Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial

Key Points

Question  Does treatment with etirinotecan pegol improve survival outcomes in patients with breast cancer and brain metastases compared with chemotherapy of the physician’s choice?

Findings  In the phase 3 ATTAIN randomized clinical trial, there was no statistically significant difference in overall or progression-free survival in 92 patients treated with etirinotecan pegol or 86 patients treated with chemotherapy.

Meaning  The study results, although not positive, represent the largest published trial dedicated to this understudied population of patients with breast cancer and brain metastases and may help to inform future research.

Importance  Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician’s choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM.

Objective  To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician’s choice in a confirmatory trial.

Design, Setting, and Participants  This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019.

Interventions  Patients were randomized to receive etirinotecan pegol, 145 mg/m², every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel).

Main Outcomes and Measures  The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate.

Results  A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non–central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable.

Conclusions and Relevance  The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research.

Trial Registration  ClinicalTrials.gov Identifier: NCT02915744

Brain metastases (BMs) are common in patients with metastatic breast cancer, especially in high-risk patient subsets.¹ Brain metastases are associated with a poor prognosis, yet there is a lack of treatment options, specifically for patients with BM either treated or untreated.²

Etirinotecan pegol (NKTR-102) is a long-acting polymer conjugate of the topoisomerase I inhibitor irinotecan that comprises irinotecan molecules attached to a polyethylene glycol polymer core by a cleavable ester-based linker. Compared with short-acting irinotecan, etirinotecan pegol achieved more sustained tumor exposure in various mouse models of cancer, including those with BM, that correlated with prolonged suppression of tumor growth, including in the brain.³

The phase 3 BEACON trial evaluated etirinotecan pegol vs chemotherapy treatment of the physician’s choice in patients with locally recurrent or metastatic breast cancer who previously received anthracycline, taxane, and capecitabine treatment.⁴ Based on the preclinical evidence and the high clinical need for systemic therapy options, the BEACON trial prespecified an analysis of patients with BM as 1 of 2 prespecified subgroups. Although BEACON did not meet its primary end point of improving overall survival (OS), patients with stable, pretreated BM demonstrated a significant survival advantage with treatment with etirinotecan pegol vs chemotherapy.⁵

We conducted the phase 3 ATTAIN study (NCT02915744) to compare treatment with etirinotecan pegol vs the physician’s choice of chemotherapy in patients with metastatic breast cancer and stable, treated BM. To our knowledge, ATTAIN is the first study dedicated to this patient population.

This was an open-label, randomized, multicenter, international phase 3 clinical trial (Supplement 1 and Supplement 2).⁶ Patients were randomized 1:1 to treatment with etirinotecan pegol (145 mg/m² every 21 days as a 90-minute intravenous infusion on day 1 of each treatment cycle) or the physician’s choice of chemotherapy every 21 to 28 days (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel).

The trial was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines. Relevant institutional review board approvals were obtained, and patients provided written informed consent.

Patients had histologically confirmed breast carcinoma for which treatment with single-agent chemotherapy was indicated. Nonmeasurable Response Evaluation Criteria in Solid Tumors (RECIST) metastatic disease was permitted (eMethods in Supplement 3). Race and ethnicity were self-reported based on the following categories: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific Islander, White, or Other for race and Hispanic or Latino, not Hispanic or Latino, not reported, or Unknown for ethnicity. Patients were required to have a history of nonprogressing BM that was previously treated with either a combination of local BM-directed therapies (whole-brain radiotherapy [WBRT], stereotactic radiosurgery, and/or surgery) 14 days or more before randomization or a single-agent modality (WBRT, stereotactic radiosurgery, or surgical resection alone) if combination therapy was contraindicated 7 days or more before randomization. Patients were required to have stable signs and symptoms of BM.

The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and the clinical benefit rate (CBR) by blinded independent central review (BICR) and investigator assessment. The ORR and PFS were assessed for non– central nervous system (CNS) metastases per RECIST, version 1.1, and CNS metastases per Response Assessment in Neuro-Oncology Brain Metastases criteria.⁷ Safety and patient-reported outcomes were evaluated. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Between March 7, 2017, and November 6, 2019, 178 patients were enrolled and randomized to treatment (eFigure 1 in Supplement 3) at 47 sites across 10 countries. The treatments chosen by physicians were eribulin (n = 34), vinorelbine (n = 17), gemcitabine (n = 16), nab-paclitaxel (n = 7), paclitaxel (n = 5), ixabepilone (n = 4), and docetaxel (n = 3). As of November 6, 2019 (primary analysis cut-off date), 156 patients (88%) had discontinued participation in the study (98 [63%] because of progression), and 22 patients (12%) continued to participate (eFigure 1 in Supplement 3). Baseline characteristics were well balanced (Table 1). The median duration of exposure was 1.4 (range, <1 to 30.2 months) and 1.6 months (range, <1 to 10.9 months) with treatment with etirinotecan pegol and chemotherapy, respectively. Both treatment groups completed a median of 3 cycles (range in etirinotecan pegol group, 1-44; range in physician's choice group, 1-15); 20 patients (22.2%) in the etirinotecan pegol group and 8 (10.4%) patients in the chemotherapy group completed 7 or more cycles.

