Research Spotlight

Metzger-Filho, O., Collier, K., Asad, S., Ansell, P.J., Watson, M., Bae, J., Cherian, M., O’Shaughnessy, J., Untch, M., Rugo, H.S., Huober, J.B., Golshan, M., Sikov, W.M., von Minckwitz, G., Rastogi, P., Li, L., Cheng, L., Maag, D., Wolmark, N., Denkert, C., Symmans, W.F., Geyer, C.E., Jr., Loibl, S. and Stover, D.G. (2021). “Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness.” NPJ Breast Cancer 7(1): 142.

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In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

Harbeck, N., Rastogi, P., Martin, M., Tolaney, S.M., Shao, Z.M., Fasching, P.A., Huang, C.S., Jaliffe, G.G., Tryakin, A., Goetz, M.P., Rugo, H.S., Senkus, E., Testa, L., Andersson, M., Tamura, K., Del Mastro, L., Steger, G.G., Kreipe, H., Hegg, R., Sohn, J., Guarneri, V., Cortés, J., Hamilton, E., André, V., Wei, R., Barriga, S., Sherwood, S., Forrester, T., Munoz, M., Shahir, A., San Antonio, B., Nabinger, S.C., Toi, M., Johnston, S.R.D. and O’Shaughnessy, J. (2021). “Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.” Ann Oncol 32(12): 1571-1581.

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BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

Liebman, C., Loya, S., Lawrence, M., Bashoo, N. and Cho, M. (2021). “Stimulatory responses in α- and β-cells by near-infrared (810 nm) photobiomodulation.” J Biophotonics Nov 26;e202100257. [Epub ahead of print]. e202100257.

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Significant efforts have been committed to better understand and regulate insulin secretion as it has direct implications on diabetes. The first phase of biphasic insulin secretion in response to glucose lasts about 10 minutes, followed by a more sustained release persisting several hours. Attenuated insulin release in the first phase is typically associated with abnormal β-cells. While near-infrared photobiomodulation (PBM) demonstrates potential for multiple therapeutic applications, photostimulatory effects on α- and β-cells remain to be further elucidated. Herein, we demonstrate that 810 nm PBM exposure at fluence of 9 J/cm(2) can elevate the intracellular reactive oxygen species within 15 minutes following photostimulation. In addition, calcium spiking showed an approximately 3-fold increase in both ATC1 (α-cells) and BTC6 (β-cells) and correlates with hormone secretion in response to PBM stimulation. Our findings could lay a foundation for the development of non-biologic therapeutics that can augment islet transplantation.

Taylor, M.H., Betts, C.B., Maloney, L., Nadler, E., Algazi, A., Guarino, M.J., Nemunaitis, J., Jimeno, A., Patel, P., Munugalavadla, V., Tao, L., Adkins, D., Goldschmidt, J.H., Cohen, E.E.W. and Coussens, L.M. (2021). “Safety and Efficacy of Pembrolizumab in Combination With Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study.” Clin Cancer Res Dec 3;clincanres.2547.2021. [Epub ahead of print].

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PURPOSE: Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton’s tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8(+) T cell responses, resulting in enhanced anti-tumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti-PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC. EXPERIMENTAL DESIGN: Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival. RESULTS: Seventy-six patients were evaluated (pembrolizumab, n=39; pembrolizumab + acalabrutinib, n=37). Higher frequencies of grade 3-4 treatment-emergent adverse events (AEs) (65% vs 39%) and serious AEs (68% vs 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 (95% confidence interval [CI], 1.4-6.8) months in the combination arm and 1.7 (95% CI, 1.4-4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was impacted by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45(+) leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n=5; combination, n=2), which appeared to be higher in combination-treated patients; however, definitive conclusions cannot be drawn due to limited sample size. CONCLUSIONS: Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.

Reich, K., Mrowietz, U., Menter, A., Griffiths, C.E.M., Bagel, J., Strober, B., Nunez Gomez, N., Shi, R., Guerette, B. and Lebwohl, M. (2021). “Effect of baseline disease severity on achievement of treatment target with apremilast: results from a pooled analysis.” J Eur Acad Dermatol Venereol 35(12): 2409-2414.

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BACKGROUND: Treating to absolute treatment targets rather than relative measures such as Psoriasis Area and Severity Index (PASI)-75 is emerging as an important clinical concept included in psoriasis guidelines and clinical practice. Achieving treatment targets is associated with achievement of long-term outcomes. OBJECTIVE: To evaluate the relationship between psoriasis severity, disease characteristics and achievement of PASI ≤2 with apremilast in a pooled analysis of the phase 3 ESTEEM 1 and 2 (NCT01194219 and NCT01232283), phase 3b LIBERATE (NCT01690299) and phase 4 UNVEIL (NCT02425826) clinical trials. METHODS: Pooled data from patients with moderate-to-severe plaque psoriasis randomized to apremilast 30 mg BID were analysed by baseline PASI quartiles (Q1: 2.4-13.1; Q2: 13.2-15.9; Q3: 16.0-20.0; Q4: 20.1-57.8). Assessments included PASI, Dermatology Life Quality Index (DLQI), Scalp Physician’s Global Assessment (ScPGA; ScPGA ≥1) and target (worst) Nail Psoriasis Severity Index (NAPSI; NAPSI ≥1). RESULTS: Of 1062 patients, 963 had ScPGA ≥1 and 643 had NAPSI ≥1; 771 patients with baseline and Week 32 PASI assessments were included in analyses of Week 32 PASI target achievement. Rates of PASI ≤2 at Week 32 were greater in lower PASI quartiles (Q1: 43.5%; Q2: 31.2%; Q3: 26.8%; Q4: 18.4%). Most patients achieving PASI ≤2 target (83.6%) achieved DLQI ≤5 at Week 32; 59.3% of patients who did not achieve PASI ≤2 target achieved DLQI ≤5. At Week 32, mean improvements in ScPGA and NAPSI were similar with more moderate vs. more severe disease (ScPGA, range: 1.1-1.4; NAPSI, range: 1.6-2.5). In a subgroup analysis, achievement of PASI ≤2 target was higher in the lowest PASI quartile and with disease duration <5 years. CONCLUSIONS: Greater achievement of PASI ≤2 was observed in patients with more moderate vs. more severe skin disease. Apremilast may be particularly beneficial in more moderate disease early in the treatment paradigm.