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International Congress on the Future of Breast Cancer East

Examining the best way to utilize CDK4/6 inhibitors in both the neoadjuvant and adjuvant settings for patients with breast cancer is necessary to improve care, said Angela DeMichele, MD, MSCE, in a presentation during the 

International Congress of the Future of Breast Cancer

“In the neoadjuvant setting, I’m going to focus on what these studies tell us about the mechanism of action of CDK4/6 inhibitors. I'm going to talk a little bit about what the best end point would be and how could we use these agents in the neoadjuvant setting to improve care,” said DeMichele. “Then, I will focus on the adjuvant setting, where we have very early data. We’re living in a time of press releases; that’s where we get most of our first reads on scientific outcomes, and so we'll just touch on where we are at in that area.”

In her presentation, DeMichele, a professor of medicine and epidemiology at the University of Pennsylvania; the Jill and Alan Miller Endowed Professorship in Breast Cancer Excellence; and the co-leader of the Breast Cancer Research Program in the Abramson Cancer Center, highlighted key updates with CDK4/6 inhibitors and shed light on where research is headed.

DeMichele kicked off her talk by examining how the use of endocrine therapy plus CDK4/6 inhibitors in the neoadjuvant setting could potentially improve patient care. This approach could help identify primary endocrine resistance; it could potentially replace chemotherapy with equivalent outcomes and less toxicity; it could improve neoadjuvant chemotherapy in patients with the highest risk; and it might enable the selection of the best adjuvant combination treatment.

“However, in order to do this we need to know which population of tumors and patients are appropriate for this approach and we need to have really robust surrogate outcomes to tell us whether patients have achieved the best outcome for a long-term recurrence end point,” stressed DeMichele. “These are areas where we are still struggling to understand how to use these agents.”

With regard to considering the best end point, a lot of attention has been turned to the Preoperative Endocrine Prognostic Index (PEPI) score, which was developed to identify patients who are at a low risk for recurrence after neoadjuvant endocrine therapy. With endocrine therapy, DeMichele said that it is unlikely that a pathologic complete response (pCR) will be observed; as such, other end points are needed to understand how the tumor responded to treatment.

The modified PEPI (mPEPI) score 0 (without ER) at surgery is defined as a primary tumor of up to 5 cm (pT1-2), negative nodes (pN0), and a Ki-67 of <2.7%. Results from early studies, such as P024 and IMPACT, indicated that patients who achieved a PEPI 0 score with neoadjuvant endocrine therapy alone were found to have a significantly lower risk of recurrence, according to DeMichele.

In the phase 3 ALTERNATE trial (NCT01953588), investigators set out to prospectively validate the mPEPI score as a surrogate end point for relapse-free survival (RFS) in patients with early, estrogen receptor (ER)–positive, HER2-negative breast cancer who were treated only with neoadjuvant endocrine therapy.

Specifically, the goal was to identify which patients could avoid treatment with chemotherapy and identify the optimal endocrine therapy options for neoadjuvant treatment, said DeMichele. A secondary end point of this research was to understand whether an early change in Ki-67 could adequately triage patients to chemotherapy. The primary end point was based on mPEPI, which notably, does not include the estrogen receptor component of PEPI. Additionally, a composite end point was used, an endocrine-sensitive disease rate (ESDR), which was the sum of partial complete response plus mPEPI following 6 months of neoadjuvant endocrine treatment.

In the trial, investigators compared anastrozole, fulvestrant, or the combination as the initial therapy for postmenopausal patients with clinical stage II or III, ER-positive, HER2-negative disease. Results from the surgical time point were presented during the 

 and results showed that almost all patients with Ki-67 of ≤10% at baseline remained at Ki-67 of ≤10% at week 4 of the study.

 However, about two-thirds of those with a Ki-67 of ≥10% at baseline were able to be covered to a lower Ki-67 of ≤10% at week 4. Moreover, the ESDR was 18.6% in those who received anastrozole (n = 434), 22.7% in those given fulvestrant alone (n = 431), and 20.5% in those given the combination (n = 434).

“We saw that 20% of the patients would have the desirable end point at surgery that we would hope would predict for very good long-term outcomes,” said DeMichele. “However, longer-term follow-up is needed to determine whether this surrogate endpoint will correlate with recurrence outcomes.”

In the neoadjuvant, single-arm phase 2 NeoPalAna trial (NCT01723774), patients with pre-/post-menopausal stage II/III ER-positive, HER2-negative breast cancer received 4 weeks of anastrozole, followed by 4 cycles of anastrozole plus palbociclib (Ibrance). The trial stratified by 

 mutational status. The primary objective of the trial was to determine whether the addition of the CDK4/6 inhibitor to anastrozole would lead to a higher rate of complete cell cycle arrest (CCCA), defined as a Ki-67 of <2.7%, compared with anastrozole alone.

Results showed that CCCA was only about 28% following treatment with anastrozole alone and that increased to 87% following 2 weeks of treatment with the combination.

“That meant that 84% of patients who were resistant to anastrozole alone could become sensitive with the addition of a CDK4/6 inhibitor,” said DeMichele.

Additionally, prior to this study, it was thought that there might be a differential response between luminal A and luminal B tumors with palbociclib. Results showed that at day 15, both subtypes reported a significant drop in Ki-67 and a higher CCCA. Patients with luminal A tumors went from 40% to 100%, and those with luminal B tumors went from 9% to 75%. “Both subtypes responded to the CDK4/6 inhibitor,” stressed DeMichele.

In the randomized, multicenter phase 2 FELINE trial (NCT02712723), investigators evaluated letrozole plus ribociclib (Kisqali) compared with letrozole plus placebo in postmenopausal patients with ER-positive, HER2-negative anatomical stage II/III disease and a primary tumor of >2 cm. Patients were randomized 1:1:1 to either placebo plus letrozole, intermittent ribociclib plus letrozole, or continuous ribociclib plus letrozole. Patients continued treatment until the day before surgery. Importantly, patients with a Ki-67 of >10% on day 14 were removed from the trial.

The primary objective of the trial was to understand whether the addition of ribociclib to endocrine therapy would lead to more patients with a PEPI of 0 at the time of surgery. “Really, the goal of which is to obviate the need for adjuvant chemotherapy,” noted DeMichele. The primary end point of the trial was PEPI score of 0 at surgery, which was established with 80 patients in groups B plus C and 40 patients in group A needed to show an increase in PEPI 0 by 20%.

Results showed that the addition of ribociclib to letrozole as neoadjuvant therapy did not result in the number of patients with a PEPI score of 0.

 The addition of the CDK4/6 inhibitor to endocrine therapy did result in a near doubling in the proportion of patients who achieved CCCA at day 14, but that did not persist all the way to surgery, according to DeMichele. Early suppression of Ki-67 from the combination achieved at day 14, was not upheld at the time of surgery. Additionally, the continuous dose of ribociclib in the neoadjuvant setting was found to have similar efficacy to what was seen with the intermittent dose, although difference existed with regard to toxicity.

Neoadjuvant Endocrine Therapy Plus CDK4/6 Inhibitors Versus Chemotherapy

The next question to consider is whether the combination of neoadjuvant endocrine therapy and CDK4/6 inhibitors could replace chemotherapy in patients to improve outcomes and decrease treatment-associated toxicities.

“We need to think about the surrogate that might be important here,” said DeMichele.

For chemotherapy, pCR and residual cancer burden (RCB) have proven to be prognostic in patients with HER2-positive or triple-negative disease, according to DeMichele. However, not many patients with ER-positive, HER2-negative disease are able to achieve pCR/RCB on endocrine treatment.

PEPI is an end point that is under consideration, but it has not been utilized in chemotherapy studies. As such, there are concerns with using this end point in the space, said DeMichele. Additionally, PEPI is strongly dependent on Ki-67, which is known to drop when CDK4/6 inhibitors are administered.

Another end point under exploration is risk of recurrence (ROR) score, which uses the Prosigna assay to incorporate subtype switch from luminal B to luminal A as an alternative end point that might be more sensitive to differences and more predictive of ultimate outcome.

 “Essentially, what you get back when you submit tumor for an ROR score, is a ROR that is categorized as either low-, intermediate-, or high-risk and you’re told the subtype of the tumor that you submitted, and that is ultimately turned into a percentage probability of distant recurrence,” explained DeMichele.

In the randomized, parallel, phase 2 NeoPAL study (NCT02400567), investigators examined neoadjuvant letrozole plus palbociclib versus chemotherapy in patients with stage II/III, ER-positive, HER2-negative disease; notably, the trial included both patients with Luminal A and Luminal B disease. Treatment with palbociclib was continued until 24 hours prior to surgery. The primary end point of the trial was RCB 0-1 and the secondary end point was PEPI 0.

Results showed that the median ROR score for patients with high-risk Luminal B disease was 70 with letrozole/palbociclib versus 73 with chemotherapy alone.

