Jame Abraham, MD, FACP
Each year, The ASCO Post asks Jame Abraham, MD, FACP, Chairman of the Department of Hematology and Medical Oncology at Taussig Cancer Institute and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine, to offer his picks for the most important research presented at 2019 San Antonio Breast Cancer Symposium (SABCS). The following are his choices for and comments about studies that may impact clinical practice. Dr. Abraham’s comments on these presentations appear in italics.
Tucatinib in HER2-Positive Metastatic Breast Cancer
When added to trastuzumab/capecitabine, the orally bioavailable, small-molecule tyrosine kinase inhibitor tucatinib, significantly improved both progression-free and overall survival in the international phase III HER2CLIMB study of 615 patients with progressive HER2-positive metastatic breast cancer.1 The results were concurrently published in The New England Journal of Medicine.2
Patients were randomly assigned to oral tucatinib at 300 mg twice daily plus trastuzumab/capecitabine or trastuzumab/capecitabine alone. At a median follow-up of 14 months, 33% of patients in the tucatinib group were alive with no worsening of their disease compared with 12% of the control group (P < .001); the median progression-free survival was 7.8 months and 5.6 months, respectively. The 2-year overall survival was 45% with tucatinib and 27% with placebo (P = .005). Notably, among patients with brain metastases (almost half the population), 25% of tucatinib-treated patients were alive, compared with none of the placebo arm, reported Rashmi K. Murthy, MD.
Rashmi K. Murthy, MD
Dr. Abraham: Among patients with progressing HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), 50% will develop brain metastases, and many will have a short duration of response to subsequent treatments. Tucatinib, an investigational, highly selective oral inhibitor of the HER2 tyrosine kinase, has the potential to meet this major unmet need by significantly reducing the risk of death and disease progression when added to trastuzumab/capecitabine.
The impressive results of this trial represent significant progress. It’s the first evidence from a clinical trial of a targeted agent that can improve survival for patients with HER2-positive breast cancer that has metastasized to the brain. The study also found that tucatinib has less toxicity than some of the other options for heavily pretreated patients with HER2-positive disease. Because of its milder toxicity profile, it can be given at a higher dose.
“I predict that tucatinib and HER2 tyrosine kinase inhibitors like it will soon change the standard of care [in HER2-positive breast cancer].”— Jame Abraham, MD, FACP
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I predict that tucatinib and HER2 tyrosine kinase inhibitors like it will soon change the standard of care. Although tucatinib will initially be used in the third-line setting, it will begin to be studied earlier in the disease. With drugs like this one, we are starting to change the long-term outcome of HER2-positive metastatic breast cancer.
Novel Antibody-Drug Conjugate
results in metastatic HER2-positive breast cancer were reported for the novel antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in heavily pretreated patients in the phase II DESTINY-Breast 01 trial.3 The results reported by Ian E. Krop, MD, PhD, were published simultaneously in The New England Journal of Medicine.4 On December 20, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to T-DXd for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti–HER2-based regimens in the metastatic setting.
Ian E. Krop, MD, PhD
T-DXd is an antibody-drug conjugate with the same amino acid sequence as trastuzumab, linked to a payload of topoisomerase 1 inhibitor. With a much higher ratio of cytotoxic drug to antibody (8:1) than T-DM1, it is more potent against cancer cells, and given its greater ability to permeate cell membranes, T-DXd can kill neighboring tumor cells regardless of HER2 expression.
The study included 249 patients whose disease was resistant or refractory to T-DM1. In the heavily pretreated population (median of six prior lines), the objective response rate was 60.9% (95% confidence interval [CI] = 53.4%–68.0%), the disease control rate was 97.3% (95% CI = 93.8%–99.1%), the median duration of response was 14.8 months (95% CI = 13.8%–16.9%), the median progression-free survival was 16.4 months (95% CI = 12.7 months to not evaluable), and the median overall survival was not reached (95% CI = not evaluable). Measures of response were substantially higher than have been seen in other studies in this treatment setting.
