A multicenter open-label phase II study of the efficacy and safety of palbociclib a cyclin-dependent kinases 4 and 6 inhibitor in patients with recurrent ovarian cancer.

Konecny, Gottfried E.; Hendrickson, Andrea E. Wahner; Jatoi, Aminah; Burton, Jill K.; Paroly, Jill; Glaspy, John A.; Dowdy, Sean C.; Slamon, Dennis J.

doi:10.1200/jco.2016.34.15_suppl.5557

Cited by 26 publications

(24 citation statements)

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“…10 One prospective phase II study of 40 molecularly unselected patients with high-grade ovarian cancer demonstrated good tolerance of the CDK4/6 inhibitor as a single agent, with a modest median PFS of 3.7 months, corresponding to 30% at 6 months. 2 Only one patient attained an objective radiological response (1 of 26 evaluable). An additional three patients attained a response using the GCIG CA125 criteria (4/30 evaluable).…”

Section: Discussionmentioning

confidence: 98%

“…Despite extensive use of chemotherapy, the prognosis of recurrent disease remains unfavorable. 1 CDK4/6 inhibitors are currently being investigated in ovarian cancer and other tumor types, 2,3 but their clinical efficacy is modest in an unselected population and predicting which patient will benefit is difficult. The combination of CDK4/6 inhibitors with fulvestrant or aromatase inhibitors was associated with longer progression-free survival 4 and overall survival 5 in hormone receptor-positive breast cancer but the identification of predictive biomarkers is still lacking.…”

Section: Introductionmentioning

confidence: 99%

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Durable response to palbociclib and letrozole in ovarian cancer withCDKN2Aloss

Frisone

Charrier

Clément

et al. 2019

Cancer Biology & Therapy

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Alterations of the Retinoblastoma (Rb) pathway are frequent in ovarian cancer, typically resulting from CDKN2A down-regulation, CCNE1 amplification, CCND1/2 amplification, and RB1 loss. However, bi-allelic CDKN2A mutation or homozygous deletion is a very rare event, concerning less than 5% of patients. Initial trials with palbociclib in serous ovarian cancer have shown very modest benefit in unselected patient populations, thus underlining the need for a biomarker predicting response. We report the case of a heavily pre-treated patient with a serous ovarian tumor harboring a homozygous deletion of the CDKN2A gene that derived significant, prolonged clinical benefit from palbociclib, a CDK4/6 oral inhibitor, with letrozole. Treatment with palbociclib and letrozole started on February 2018, with an ongoing response after 12 months. In conclusion, homozygous CDKN2A deletion is rare and could be used to predict response to CDK4/6 inhibitors in association with other genomic features. We encourage further trials in this direction.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Durable response to palbociclib and letrozole in ovarian cancer withCDKN2Aloss

Frisone

Charrier

Clément

et al. 2019

Cancer Biology & Therapy

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“… 19 An unpublished report of a phase II trial of palbociclib and letrozole in OC, showed a PFS of 3.7 months and a Partial Remission (PR) rate of 4% with 60% stable disease. 20 Given these findings, we decided to explore if the possibility that combination ribociclib and letrozole could improve outcomes against relapsed OR-positive OC and EC.…”

Section: Introductionmentioning

confidence: 99%

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

et al. 2020

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ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

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“…According to the results of a clinical trial (NCT01536743) which evaluated the efficacy and safety of palbociclib (another CDK4/6 inhibitor) in recurrent ovarian cancer, CDK4/6 inhibition with Palbociclib showed single-agent activity and is well tolerated in heavily pretreated ovarian cancer patients, with 30% of patients were free from disease progression at 6 months after treatment 52 . In accordance with this, our study also find that CDK4/6 inhibition can suppress tumor progression in syngeneic mouse ovarian cancer model.…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner

Zhang

Jiang

et al. 2020

Theranostics

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Great progress has been made in the field of tumor immunotherapy in the past decade. However, the therapeutic effects of immune checkpoint blockade (ICB) against ovarian cancer are still limited. Recently, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6i) has been reported to enhance antitumor immunity in preclinical models. The combined use of CDK4/6i and ICB may be beneficial, but the effects of CDK4/6is on the tumor immune microenvironment and whether they can synergize with ICB in treating ovarian cancer remain unknown. Methods: In this study, we first assessed the antitumor efficacy of abemaciclib, an FDA-approved CDK4/6i, in a syngeneic murine ovarian cancer model. Then, immunohistochemistry, immunofluorescence and flow cytometry were performed to evaluate the number, proportion, and activity of tumor-infiltrating lymphocytes. Cytokine and chemokine production was detected both in vivo and in vitro by PCR array analysis and cytokine antibody arrays. The treatment efficacy of combined abemaciclib and anti-PD-1 therapy was evaluated in vivo , and CD8+ and CD4+ T cell activities were analyzed using flow cytometry. Lastly, the requirement for both CD8+ T cells and B cells in combination treatment was evaluated in vivo, and potential cellular mechanisms were further analyzed by flow cytometry. Results: We observed that abemaciclib monotherapy could enhance immune infiltration, especially CD8+ T cell and B cell infiltration, in the ID8 murine ovarian cancer model. Immunophenotyping analysis showed that abemaciclib induced a proinflammatory immune response in the tumor microenvironment. PCR array analysis suggested the presence of a Th1-polarized cytokine profile in abemaciclib-treated ID8 tumors. In vitro studies showed that abemaciclib-treated ID8 cells secreted more CXCL10 and CXCL13, thus recruiting more lymphocytes than control groups. Combination treatment achieved better tumor control than monotherapy, and the activities of CD8+ and CD4+ T cells were further enhanced when compared with monotherapy. The synergistic antitumor effects of combined abemaciclib and anti-PD-1 therapy depended on both CD8+ T cells and B cells. Conclusion: These findings suggest that combined treatment with CDK4/6i and anti-PD-1 antibody could improve the efficacy of anti-PD-1 therapy and hold great promise for the treatment of poorly immune-infiltrated ovarian cancer.

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A multicenter open-label phase II study of the efficacy and safety of palbociclib a cyclin-dependent kinases 4 and 6 inhibitor in patients with recurrent ovarian cancer.

Cited by 26 publications

References 0 publications

Durable response to palbociclib and letrozole in ovarian cancer withCDKN2Aloss

Durable response to palbociclib and letrozole in ovarian cancer withCDKN2Aloss

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

CDK4/6 inhibition promotes immune infiltration in ovarian cancer and synergizes with PD-1 blockade in a B cell-dependent manner

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