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]. 

Articles

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

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

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

The combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) plus paclitaxel (PHP) is commonly being used in the community for the treatment of patients with HER2-positive breast cancer, and appears to be as effective as pertuzumab and trastuzumab plus docetaxel (PHD) according to real-world findings from a retrospective cohort study reported at the 2019 San Antonio Breast Cancer Symposium (SABCS).

In the study, the median real-world progression-free survival (rwPFS) was 12.9 months (95% CI, 11.2-15.8) for PHP and 14.9 months (95% CI, 13.2-16.9) for PHD.

Time to last administration (TTLA) was used as a proxy for treatment duration for PH and chemotherapy. The median TTLA of the index taxane was 3.7 months (range, 3.42-3.91) in the PHP group versus 3.5 months (range, 3.45-3.45) in the PHD group. The median TTLA of PH was 10.6 months (95% CI, 8.51-11.8) for PHP and 11.8 months (95% CI, 10.49-13.3) for PHD.

No statistically significant difference was found between PHP and PHD for TTLA of PH and for rwPFS, either in the unadjusted models or in the models adjusted for potential confounders.

“The potential difference in the effectiveness of the PHD versus the PHP regimen was not large enough to be observed in the study cohort, regardless of the statistical adjustment used, supporting the evidence from the PERUSE trial (NCT01572038),

 suggesting that paclitaxel appears to be a valid alternative taxane backbone to docetaxel, and extending the evidence to a more heterogeneous population,” the investigators, led by Letizia Polito, PhD, wrote in their poster presentation.

“This confirmed in the real world that the 2 treatments are equally effective, which is what we expected,” Polito, a real-world data scientist, biostatistician, and epidemiologist, of F. Hoffmann-La Roche Ltd., said in an interview with 

“No previous data in the real world have shown that the 2 treatments are comparable in terms of treatment duration and PFS. Treating with either docetaxel or paclitaxel in a pertuzumab-based regimen made no difference on outcome, but we know that paclitaxel has a better safety profile,” Polito added. “We also adjusted for potential confounding variables, we accounted for all the imbalances in the baseline characteristics, and observed that the rwPFS curves between paclitaxel and docetaxel are even more overlapping.”

The nationwide Flatiron Health Electronic Health Record (EHR)-derived database was used to identify 1054 patients who received a taxane with PH as initial systemic therapy after diagnosis of metastatic breast cancer between June 1, 2012 and April 30, 2019.

“In the real world, it still seems like docetaxel is the preferred option, but paclitaxel is increasingly being used together with pertuzumab and trastuzumab,” said Polito. Of the 1054 patients, 29.3% received PHP (26.9% paclitaxel and 2.4% nab-paclitaxel [Abraxane]) and 70.7% received PHD.

The median age of the overall cohort was 59.0 years (range, 51-67). ECOG performance status was missing in 42.9% of patients; of the remaining patients for whom ECOG performance status data were available, 31.3% had a status of 0, 19.4% a status of 1, and 6.5% a status of ≥2. Almost half (45.7%) of the participants had 1 metastatic site, 32.3% had 2, and 21.5% had ≥3. Furthermore, 46.5% of participants had recurrent disease.

The median time since initial breast cancer diagnosis was 46.2 months (range, 29.4-84.5). About three-fourths (70.8%) of patients had estrogen receptor— or progesterone receptor–positive disease, and nearly all cases (93.5%) were from the community setting.

In both the patients with de novo disease (n = 564) and the patients with recurrent disease (n = 490), those treated with PHD were more often treated in the community setting as compared with those treated with PHP. Specifically, 95.4% of patients with de novo disease were treated with PHD in the community setting versus 83.2% of those treated with PHP; of the patients with recurrent disease, 97.6% and 90% were treated in community practice with PHD and PHP, respectively.

Among the patients with de novo disease, those treated with PHP were significantly older (

 = .001), had an ECOG performance status of 0 less often (

 = .002), and were more likely to have metastatic sites (

 = .007) than those treated with PHD. An ECOG performance status of 0 was also less likely in the patients with recurrence who were treated with PHP compared with PHD (

Fifty-four (5.1%) patients switched taxane during first-line therapy, 15 (5.3%) of whom switched from paclitaxel to nab-paclitaxel and 39 (5.2%) of whom switched from docetaxel to either paclitaxel or nab-paclitaxel. No patient switched from paclitaxel or nab-paclitaxel to docetaxel.

One limitation to the study was that the analysis only included patients who were part of the Flatiron Health network; this could result in potential selection bias—due to different coverage of different geographic areas in the United States or because of an imbalance between academic and community settings&mdash;in favor of community settings, according to the investigators. Furthermore, results may have been impacted by unmeasurable and unobserved confounding.