Interstitial lung disease, however, was reported in 25 patients (13.6%), 4 of whom died. The investigators will monitor for this adverse event closely in future studies and are developing a management approach. Clinically significant cardiac toxicity was not observed in DESTINY-Breast01. Future phase III studies will compare T-DXd with T-DM1 and with chemotherapy.
Dr. Abraham: The promising data from DESTINY-Breast01 suggest the potential for a new standard of care in previously treated patients with HER2-positive advanced breast cancer. The response rate, clinical benefit rate, and waterfall plot (all but four patients showed tumor shrinkage) are impressive in this heavily pretreated population, especially after T-DM1 treatment. We eagerly await the results of the ongoing phase III DESTINY trials, which are looking at the role of T-DXd in the second-line setting in HER- positive patients. Studies of this drug in patients with HER2-negative or HER2–low-expressing metastatic breast cancer are also intriguing.
The drug is now approved by the FDA and offers an important treatment option for our patients, so it is important for clinicians to make an early diagnosis of interstitial lung disease and manage it promptly.
Neoadjuvant Pembrolizumab in Triple-Negative Disease
The addition of pembrolizumab to neoadjuvant or adjuvant chemotherapy achieved higher rates of pathologic complete response compared with placebo in patients with triple-negative breast cancer in the phase III KEYNOTE-522 trial, presented by Peter Schmid, MD, PhD.5 The benefits of pembrolizumab were consistent across subgroups, with the greatest benefit observed in node-positive and stage IIIB disease.
Peter Schmid, MD, PhD
KEYNOTE-522 evaluated 1,174 patients with newly diagnosed stage II or III triple-negative breast cancer treated with both neoadjuvant and adjuvant systemic therapies. Neoadjuvant therapy included pembrolizumab or placebo plus carboplatin and paclitaxel followed by doxorubicin or epirubicin plus cyclophosphamide. After neoadjuvant treatment and surgery (with or without radiation therapy), patients received adjuvant pembrolizumab or placebo continuously.
Regardless of the expression of the programmed cell death ligand 1 (PD-L1) and across disease stages, more patients in the pembrolizumab arm achieved a pathologic complete response: 64.8% vs 51.2% for placebo (P = .00055). The greatest magnitude of benefit was seen in patients with stage IIIB disease: 48.6% vs 23.1% for the placebo group, respectively, for an absolute difference of 25.6%. Similarly, in patients with lymph node–positive disease, the rates were 64.8% and 44.1%, respectively, for an absolute difference of 20.6%. The 18-month event-free survival was 91.3% vs 85.3%, respectively, which is not yet statistically significant.
Dr. Abraham: Patients who achieve pathologic complete response after neoadjuvant or adjuvant therapy have an improved survival and low recurrence risk, especially those with aggressive subtypes such as triple-negative breast cancer. With standard approaches, pathologic complete response rates are around 40% to 55%, so there continues to be a significant need for new regimens that can further improve upon these rates and can increase long-term, event-free survival in triple-negative breast cancer. The KEYNOTE-522 results suggest that the addition of pembrolizumab may be able to achieve this. I think the results of this trial, therefore, have the potential to change practice.
“The use of immunotherapy in early breast cancer is still evolving, and there are many unanswered questions.”— Jame Abraham, MD, FACP
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Interestingly, PD-L1 status was not associated with a tumor response in these early cancers—which is different from what is seen in metastatic breast cancer subjected to checkpoint inhibition. The investigators have hypothesized that the tumor biology in early disease may be less responsive to immune therapy. The use of immunotherapy in early breast cancer is still evolving, and there are many unanswered questions.
