. Almost all (98.3%) patients were treated in a community oncology setting.

“It’s important to understand how abemaciclib is being used because you want to understand if it’s similar to its indication,” said Carter, research scientist at Eli Lilly and Company, Indianapolis. “Clinical trial patients are often a homogeneous patient population…only 3% of cancer patients participate in clinical trials…it’s important to understand utilization in a more heterogeneous patient population in a clinical practice setting. You’re looking at patients who are often excluded or choose not to participate in clinical trials or don’t have the option to participate.”

“The follow-up time is 6 months, so it’s early utilization with limited follow-up time,” she said. “So we were limited in some of the outcomes we could assess. We did look at real-world tumor response, which is one that we felt was more robust at the time.”

Real-world best response in all abemaciclib recipients who had at least 1 real-world response assessment was 41.2% (n = 28 of 68), including a partial response (PR) in 35.3%, stable disease (SD) in 33.8%, and complete response (CR) in 5.9%. One-fourth of patients (25%) had progressive disease.

Response rates declined with use of abemaciclib in each subsequent line, but even in the fourth or later line, the response rate was 22.3% (n = 4 of 18) , with 1 (5.6%) CR and 3 (16.7%) PRs. Eight (44.4%) patients had SD as their best response to fourth or later line abemaciclib. The real-world time to first response across all abemaciclib-containing regimens was 3.6 months.

Abemaciclib was used in the first-line setting in 34 of the 118 (28.8%) abemaciclib recipients, in the second line in 25 (21.2%), in the third line in 24 (20.3%), and in the fourth or later line in 35 (29.7%).

As part of a combination, abemaciclib was most often used with fulvestrant (n = 70), followed by an aromatase inhibitor (AI; n = 27), and the combination of fulvestrant and an AI (n = 6).

In the first line, abemaciclib was most often used with fulvestrant (n = 18) or an AI (11), and was used as monotherapy in the first line in 2 patients. In the 25 patients in whom abemaciclib was used in the second-line setting, use in combination with fulvestrant was the most common use (n = 18). Abemaciclib was not used as monotherapy in the second line. In the third line, abemaciclib was again used most often with fulvestrant (n = 17). When used in the fourth line or later, abemaciclib was used most often with fulvestrant (n = 17), followed by abemaciclib monotherapy (n = 12).

About one-fourth (24.6%) of the 118 abemaciclib recipients received prior treatment with a CDK4/6 inhibitor (palbociclib [Ibrance] or ribociclib [Kisqali]).

According to stage at initial diagnosis, abemaciclib was used most often in patients with stage IV (34.7%) and stage III (28.8%) metastatic breast cancer. Stage was not documented in 8.5%.

According to tumor grade at initial diagnosis, abemaciclib was used most often in patients with tumor grade 2 (45.8%) followed by grade 3 (22.9%), and grade 1 (9.3%). Tumor stage was unknown or undocumented in 22.0% of abemaciclib recipients.

Some 86.4% of abemaciclib recipients were progesterone receptor—positive. The time between initial diagnosis and diagnosis of metastasis among the patients who were not metastatic at initial diagnosis was ≥2 years in 79.2% of abemaciclib-treated patients and ≤2 years in 20.8%. The median number of sites of metastases was 2.0. About half (49.2%) had visceral metastases, and sites of metastases were lung in 34.7%, liver in 22.9%, bone in 82.2%, distant lymph nodes in 30.5%, brain in 7.6%, and central nervous system in 3.4%.

About 85% of patients initiated abemaciclib at a starting dosage that is consistent with FDA-approved labeling. Most patients appeared to tolerate treatment: dose reduction was not required in 93.2%, 62.7% did not have a dose held, and 78.8% of patients did not have a change in dosing schedule.

“Some of our follow-up steps are to get a more robust sample size so that we can explore some of these regimen-specific cohorts in the future,” said Carter.