 As expected, the combination was also found to be less toxic, with only 2 serious adverse effects reported in those who received it versus 14 of those who were given chemotherapy. However, the trial’s primary objective of RCB 0-1 in ≥20% of patients was not met. Notably, a greater drop in Ki-67 was noted with the combination and thus, a higher PEPI 0 was observed. PEPI 0 was 17.6% in the combination arm versus 8% in the chemotherapy arm. Additional follow-up are needed, said DeMichele.

The phase 2 CORALLEEN trial (NCT03248427) is another notable trial that set out to examine neoadjuvant letrozole in combination with ribociclib versus multiagent chemotherapy in patients with postmenopausal HR-positive, HER2-negative, stage I-IIIA breast cancer with a tumor size of ≥2 cm; this trial only enrolled patients who were Luminal B. The primary end point of the trial was ROR score.

“At the time of surgery, the proportion of patients who became ROR low were similar in the chemotherapy arm at 46.1% and the ribociclib/letrozole arm at 46.9%,” said DeMichele.

 “So almost 50% of the patients converted to a low ROR which would be presumed to afford these patients a good long-term outcome.”

Results also showed intrinsic subtype conversion from Luminal B to Luminal A, added DeMichele. Furthermore, the combination had a lower RCB 0-1 rate, at 6.1%, versus 11.8% with chemotherapy.

Early Data With Adjuvant CDK4/6 Inhibitors

Currently, 4 key adjuvant phase 3 trials are ongoing: NATALEE (NCT03701334), PALLAS (NCT02513394), monarchE (NCT03155997), and PENELOPE-B (NCT01864746).

In May 2020, the independent data monitoring committee for the PALLAS trial, which is comparing palbociclib plus adjuvant endocrine therapy with adjuvant endocrine therapy alone in patients with hormone receptor–positive, HER2-negative, early-stage breast cancer, announced that the trial is unlikely to demonstrate a statistically significant improvement in the primary end point of invasive disease-free survival (iDFS) at a pre-planned interim analysis.

In June 2020, a press release on the monarchE trial, with is examining abemaciclib (Verzenio) in combination with adjuvant endocrine therapy versus adjuvant endocrine therapy alone in patients with HR-positive, HER2-negative early breast cancer, showed that the combination led to a significant reduction in the risk of breast cancer recurrence or death, meeting the primary end point of iDFS.

Notably, based on the activity reported in the study, abemaciclib is now the only CDK4/6 inhibitor to achieve a statistically significant reduction in the risk of recurrence in this patient population.

“Completely different results were seen between the 2 trials. The question, of course, is why? One difference is the risk groups that were enrolled on the trials. For PALLAS, 1,000 of the 5,800 patients had stage IIA disease; no patients with stage IIA disease were enrolled on monarchE. In fact, monarchE had a much higher-risk population,” said DeMichele. “That could be important, given that this is very early follow up. A higher-risk population at an early 2-year follow-up may be skewed in having more recurrences. As such, it’s important to be careful when interpreting early results. What we learn in the first 2 years is important, but it might not be the whole story.”

Full data from these trials are expected to be reported at the 2020 ESMO Congress.

DeMichele A. Neo/adjuvant CDK4/6 inhibitors. Presented at: 

International Congress of the Future of Breast Cancer® East meeting; July 17-18, 2020. Accessed July 17, 2020.

Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor–positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. 

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Ma CX, Suman VJ, Leitch M, et al. ALTERNATE: neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106. 

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Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. 

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Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). 

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Cottu P, D’Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. 

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Gavilá J, Saura C, Pascual T, et al. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: an open-label, multicenter, two-arm, randomized study. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019. Session GS2. 

Verzenio (abemaciclib) significantly reduced the risk of cancer returning in people with high risk hr+, her2- early breast cancer. News release. Eli Lilly and Company. June 16, 2020. Accessed July 17, 2020. 

Pfizer provides update on phase 3 PHALLAS trial of Ibrance (palbociclib) plus endocrine therapy in HR+, HER2-, early breast cancer. News release. Pfizer. May 29, 2020. Accessed July 17, 2020. https://bit.ly/2BegYrc.

Angela DeMichele, MD, MSCE, shares how to utilize available data with CDK4/6 inhibitors in the neoadjuvant and adjuvant settings to optimize outcomes for patients with hormone receptor–positive breast cancer.

Leveraging CDK4/6 Inhibitors in Earlier Settings to Boost Outcomes in HR+ Breast Cancer

Eleftherios (Terry) P. Mamounas, MD, MPH, FACS, medical director of the Comprehensive Breast Program at the University of Florida Health Cancer Center, discusses common recurrence rates in breast cancer.