Failed ATEMPT With Adjuvant T-DM1
The antibody-drug conjugate T-DM1 failed to show improved safety when compared with paclitaxel plus trastuzumab as adjuvant therapy in patients with stage 1 HER2-positive breast cancer in the phase III ATEMPT trial presented by Sara M. Tolaney, MD, MPH.6
Sara M. Tolaney, MD, MPH
The ATEMPT investigators sought to determine whether T-DM1 would be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk of recurrence compared with paclitaxel/trastuzumab, which is associated with a 93% rate of disease-free survival. In this first report of the use of adjuvant T-DM1 for stage I disease, recurrences were few, but the preplanned endpoint of significantly improved safety was not met. The rate of clinically relevant toxicities was similar to, but not better than, that seen with paclitaxel/trastuzumab, and there were some individual differences in adverse events.
Although the study was not designed to compare disease-free survival between the two treatment arms, disease-free survival was 97.7% in the T-DM1 arm and 92.8% with paclitaxel/trastuzumab. Clinically relevant toxicities were reported in 46% of patients in each arm. The only notable differences were a higher incidence of neurotoxicity with paclitaxel/trastuzumab (23% vs 11%) and more toxicity-related early treatment discontinuations with T-DM1 (17% vs 6%).
Dr. Abraham: Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to paclitaxel/trastuzumab for select patients with stage 1 HER2-positive disease who are concerned about specific side effects and who understand the potential for T-DM1 toxicities. The rate of discontinuation of T-DM1 was high (17%), suggesting that low-grade toxicities may be impacting patients’ well-being. It would be good to see a study of a shorter duration of treatment with T-DM1 followed by trastuzumab.
Another concern, however, is the cost of 1 year of T-DM1, which is about twice that of paclitaxel/trastuzumab. This “financial toxicity” is an important factor for some patients when making treatment decisions. The selection of this agent in stage 1 disease should clearly be individualized based on patients’ circumstances and preferences.
Margetuximab
Patients with HER2-positive metastatic breast cancer who had received prior anti-HER2 therapies continued to experience a progression-free survival benefit with margetuximab and a trend toward overall survival benefit compared with trastuzumab (both with chemotherapy), in the updated analysis of the phase III SOPHIA trial.7 Margetuximab is designed to alter Fcy receptor affinities in ways that enhance innate immunity and adaptive HER2-targeted immunity. CD16a is a receptor found on the surface of some immune cells, and in patients with genotypes for low-affinity CD16a, the benefit of the drug was enhanced, Hope S. Rugo, MD, FASCO, reported.
Hope S. Rugo, MD, FASCO
In the SOPHIA trial, 538 patients with pretreated HER2-positive metastatic breast cancer were randomly assigned to chemotherapy plus margetuximab or trastuzumab given every 3 weeks. In the prespecified second interim overall survival analysis, at a median follow-up of 15.6 months, the median overall survival was 21.6 months with margetuximab compared with 19.8 months with trastuzumab (hazard ratio [HR] = 0.89; P = .326). The median progression-free survival was 5.7 months and 4.4 months, respectively (HR = 0.71; P = .0006), response rates were 25.2% and 13.7%, and the clinical benefit rate was 48.1% and 35.6%, respectively (P = .0025).
In the low-affinity CD16a carriers, the absolute benefit was a bit greater—4.3 months—but this fell shy of statistical significance as well (P = .087). Patients who were homozygous and fully lacking the allele (15% of participants) did not benefit. The final overall survival analysis of the SOPHIA trial is expected in 2020. A neoadjuvant trial is being planned to explore margetuximab in patients with HER2-positive disease who carry the allele for CD16a.
Dr. Abraham: The current standard of care for the treatment of HER2-positive metastatic breast cancer is the sequential use of trastuzumab, pertuzumab, T-DM1, and T-DXd. Results of the SOPHIA trial are not likely to change the standard of care, but the results are interesting because of the novel design of margetuximab, a modified version of trastuzumab that increases its immune effects. The idea is to exploit the ability of margetuximab to increase the affinity for the allele for CD16a and to make the drug more effective. It is not clear how well that worked, as the benefit was still somewhat modest. It may turn out, however, that margetuximab becomes an option for patients expressing the allele for CD16a who experience disease progression after trastuzumab.