Polito L, Shim J, Du Toit Y, et al. Use of pertuzumab in combination with taxanes for HER2-positive metastatic breast cancer (MBC): analysis of US electronic health records. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P1-18-14. bit.ly/2S7qtyu.

Bachelot T, Ciruelos E, Schneeweiss A, et al. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE). 

. 2019;30(5):766-773. doi: 10.1093/annonc/mdz061.

Nonrandomized trials had already suggested the utility of PHP as an alternative to PHD.

The combination of pertuzumab and trastuzumab plus paclitaxel is commonly being used in the community for the treatment of patients with HER2-positive breast cancer, and appears to be as effective as pertuzumab and trastuzumab plus docetaxel according to real-world findings from a retrospective cohort study.

Taxane Choice With Pertuzumab/Trastuzumab in HER2+ MBC Does Not Affect Outcome

The KATHERINE trial included 1486 patients with HER2-positive, nonmetastatic invasive primary breast cancer who were randomized in a 1:1 ratio to adjuvant T-DM1 or trastuzumab. Prior neoadjuvant therapy had to consist of ≥6 cycles of chemotherapy containing a taxane (with or without anthracycline) and ≥9 weeks of trastuzumab.

At the 2019 San Antonio Breast Cancer Symposium (SABCS), lead study author Max S. Mano, MD, PhD, presented a poster with several subanalyses of the trial, including a comparison of patients who received anthracycline (AC)-based NACT versus those who received non-AC&shy;—based NACT.

The HR for iDFS was 0.51 (95% CI, 0.38-0.67) and 0.43 (95% CI, 0.22-0.82) favoring T-DM1 for the AC and non-AC groups, respectively. In the AC arm, the 3-year iDFS rates were 87.4% with T-DM1 versus 75.7% with trastuzumab. In the non-AC arm, the 3-year iDFS rates were 91.7% versus 81.4%, respectively. 

These data compare favorably with the overall population results of the KATHERINE trial, in which T-DM1 reduced the risk of invasive disease recurrence or death by 50% (HR, 0.50; 95% CI, 0.39-0.64;

 <.001), and the 3-year iDFS rates were 88.3% with T-DM1 versus 77.0% with trastuzumab. 

For their analysis, the researchers also identified 4 mutually exclusive high-risk subgroups. Although these were small subsets, there was an improvement in the 3-year iDFS rate with T-DM1 across all 4 subgroups.

Among 375 patients who were inoperable at presentation irrespective of hormone receptor and ypN status, the 3-year iDFS rates were 76% and 60.2% with T-DM1 and trastuzumab, respectively (HR, 0.54; 95% CI, 0.37-0.80). The corresponding rates were 76% and 69.5% (HR, 0.72; 95% CI, 0.35-1.50), respectively, among 110 patients who were operable at presentation with ypN-positive nodes and hormone receptor—negative disease.

In 335 patients who were operable at presentation with ypN-positive nodes and hormone receptor—positive disease, the 3-year iDFS rates were 91.4% and 77.2% with T-DM1 and trastuzumab, respectively (HR, 0.43; 95% CI, 0.25-0.75). The corresponding rates were 91.1% and 77.2% (HR, 0.43; 95% CI, 0.17-1.06), respectively, among 137 patients who were operable at presentation with ypN-negative nodes and hormone receptor–negative disease. 

“All of the high-risk patient subgroups benefited from T-DM1,” Mano, who is from the Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil, said in an interview with 

Outcomes were also assessed in 77 lower-risk patients with small tumors (cT1 cN0) at presentation—45 patients in the T-DM1 arm and 32 in the trastuzumab arm. Overall, patient characteristics were well balanced between the 2 arms. Results showed that there were 6 iDFS events in the trastuzumab group and none in the T-DM1 group.

“The benefit from T-DM1 was the same in these patients as in the full trial population.” These patients with small tumors are usually referred to surgery, but Mano said these data may cause him to rethink this. “Perhaps we should be more careful in this patient population. Maybe some of these patients are better treated with neoadjuvant chemotherapy.”

In their poster, the Mano et al also drilled down on patient demographic and safety data across the NACT cohorts. 

Overall, 77% of patients received AC-based NACT. In the AC arm, 579 patients received T-DM1 and 564 patients received trastuzumab. In the non-AC arm, 164 patients received T-DM1 and 179 patients received trastuzumab. 