When it comes to early stage estrogen receptor (ER)–positive breast cancer, over time, the risk of recurrence is generally stable, says Mamounas. Conversely, with triple-negative breast cancer, the risk of reoccurrence is high in the first 2 to 3 years but, after 5 plus years, it can drop to nearly 0%. 

However, for patients with ER-positive breast cancer, several studies demonstrated that the rate of risk of recurrence and death are typically the highest after the first 5 years, Mamounas adds. 

As shown in larger studies, the rate of distant recurrence is stable from year 5 to 20; however, this depends, to some extent, on the original tumor presentation. Regardless, this is a remarkable rate, Mamounas concludes.



Terry P. Mamounas, MD, MPH, FACS, discusses common recurrence rates in breast cancer.

Dr. Mamounas on Recurrence Rates in Breast Cancer 

The growing number of treatments within the HER2-positive breast cancer armamentarium signals a need to redefine and tailor neoadjuvant and adjuvant strategies to individual patients, said Sarah M. Tolaney, MD, MPH, in a presentation during the 

International Congress of the Future of Breast Cancer® East meeting.

“We’ve learned that we can change long-term outcomes for our patients with HER2-positive disease by adapting adjuvant therapy based on response to preoperative therapy,” said Tolaney, associate director of the Susan F. Smith Center for Women’s Cancers and director of Clinical Trials and Breast Oncology at Dana-Farber Cancer Institute. “This is really a paradigm shift. This adaptive treatment approach puts an end to future adjuvant trials that are focused on stage II/III patients.”

At the meeting, Tolaney discussed key data to inform treatment de-escalation and escalation, the push toward less chemotherapy-intensive regimens and more precision medicine-based approaches, and where future research efforts should be focused in the HER2-postive breast cancer paradigm.

Era of Targeted Therapy Signals Treatment De-Escalation

Substitution of traditional chemotherapy regimens with less toxic chemotherapies or targeted therapies has been an area of significant interest in the HER2-positive breast cancer space.

Final results of the randomized phase 3 BCIRG-006 trial1 confirmed that adjuvant trastuzumab (Herceptin)-containing regimens elicited significant disease-free survival (DFS) benefit in patients with operable node-positive or high-risk node-negative HER2-positive breast cancer.

At 10 years, investigators showed an insignificant difference in efficacy with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCH).

At a median follow-up of 10.3 years, DFS was 67.9% with doxorubicin plus cyclophosphamide followed by docetaxel (AC-T; HR, 1), 74.6% with AC-TH (HR, 0.72; 95% CI, 0.61%-0.85%; 

 <.0001), and 73% with TCH (HR, 0.77; 95% CI, 0.65%-0.90%; 

 An overall survival (OS) benefit was also observed in the trastuzumab-containing arms.

Regarding safety, patients who received TCH had less cardiac toxicity and a lower incidence of secondary leukemia.

These findings demonstrate that even in high-risk patients with HER2-positive breast cancer, anthracycline-based therapies do not provide a DFS advantage, explained Tolaney.

Moreover, the randomized phase 3 TRAIN-2 trial evaluated whether taxanes could replace anthracyclines as the chemotherapy backbone in combination with dual HER2 blockade in the neoadjuvant setting in patients with HER2-positive breast cancer.

In the study, patients with previously untreated, histologically confirmed stage II/III disease were randomized to receive 5-fluorouracil, epirubicin, and cyclophosphamide, followed by paclitaxel and carboplatin, or paclitaxel and carboplatin alone. Patients received concurrent trastuzumab and pertuzumab (Perjeta) with all chemotherapy cycles.

Results showed that the pathologic complete response (pCR) rates were comparable in both arms. However, the rates of grade 3/4 febrile neutropenia were significantly higher in the anthracycline arm versus the paclitaxel/carboplatin-alone arm, at 10% versus 1%, respectively.

Additionally, 97% of patients completed a full year of trastuzumab in the paclitaxel/carboplatin alone arm compared with 89% in the anthracycline arm.

These findings suggest that omitting anthracyclines may be a preferred neoadjuvant strategy for patients with early-stage HER2-positive breast cancer receiving concurrent dual HER2 blockade. Although longer-term follow-up is needed, Tolaney said that it is difficult to justify using anthracyclines in the era of HER2-directed therapies.

Whether ado-trastuzumab emtansine (T-DM1; Kadcyla) could serve as a substitute for taxanes remained another question in this space.