Oral Paclitaxel Plus Encequidar
The first phase III data were reported for an oral taxane (paclitaxel) plus encequidar, a minimally absorbed P-glycoprotein pump inhibitor that aids absorption of the taxane.8 Compared with intravenous (IV) paclitaxel, oral paclitaxel plus encequidar improved response rates from 26% to 40% (P = .005). and was associated with significantly less grade ≥ 2 neuropathy (8% vs 31%) in a study of 402 patients with metastatic breast cancer from 45 sites in Central and South America.
A numerical trend favoring oral paclitaxel plus encequidar was observed for progression-free survival, with a median of 9.3 months vs 8.3 months with IV paclitaxel (HR = 0.760; P = .077), and a statistically significant overall survival benefit was shown, 27.9 months vs 16.9 months, respectively (HR = 0.684; P = .035).
Administration of the treatment, however, requires an average of 11 pills and long periods of fasting, which is done 3 consecutive days a week. A number of experts at the meeting questioned whether patients would comply with this type of treatment.
Dr. Abraham: This study generated some controversy at SABCS. For one thing, the study used a modified intention-to-treat analysis, which could be considered a flaw in the design, as it excludes a number of patients—those who experienced early treatment failure—and this can potentially skew the results in favor of oral paclitaxel plus encequidar. Second, the comparator to oral paclitaxel plus encequidar was paclitaxel given every 3 weeks, not weekly, and we know that the weekly schedule is preferred—again, favoring oral paclitaxel plus encequidar. However, the main concern of many experts was how oral paclitaxel plus encequidar is administered: up to 12 or so pills a day (depending on body weight) and around 4 hours or more of fasting twice a day.
“Although paclitaxel plus encequidar is an oral treatment, which we know many patients prefer, it is a complicated one, and we need patients to weigh in on this issue.”— Jame Abraham, MD, FACP
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Although paclitaxel plus encequidar is an oral treatment, which we know many patients prefer, it is a complicated one, and we need patients to weigh in on this issue. It is true, however, that if this treatment reduces the risk of neuropathy—which is also important to our patients—then it could all be worth it.
NSABP B-42 Update
In the 10-year analysis of the NSABP B-42, the use of extended letrozole after 5 years of hormonal therapy led to a statistically significant 4% absolute improvement in disease-free survival, the primary endpoint.9 The study randomly assigned 3,966 postmenopausal patients with stage I to III, hormone receptor–positive breast cancer to extended letrozole or no additional treatment. The previous 7-year update showed a nonsignificant trend for improvement.10
NSABP B-42 asked whether 5 years of letrozole at 2.5 mg/d would improve disease-free survival in patients who have completed 5 years of hormonal therapy (with either an aromatase inhibitor or tamoxifen for up to 3 years followed by an aromatase inhibitor for the remainder of the 5 years).
There were also a 3% absolute improvement in breast cancer–free interval and a 1.8% absolute improvement in distant recurrences, which were both statistically significant. There was no significant improvement in overall survival with extended letrozole, but the additional treatment did significantly improve the breast cancer–free interval (HR = 0.71; P = .003) and distant recurrence (HR = 0.72; P = .03). Fracture risk was not significantly increased with extended letrozole, according to Terry P. Mamounas, MD, MPH.
Terry P. Mamounas, MD, MPH
Dr. Abraham: NSABP B-42 confirms the benefits that have been emerging for extended endocrine therapy after 5 years of initial therapy in early breast cancer. Moreover, the updated analysis now shows a significant 4% advantage in disease-free survival—a number we should relay to our patients, who often ask “what more they can do” to reduce their risk of recurrence. It’s clear there are some patients in our practices who could benefit from, and should be offered, this additional protection, and we can now tell them their risk for fracture will not be increased by this.
