15/Feb/2022

Adjuvant Olaparib for Patients with BRCA1– or BRCA2-Mutated Breast Cancer

BACKGROUND
Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer.

METHODS
We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival.

RESULTS
A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease–free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest.

CONCLUSIONS
Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823. opens in new tab.)

Andrew N.J. Tutt, M.B., Ch.B., Ph.D., Judy E. Garber, M.D., M.P.H., Bella Kaufman, M.D., Giuseppe Viale, M.D., Debora Fumagalli, M.D., Ph.D., Priya Rastogi, M.D., Richard D. Gelber, Ph.D., Evandro de Azambuja, M.D., Ph.D., Anitra Fielding, M.B., Ch.B., Judith Balmaña, M.D., Ph.D., Susan M. Domchek, M.D., Karen A. Gelmon, M.D., et al., for the OlympiA Clinical Trial Steering Committee and Investigators

This article was published on June 3, 2021, at NEJM.org.22

Breast Cancer

Susana Ferreira

08/Feb/2022

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer

BACKGROUND
For postmenopausal women with hormone-receptor–positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.

METHODS
In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture.

RESULTS
Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84).

CONCLUSIONS
In postmenopausal women with hormone-receptor–positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620. opens in new tab.)

Michael Gnant, M.D., Florian Fitzal, M.D., Gabriel Rinnerthaler, M.D., Guenther G. Steger, M.D., Sigrun Greil-Ressler, M.D., Marija Balic, M.D., Dietmar Heck, M.D., Raimund Jakesz, M.D., Josef Thaler, M.D., Daniel Egle, M.D., Diether Manfreda, M.D., Vesna Bjelic-Radisic, M.D., et al., for the Austrian Breast and Colorectal Cancer Study Group

This article was updated on July 29, 2021, at NEJM.org.

Breast Cancer

Susana Ferreira

01/Feb/2022

Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer

BACKGROUND
Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not been approved for patients with non–small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody–drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.

METHODS
We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.

RESULTS
A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.

CONCLUSIONS
Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710. opens in new tab.)

Bob T. Li, M.D., Ph.D., M.P.H., Egbert F. Smit, M.D., Ph.D., Yasushi Goto, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Hibiki Udagawa, M.D., Julien Mazières, M.D., Misako Nagasaka, M.D., Ph.D., Lyudmila Bazhenova, M.D., Andreas N. Saltos, M.D., Enriqueta Felip, M.D., Ph.D., Jose M. Pacheco, M.D., Maurice Pérol, M.D., et al., for the DESTINY-Lung01 Trial Investigators

This article was published on September 18, 2021, at NEJM.org.

Lung Cancer

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