Carter GC, Sheffield KM, Gossan A, et al. Initial real world treatment patterns and outcomes of Abemaciclib for the treatment of HR+,HER2- metastatic breast cancer. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P2-08-12.

In the first 11 months following the FDA approval of the CDK4/6 inhibitor abemaciclib as a single agent and in combination with endocrine therapy for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer, it is being used heterogeneously, including in patients with characteristics indicative of worse prognosis.

Real-World Abemaciclib Use in MBC Is Heterogeneous

A high absolute lymphocyte count (ALC) at baseline appears to be an independent predictor for longer overall survival (OS) in patients with metastatic breast cancer who are treated with eribulin mesylate (Halaven), according to a poster presented at the 2019 San Antonio Breast Cancer Symposium.

In examining data from 2 phase III studies—EMBRACE and Study 301&mdash;patients with high baseline ALC values were found to experience greater eribulin benefit on OS versus patients with low baseline ALC across cutoff values from 1300 µL to 1750/µL, lead investigator Javier Cortes, MD, and colleagues reported.

In the multicenter open-label EMBRACE study, which enrolled women with locally recurrent or metastatic breast cancer who were randomized to eribulin or treatment of physician’s choice (TPC), patients with a baseline ALC ≥1500/µL who were randomized to eribulin had significantly longer OS than those randomized to TPC (median OS, 15.6 vs 11.4 months; HR, 0.586; 95% CI, 0.437-0.784; 

In the open-label Study 301, which randomized patients with advanced or metastatic breast cancer who had received prior anthracycline- and taxane-based therapy to eribulin or capecitabine. Among patients with baseline ALC ≥1500/µL, those in the eribulin arm of the study had significantly prolonged OS compared with those in the capecitabine arm (median OS, 19.6 vs 16.0 months; HR, 0.81; 95% CI, 0.662-0.993; 

“This hypothesis-generating study speculates that baseline ALC may be useful in the selection of patients to be treated with eribulin,” Cortes et al wrote.

Eribulin is a nontaxane synthetic inhibitor of microtubule dynamics approved for use in locally advanced or metastatic breast cancer after 2 previous lines of chemotherapy.

In EMBRACE, 762 women were enrolled and randomized to eribulin at 1.4 mg/m

 intravenously on days 1 and 8 of a 21-day cycle or TPC. Median OS of the patients assigned to eribulin was significantly better than the TPC arm, although no significant difference was observed in progression-free survival by independent review.

 There were 500 and 251 patients in the eribulin and TPC arms, respectively, who had an evaluable baseline ALC.

Study 301 enrolled 1102 women who were randomized to the same dosing schedule on eribulin as in Study 301 or capecitabine at 1.25 g/m

 orally on days 1 to 14 of a 21-day cycle. The study did not meet its primary endpoint of an improvement in OS, but median OS was numerically longer in the eribulin arm versus the capecitabine arm (15.9 vs 14.5 months, respectively; 

 Of those enrolled, 553 in the eribulin arm and 547 in the capecitabine arm had an evaluable baseline ALC.

The posthoc analysis presented at SABCS assessed predictors for OS in patients treated with eribulin in the 2 phase III studies, focusing on ALC, a peripheral immune parameter.

In EMBRACE, baseline characteristics were similar between the eribulin and TPC groups and between the ALC cutoff groups, except for a higher percentage of patients with >2 organs involved in both treatment arms in the ALC <1500/ µL cohorts.

Whereas the median OS in EMBRACE was superior with eribulin among patients with baseline ALC ≥1500/µL, among those with ALC <1500/ µL at baseline, the median OS was 11.6 months in the eribulin arm versus 10.3 months in the TPC arm (HR, 1.002; 95% CI, 0.800-1.253).

“Patients in EMBRACE with high baseline ALC (≥1500/µL) experienced greater OS benefit following eribulin treatment versus patients with low baseline ALC (<1500/uL) across cutoff values from 1400/µL to 1700/µL (interaction 

In Study 301, baseline characteristics were similar between treatment arms and between the ALC cutoffs, except that there was a higher percentage of patients with hormone receptor—positive disease at baseline in both the ALC ≥1500/µL versus the ALC <1500/µL cohorts in both treatment arms.

The median OS with eribulin in Study 301 was 19.6 months in patients who had baseline ALC ≥1500/µL versus 14.6 months in those with baseline ALC <1500/ µL. Among the patients with ALC <1500/µL at baseline, the median OS was 14.6 versus 12.5 months in the eribulin and capecitabine arms, respectively (HR, 0.907; 95% CI, 0.758-1.084).

Cortes J, Perez-Garcia JM, Nomoto K, et al. Absolute lymphocyte count (ALC) is a predictor of eribulin benefit in advanced or metastatic breast cancer (MBC). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract P4-10-08. doi: 10.1016/S0140-6736(11)60070-6.

Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. 

Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. 

. 2015;33:594-601. doi: 10.1200/JCO.2013.52.4892.

A high absolute lymphocyte count at baseline appears to be an independent predictor for longer overall survival in patients with metastatic breast cancer who are treated with eribulin mesylate.

Absolute Lymphocyte Count May Predict Eribulin Benefit in Breast Cancer

Mathematical modeling was unable to harmonize the VENTANA SP263 and Dako 22C3 PD-L1 assays with the FDA-approved VENTANA PD-L1 SP142 companion diagnostic for the selection of patients with advanced triple-negative breast cancer (TNBC) appropriate for atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane), according to an exploratory analysis of the IMpassion130 trial.

Accordingly, lead study author Hope S. Rugo, MD, and coinvestigators wrote in the conclusion of their poster at the 2019 San Antonio Breast Cancer Symposium (SABCS) that “the assays

cannot be considered equivalent,” leaving the SP142 assay as “the only clinically validated companion assay to select patients with metastatic TNBC for treatment with atezolizumab plus nab-paclitaxel.”

IMpassion130 was the first phase III trial to demonstrate clinical benefit of immunotherapy in patients with PD-L1—positive metastatic TNBC. Based on this study, the combination of atezolizumab and nab-paclitaxel was approved in the United States and Europe for this indication. 

PD-L1 status in IMpassion130 was determined using SP142. Testing predicted progression-free survival (PFS) and overall survival (OS) with the combination of atezolizumab and nab-paclitaxel compared with nab-paclitaxel plus placebo. The absolute improvement in median OS in the PD-L1-positive population was 7 months (HR, 0.71; 95% CI, 0.54-0.94).

SP142 is clinically validated and has been approved by the FDA for use as a companion diagnostic to identify the appropriate patients with metastatic triple-negative breast cancer (mTNBC) to receive the atezolizumab combination. The assay determines PD-L1 status as PD-L1 expression on immune cells (ICs) as a percentage of tumor area. As determined by SP142 testing, the PD-L1  expression cutoff was ≥1% for PD-L1—positive status in IMpassion130.

However, in several countries outside of the United States where atezolizumab plus nab-paclitaxel is approved for patients with metastatic TNBC and PD-L1 IC ≥1% status, there is no specific PD-L1 assay identified for use with this regimen. Further, despite the success with SP142 in IMpassion130, questions remain regarding the  optimal approach for identifying which patients will benefit from the atezolizumab combination. 

Accordingly, Rugo a professor in the Department of Medicine, Hematology/Oncology, and director, Breast Oncology and Clinical Trials Education at University of California, San Francisco, and coinvestigators conducted a posthoc analysis of the biomarker-evaluable population (BEP) from IMassion130, comparing SP142 with the 2 other PD-L1 assays: the complementary diagnostic VENTANA SP263 and the companion diagnostic Dako 22C3. These tests have been used for other immunotherapy agents in other tumor types. Results of this posthoc analysis were previously presented by Rugo et al at the 2019 ESMO Congress.

