Phase II Study of Palbociclib (PD-0332991) in CCND1, 2, or 3 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1B

Amy S Clark, Fangxin Hong, Richard S Finn, Angela M DeMichele, Edith P Mitchell, James Zwiebel, Fernanda I Arnaldez, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David Patton, P Mickey Williams, Stanley R Hamilton, Mehmet S Copur, Samer S Kasbari, Ravneet Thind, Barbara A Conley, Carlos L Arteaga, Peter J O'Dwyer, Lyndsay N Harris, Alice P Chen, Keith T Flaherty, Amy S Clark, Fangxin Hong, Richard S Finn, Angela M DeMichele, Edith P Mitchell, James Zwiebel, Fernanda I Arnaldez, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David Patton, P Mickey Williams, Stanley R Hamilton, Mehmet S Copur, Samer S Kasbari, Ravneet Thind, Barbara A Conley, Carlos L Arteaga, Peter J O'Dwyer, Lyndsay N Harris, Alice P Chen, Keith T Flaherty

Abstract

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3.

Patients and methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles.

Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%).

Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification.

©2023 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Best response to palbociclib in patients with tumors containing a CCND1, 2, or 3 amplification. A, Waterfall plot of best change from baseline for n = 22 patients with follow-up target lesion measurements. Color shows histology. For the remaining n = 10 patients: unevaluable (n = 8), PD due to new lesion (n = 2). B, Treatment duration for n = 12 patients who achieved SD. Abbreviations: PD, progressive disease; SCC, squamous cell carcinoma; AdenoCA, adenocarcinoma; GEJ, gastroesophageal junction; CA, carcinoma.
Figure 2.
Figure 2.
A, PFS among patients with CCND1, 2, or 3 amplification receiving palbociclib on NCI-MATCH subprotocol Z1B. B, Overall survival among patients with CCND1, 2, or 3 amplification receiving palbociclib on NCI-MATCH subprotocol Z1B.

References

    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74.
    1. Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer 2011;18:C19–24.
    1. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem 2006;97:261–74.
    1. Buckley MF, Sweeney KJ, Hamilton JA, Sini RL, Manning DL, Nicholson RI, et al. . Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993;8:2127–33.
    1. Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, et al. . Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett 1995;90:43–50.
    1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. . Final results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2-advanced breast cancer (PALOMA-1; TRIO-18). Cancer Res 2014;74 (19_suppl): CT101.
    1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. . The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncology 2015;16:25–35.
    1. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K, et al. . Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016;375:1925–36.
    1. Narayan V, Hwang W-T, Lal P, Rosen MA, Gallagher M, O'Dwyer PJ, et al. . Cyclin-dependent kinase 4/6 inhibition for the treatment of unresectable mature teratoma: long-term follow-up of a Phase II study. Clin Genitourin Cancer 2016;14:504–10.
    1. Schultz KAP, Petronio J, Bendel A, Patterson R, Vaughn DJ. PD0332991 (palbociclib) for treatment of pediatric intracranial growing teratoma syndrome. Pediatr Blood Cancer 2015;62:1072–4.
    1. Lee C, Huang X, Di Liberto M, Martin P, Chen-Kiang S. Targeting CDK4/6 in mantle cell lymphoma. Ann Lymphoma 2020;4:1.
    1. Flaherty KT, Gray R, Chen A, Li S, Patton D, Hamilton SR, et al. . The molecular analysis for therapy choice (NCI-MATCH) trial: lessons for genomic trial design. J Natl Cancer Inst 2020;112:1021–9.
    1. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24:1770–83.
    1. Lih C-J, Harrington RD, Sims DJ, Harper KN, Bouk CH, Datta V, et al. . Analytical validation of the next-generation sequencing assay for a nationwide signal-finding clinical trial molecular analysis for therapy choice clinical trial. J Mol Diagn 2017;19:313–27.
    1. Khoury JD, Wang W-L, Prieto VG, Medeiros LJ, Kalhor N, Hameed M, et al. . Validation of immunohistochemical assays for integral biomarkers in the NCI-MATCH EAY131 clinical trial. Clin Cancer Res 2018;24:521–31.
    1. Schwartz LH, Seymour L, Litière S, Ford R, Gwyther S, Mandrekar S, et al. . RECIST 1.1-Standardisation and disease-specific adaptations: perspectives from the RECIST working group. Eur J Cancer 2016;62:138–45.
    1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. . Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;2:3059.
    1. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. . Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963–72.
    1. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. . International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncology 2016;17:E328–46.
    1. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al. . Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209–19.
    1. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al. . CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21:995–1001.
    1. Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S, et al. . Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J Clin Oncol 2019;37:1169–78.
    1. Chen Y, Huang Y, Gao X, Li Y, Lin J, Chen L, et al. . CCND1 amplification contributes to immunosuppression and is associated with a poor prognosis to immune checkpoint inhibitors in solid tumors. Front Immunol 2020;11:1620.
    1. Maiani E, Milletti G, Nazio F, Holdgaard SG, Bartkova J, Rizza S, et al. . AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature 2021;592:799–803.
    1. Chaikovsky AC, Li C, Jeng EE, Loebell S, Lee MC, Murray CW, et al. . The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature 2021;592:794–8.
    1. Simoneschi D, Rona G, Zhou N, Jeong Y-T, Jiang S, Milletti G, et al. . CRL4(AMBRA1) is a master regulator of D-type cyclins. Nature 2021;592:789–93.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren