Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.

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.

Beyond Skin Rash: Alpelisib-Induced Anaphylactic Reactions.

Alpelisib is a specific oral PI3K inhibitor used combined with fulvestrant for the treatment of patients with HR+/HER2-/PIK3CA-mutated metastatic breast cancer. Adverse drug reactions with alpelisib are common, including hyperglycemia and rash. Here we describe extraordinary and life-threatening reactions beyond skin rash in two patients with progressive PIK3CA-mutated metastatic cancer in whom alpelisib was initiated. Case-A (vaginal cancer): After 10 days on treatment, she developed dry eyes, generalized rash and itching. Alpelisib was interrupted and symptomatic treatment initiated. Because of an initial tumor response, a rechallenge was done. Ninety minutes after a reduced dose of alpelisib, she developed an anaphylactic reaction with angioedema, hypotension, and skin rash. Case-B (breast cancer): After 11 days on treatment, she developed skin rash and alpelisib was interrupted. At re-initiation, she felt tingles in her face and ears and some skin erythema. Given the mild rash, a second rechallenge with premedication was performed. Ninety minutes after a reduced dose of alpelisib, she developed a type-1 allergic reaction with angioedema, tingles, and skin rash. In both cases, a type-1 allergic reaction was diagnosed and symptomatic treatment was initiated, alpelisib was permanently discontinued and the patients fully recovered the next week(s). This report underlines the critical importance to consider type-I allergic reactions in the differential diagnosis in cases of rash associated with alpelisib. Even if a reaction develops after days on treatment, a type-I allergic reaction cannot be excluded. A rechallenge can be dangerous and should always be well contemplated or even avoided.