Assessing the Changing Treatment Landscape in Triple-Negative Breast Cancer

Supplements And Featured Publications, The Role of Chemotherapy and Novel Combinations in Triple Negative Breast Cancer, Volume 1, Issue 1

Treatment options for triple-negative breast cancer are historically limited; however, recent developments regarding the use of targeted therapies and various combination regimens have broadened the treatment spectrum and ushered in new clinical approaches.

Triple-negative, basal-like breast cancers are historically more invasive subtypes of breast cancer.1 The difficulty of discovering triple-negative breast cancer (TNBC) through a mammogram coupled with its rapid growth contribute to a poor prognosis for many patients.1 Treatment options for TNBC are historically limited; however, recent developments regarding the use of targeted therapies and various combination regimens have broadened the treatment spectrum and ushered in new clinical approaches.2

On July 29, 2020, OncLive® brought together a group of international oncologists to discuss the evolving treatment landscape in TNBC and identify factors that influence treatment decisions and planning, especially in patients who progress on frontline therapies. The stakeholders also explored clinical challenges regarding selection of later lines of therapy and novel therapeutic options in TNBC that may affect the future treatment landscape. This article summarizes key data presented during the meeting, as well as key discussion points from stakeholders.

Chemotherapy

The current standard of care for TNBC3 chemotherapy has been studied widely in the frontline setting. A phase 3, multicenter, randomized trial evaluated paclitaxel and gemcitabine as a first-line chemotherapy vs observation in patients with metastatic breast cancer (mBC). Of 324 patients from 10 registered centers, 231 achieved disease control with first-line paclitaxel and gemcitabine; they were then randomly delegated to observation (n = 115) or maintenance paclitaxel/gemcitabine chemotherapy (n = 116). At a median follow-up of 33 months, those on maintenance chemotherapy had achieved better progression-free survival (PFS) and overall survival (OS) compared with observation (PFS, 7.5 months vs 3.8 months, respectively; P = .026; OS, 32.3 months vs 23.5 months, respectively; P = .047).4

The phase 2 tnAcity trial (NCT01881230) showed significantly improved median PFS outcomes with frontline nab-paclitaxel plus carboplatin vs nab-paclitaxel plus gemcitabine (8.3 months vs 5.5 months; HR, 0.59; 95% CI, 0.38-0.92; P = .02) and nab-paclitaxel plus carboplatin vs gemcitabine plus carboplatin (8.3 months vs 6.0 months; HR, 0.58; 95% CI, 0.37-0.90; P = .02). Patients with metastatic TNBC (N = 191) were randomized 1:1:1 for each regimen. In the nab-paclitaxel/carboplatin, nab-paclitaxel/gemcitabine, and gemcitabine/carboplatin arms, 80%, 77%, and 84% of patients, respectively, experienced at least 1 grade 3 or higher adverse event (AE). The nab-paclitaxel/carboplatin group also showed superior OS and overall response rates compared with the other chemotherapy options.5

Although chemotherapy has been the standard of care for TNBC, patients often develop a resistance to it. Because of this, there has been an increasing effort to identify new targets to better treat patients with this cancer.3

Targeted Therapy

About 80% of patients with TNBC do not achieve a complete response with chemotherapy. However, the discovery of genetic targets with high rates of altered expression in TNBC has led to an emphasis on the potential of targeted therapy for TNBC.6

Atezolizumab plus nab-paclitaxel. The IMpassion130 trial (NCT02425891) randomized patients 1:1 with untreated metastatic TNBC to either atezolizumab plus nab-paclitaxel (n = 451) or placebo plus nab-paclitaxel (n = 451). Primary end points included PFS and OS in the intention-to-treat population. The median PFS in the intention-to-treat population was 7.2 months with atezolizumab plus nab-paclitaxel vs 5.5 months with placebo plus nab-paclitaxel (HR for progression or death, 0.80; 95% CI, 0.69-0.92; P = .002); the median OS was 21.3 months vs 17.6 months, respectively (HR for death, 0.84; 95% CI, 0.69-1.02; P = .08). For those with PD–L1-positive tumors, the median PFS was 7.5 months with atezolizumab plus nab-paclitaxel and 5.0 months with placebo plus nab-paclitaxel (HR, 0.62; 95% CI, 0.49-0.78; P < .001); median OS was 25.0 months compared with 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). AEs were consistent with previous studies involving both agents. Discontinuation due to AEs occurred in 15.9% of those in the atezolizumab/nab-paclitaxel group and 8.2% of those in the placebo/nab-paclitaxel group.7

