Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclinD‐CDK4/6 pathway alterations in the DutchDRUPand AustralianMoSTtrials

Abstract

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan‐cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D‐CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy‐refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression‐free survival was 4 months (95% CI: 3‐5 months), and median overall survival 5 months (95% CI: 4‐6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D‐CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.

The evolution of precision oncology: The ongoing impact of the Drug Rediscovery Protocol (DRUP)

“…Nonetheless, it is important to note that not only successful DRUP cohorts are being published, as exemplified in a recent article by Zeverijn et al [20]. The article reported the results of 139 patients with various tumor types, either enrolled in DRUP or the Australian Cancer Molecular Screening and Therapeutic (MoST) trial, that were treated with one of the CDK4/6 inhibitors palbociclib or ribociclib as monotherapy, based on complete loss of CDKN2A or SMARCA4 or amplifications of CDK4, CDK6, CCND1, CCND2, or CCND3.…”

“…Notably, the outcomes of DRUP have led to the reimbursement of nivolumab for all patients in the Netherlands with pretreated advanced tumors that harbor MSI, highlighting the potential opportunities an investigator-initiated study can provide [4,17]. Concurrently, addressing the limited therapeutic efficacy of palbociclib or ribociclib as monotherapy for patients with alterations in the cyclin D-CDK4/6 pathway, underscores the importance of reporting negative evidence to prevent futile treatments in the future [20]. The ongoing CBR of 33% observed in DRUP demonstrates that matched targeted anticancer therapies benefit a considerable number of patients [14].…”

Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib

“…Specific CDK4/6-inhibitors, such as palbociclib and ribociclib, have been approved for the treatment of hormone receptor-positive metastatic breast cancer in combination with fulvestrant or an aromatase inhibitor 16 . However, in three single-agent CDK4/6 inhibitor pan-cancer trials with patient selection based on specific molecular aberrations of cell cycle genes, only limited clinical activity was observed with no partial or complete responses 17 , 18 .…”

Treatment of Thoracic SMARCA4-Deficient Undifferentiated Tumors: Where We Are and Where We Will Go

“…Moreover, SMARCA2 loss also contributes to inhibited CCND1 expression, making CDK4/6 inhibitors a promising treatment for SMARCA4-UT, as they are often characterized by a loss of both SMARCA4 and SMARCA2 expression [ 86 ]. However, in a recent nonrandomized, multidrug, pan-cancer trial with tumors harboring cyclin CDK4/6 pathway alterations, including SMARCA4 expression loss, only limited clinical activity for palbociclib and ribociclib monotherapy was observed [ 87 ]. AURKA expression is often elevated in several cancer types, and a link between SW1/SNF complex dysfunction and AURKA overexpression has been reported for rhabdoid tumors.…”