At the 2020 ASCO Virtual Scientific Program, findings from the phase 3 KAITLIN study

 demonstrated that anthracycline-based chemotherapy followed by T-DM1 plus pertuzumab (AC-KP) did not induce a clinically meaningful improvement in invasive DFS (iDFS) compared with taxane-based chemotherapy plus concurrent trastuzumab and pertuzumab (AC-THP) in the node-positive and intent-to-treat (ITT) populations, missing the coprimary end points of the trial.

In the ITT population, 86 iDFS events were observed in the AC-KP arm versus 88 in the AC-THP arm(stratified HR, 0.98; 95% CI, 0.72-1.32). The 3-year iDFS rates were 93.1% versus 94.2%, respectively.

Patient-reported outcomes (PROs) demonstrated a lower risk of patient deterioration with AC-KP versus AC-THP from the start of HER2-targeted therapy (stratified HR, 0.71; 95% CI, 0.62-0.80).

The phase 3 KRISTINE trial demonstrated similar iDFS findings when patients with HER2-positive breast cancer were randomized to receive TCH plus pertuzumab (TCHP) or TDM-1 plus pertuzumab in the neoadjuvant setting followed by trastuzumab/pertuzumab or T-DM1/pertuzumab in the adjuvant setting.

The pCR rate was 11.3 percentage points lower with T-DM1/pertuzumab compared with TCHP. At 3 years, iDFS was 92% with TCHP versus 93% with T-DM1/pertuzumab (stratified HR, 1.11; 95% CI, 0.52-2.40).

According to Tolaney, these results do not establish a clear role for pertuzumab in combination with T-DM1; however, T-DM1/pertuzumab was associated with less toxicity than TCHP.

The Move Toward Chemotherapy-Free Regimens

Attempts to de-escalate or eliminate patients’ exposure to chemotherapy has been an ongoing challenge.

Longer-term follow-up from the phase 2 APT study continued to show favorable outcomes with 12 weeks of paclitaxel and trastuzumab followed by 9 months of trastuzumab in patients with HER2-positive breast cancer whose tumors were 3 cm or smaller and were node negative.

The 7-year DFS rate 93.3% (95% CI, 90.4%-96.2%), and the recurrence-free interval (RFI) was 97.5% (95% CI, 95.9%-99.1%).

These findings support the use of the combination in the adjuvant setting for patients with stage I disease and shed light on the potential to maintain positive outcomes with de-escalated treatment.

In the same population, the phase 2 ATEMPT trial demonstrated high rates of disease control and minimal recurrence rates with adjuvant T-DM1 compared with the combination of paclitaxel and trastuzumab.

At 3 years, the DFS rate was 97.7% (95% CI, 96.2%-99.3%; 

 <.0001), and the RFI rate was 99.1% with postoperative T-DM1 (95% CI, 98.1%-100%).

Regarding toxicity, T-DM1 was associated with lower rates of grade 2 or higher neurotoxicity compared with paclitaxel/trastuzumab. However, a greater percentage of patients required early treatment discontinuation due to any toxicity with T-DM1 (17%) versus paclitaxel/trastuzumab (6%).

PROs revealed that patients who received T-DM1 reported better quality of life (QOL) versus patients who received paclitaxel/trastuzumab. Moreover, T-DM1 led to significantly improved rates of alopecia compared with chemotherapy.

Given the low incidence of events reported with T-DM1, the regimen may provide a potentially less toxic alternative to chemotherapy, said Tolaney.

Planned studies, such as the phase 2 ATEMPT 2.0 trial will further evaluate alternative options to standard chemotherapy in this setting.

Finally, multiple studies have sought to determine whether shorter treatment duration leads to a difference in outcomes in patients with HER2-positive breast cancer.

Although 1 year of trastuzumab remains a standard of care in this patient population, trials such as SOLD, Short-HER, PHARE, Hellenic Oncology, and Persephone appear to unanimously indicate that stopping treatment with trastuzumab plus chemotherapy early due to toxicity in patients with lower-risk disease will likely not have a significant impact on patient outcomes. Additionally, some of these studies reported less cardiac toxicity with the shorter duration of trastuzumab.

Escalation Strategies for Higher-Risk Patients

Escalating therapy for patients with higher-risk disease has also been of great clinical interest, said Tolaney.

The phase 3 APHINITY trial randomized patients with HER2-positive early disease to receive chemotherapy plus trastuzumab and pertuzumab versus chemotherapy plus trastuzumab and placebo in the adjuvant setting.

The updated 6-year analysis showed an iDFS rate of 90.6% with the addition of pertuzumab versus 87.8% with placebo (HR, 0.76). Clinically meaningful benefit was observed among patients with hormone receptor (HR)–positive, hormone receptor–negative, and node-positive disease. iDFS benefit was not observed in patients with node-negative disease.