Patient characteristics were, for the most part, well balanced across the treatments arms, regardless of the type of neoadjuvant regimen. The median patient age was around 50 years old, about two-thirds of patients were white, approximately three-fourths of patients were ER- and/or PgR-positive, and about 80% of patients received adjuvant radiotherapy. 

A higher percent of patients in the AC arm had an ECOG performance status of 0, at about 84% versus about 72% in the non-AC arm. The authors also noted in their poster that “patients treated with AC-based NACT were less likely to be from North America and less likely to be Asian.”

Regarding neoadjuvant HER2-targeted therapy, about 90% of patients in the AC arm had received trastuzumab alone and about 10% had received trastuzumab plus pertuzumab (Perjeta). The corresponding rates in the non-AC arm were about 55% and 45%, respectively. 

Also across the non-AC arm, about three-fourths of patients received neoadjuvant carboplatin/cisplatin and about 95% were treated with a neoadjuvant taxane for >12 weeks. 

Overall, the safety profile was similar between the AC and non-AC arms. Adverse events (AEs) reported in previous studies to have occurred more commonly with T-DM1 or trastuzumab (eg, hepatotoxicity, peripheral neuropathy, hemorrhage, infusion-related reaction/hypersensitivity, and cardiac dysfunction) had similar all-grade incidence rates between the AC- and non-AC cohorts. 

The researchers did note, however, that all-grade thrombocytopenia occurred at a higher rate (32.5% vs 27.4%) in the T-DM1 non-AC arm compared with the T-DM1 

AC group. The non-AC T-DM1 arm also had higher all-grade pulmonary toxicity at 6.7% versus 1.7% in the AC T-DM1 arm.  

Grade ≥3 AEs occurred at higher rates in the non-AC T-DM1 group versus the AC T-DM1 group at 39.9% versus 21.7%, respectively. The largest differences in grade ≥3 AEs  between the 2 arms occurred with thrombocytopenia (10.4% vs 4.3%, respectively) and peripheral sensory neuropathy (4.3% vs 0.5%, respectively). 

Addressing these disparities, Mano et al wrote, “Factors that may have contributed to the increased toxicity [in the non-AC T-DM1 group] include differences in baseline characteristics (eg, a higher proportion of patients with ECOG performance status 1 and a higher proportion of Asian patients) and prior therapy (eg, a higher proportion of patients receiving platinum-based therapy and >12 weeks of taxane therapy in the non-AC group).”

Mano noted that the increased AEs in the non-AC T-DM1 group were usually resolved and “did not impact treatment continuation.”

AE-related discontinuation rates of T-DM1 (19.6% vs 17.5%) and AE-related T-DM1 dose-reduction rates (14.1% vs 11.6%) were similar, regardless of the type of NACT regimen.

Based on the overall population analysis of KATHERINE, the FDA approved T-DM1 in May 2019 for use as an adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab and chemotherapy.

Mano MS, Loibl S, Mamounas, EP et al. Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: KATHERINE subgroup analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract P3-14-01.

View more from 2019 San Antonio Breast Cancer Symposium

The invasive disease-free survival (iDFS) benefit with adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) versus trastuzumab (Herceptin) in patients with HER2-positive early breast cancer who had residual invasive disease following neoadjuvant therapy was observed regardless of the type of neoadjuvant chemotherapy (NACT) used. A benefit with T-DM1 was also observed across several high-risk patient populations, according to subgroup analyses from the phase III KATHERINE trial.

The invasive disease-free survival benefit with adjuvant T-DM1 versus trastuzumab in patients with HER2-positive early breast cancer who had residual invasive disease following neoadjuvant therapy was observed regardless of the type of neoadjuvant chemotherapy used.

Adjuvant T-DM1 Benefit in HER2+ Breast Cancer Observed Across Key Subgroups

A subcutaneous (SC) fixed-dose combination (FDC) of pertuzumab (Perjeta) and trastuzumab (Herceptin) demonstrated noninferiority to intravenous formulations of the 2 drugs with respect to pharmacokinetics, clinical activity, and safety, a randomized trial demonstrated.

The 500-patient study met the primary end point, demonstrating noninferiority on the basis of predose cycle 8 serum C

 for the pertuzumab component of the FDC, with a mean value of 93.7 versus 78.5 µg/mL for IV pertuzumab. Geometric means were 88.7 and 72.4 µg/mL, respectively (geometric mean ratio [GMR], 1.22; 90% CI, 1.14-1.31).

The trial also demonstrated noninferiority for the predose cycle 8 serum C

 for the trastuzumab component of the FDC compared with IV: 62.9 versus 48.1 µg/mL. Geometric means were 58.7 and 44.1 µg/mL for the SC and IV formulations of trastuzumab (GMR 1.33; 90% CI, 1.24-1.43).