There was no difference between treatment groups in median OS or OS rates at 6 months or 12 months (Table 2). There was also no difference in median PFS or PFS rates at 3 months and 6 months by BICR (Table 2) or investigator assessment (eTable 1 in Supplement 3). Analysis of OS (eFigure 2 in Supplement 3) and PFS (eFigure 3 in Supplement 3) by subgroup did not show any notable differences between treatment groups. Response rates by BICR and investigator assessment are shown in Table 2 and eTable 1 in Supplement 3, respectively.

Table 3 summarizes the overall safety of treatments and the most common treatment-related adverse events. There were no significant treatment differences in any patient-reported outcomes with the exception of vomiting (treatment difference, 6.1; 95% CI, 0.5-11.6) (eTable 2 in Supplement 3).

To our knowledge, ATTAIN is the first phase 3 systemic therapy trial and one of the largest data sets that is dedicated to patients with breast cancer and preexisting BM. The trial was conducted to confirm the results from the BM subgroup analysis in BEACON.⁴ While investigator-assessed PFS findings were comparable with BEACON, the improvement in median OS observed in BEACON (10.0 months for etirinotecan pegol vs 4.8 months for chemotherapy) was not observed in ATTAIN (7.8 vs 7.5 months). There was also disparity in the response rates with etirinotecan pegol between studies.

Did differences in patient populations contribute to the different outcomes between studies? Despite few differences in eligibility (ATTAIN allowed a shorter interval between definitive local treatment for BM and randomization than BEACON), the studies enrolled noncomparable populations. ATTAIN had more patients with triple-negative breast cancer (40%) than the BEACON BM subgroup (27%), more patients had received prior eribulin-containing regimens (42% vs 24%), and fewer patients had prior WBRT (49% vs 91%). It is possible that the relatively short interval between local treatment for BM and randomization was insufficient to permit stabilization of BM; there is a lack of consensus on what constitutes stable or nonprogressive BM. There was also a difference in Graded Prognostic Assessment scores, a prognostic index for patients with BM that incorporates performance status, age, molecular phenotype, and number of BMs.⁸ While the Graded Prognostic Assessment score was balanced between treatment arms in both trials, fewer patients in ATTAIN had better prognosis scores of more than 2 (etirinotecan pegol, 48 [52%]; chemotherapy, 49 [57%]) than in the BEACON BM subgroup (23 [64%] and 21 [68%], respectively).⁴

Given the growing number of patients living with BM and the distinct biology,⁹ there is a clear need for trials dedicated to this patient population or allowing for inclusion of patients with treated/untreated BM in other studies and trials. Several studies have recently reported results in these patients,^10-15 and other studies are ongoing (NCT03765983, NCT04647916, and NCT01494662). Compelling data for subset analyses of controlled trials or preclinical data could serve as the basis for such trials and include multiple tumor types. The present trial illustrates the potential and pitfalls of this strategy and the need for further innovations in CNS imaging techniques, quality-of-life tools, and statistical approaches.

It is possible that the broad eligibility criteria that permitted all breast cancer subtypes may have distorted the interpretation of our study results given that the standard-of-care treatment for ERBB2-positive and negative disease is substantially different; this should be considered in future trials. A protocol amendment that reduced the power of ATTAIN to 80% could have increased the likelihood of a false-positive or false-negative result and possibly hindered the detection of any true treatment effect by reducing the sample size and OS events required at the interim analysis. There is also the possibility that the BEACON BM subgroup results were a false-positive (chance) outcome.⁴

The phase 3 ATTAIN randomized clinical trial did not replicate the positive OS benefit of treatment with etirinotecan pegol compared with chemotherapy in patients with breast cancer and BM that was observed in BEACON, emphasizing the need to closely mirror the original trial design in confirmatory studies. Results from this and other studies demonstrate the feasibility of trials in this population of patients with breast cancer and BM and highlight the importance of confirming findings from subgroup analyses.

Accepted for Publication: January 19, 2022.

