A multi-center phase II trial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma

Swiecicki, Paul; Durm, Greg Andrew; Bell, R. Bryan; Bhangale, Apurva; Brenner, J. Chad; Worden, Francis P.

doi:10.1007/s10637-020-00898-2

Cited by 20 publications

(16 citation statements)

References 29 publications

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“…Specifically, pre- or co-administration of palbociclib with platinum may inadvertently synchronise cells in late G1/early S phase, resulting in a higher proportion of cells repairing the damage during the first cell cycle and maintaining proliferative capacity. In support, current clinical trials in head and neck cancer where both agents were given at the same time have resulted in no improvement to cisplatin therapy and resulted in significant treatment related toxicity (Swiecicki et al, 2020). Conversely, administering palbociclib after cisplatin (and other chemotherapies), improves response and notably represses HR-dependent DNA repair (Salvador-Barbero et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

A Non-Genetic, Cell Cycle Dependent Mechanism of Platinum Resistance in Lung Adenocarcinoma

González-Rajal

Marzec

McCloy

et al. 2020

Preprint

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Innate resistance to platinum-based chemotherapies has significantly reduced their impact in lung adenocarcinoma. We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with this resistant phenotype (Hastings et al., 2020). Here we advanced this model system and identify a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater capacity to repair damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP inhibitors, were unable to sufficiently repair the damage and underwent prolonged S/G2 phase arrest and senescence. These data indicate that there is a fundamental non-genetic mechanism of resistance in lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

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Section: Discussionmentioning

confidence: 99%

A Non-Genetic, Cell Cycle Dependent Mechanism of Platinum Resistance in Lung Adenocarcinoma

González-Rajal

Marzec

McCloy

et al. 2020

Preprint

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“…The combination of platinum-based chemotherapy with CDK4/6i has been tested in several solid malignancies. The study by Swiecicki et al was of particular interest because the combination was specifically tested to improve the efficacy of platinum [ 103 ]. This phase II trial enrolled recurrent and metastatic head and neck cancer patients, treated with carboplatin on day 1 (with a starting dose of 5AUC) and palbociclib (125 mg daily) on days 1–14, every three weeks.…”

Section: Clinical Experiences On the Use Of Cdk 4/6i With Chemotherapymentioning

confidence: 99%

“…This phase II trial enrolled recurrent and metastatic head and neck cancer patients, treated with carboplatin on day 1 (with a starting dose of 5AUC) and palbociclib (125 mg daily) on days 1–14, every three weeks. This schedule of carboplatin and palbociclib showed disappointing antitumor activity, with a 12-week disease control rate of 33% (5/18 stable disease and 1/18 partial response), a median PFS of 2.9 months and significant associated toxicities: grade 3 or higher toxicities were seen in 79% of patients, with the most common being myelosuppression [ 103 ]. It is conceivable that this weak anti-tumor activity is due, at least in part, to an incorrect timing of palbociclib administration: given in concomitance with platinum and not sequentially, palbociclib may not be able to prevent the recovery from cytotoxic DNA damage.…”

Section: Clinical Experiences On the Use Of Cdk 4/6i With Chemotherapymentioning

confidence: 99%

“…In HGSOC, which almost invariably carry mutations in the tumor suppressor gene TP53 and, for this reason, are predicted to be highly sensitive to ATR inhibition [ 27 , 109 ], it would be worth testing the association between CDK4/6i and cisplatin, using CDKi as maintenance therapy. This schedule should, in principle, allow the strongest synergistic effect and avoid the accumulation of hematological toxicities, as observed in head and neck patients that were concomitantly treated with carboplatin and palbociclib [ 103 ]. This regimen could be promising also in recurrent ovarian cancer patients that have been treated with platinum-based therapy and still display partial response to platinum.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

Dall'Acqua

Bartoletti

Masoudi-Khoram

et al. 2021

Cancers

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Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.

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“…Created with BioRender.com Still, the lack of a control cohort hampers data interpretation. Just recently, results from a multicenter phase II trial were published [32]. Palbociclib was here given in combination with carboplatin for the treatment of unresectable recurrent or metastatic HNSCC (N = 18 patients).…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

Riess

Irmscher

Salewski

et al. 2020

Cancer Metastasis Rev

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Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.

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A multi-center phase II trial evaluating the efficacy of palbociclib in combination with carboplatin for the treatment of unresectable recurrent or metastatic head and neck squamous cell carcinoma

Cited by 20 publications

References 29 publications

A Non-Genetic, Cell Cycle Dependent Mechanism of Platinum Resistance in Lung Adenocarcinoma

A Non-Genetic, Cell Cycle Dependent Mechanism of Platinum Resistance in Lung Adenocarcinoma

Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

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