Total pathologic complete response (tpCR) in the breast and axilla and safety also were similar between the 2 treatment regimens, Antoinette R. Tan, MD, reported at the 2019 San Antonio Breast Cancer Symposium. Tan is chief of Breast Medical Oncology and co-director of the Phase I Program at the Levine Cancer Institute of Atrium Health in Charlotte, North Carolina.

“The key takeaways are that the pharmacokinetics of the subcutaneous fixed-dose formulation of pertuzumab was noninferior compared to the intravenous counterpart, the efficacy was also nearly identical as measured by pathologic complete response rate, and the safety also was comparable, including cardiac safety,” Tan told OncLive

“I think another key takeaway is that this offers patients a simpler, faster, more convenient treatment experience, because they’re getting a drug that’s given subcutaneously versus intravenously. They would spend less time in an infusion chair. I think there are implications for reducing resource utilization in terms of pharmacy, because of a shorter preparation time and a shorter administration time.”

IV pertuzumab plus IV trastuzumab and chemotherapy have been shown to improve outcomes in patients with HER2-positive breast cancer, as compared with IV trastuzumab plus chemotherapy. A first-ever SC FDC combines the 2 monoclonal antibodies with recombinant hyaluronidase in premeasured single-use vials. The FDC is administered subcutaneously in the thigh over 5 to 8 minutes.

The dose of trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) was established in the phase III HannaH trial,

 and the dose of SC pertuzumab was determined in a phase Ib dose-finding study.

To compare the SC FDC with conventional IV treatment, investigators at 122 sites enrolled patients with newly diagnosed stage II-IIIc HER2-positive breast cancer in the trial of neoadjuvant therapy. The patients were randomized to 4 cycles of doxorubicin and cyclophosphamide chemotherapy followed by 4 cycles of docetaxel administered with randomized therapy: IV pertuzumab and trastuzumab or the SC FDC.

Following surgery, patients received adjuvant therapy with the same pertuzumab-trastuzumab formulation they received in the neoadjuvant setting. The primary analysis for the trial occurred before the start of adjuvant therapy.

The patients had a median age of about 50, 80% had stage II-IIIa disease, and 61% were hormone-receptor positive.

The comparison of predose cycle 8 Ctrough values for IV pertuzumab and trastuzumab versus the individual components of the FDC produced GMRs that fell within the 90% confidence intervals for noninferiority.

The 2 treatment arms had almost identical rates of tpCR (defined as ypT0/Tis, ypN0): 59.5% with the IV drugs and 59.7% with the SC FDC.

The safety analysis showed that incidences of the most common adverse events (AEs) were similar between the 2 arms, including alopecia, nausea, diarrhea, anemia, and asthenia. Rates of specific AEs to monitor also were comparable, including diarrhea, neutropenia/febrile neutropenia, cardiac dysfunction, infusion/administration-related reactions within 24 hours of anti-HER2 therapy, interstitial lung disease, serious rash/skin reactions, serious mucositis, and pregnancy/neonatal-related AEs.

Tan AR, Im S-A, Mattar A, et al. Subcutaneous administration of the fixed-dose combination of trastuzumab and pertuzumab in combination with chemotherapy in HER2-positive early breast cancer: primary analysis of the phase III, multicenter, randomized, open-label, two-arm FeDeriCa study. Presented at: 2019 San Antonio Breast Cancer Symposium. Poster PD4-07.

Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. 

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Kirschbrown WP, Wynne C, Kagedal M, et al. Development of a subcutaneous fixed-dose combination of pertuzumab and trastuzumab: results from the phase Ib dose-finding study. 

. 2019 May;59(5):702-716. doi: 10.1002/jcph.1362.

A subcutaneous fixed-dose combination of pertuzumab and trastuzumab demonstrated noninferiority to intravenous formulations of the 2 drugs with respect to pharmacokinetics, clinical activity, and safety, a randomized trial demonstrated.

Subcutaneous Fixed-Dose Pertuzumab/Trastuzumab Proves Noninferiority Versus IV Drugs

Subcutaneous (SC) trastuzumab with hyaluronidase-oysk (Herceptin Hylecta) in combination with intravenous (IV) pertuzumab (Perjeta) and chemotherapy had a safety profile consistent with IV trastuzumab as first-line treatment for metastatic HER2-positive breast cancer, according to results of a large single-arm phase IIIb trial.