Results from a recent second interim OS analysis of the IMpassion130 trial showed that there was not a considerable difference in OS between the intention-to-treat population groups (median, 21.0 months vs 17.5 months in the atezolizumab and placebo groups, respectively). However, in those with PD–L1-positive disease, OS was higher in those treated with atezolizumab plus nab-paclitaxel: 25 months (95% CI, 19.6-30.7) vs 18 months (95% CI, 13.6-20.1; stratified HR, 0.71; 95% CI, 0.54-0.94). Two treatment-related deaths occurred in the atezolizumab group (septic shock and autoimmune hepatitis) and 1 in the placebo group (hepatic failure). Neutropenia, peripheral neuropathy, decreased neutrophil count, and fatigue were the most frequent grade 3/4 AEs. Overall, atezolizumab plus nab-paclitaxel was noted as a noteworthy treatment option for those with PD–L1-positive metastatic TNBC.8

Pembrolizumab. Pembrolizumab monotherapy has shown both favorable antitumor activity and controllable safety in patients with previously untreated inoperable or metastatic TNBC. In the KEYNOTE-355 (NCT02819518) trial, investigators randomized patients 2:1 to either pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) or placebo plus chemotherapy for up to 35 administrations of pembrolizumab/ placebo or until disease progression or unbearable toxicity. Patients had at least 6 months of a disease-free interval, and primary end points included PFS per RECIST 1.1 blinded independent central review and OS per PD-L1 expression and in all participants. Median follow-up for the pembrolizumab plus chemotherapy group (n = 566) was 17.5 months; it was 15.5 months for the chemotherapy group (n = 281). PFS showed considerable benefit in patients with a combined positive score greater than or equal to 10 who were treated with pembrolizumab plus chemotherapy compared with chemotherapy alone (9.7 months vs 5.6 months). Approximately 68% of patients treated with pembrolizumab plus chemotherapy experienced grade 3 to 5 AEs (2 deaths) vs about 67% in the chemotherapy group (0 deaths).9

Pembrolizumab plus eribulin. The safety and efficacy of pembrolizumab plus eribulin, a halichondrin antineoplastic drug, were evaluated in the phase 1b/2 ENHANCE1 study (NCT02513472). Patients with metastatic TNBC who had been previously treated with 2 or fewer anticancer treatments for metastatic disease were stratified by number of previous therapies and were administered intravenous (IV) eribulin 1.4 mg/m2 on days 1 and 8 and IV pembrolizumab 200 mg on day 1 throughout a 21-day cycle. Safety and objective response rate (ORR) per RECIST were the primary end points. At data cutoff, 167 patients had been enrolled and put on treatment.

According to results presented at the American Society of Clinical Oncology 2020 virtual meeting, the combination of eribulin plus pembrolizumab yielded an overall ORR of 23.4% (95% CI, 17.2%-30.5%). The ORR in stratum 1 (n = 66) was 25.8% (95% CI, 15.8%-38.0%), and the ORR in stratum 2 (n = 101) was 21.8% (95% CI, 14.2-31.1). For the entire study population, median PFS was 4.1 months (95% CI, 3.5-4.2), and median OS was 16.1 months (95% CI, 13.3-18.5), which were secondary end points of the study. The combination showed particularly robust activity in patients with PD–L1-positive tumors, demonstrating ORRs of 34.5% and 24.4% in patients who received it in the first line and second line, respectively.

No dose-limiting toxicities and no treatment-related deaths occurred; the most frequent treatment-emergent AEs included fatigue, nausea, peripheral sensory neuropathy, alopecia, and constipation.10

Stakeholder insights. The IMpassion130 study was a practice-changing trial in the United States for PD–L1-positive patients, according to stakeholders. Faculty from Ireland noted that the IMpassion130 regimen is available through a compassionate access program, where there is testing for PD-L1 and in first-line use, but it is limited at this time. Faculty from Russia said that there were more obstacles in testing than with access to atezolizumab. Stakeholders questioned if the regimen is appropriate for use in patients who do not meet the criteria of the trial, specifically those who relapse within a year.

Stakeholders also speculated that patients in the KEYNOTE-355 trial who were treated for fewer than 12 months did not show benefit from pembrolizumab because of intrinsic immune suppression or chemotherapy-resistant disease. Faculty in Germany use a regimen of atezolizumab plus nab-paclitaxel in patients who are PD–L1-positive, as well as in those who have a shorter relapse time than was in the trial. It is too early to draw the conclusion that immunotherapy will not have benefit in cases of relapse. Many stakeholders said that they prefer to use combination therapy or a clinical trial for patients with PD–L1-negative TNBC; 1 stakeholder expressed a preference for the sequential uses of single-agent chemotherapy.