There were 614 patients in the BEP, making up about 68% of the intent-to-treat (ITT) population. Baseline characteristics were well-balanced overall between the BEP and the ITT, except that there were more patients with PD-L1 IC—positive tumors per SP142 testing in the BEP at 46% versus 41%, respectively. The median PFS was 8.3 months with the atezolizumab regimen versus 4.1 months with nab-paclitaxel plus placebo in the PD-L1–positive BEP population. In the PD-L1–positive ITT population, the median PFS was 7.5 months versus 5.3 months, respectively. 

To measure PD-L1 status in the BEP for their posthoc analysis, Rugo et al used the standard cutoffs for the 3 assays: IC 1% for SP142 and SP263, and combined positive score (CPS) 1 for 2263. The CPS is the total PD-L1 expression on both tumor cells and ICs.

Data presented at ESMO showed that 22C3 and SP263 were not concordant with SP142. The assays had what Rugo et al described as “subpar” overall percentage agreements (OPAs) with SP142 IC 1%, at 64% for 22C3 CPS 1 and 69% for SP263 IC 1%. 

of the assays, the PD-L1—positive populations identified by 22C3 and SP263 were larger than the SP142 population at 81% and 75% of the ITT, respectively. The SP142 population was a subgroup of these populations. 

Rugo et al observed that the improved outcomes with the atezolizumab regimen in the 22C3 and SP263 populations were actually driven by the SP142 subgroup. Patients with the longest median PFS and OS and smallest hazard ratio estimates were identified by SP142. Also of note, little-to-no PFS and OS benefit was observed in patients who were PD-L1—positive by 22C3 or SP263, but PD-L1–negative by SP142. 

At SABCS, Rugo et al presented a poster highlighting an additional exploratory analysis with 2 objectives: to evaluate whether using IC 1% as the cutoff with 22C3, instead of the standard CPS ≥1 used with this assay, would lead to analytical concordance with SP142 and enhance clinical utility; and identify alternative PD-L1 cutoffs for 22C3 or SP263 that would both analytically and clinically replicate the SP142 population.

With the first objective, Rugo et al did not find greater concordance with SP142 regarding the population identified or clinical outcomes when using the IC 1% cutoff with 22C3; the change in cutoff yielded similar outcomes as with the 22C3 standard cutoff of CPS 1, with an OPA now of 69%. SP142 IC was again a subgroup of the 22C3 population and again drove the clinical benefit observed. 

Regarding the second objective of the exploratory analyses, mathematical modeling identified the optimal cutoff as CPS 10 for 22C3 and IC 4% for SP263. These were the cutoffs with the highest combined OPA, positive percentage agreement (PPA), and negative percentage agreement (NPA) between each assay and SP142. 

For SP142 IC 1% and 22C3 CPS 10, the OPA, PPA, and NPA were all 74%. For SP142 IC 1% and SP263 IC 4%, the OPA, PPA, and NPA were 75%, 73%, and 77%, respectively. 

“The clinical activity of atezolizumab plus nab-paclitaxel in patients identified by 22C3 CPS ≥10 and SP263 IC ≥4% yielded mixed results and was not equivalent to that observed in patients identified by SP142 IC ≥1%,” Rugo et al wrote. 

The authors noted, however, that although analytical harmonization was not achieved, there was a similar PFS and OS benefit reached between the SP263 IC ≥4% subgroup and the SP142 IC ≥1% subgroup. 

The median OS was 28.9 months in the atezolizumab arm of the SP263 IC ≥4% subgroup compared with 19.6 months with placebo (HR, 0.71). The corresponding OS figures were 27.3 months versus 17.9 months (HR, 0.74), respectively, in the in the SP142 IC ≥1% subgroup.

The median PFS in the SP263 IC ≥4% subgroup was 8.7 months for the atezolizumab regimen versus 5.5 months with nab-paclitaxel alone (HR, 0.64). The corresponding PFS figures were 8.3 versus 4.1 months (HR, 0.60), respectively, in the SP142 IC ≥1% subgroup.