The addition of pertuzumab led to a 0.9% reduction in the risk of death compared with placebo which was not found to be statistically significant as per a predetermined 

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

Additional research is needed to flesh out which patients should receive preoperative pertuzumab up front to minimize overtreatment, explained Tolaney.

Neratinib (Nerlynx) has also been the subject of investigation in an attempt to solidify the agent’s role in the management of patients with HER2-positive disease.

 investigators reported a modest improvement in iDFS with neratinib compared with placebo as extended adjuvant therapy following prior trastuzumab and chemotherapy.

Long-term data from the study showed that at 5 years, neratinib reduced the risk of invasive disease recurrence or death by 27% versus placebo (HR, 0.73; 95% CI, 0.57-0.92; 

 = .008). Rates of iDFS were 90.2% versus 87.7%, respectively.

Patients with HR–positive disease derived a significant benefit with neratinib, which translated to a 40% reduction in the risk of invasive disease recurrence or death with neratinib versus placebo (HR, 0.60; 95% CI, 0.43-0.83; 

As diarrhea is an associated toxicity with neratinib, the phase 2 CONTROL trial evaluated whether prophylactic treatment could reduce treatment-related diarrhea in patients with HER2-positive early-stage breast cancer.

Results from the trial showed that adding budesonide or colestipol to loperamide prophylaxis reduced the incidence of diarrhea, which may lead to improved adherence rates and overall outcomes, explained Tolaney.

Updated findings from the study revealed that utilizing a dose escalation regimen of neratinib plus loperamide prophylaxis was associated with the lowest rate of treatment discontinuation due to diarrhea, as well as the lowest incidence of grade 3/4 diarrhea.

Taken collectively, Tolaney advised that although neratinib demonstrated significant benefit in patients with high-risk HR–positive HER2-positive disease, the benefit should be weighed with the toxicity. Additionally, further studies are needed to determine the utility of neratinib in patients who have previously received pertuzumab and/or T-DM1.

Finally, the influx of FDA approvals and novel agents recently opens the door to replace current standards with more effective agents.

For example, results from the phase 3 KATHERINE study showed a 50% reduction in the risk of invasive disease recurrence or death with T-DM1 compared with trastuzumab (HR, 0.50; 95% CI, 0.39-0.64; 

 <.001) in patients with HER2-positive breast cancer who did not achieve a pCR at surgery after completing neoadjuvant chemotherapy and HER2-directed therapy.

Notably, improved iDFS rates were observed with T-DM1 versus neratinib or pertuzumab, said Tolaney.

The findings from the KATHERINE study suggest that a patient’s response to neoadjuvant chemotherapy rather than tumor size or nodal status at diagnosis informs risk in this patient population.

Although the results of KATHERINE are encouraging, Tolaney questioned whether these findings can be improved upon. Further studies evaluating additive agents such as tucatinib (Tukysa) or substitutional agents such as fam-trastuzumab deruxtecan-nxki (Enhertu) are ongoing.

The future appears bright in the neoadjuvant and adjuvant treatment of patients with HER2-positive breast cancer, concluded Tolaney.

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2019;380(7):617-628. doi:10.1056/NEJMoa1814017

The growing number of treatments within the HER2-positive breast cancer armamentarium signals a need to redefine and tailor neoadjuvant and adjuvant strategies to individual patients.

Key Data Inform Treatment Decisions in Early HER2+ Breast Cancer

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; and senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, discusses appropriately de-escalating treatment to reduce toxicities in stage I HER2-positive breast cancer.

One of the questions that arises with the use of HER2-targeted therapies is: Can therapy be appropriately de-escalated for patients who may be at lower clinical risk? Some pivotal trials focus on de-escalation strategies, specifically in patients with stage I HER2-positive disease. Previous data from the phase 2 APT trial suggest that patients with stage I HER2-positive cancers can have good outcomes with paclitaxel and trastuzumab (Herceptin). However, that is still a chemotherapy-based regimen that is associated with risks of neuropathy and alopecia. There has been interest in determining whether toxicities can be further reduced, adds Tolaney.

19th Annual International Congress on the Future of Breast Cancer® East

 is the ATEMPT trial, which looked at administering 1 year of T-DM1 to patients with stage I HER2-positive disease. Patients were randomized to either T-DM1 or to the paclitaxel/trastuzumab regimen, as was administered in the APT trial. The ATEMPT trial did demonstrate that 1 year of T-DM1 was associated with a 3-year disease-free survival rate of 97.7%. The trial was then randomized to compare toxicities between the 2 arms. Higher rates of neutropenia, infusion reactions, alopecia, and neuropathy were seen with trastuzumab and paclitaxel, whereas with T-DM1, there were higher rates of thrombocytopenia and liver function abnormalities, concludes Tolaney.