Careful assessment of the potential risks and benefits is necessary for identifying the appropriate candidates. I think patients should be selected based on patient- and tumor-related characteristics, existing comorbidities, bone mineral density status, and tolerance of the aromatase inhibitor during the initial 5 years.
Residual Cancer Burden
After neoadjuvant chemotherapy, residual cancer burden can accurately predict disease recurrence and survival across all breast cancer subtypes, according to the findings of a pooled analysis from the I-SPY Clinical Trials Consortium encompassing 5,160 patients.11 The study examined the relationship between the continuous residual cancer burden index and event-free survival as well as distant relapse–free survival for four breast cancer phenotypes.
The residual cancer burden index categorizes patients with breast cancer into four groups (RCB 0–IV) based on the level of residual disease after neoadjuvant therapy and several other factors, as assessed by pathologists. The residual cancer burden calculator is available to all pathologists through an online calculator (www.mdanderson.org/breastcancer_RCB).
A pathologic complete response (RCB-0) was most likely to be achieved by patients with hormone receptor–negative/HER2-positive disease (69%) and least likely, by those with hormone receptor–positive/HER2-negative disease (11%). Pathologic complete response tracked well with long-term outcomes, and the residual cancer burden index values were associated with 5-year and 10-year event-free survival for all subtypes. For example, 5-year event-free survival rates were 80% for patients with triple-negative breast cancer who were RCB-I but 28% for those who were RCB-III; within the hormone receptor–positive/HER2-positive subtype, the 5-year event-free survival rates were 91% for the RCB-I group and 54% for the RCB-III group. The residual cancer burden index remained independently prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis, according to Fraser Symmans, MD.
Fraser Symmans, MD
Dr. Abraham: In a pooled analysis of I-SPY data, investigators found a generally linear relationship between residual cancer burden index value and log of risk, suggesting the potential to accurately calibrate an individual’s residual cancer burden index score to her prognosis. In the post-neoadjuvant setting, being able to stratify patients is incredibly important for affecting outcomes and also for minimizing treatment (and toxicity) for patients who may have some residual disease but whose outlook is very good despite this.
The value of the residual cancer burden index is evident by the fact that, for 10 years, across 22 trial sites, the I-SPY basket trials have used it as a standard for evaluating residual disease. Dr. Symmans has standardized the process for how to evaluate the disease left after neoadjuvant treatment. This is not accomplished by examining one tissue section. It must be examined in a careful, specific way, and pathologists must be committed to using the online calculator and learning this approach. The website offers instructional videos, protocols, illustrations, and diagrams as resources for pathologists. We were told that the calculator receives about 16,000 visits per month, so it is being used. Let’s hope oncologists start asking for it, and even more pathologists start using it.
Circulating DNA and Tumor Cells After Neoadjuvant Therapy
In early triple-negative breast cancer, the presence of circulating tumor DNA (ctDNA) and circulating tumor cells after neoadjuvant chemotherapy predicted outcomes in a preplanned correlative analysis of the phase II BRE12-158 trial (circulating tumor cell positivity was defined as at least one circulating tumor cell detected).12 The study analyzed plasma samples from 196 patients with early triple-negative breast cancer who underwent neoadjuvant chemotherapy and were found to have significant residual disease at the time of surgery. Tumors from these patients were genomically sequenced, and patients were randomly assigned to receive either genomically directed treatment or physician’s choice of treatment.
The median distant disease–free survival was 32.5 months in ctDNA-positive patients and not reached in ctDNA-negative patients (HR = 2.99; P = .0055); the 2-year distant disease–free survival was 56% vs 81%, respectively. The addition of circulating tumor cell findings increased the sensitivity of testing. Patients who tested positive for both ctDNA and circulating tumor cell had a five times increased risk of a distant recurrence, vs patients who tested negative for both, reported Milan Radovich, PhD.