Regarding the efficacy performance of the experimental SP263 cutoff, the authors noted, “Although SP263 IC ≥4% identified an additional population that may have PFS benefit, this cutoff also excluded 26% of SP142 IC ≥1% patients who may have derived PFS benefit from atezolizumab plus nab-paclitaxel.”

Unlike the SP263 cutoff, the experimental 22C3 cutoff did not reach a similar level of clinical benefit with the atezolizumab regimen as SP142 IC ≥1%. 

The median OS was 22 months in the atezolizumab arm of the 22C3 CPS ≥10 subgroup compared with 18.7 months in nab-paclitaxel plus placebo arm (HR, 0.77). The median PFS was 7.5 months versus 5.5 months, respectively (HR, 0.71). 

These median OS and PFS data, as well as the hazard ratios, are inferior to those derived with SP142 IC ≥1%.

Rugo HS, Loi S, Adams S, et al. Exploratory analytical harmonization of PD-L1 immunohistochemistry assays in advanced triple-negative breast cancer: A retrospective substudy of IMpassion130. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract PD1-07.

Schmid P, Rugo HS, Adams S. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial [published online Nov 27, 2019]. 

Rugo HS, Loi S, Adams S, et al. Performance of PD-L1 immunohistochemistry (IHC) assays in unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): Post-hoc analysis of IMpassion130. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA20.

View more from 2019 San Antonio Breast Cancer Symposium

Mathematical modeling was unable to harmonize the VENTANA SP263 and Dako 22C3 PD-L1 assays with the FDA-approved VENTANA PD-L1 SP142 companion diagnostic for the selection of patients with advanced triple-negative breast cancer appropriate for atezolizumab plus nab-paclitaxel.

Analysis Unable to Achieve Concordance Among PD-L1 Assays in TNBC

Patients with premenopausal breast cancer and discordant clinical and genomic risk had a small increase in distant metastasis if they did not receive adjuvant chemotherapy, according to a post hoc analysis of the MINDACT trial that were presented at the 2019 San Antonio Breast Cancer Symposium.

The difference was about 3% in absolute terms and was based on a data for patients who were younger than <50 years that were at high clinical risk of recurrence but low genomic risk by the 70-gene MammaPrint assay. In contrast, women >50 years had nearly identical 5-year distant metastasis-free survival (DMFS) rates with or without adjuvant chemotherapy.

The implications of the findings from the MINDACT trial

 remain unclear, but are consistent with a trend seen in a subgroup analysis of the phase III TAILORx trial

 that also employed a genomic test to evaluate the need for adjuvant chemotherapy in patients with early breast cancer.

“This was an unplanned and underpowered subgroup analysis,” study investigator Fatima Cardoso, MD, of the Champalimaud Cancer Center in Lisbon, Portugal, said in a presentation during the meeting. “Cautious interpretation is needed because of the large confidence intervals associated with the hazard ratios. Nonetheless, the analysis suggests that in women younger than 50 years, who were in the clinical high risk/genomic low risk group (discordant), tamoxifen alone might not be the optimal treatment, although the difference seen between the chemotherapy and no-chemotherapy groups is small.”

“It is possible that this age-dependent effect is due to chemotherapy-induced ovarian function suppression,” Cardoso added. “Neither the MINDACT nor TAILORx trial is able to answer this question.”

MINDACT involved 6693 women with newly diagnosed, early breast cancer. Their risk of postoperative recurrence was evaluated by a clinical risk assessment tool and by the MammaPrint 70-gene assay. Patients at high risk by both assessments received adjuvant chemotherapy, while those with a low risk by both methods received no chemotherapy. Patients who had discordant clinical and genomic risk assessments were randomized to adjuvant chemotherapy or no chemotherapy. All patients with hormone receptor (HR)—positive disease received adjuvant endocrine therapy.