Sara M. Tolaney, MD, MPH, discusses appropriately deescalating treatment to reduce toxicities in stage I HER2-positive breast cancer.

Dr. Tolaney on Deescalating Therapy in Stage I HER2+ Breast Cancer

The optimal sequence of therapies for patients with metastatic HER2-positive breast cancer must be an individualized one, and should be dependent on the presence and/or level of central nervous system (CNS) disease, according to Ian E. Krop, MD, PhD, in a presentation during the 19th Annual International Congress on the Future of Breast Cancer® East, a virtual program by Physician Education Resource® (PER®).

“We have 3 approved drugs [in the third-line and beyond setting], and a fourth that may be approved soon,” explained Krop, an associate professor of medicine with Harvard Medical School; associate chief, Division of Breast Oncology with Susan F. Smith Center for Women's Cancers; and a medical oncologist and clinical research director with the Breast Oncology Center at Dana-Farber Cancer Institute, during the presentation. “How do we sequence these in clinical practice? I don’t think we can use a once-size-fits-all approach like we used to previously; we have to tailor this to the particular patient population.”

The 4 agents garnering excitement in the HER2-positive breast cancer space include tucatinib (Tukysa), neratinib (Nerlynx), fam-trastuzumab deruxtecan-nxki (Enhertu), and the investigational agent margetuximab. Taking the clinical data from the HER2CLIMB, NALA, DESTINY-Breast01, and SOPHIA trials, respectively, into consideration, Krop proposed appropriate following sequences for patients with and without CNS metastases.

Frontline treatment should begin with trastuzumab (Herceptin) and pertuzumab (Perjeta) plus taxane chemotherapy, followed by ado-trastuzumab emtansine (T-DM1; Kadcyla) in the second-line setting. For patients with no or minor CNS disease, Krop recommended third-line trastuzumab deruxtecan, fourth-line tucatinib combined with trastuzumab/capecitabine (Xeloda), and fifth-line trastuzumab/chemotherapy or, if approved, margetuximab/chemotherapy for patients with low affinity FcR genotype.

In patients with significant CNS disease, optimal third-, fourth-, and fifth-line treatments would be tucatinib/trastuzumab plus chemotherapy, trastuzumab deruxtecan, and trastuzumab/chemotherapy or margetuximab/chemotherapy for patients with low affinity FcR genotype.

The recent additions add variety to the third-line and beyond setting in HER2-positive breast, which prior to December 2019 had limited therapeutic options beyond trastuzumab plus chemotherapy.

The potent and selective small molecule HER2 TKI tucatinib was approved by the FDA in April 2020 for use in combination with trastuzumab and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti-HER2-based regimen in the metastatic setting.

The approval is based on data from the phase II HER2CLIMB trial, which showed that the tucatinib regimen 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 the international, double-blind, placebo-controlled study, 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab, and T-DM1were randomized 2:1 to receive trastuzumab and capecitabine combined with either tucatinib (n = 410) or placebo (n = 202). Patients were permitted to have previously treated stable brain metastases, untreated brain metastases not requiring immediate local therapy, or previously treated progressing brain metastases not needing immediate local therapy.

“One of the unique features of this trial was that it allowed patients not only with stable brain metastases, but those who had untreated or progressive brain metastases, leveraging the activity of this drug in the brain,” said Krop.

Results showed that the median overall survival (OS) was 21.9 months (95% CI,18.3-31.0) with the tucatinib triplet compared with 17.4 months (95% CI, 13.6-19.9) with trastuzumab and capecitabine alone (HR, 0.66; 95% CI, 0.50-0.88

= .0048). The 1- and 2-year OS rates were 76% versus 62% and 45% versus 27% in the tucatinib and control arms, respectively, and the OS benefit was upheld across all prespecified subgroups.

The addition of the small molecule TKI tucatinib also led to a 46% reduction in the risk of disease progression or death compared with trastuzumab and capecitabine alone, with a median progression-free survival (PFS) of 7.8 months (95% CI, 7.5-9.6) versus 5.6 months (95% CI, 4.2-7.1), respectively (HR, 0.54; 95% CI, 0.42-0.71;

<.00001). The 6-month and 1-year PFS rates were 63% versus 46% and 33% versus 12%, respectively.

