PF-07104091 is a novel CDK2-selective inhibitor with the potential for increased cyclin E expression/CDK2 activity and /or loss of the Rb tumor suppressor. The drug is currently under investigation in patients with selected advanced or metastatic solid tumors. According to the results presented at ASCO 2023, at the data cutoff (August 23, 2022), around 35 patients with advanced solid tumors (n = 29 mBC) were enrolled. Among these 29 patients with mBC, all had received prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. The safety results of the trial is been presented below

• Treatment-emergent adverse events (TEAEs) were observed in 34 patients (97.1%; 20 [57.1%] grade [G] ≥ 3). The G≤3 TEAEs were nausea (14.3%), diarrhea (8.6%), vomiting (2.9%), fatigue (20.0%) and anemia (8.6%)
• Serious adverse events (SAEs) occurred in 7 (20%) patients
• Dose-limiting toxicity occurred in 5 patients: 1 patient (Grade 3 fatigue) at 300 mg BID; 2 patients (1 Grade 3 nausea and Grade 3 anorexia, 1 Grade 3 nausea) at 375 mg BID, and 2 patients (1 Grade 3 fatigue and 1 Grade 3 diarrhea) at 500 mg BID
• PF-07104091 300 mg BID was identified as the maximum tolerated dose (MTD) and selected as the monotherapy recommended dose for expansion (RDE)

In terms of efficacy findings, among 16 response evaluable mBC patients (all prior CDK4/6i+ET) partial responses were observed in 3 (18.8%) patients and stable disease in 6 (37.5%) patients. Moreover, two patients had a duration of response > 6 months, and one was ongoing at the data cut-off. Importantly, the disease control rate was found to be 61.5% in patients with mBC.

KOL insights

“Several developers looking at CDK2 inhibition as answer to CDK4/6 failure in breast cancer. Big crowds around Pfizer’s poster today, Phase I/2 of PF-07104091. Results from initial dose escalation phase shows some (early) signs of monotherapy activity.” –Expert Opinion.

Conclusion

PF-07104091 monotherapy exhibited favorable tolerability and demonstrated antitumor activity in heavily pretreated HR+/HER2- mBC patients progressing on previous CDK4/6 inhibitors. Ongoing dose expansions investigate PF-07104091 as monotherapy in ovarian cancer and in combination with fulvestrant for breast cancer patients, expanding treatment horizons.

Despite the established efficacy of CDK4/6 inhibitors - Lilly's VERZENIO, Novartis's KISQALI, and Pfizer's IBRANCE - relapse remains a challenge for a substantial patient subset. Apart from Pfizer’s CDK2 inhibitor, we also have players such as Blueprint medicines, Incyte, Incyclix, Allorian Therapeutics, and Cyclacel, evaluating CDK2 inhibitors in early phase trials. The spotlight is now shifting towards CDK2 as a potential solution for overcoming resistance to CDK4/6 inhibitors, with early data presented at ASCO highlighting promising advances in the field.

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