The primary endpoint was 5-year DMFS in patients with discordant findings randomized to no chemotherapy; the trial was statistically powered to demonstrate a significant outcome if DMFS exceeded 92%. Additionally, the primary test 5-year DMFS rate was significant if the 95% 2-sided confidence interval exceeded 92%. The results showed a 5-year DMFS of 94.7% and the 95% confidence intervals exceeded 92%.

The TAILORx trial involved more than 10,000 patients with HR-positive, HER2-negative early breast cancer. The primary results showed that adjuvant endocrine therapy was noninferior to chemotherapy plus endocrine therapy for patients with an intermediate risk of recurrence by the OncotypeDx genomic assay.

Subsequently, TAILORx investigators reported findings from a subgroup analysis, which suggested a differential benefit of chemotherapy for DMFS by age. Patients <50 years with an intermediate risk of recurrence had about a 3% higher risk of recurrence without chemotherapy versus less than 1% among older women.

Within the range of values for intermediate risk, the analysis showed that younger women with a high clinical risk benefited substantially more from chemotherapy as compared with patients who had a low clinical risk. At the upper end of the range for intermediate-risk values, younger patients derived greater benefit from chemotherapy, irrespective of clinical risk.

Cardoso and colleagues sought to determine whether a similar age-related divergence in chemotherapy benefit might exist in the MINDACT population. The analysis included 1317 patients with clinical high risk/genomic low risk profile, 452 <50 and 865 ≥50.

The data showed that the younger patients had a 5-year DMFS of 93.1% without adjuvant chemotherapy, increasing to 96.1% if they were randomized to receive chemotherapy. The finding suggested that chemotherapy reduced relative risk of distant recurrence by 46% in younger women, albeit with overlapping confidence intervals (HR, 0.54; 95% CI, 0.24-1.22). In the >50 age group, 5-year DMFS was virtually identical with chemotherapy or without (95.4% vs 95.2%).

Calculated as distant metastasis-free interval (DMFI), the results were similar: a 2.5% absolute difference favoring chemotherapy in younger patients (96.1% vs 93.6%) and no difference in the older subgroup (96.3% vs 96.7%).

Cardoso said the small differences in the younger patients could reflect the use of endocrine therapy, primarily with tamoxifen, without ovarian function suppression. Only 8.3% of younger women with a clinical high risk/genomically low risk profile had ovarian function suppression.

Piccart MJ, Poncet C, Cardoso F, et al. Should age be integrated together with clinical and genomic risk for adjuvant chemotherapy in early luminal breast cancer? MINDACT results compared to those of TAILOR-X. Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX. Abstract GS4-05.

Cardos F, van’t Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. 

. 2016;375:717-729. doi: 10.1056/NEJMoa1602253.

Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. 

. 2018.379:111-121. doi: 10.1056/NEJMoa1804710.

Sparano JA, Gray RJ, Makower DF, et al. Clinical outcomes in early breast cancer with a high 21-gene recurrence score of 26 to 100 assigned to adjuvant chemotherapy plus endocrine therapy a secondary analysis of the TAILORx randomized clinical trial [published online September 30, 2019]. 

Patients with premenopausal breast cancer and discordant clinical and genomic risk had a small increase in distant metastasis if they did not receive adjuvant chemotherapy, according to a post hoc analysis of the MINDACT trial.

Adjuvant Chemo Shows Slight Benefit in Younger Women With Breast Cancer Who Have Mixed Clinical, Genomic Risk

Hope S. Rugo, MD, a professor in the Department of Medicine, Hematology/Oncology, and director, Breast Oncology and Clinical Trials Education at University of California, San Francisco, discusses the updated data from the phase III SOPHIA trial, which compared margetuximab versus trastuzumab (Herceptin) for patients with HER2-positive metastatic breast cancer who had received prior anti-HER2 therapies, presented at the 2019 San Antonio Breast Cancer Symposium.