Notably, the tucatinib regimen reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69;

<.00001) in patients with brain metastases at baseline. The median progression-free survival (PFS) in this subpopulation was 7.6 months with tucatinib versus 5.4 months in the control arm. The 1-year PFS rates were 25% versus 0%, respectively.

Subgroup analysis also indicated an OS benefit with tucatinib in those with active brain metastases, with a median OS of 20.7 months and 11.6 months, respectively (HR, 0.49, 95% CI, 0.30-0.80; 

 = .004). The 1-year OS rates were 71.7% versus 41.1%, respectively. Investigators also measured intracranial response rate (ORR-IC) in patients with active brain metastases and measurable intracranial lesions at baseline. With tucatinib, the complete response (CR) rate was 5.5% versus 5.0% with trastuzumab/capecitabine; the partial response (PR) rate was 41.8% versus 15.0%, respectively. 

Moreover, the stable disease (SD) rate was 43.6% versus 80.0% with the addition of tucatinib versus trastuzumab/capecitabine, respectively. The duration of intracranial response was also longer with tucatinib, at 6.8 months versus 3.0 months, respectively.

The PFS benefit was also upheld in patients with isolated CNS progression who continued with assigned study treatment. The median time from randomization to second progression or death was 15.9 months and 9.7 months for the addition of tucatinib and trastuzumab/capecitabine alone, respectively (HR, 0.292; 95% CI, 0.11-0.77; 

 = .009). The median time from first CNS progression to second progression or death was 7.6 months with tucatinib and 3.1 months with trastuzumab/capecitabine (HR, 0.332; 95% CI, 0.13-0.85; 

The most common adverse effects (AEs) occurring in 20% or more of patients on tucatinib, included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, vomiting, stomatitis, decreased appetite, headache, aspartate transaminase, and alanine transaminase. Additionally, tucatinib’s HER2 selectivity leads to decreased potential for 

-related toxicities compared with dual TKIs, Krop explained.

Neratinib is a low–molecular weight, irreversible, pan-HER TKI against ErbB1/2/4. While potent, its most significant toxicity is grade 3/4 diarrhea.

In February 2020, the FDA approved a supplemental new drug application for neratinib in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti—HER2-based regimens in the metastatic setting.

The approval was based on findings from the international, open-label, phase 3 NALA trial, which enrolled 621 patients with metastatic breast cancer and centrally confirmed HER2-positive disease.

Results showed that the combination reduced the risk of disease progression or death by 24% compared with lapatinib (Tykerb) plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; log-rank 

 Moreover, the median OS was 24.0 months for neratinib plus capecitabine compared with 22.2 months with lapatinib/capecitabine (HR, 0.88; 95% CI, 0.72-1.07; 

 = .2086). The OS benefit was upheld across most prespecified subgroups, except for patients of North America (HR, 1.06; 95% CI, 0.71-1.58; 

The time to intervention for CNS metastases was also improved with neratinib, with an overall cumulative incidence of 22.8% versus 29.2% with lapatinib/capecitabine (

The phase 2 TBCRC 022 trial evaluated neratinib plus capecitabine in 49 patients with HER2-positive breast cancer and brain metastases. In a cohort of patients who did not receive prior lapatinib (n = 37), the CNS ORR was 49% and the median PFS was 5.5 months.

Regarding the safety profile in the NALA trial, as previously mentioned, diarrhea was the most frequent treatment-emergent AE for patients on neratinib/capecitabine (all-grade, 83%; grade 3/4, 24%). In the lapatinib/capecitabine arm, diarrhea was all-grade in 66% and grade 3/4 in 13% of patients.

“It’s important to note that the rate of patients having to discontinue therapy for treatment-emergent adverse events was pretty low, only about 11%, and this is consistent with our usual observation in the clinic, which is that if you get patients through the first couple cycles of neratinib, it is usually a manageable regimen," Krop said.

Due to its toxicity profile, and that its efficacy doesn’t appear to be as pronounced as tucatinib—although Krop stressed that the 2 agents have not been compared head to head—he proposed the use of third-line tucatinib versus neratinib in this patient population.

“What I would really like to know is whether neratinib works after patients progress after tucatinib-based treatment,” Krop said. “We don’t have that data yet, but I think it is something definitely worth exploring.”

Trastuzumab deruxtecan is a novel antibody-drug conjugate (ADC) designed to deliver an optimal antitumor effect. It is composed of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, a topoisomerase I inhibitor payload with an exatecan derivative, and a tetrapeptide-based cleavable linker. 

The optimal sequence of therapies for patients with metastatic HER2-positive breast cancer must be an individualized one, and should be dependent on the presence and/or level of central nervous system disease.

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