Published Online: May 12, 2022. doi:10.1001/jamaoncol.2022.0514

Corresponding Author: Debu Tripathy, MD, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1354, Houston, TX 77030 (dtripathy@mdanderson.org).

Author Contributions: Drs Tripathy and Tagliaferri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tripathy, Tolaney, Seidman, Anders, Diéras, Du, Currie, Hoch, Tagliaferri, Hannah, Cortés.

Acquisition, analysis, or interpretation of data: Tolaney, Seidman, Anders, Ibrahim, Rugo, Twelves, Diéras, Müller, Du, Currie, Hoch, Tagliaferri, Hannah.

Drafting of the manuscript: Tripathy, Seidman, Müller, Currie, Hoch, Tagliaferri.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ibrahim, Du, Tagliaferri, Hannah.

Obtained funding: Tagliaferri.

Administrative, technical, or material support: Tripathy, Ibrahim, Rugo, Currie, Tagliaferri, Hannah.

Supervision: Tripathy, Seidman, Anders, Twelves, Diéras, Currie, Hoch, Tagliaferri, Cortés.

Other - inclusion patients: Diéras.

Conflict of Interest Disclosures: Dr Tripathy reported grants from Novartis and Pfizer as well as personal fees from OncoPep, AstraZeneca, Exact Sciences, Gilead, Novartis, Pfizer, and GlaxoSmithKline outside the submitted work. Dr Tolaney reported grants and personal fees from Nektar during the conduct of the study as well as grants from AstraZeneca, Eli Lilly, Merck, Genentech/Roche, Pfizer, Novartis, Gilead, Exelixis, BMS, Sanofi, Eisai, and SeaGen and personal fees from AstraZeneca, Eli Lilly, Merck, Genentech/Roche, Pfizer, Novartis, Gilead, Puma, Daiichi Sankyo, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Samsung Bioepsis, CytomX, Mersana Therapeutics, Certara, BMS, Eisai, Sanofi, 4D Pharma, OncoSec, BeyondSpring Pharmaceuticals, Chugai Pharma, OncXerna, Zymeworks, Zentalis, and SeaGen outside the submitted work. Dr Seidman reported personal fees from Nektar during the conduct of the study. Dr Anders reported grants from Nektar during the conduct of the study as well as grants from Puma, Eli Lilly, SeaGen, Tesaro, G-1 Therapeutics, Zion, Novartis, and Pfizer; personal fees from Genentech, Eisai, Ipsen, AstraZeneca, Immunomedics, Elucida, and Athenex; and royalties from UpToDate and Jones & Bartlett Publishing Company outside the submitted work. Dr Rugo reported grants from Nektar during the conduct of the study; and research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Roche, Odonate, Daiichi Sankyo, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, OBI, Gilead, and Ayala and honoraria from Puma, Samsung, and Napo outside the submitted work. Dr Twelves reported personal fees from Nektar during the conduct of the study and personal fees from Pfizer, Daiichi Sankyo, Eisai, Zentalis, and AstraZeneca and nonfinancial support from Roche outside the submitted work. Dr Diéras reported personal fees from Roche, Genentech, Novartis, Eli Lilly, MSD, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead, SeaGen, Eisai, and Pierre Fabre outside the submitted work. Dr Müller reported personal fees from Nektar during the conduct of the study and personal fees from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, SeaGen, Onkowissen, high5 Oncology, and Medscape and honoraria from Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Sanofi, and SeaGen outside the submitted work. Dr Currie reported personal fees from Nektar Therapeutics during the conduct of the study. Drs Hoch and Tagliaferri reported being employed by Nektar Therapeutics. Dr Hannah reported personal fees from Nektar Therapeutics during the conduct of the study. Dr Cortés reported personal fees from Roche, Celgene, Cellestia, AstraZeneca, SeaGen, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Merck, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, Bioinvent, Gemoab, Gilead, Menarini, Zymeworks, Novartis, Eisai, Pfizer, and Samsung Bioepis; grants from Roche, Aria Pharmaceuticals, AstraZeneca, Baxalta, Bayer, Eisai, Guardant Health, Merck, PIQR, Puma, and Queen Mary University of London; and stock in Medsir outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by Nektar Therapeutics (San Francisco, California).

Role of the Funder/Sponsor: The funder had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The ATTAIN Investigators are listed in Supplement 4.

Data Sharing Statement: See Supplement 5.

Additional Contributions: We thank all the patients, their families, and the investigators who participated in this study. Medical writing assistance was provided by Sara Shaw and Suzanne Patel, BOLDSCIENCE Inc, who were compensated for their contributions.