PARP Inhibitors

PARP proteins facilitate DNA damage repair, gene transcription, genomic stability, and apoptosis. PARP inhibitors are of particular interest in patients with breast cancer who have BRCA1/2 mutations, as well as those with TNBC. These agents vary in their catalytic inhibitory propensities; therefore, clinical results differ across agents. Olaparib and talazoparib are FDA approved for HER2-negative mBC with germline BRCA mutations.11

Olaparib. Olaparib was evaluated as a monotherapy against standard chemotherapy in patients with HER2-negative mBC with a germline BRCA mutation in the phase 3, open-label, randomized OlympiAD trial (NCT02000622). In a 2:1 randomization, 205 patients were given olaparib and 97 were given standard chemotherapy; all patients had received 2 or fewer prior chemotherapies for metastatic disease. The olaparib group achieved a considerably longer PFS: 7.0 months vs 4.2 months in the chemotherapy group. Response rate in the olaparib group was also greater, at 59.9% compared with 28.8% for chemotherapy.12 The final OS results of the trial were comparable between the treatment groups, but olaparib treatment was potentially beneficial in the first-line setting. Median OS was 19.3 months for the olaparib group vs 17.1 months in the chemotherapy group, at 64% data maturity. Additionally, AEs in the olaparib group were manageable.13

Talazoparib. Talazoparib was evaluated against physician’s choice of standard chemotherapy in patients with advanced breast cancer with a germline BRCA1/2 mutation. In the EMBRACA trial (NCT01945775), 431 patients were randomized 2:1 to either talazoparib (n = 287) or standard chemotherapy (n = 144). Approximately 45% in the talazoparib group and 42% in the chemotherapy group had TNBC. The talazoparib group experienced a considerably longer median PFS than the chemotherapy group (8.6 months vs 5.6 months, respectively) and had a greater ORR (62.6% vs 27.2%, respectively; odds ratio, 5.0; 95% CI, 2.9-8.8; P < .001). Patient-reported outcomes favored talazoparib,14 and talazoparib was generally well tolerated.15 Final OS data showed no improvement with talazoparib compared with chemotherapy. At the time of the analysis, there were 216 deaths (75.3%) in the talazoparib group and 108 deaths (75.0%) in the chemotherapy group (HR, 0.85; 95% CI, 0.67-1.07; P = .17). In the talazoparib group, 69.6% of patients experienced grade 3/4 AEs compared with 64.3% in the chemotherapy group.

Veliparib. The BROCADE3 trial (NCT02163694) tested the combination of the PARP1/2 inhibitor veliparib with carboplatin and paclitaxel in patients with advanced HER2-negative disease, germline BRCA1/2 mutations, and 2 or fewer previous lines of therapy for metastatic disease. The median PFS for the veliparib plus carboplatin and paclitaxel arm (n = 337) was 14.5 months vs 12.6 months in the placebo plus carboplatin plus paclitaxel arm (n = 172); median interim OS was 33.5 months vs 28.2 months, respectively. The veliparib group had more durable benefit compared with the carboplatin plus paclitaxel regimen alone, as 26% of patients remained free of progression and were alive at 3 years compared with 11%.16

Stakeholder insights. The findings of these trials suggest the possibility that PARP inhibitors may offer benefits early on in treatment for patients with germline BRCA mutations. There was the question surrounding the benefit of duration of treatment of PARP inhibitors compared with platinum therapies and whether they are preferable in terms of quality of life and toxicity. However, the stakeholders noted that PARP inhibitors are a likely better option than chemotherapy agents.

Later Lines of Therapy

Therapeutic options for patients with heavily pretreated mBC are needed to prolong survival benefits, which the stakeholders discussed.17

Eribulin. Eribulin monotherapy is used as a later-line therapy for mBC. It is an inhibitor of microtubule polymerization that does not affect depolymerization and therefore is associated with less toxicity than other taxanes.18

Eribulin monotherapy was evaluated in a phase 3, randomized study against physician’s choice of treatment in patients with locally recurrent breast cancer or mBC (NCT00388726). Eligible patients were previously given 2 to 5 chemotherapy regimens (≥ 2 in advanced disease), which included an anthracycline and a taxane. OS in the intention-to-treat population was the study’s primary end point. Of 762 women, 508 were randomly assigned to eribulin and 254 to physician’s choice of treatment. Of the total population, 19% (144 patients) had triple-negative disease.17