The SOPHIA trial resulted in a significant improvement in progression-free survival compared with trastuzumab (

 = .0006), explains Rugo. Additionally, the response rate and clinical benefit were significantly increased with margetuximab, showing a clinically important difference in response, according to Rugo.

The hazard ratio showed a 24% relative improvement and the absolute difference in overall survival between margetuximab and trastuzumab was 1.3 months. About 70% of planned events have been accumulated with this analysis and there is a non-significant trend towards improved survival with margetuximab.

Hope S. Rugo, MD, discusses the updated data from the phase III SOPHIA trial for patients with HER2-positive metastatic breast cancer who had received prior anti-HER2 therapies, presented at the 2019 San Antonio Breast Cancer Symposium.

Dr. Rugo on Updated Data From the SOPHIA Trial in HER2+ Metastatic Breast Cancer

Adding the PARP inhibitor olaparib (Lynparza) to neoadjuvant platinum based-chemotherapy was determined to be a safe treatment for patients with triple-negative breast cancer (TNBC), as well as for patients with breast cancer whose tumors harbor germline 

 mutations, according to preliminary safety data from the phase II/III PARTNER trial.

“The majority of adverse events (AEs) were grade 1/2, only 5% of the AEs were grade 3 or greater. This is a tolerable regimen, it’s manageable—toxicity is not massively increased by the addition of olaparib to the chemotherapy regimen,” lead study author Karen Pinilla Alba, MD, a medical oncologist and clinical research fellow at the University of Cambridge, said in an interview with 

 at the 2019 San Antonio Breast Cancer Symposium (SABCS).

PARTNER is a randomized international 3-stage trial—stages 1 and 2 evaluated the safety of the olaparib regimen and determined the optimal treatment schedule, and stage 3 will evaluate the efficacy of the regimen with a primary endpoint of pathologic complete response (pCR).

To enroll on the study, patients must be aged 16 to 70; have an ECOG performance status of 0 or 1; have histologically confirmed invasive breast cancer; have confirmed ER-negative and HER2-negative disease with a TNBC basal phenotype or have germline 

-positive breast cancer, regardless of hormone status; and have clinical stage T1-4 N0-2 disease (tumor or node diameter >10 mm).

The recruitment goal for the trial is 750 patients, including at least 180 patients with 

-positive tumors. Stages 1 and 2 are complete, while recruitment is ongoing for stage 3.

Stages 1 and 2 involved a 1:1:1 randomization of patients to a control arm of 4 cycles of neoadjuvant paclitaxel plus carboplatin or the same chemotherapy regimen plus olaparib at 150-mg orally twice daily on days 2 to 10 every 3 weeks (research arm 1), or olaparib at 150-mg orally twice daily on days 3 to 14 every 3 weeks (research arm 2). In the study design, after completing their initial regimen, all patients receive anthracycline-based chemotherapy followed by surgery.

Between June 2016 and April 2018, the study accrued 159 patients across the 3 arms of stage 1 and 2, with 53 patients randomized to each arm. In research arm 1, 7 patients were aged <40 years and 15 patients were aged 60 to 70 years. The ECOG performance score was 0 for 48 patients and 1 for 5 patients. Eleven patients were 

-positive, 88.7% had a tumor size ≤ 50 mm, 32.1% had axillary node involvement, and 68% had a TILs rate <60%.

In research arm 2, 13 patients were aged <40 years and 14 patients were aged 60 to 70 years. The ECOG performance score was 0 for 45 patients and 1 for 8 patients. Seven patients were 

-positive, 92.5% had a tumor size ≤50 mm, 34% had axillary node involvement, and 68% had a TILs rate <60%.

Adding the PARP inhibitor olaparib to neoadjuvant platinum based-chemotherapy was determined to be a safe treatment for patients with triple-negative breast cancer, as well as for patients with breast cancer whose tumors harbor germline BRCA mutations.