Joyce O'Shaughnessy M.D.

Schmid, P., Cortes, J., Dent, R., Pusztai, L., McArthur, H., Kümmel, S., Bergh, J., Denkert, C., Park, Y. H., Hui, R., Harbeck, N., Takahashi, M., Untch, M., Fasching, P. A., Cardoso, F., Andersen, J., Patt, D., Danso, M., Ferreira, M., Mouret-Reynier, M. A., Im, S. A., Ahn, J. H., Gion, M., Baron-Hay, S., Boileau, J. F., Ding, Y., Tryfonidis, K., Aktan, G., Karantza, V. and O’Shaughnessy, J. (2022). “Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer.” N Engl J Med 386(6): 556-567.

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BACKGROUND: The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

Rugo, H. S., Lacouture, M. E., Goncalves, M. D., Masharani, U., Aapro, M. S. and O’Shaughnessy, J. A. (2022). “A multidisciplinary approach to optimizing care of patients treated with alpelisib.” Breast 61: 156-167.

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PURPOSE: The oral, α-specific phosphatidylinositol-3-kinase (PI3Kα) inhibitor alpelisib is the first PI3K inhibitor approved for the treatment of advanced breast cancer. As alpelisib is a relatively new therapeutic option, specific guidance and a multidisciplinary approach are needed to provide optimal patient care. The primary objective of this manuscript is to provide comprehensive guidance on minimizing and managing adverse events (AEs) for patients with advanced breast cancer who are receiving alpelisib. METHODS: Clinical studies, prescribing information, published literature, and relevant guidelines were reviewed to provide recommendations on the prevention and management of alpelisib-associated AEs. RESULTS: The most common AEs associated with alpelisib in the phase 3 SOLAR-1 trial were hyperglycemia and rash (which are considered on-target effects of PI3Kα inhibition) and gastrointestinal AEs, including diarrhea, nausea, and decreased appetite. These AEs require regular monitoring, early recognition, and prompt initiation of appropriate treatment. In addition, there are effective strategies to reduce the onset and severity of frequently observed AEs-in particular, onset of hyperglycemia and rash may be reduced by lifestyle changes (such as reduced intake of carbohydrates and regular exercise) and antihistamine prophylaxis, respectively. To reduce risk of severe hyperglycemia, it is essential to achieve adequate glycemic control prior to initiation of alpelisib treatment. CONCLUSION: Overall, alpelisib-associated AEs are generally manageable with prompt recognition, regular monitoring, and appropriate intervention, preferably with a multidisciplinary approach.

Huang, M., Haiderali, A., Fox, G. E., Frederickson, A., Cortes, J., Fasching, P. A. and O’Shaughnessy, J. (2022). “Economic and Humanistic Burden of Triple-Negative Breast Cancer: A Systematic Literature Review.” Pharmacoeconomics.

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BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers (BCs). It is more commonly diagnosed in younger women and often has a less favorable prognosis compared with other BC subtypes. OBJECTIVE: The objective of this study was to provide a literature-based extensive overview of the economic and humanistic burden of TNBC to assist medical decisions for healthcare payers, providers, and patients. METHODS: A systematic literature review was performed using multiple databases, including EMBASE, MEDLINE, Econlit, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from database inception to 16 May 2021. In addition, a targeted search was performed in the Northern Light Life Sciences Conference Abstracts database from 2016 through June 2021. The bibliographies of included articles were reviewed to identify other potentially relevant publications. Quality assessment of the included studies was conducted. RESULTS: The review identified 19 studies assessing the economic burden and 10 studies assessing the humanistic burden of TNBC. Studies varied widely in study design, settings, patient populations, and time horizons. The estimates of mean per-patient annual direct medical costs ranged from around $20,000 to over $100,000 in stage I-III TNBC and from $100,000 to $300,000 in stage IV TNBC. Healthcare costs and resource utilization increased significantly with disease recurrence, progression, and increased cancer stage or line of therapy. Compared with the costs of systemic anticancer therapy, cancer management costs comprised a larger portion of total direct costs. The estimates of indirect costs due to productivity loss ranged from $207 to $1573 per patient per month (all costs presented above were adjusted to 2021 US dollars). Cancer recurrence led to significantly reduced productivity and greater rates of leaving the workforce. A rapid deterioration of health utility associated with disease progression was observed in TNBC patients. Treatment with pembrolizumab or talazoparib showed significantly greater improvements in health-related quality of life (HRQoL) compared with chemotherapy, as measured by EORTC QLQ-C30, QLQ-BR23, and FACT-B. CONCLUSION: TNBC is associated with a substantial economic burden on healthcare systems and societies and considerably reduced productivity and HRQoL for patients. This study synthesized the published literature on the economic and humanistic burden of TNBC and highlighted the need for continued research due to the rapidly changing landscape of TNBC care.

Geyer, C. E., Jr., Sikov, W. M., Huober, J., Rugo, H. S., Wolmark, N., O’Shaughnessy, J., Maag, D., Untch, M., Golshan, M., Ponce Lorenzo, J., Metzger, O., Dunbar, M., Symmans, W. F., Rastogi, P., Sohn, J., Young, R., Wright, G. S., Harkness, C., McIntyre, K., Yardley, D. and Loibl, S. (2022). “Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase 3 trial.” Ann Oncol.

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BACKGROUND: Primary analyses of the phase 3 BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. DESIGN: Women with untreated stage II-III TNBC were randomized (2:1:1) to paclitaxel (weekly for 12 doses) plus either: (a) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (b) carboplatin plus veliparib placebo; or (c) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide (AC) every 2‒3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio [HR] for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 (95% confidence interval [CI] 0.43‒0.92, P=0.02), but 1.12 (95% CI 0.72‒1.72, P=0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, HR for EFS was 0.57 (95% CI 0.36‒0.91, P=0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSION: Improvement in pCR with addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, while adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by AC neoadjuvant chemotherapy for early stage TNBC.

Tan, A.R., Wright, G.S., Thummala, A.R., Danso, M.A., Popovic, L., Pluard, T.J., Han, H.S., Vojnović, Ž., Vasev, N., Ma, L., Richards, D.A., Wilks, S.T., Milenković, D., Xiao, J., Sorrentino, J., Horton, J. and O’Shaughnessy, J. (2021). “Trilaciclib prior to chemotherapy in patients with metastatic triple-negative breast cancer: final efficacy and subgroup analysis from a randomized phase II study.” Clin Cancer Res Dec 9;clincanres.2272.2021. [Epub ahead of print].

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PURPOSE: We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716). EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to group 1 (GCb [days 1, 8]; n = 34), group 2 (trilaciclib prior to GCb [days 1, 8]; n = 33), or group 3 (trilaciclib [days 1, 8] and trilaciclib prior to GCb [days 2, 9]; n = 35). Subgroup analyses were performed according to CDK4/6 dependence, level of PD-L1 expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCR β CDR3 at baseline and on treatment. RESULTS: Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (hazard ratio [HR] 0.31; P = 0.0016), 17.8 months in group 3 (HR 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population. T-cell activation was enhanced in patients receiving trilaciclib. CONCLUSIONS: Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.