Milan Radovich, PhD
Dr. Abraham: We are all interested in the ability to use blood as a means of looking at tumor-related material, both in the metastatic and early stages, across many malignancies. The question in this study was, which patients are most at risk for recurrence after neoadjuvant therapy. By examining ctDNA and circulating tumor cells, we learned that patients with tumor-related material in the blood did have a higher risk of recurrence. The question is whether we should act on this information when we find it. Just finding it does not guarantee a recurrence, and the lack of it does not guarantee the patient is cured.
The finding that ctDNA (and circulating tumor cells) is prognostic is not ready for clinical practice but should be informative for clinical trial design (as a stratification factor). We do not yet have predictive data as to how to improve patient outcomes. What we need is a trial to determine whether the results of such testing can help in selecting treatments and improving outcomes. Such a trial has actually been designed: the PERSEVERE trial. Patients with ctDNA-negative disease will automatically receive physician’s choice of therapy, whereas those with ctDNA-positive disease will undergo molecular testing and receive a genomically directed or standard therapy. This trial should answer some of these questions.
DISCLOSURE: HER2CLIMB was supported by Seattle Genetics. The DESTINY Breast-01 trial was supported by Daiichi Sankyo and AstraZeneca. KEYNOTE-522 was sponsored by Merck Sharp & Dohme. The ATEMPT trial was funded by Genentech. The SOPHIA trial was supported by MacroGenics. The oral paclitaxel study was funded by Athenex. Dr. Abraham has received institutional research funding from Pfizer, Daiichi Sankyo, Merck, and Seattle Genetics.
REFERENCES
1. Murthy RK, Loi S, Okines A, et al: Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 11, 2019.
2. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER-2 positive metastatic breast cancer. N Engl J Med 382:597-609, 2020.
3. Krop IE, Saura C, Yamashita T, et al: [Fam-] trastuzumab deruxtecan in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase II, multicenter, open-label study (DESTINY-Breast01). 2019 San Antonio Breast Cancer Symposium. Abstract GS1-03. Presented December 11, 2019.
4. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.
5. Schmid P, Park YH, Ferreira M, et al. KEYNOTE-522: Phase 3 study of neoadjuvant pembrolizumab + chemotherapy versus placebo + chemotherapy, followed by adjuvant pembrolizumab versus placebo for early triple-negative breast cancer: Pathologic complete response in key subgroups and by treatment exposure and residual cancer burden. 2019 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 12, 2019.
6. Tolaney SM, Trippa L, Barry W, et al: TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage 1 HER2-positive breast cancer (ATEMPT). 2019 San Antonio Breast Cancer Symposium. GS1-05. Presented December 11, 2019.
7. Rugo HS, Im SA, Cardoso F, et al: Phase III 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. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 11, 2019.
8. Umanzor G, Cutler DL, Barrios FJ, et al: Oral paclitaxel with encequidar: The first orally administered paclitaxel shown to be superior to IV paclitaxel on confirmed response and survival with less neuropathy: A phase III clinical study in metastatic breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract GS6-01. Presented December 13, 2019.
9. Mamounas EP, Bandos H, Lembersky BC, et al: Ten-year results from NRG Oncology/NSABP B-42: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone receptor+ breast cancer who have completed previous adjuvant therapy with an aromatase inhibitor. 2019 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 12, 2019.
10. Mamounas EP, Bandos H, Lembersky BC, et al: Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): A randomised, double-blind, placebo-controlled, phase III trial. Lancet Oncol 20:88-99, 2019.
11. Yau C, van der Noordaa M, Wei J, et al: Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis. 2019 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 13, 2019.
12. Radovich M, Jiang G, Chitambar C, et al: Detection of circulating tumor DNA after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer: Preplanned correlative results from clinical trial BRE12-158. 2019 San Antonio Breast Cancer Symposium. Abstract GS5-02. Presented December 13, 2019.