Overall, about half of 412 patients had grade ≥3 adverse events (AEs), one fifth had AEs leading to drug withdrawal, and about a third had AEs leading to drug interruption. Among AEs to monitor, diarrhea, mucositis, and rash occurred most often. Aside from hematologic AEs, grade ≥3 AEs to monitor were uncommon. Investigator-reported AEs/grade ≥3 AEs also were infrequent.

An exploratory efficacy analysis also yielded results consistent with historical data from the landmark CLEOPATRA trial, Sherko Kümmel, MD, of Kliniken Essen-Mitte in Germany, reported at the 2019 San Antonio Breast Cancer Symposium (SABCS).

“The CLEOPATRA trial was practice changing and established IV pertuzumab plus IV trastuzumab with chemotherapy, followed by IV trastuzumab and chemotherapy, as standard of care for patients with HER2-overexpressing metastatic breast cancer,”. Kümmel told

. “This is the second trial of that treatment, and even though it is not a randomized trial, it affirms the efficacy of the CLEOPATRA trial, in terms of PFS (progression-free survival) and OS (overall survival).”

“These are the first data where we have both the efficacy and safety from the trastuzumab subcutaneous formulation together with pertuzumab IV,” he added.

Early studies of SC trastuzumab demonstrated noninferiority to IV trastuzumab with respect to pathologic complete response in the breast and serum trough concentration at pre-dose cycle 8.

 Subsequent studies confirmed noninferiority with respect to event-free survival, OS, and safety.

The SC formulation offers the potential to reduce treatment burden for patients and increased satisfaction health care professionals, Dr. Kummel noted. Those qualities were confirmed in studies of early and metastatic HER2-positive breast cancer.

Dr. Kummel presented results from the primary and final analysis of the MetaPHER study, the largest trial conducted to date to evaluate the safety and tolerability of first-line SC trastuzumab plus IV pertuzumab and docetaxel in patients with advanced (locally recurrent or metastatic) HER2-positive breast cancer. All patients received SC trastuzumab at a fixed dose of 600 mg/5mL every 3 weeks, IV pertuzumab with an 840-mg loading dose followed by 420-mg maintenance doses every 3 weeks, and 6 or more doses of IV docetaxel at 75 mg/m

 every 3 weeks. Treatment continued until disease progression or development of unacceptable toxicity.

The primary objective was to evaluate the safety and tolerability of the regimen. Efficacy (objective response, investigator-assessed PFS and OS) was a secondary objective.

The patients had a median age of 56 years, 62.4% were postmenopausal, 97.3% had metastatic disease, 70.4% were hormone-receptor positive, and 52.7% had been treated previously, including trastuzumab (31.8%), a taxane (32.8%), and hormonal therapy (33.7%).

Median treatment exposure was 22.0 cycles of SC trastuzumab, 21.5 cycles of IV pertuzumab, and six cycles of docetaxel.

Overall, 98.5% of patients had one or more AEs, 53.6% had grade ≥3 AEs, and 26% had serious AEs. Nine patients had fatal AEs, 96.8% of AEs were considered treatment relate, 21% had AEs leading to withdrawal, and 35.7% had AEs leading to drug interruption.

Diarrhea was the most commonly reported AE (63.3%), followed by mucositis (36.9%), rash (34.7%), leukopenia (26.9%), and neutropenia (18.2%). Grade ≥3 AEs were led by leukopenia (20.4%), neutropenia (12.6%), febrile neutropenia (8.5%), and diarrhea (5.1%). The frequency of investigator-reported administration-related and injection-site reactions of 21.1% (5.1% SC trastuzumab, 5.3% IV pertuzumab, and 11.7% docetaxel). Grade ≥3 investigator-reported AEs consisted of one case involving IV pertuzumab and four involving docetaxel.

Three grade ≥3 cardiac AEs occurred, as well as one serious AE suggestive of heart failure. Dr. Kummel reported a 10.1% of evaluable patients had at least a 10% reduction in left ventricular ejection fraction or a decrease to <50%. Two patients had symptomatic LV dysfunction. The decrease in LVEF resolved in most cases.

Investigator assessed median PFS was 18.7 months. OS at 12 and 24 months was 92.9% and 81.1%, respectively.

Analysis of objective response in 336 patients showed an overall response rate of 75.6%, including complete responses in 12.5%. An additional 16.4% of patients had stable disease, resulting in a clinical benefit rate of 92%.

Final analysis of the Phase IIIb, multicenter, open-label, single-arm MetaPHER study. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract P1-18-05.

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Subcutaneous trastuzumab with hyaluronidase-oysk in combination with intravenous pertuzumab and chemotherapy had a safety profile consistent with IV trastuzumab in first-line metastatic HER2-positive breast cancer treatment.