Patients given eribulin showed a notable improvement in OS, with a median of 13.1 months compared with 10.6 months in those receiving treatment of physician’s choice. Median PFS was 3.7 months with eribulin vs 2.2 months with physician’s choice. Almost all patients experienced AEs: 99% and 93% of those taking eribulin and physician’s choice, respectively. Serious AEs were seen in 25% and 26%, and AEs leading to treatment discontinuation occurred in 13% and 15% of patients, respectively.17

Eribulin (n = 554) was also evaluated against capecitabine (n = 548) in advanced breast cancer or mBC following 3 or fewer previous chemotherapies (≤ 2 for advanced or metastatic), including anthracycline and taxane therapy (NCT00337103). Approximately 80% of the total intent-to-treat population had received at least 1 previous chemotherapy treatment for advanced disease. Twenty-seven percent of patients treated with eribulin and 24.5% of patients treated with capecitabine had TNBC. Both patient groups were treated until disease progression.19 OS was longer in the eribulin group vs the capecitabine group (15.9 months vs 14.5 months, respectively; HR, 0.88; 95% CI, 0.77-1.00; P = .056), with PFS outcomes comparable between the groups (4.1 and 4.2 months, respectively). Investigators concluded that those with advanced breast cancer or mBC may benefit from eribulin therapy.19

Sacituzumab govitecan. Another agent being investigated in patients with previously treated metastatic TNBC is sacituzumab govitecan. This antibody-drug conjugate targets the human trophoblast cell-surface antigen 2 using SN-38, which is conjugated to the antibody by a cleavable linker. This enables the delivery of high concentrations of SN-38.20

In a phase 1/2 multicenter study (NCT01631552), 108 patients who had previously received ≥2 treatments for metastatic TNBC were administered IV sacituzumab govitecan-hziy on days 1 and 8 of a 21-day cycle until disease progression or unbearable toxicity. Patients achieved 3 complete responses and 33 partial responses, a 33% response rate, and a median duration of response of 7.7 months (95% CI, 4.9-10.8). Median OS was 13.0 months and median PFS was 5.5 months, with a 45.4% clinical benefit rate. During the study, a total of 4 deaths occurred, and 3 patients stopped therapy due to AEs, mostly due to neutropenia. With diarrhea and myelosuppression being the most frequent AEs, sacituzumab govitecan-hziy showed durable objective responses in this patient population.20

Sacituzumab govitecan-hziy was also evaluated in the phase 3 ASCENT study (NCT02574455), in which investigators examined its potential in patients with metastatic TNBC who were negative for brain metastasis and had received ≥ 2 previous therapies for metastatic disease. The trial met its primary end point, with sacituzumab govitecan-hziy having a statistically significant improvement vs chemotherapy (HR, 0.41, 95% CI, 0.32-0.52; P < 0.0001). Sacituzumab govitecan-hziy had a median PFS of 5.6 months vs 1.7 months with chemotherapy. The trial also met its secondary end points of OS and ORR. Full results of this trial are expected to be presented at a future medical conference.21

Stakeholder insights. Stakeholders noted that eribulin is most often used in the second-line setting but occasionally used up front in those who have relapsed early on. They further noted that dose reduction may be necessary due to risk of neutropenia. Because of reimbursement issues, 1 stakeholder noted using eribulin in the third-line setting in the United Kingdom and stated that they would like to use it in earlier lines.

Sacituzumab govitecan is approved in the United States but not yet in Europe. Providers await the full readout of the ASCENT trial and hope that this agent may be able to be used in first- and second-line settings. The stakeholders also expressed interest in seeing sacituzumab govitecan potentially used in combination with immunotherapy and PARP inhibitors.

Future Directions

Stakeholders noted that unmet needs remain in the treatment of TNBC. Specifically, a high need exists for more durable and effective therapies, particularly in the management of patients who relapse early or are resistant to chemotherapy. Additionally, there is a need to determine why immune reactions are increasingly suppressed as patients get further into their disease course with later lines of therapy, which will be important for future considerations.

References

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  21. Immunomedics announces positive results from phase 3 ASCENT study of TRODELVY. News release. Immunomedics; July 6, 2020. Accessed August 27, 2020. https://www.globenewswire.com/news-release/2020/07/06/2057876/0/en/Immunomedics-Announces-Positive-Results-from-Phase-3-ASCENT-Study-of-TRODELVY-in-Previously-Treated-Patients-with-Metastatic-Triple-Negative-Breast-Cancer-mTNBC.html