On September 2, 2021 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported key clinical and regulatory updates across its pipeline (Press release, Zentalis Pharmaceuticals, SEP 2, 2021, View Source [SID1234587162]).
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"We continue to build substantial value in Zentalis’ portfolio, driving toward approval of our differentiated cancer therapeutics to help patients worldwide," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis. "Based on our clinical results reported to date, the emerging clinical profiles of our candidates support the potential for best-in-class positioning for a range of tumor types addressing large patient populations, is use as a monotherapy or in combinations. In particular, we are excited about the compelling profile of ZN-c3, our WEE1 inhibitor, as it demonstrated additional, deepening and durable tumor responses as a monotherapy in heavily pretreated solid tumors. These promising data set the stage for the many upcoming planned trials – two of which have the potential to be registrational monotherapy studies in indications with significant unmet medical needs. We look forward to a productive second half of 2021, as we focus on delivering on our milestones across our entire pipeline."
ZN-c3: Oral WEE1 Inhibitor for Solid Tumors
Updates from our ongoing trials of ZN-c3 continue to support the potential for our WEE1 inhibitor, ZN-c3, to be both first-in-class and best-in-class. Since our last update at AACR (Free AACR Whitepaper) in April 2021, and as of the data cut-off date of May 15, 2021:
The 2 unconfirmed Partial Responses (PRs) reported at AACR (Free AACR Whitepaper) were confirmed, bringing the total number of confirmed PRs from our monotherapy trial from 3 to 5. Since AACR (Free AACR Whitepaper), an additional unconfirmed PR was reported in a patient with uterine serous carcinoma (USC), resulting in 3 out of 7 USC patients enrolled having responded to treatment. Overall, the objective response rate (ORR) in the USC population increased from 40% to 43% based on RECIST criteria.
Additionally, within the exceptional responder population in the Phase 1 monotherapy trial, we have observed a patient with an ongoing treatment duration of more than 8 months, with a deepening response of 65% to 69% tumor size decrease based on RECIST criteria.
Lower overall severe hematological adverse event rates – severe neutropenia adverse event rates decreased from 2.9% to 2.2% with an additional 11 patients enrolled since AACR (Free AACR Whitepaper) 2021.
Following an End-of-Phase 1 meeting, the U.S. Food and Drug Administration (FDA) concurred in principle with the proposal that ZN-c3 has the potential for an accelerated approval pathway based on the proposed global study design of a Phase 2 monotherapy trial in women with recurrent or persistent USC. The trial has initiated with multiple sites open.
Zentalis is planning to launch a biomarker-driven Phase 2 study pending FDA feedback. The tumor-agnostic trial will investigate ZN-c3 in patients with solid tumors that express the identified predictive biomarker, and is expected to initiate by year-end.
ZN-c3 has received orphan drug designation, and rare pediatric disease designation from the FDA for pediatric osteosarcoma. The Phase 1/2 trial of ZN-c3 in combination with chemotherapy in pediatric patients with osteosarcoma is expected to initiate in 3Q 2021. If ZN-c3 were to obtain approval for the designated indication, it could be eligible for a rare pediatric disease priority voucher upon approval.
Zentalis will also support two planned additional investigator-initiated trials: a trial with the Ivy Brain Center in glioblastoma multiforme (GBM) and a trial with immunotherapy with Dana Farber in triple negative breast cancer.
Zentalis’ China JV Zentera is advancing corresponding clinical trials in China with ZN-c3.
ZN-c5: Oral SERD for ER+/HER2- Advanced or Metastatic Breast Cancer
Based on the interim results from multiple ongoing trials, ZN-c5 has demonstrated the potential to support best-in-class tolerability in both monotherapy and combination settings, with strong clinical results observed. As of May 11, 2021, the following data were collected:
Monotherapy Trials (Expansion and Dose Escalation)
In total, 56 patients with 2 median prior lines of treatment were evaluated for safety and efficacy. Across all doses from 50 mg QD to 300 mg QD, the observed CBR was 33% and the ORR was 5%. ZN-c5 generated 2 PRs at the 150 mg and 300 mg doses. Adverse events (AEs) were found in less than 10% of the patients and there were no observed cases of bradycardia, visual disturbances, QTC or dizziness. Of note, treatment related diarrhea adverse event rate was 3.6%, with only grade 1 or 2 events observed. The Phase 2 monotherapy trial has been initiated and Zentalis may take multiple doses into this study.
An oral dose of 50 mg QD (n=16) demonstrated a CBR of 40%, with many patients in this dose cohort remaining on study drug and in the trial. Final determination of the monotherapy RP2D will occur following completion of this 50 mg QD dose cohort.
Combination Dose Escalation Trials with Pfizer’s CDK4/6 Palbociclib and Lilly’s CDK4 and 6 Abemaciclib
Tolerability data for ZN-c5 suggests it could be best-in-class in oral SERDS, making this candidate ideal for further evaluation in combination. The two separate trials will continue to enroll patients and the Company expects to report interim results in 1H 2022 from one or more of these trials.
Window of Opportunity Trial
The Window of Opportunity trial (n=35) demonstrated ER degradation across all doses tested.
ZN-d5: Highly Selective Oral BCL-2 Inhibitor for Hematologic Tumors
The Phase 1 monotherapy dose-escalation trial, initiated in 4Q 2020, has enrolled 14 patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) thus far in the fifth dose cohort. Additionally, no dose-limiting toxicities have been identified. Patients with acute myeloid leukemia will begin enrollment in 3Q 2021. Interim results from this Phase 1 trial are expected in 1H 2022.
ZN-e4: 3rd Generation Oral EGFR Inhibitor for Non-Small-Cell Lung Carcinoma
The Phase 1/2 dose-escalation trial in patients with advanced non-small cell lung cancer is ongoing with 26 patients (both osimertinib-naïve and experienced) enrolled to date. ZN-e4 has been well-tolerated at all doses as of the March 25, 2021 data cut-off, and clinical activity was identified at doses greater than 80 mg QD. Interim results from the Phase 1/2 trial are expected in 4Q 2021.
Webcast Event:
Zentalis will host a webcast event today, June 28, 2021 at 8:30 a.m. EDT. To register and access the event, the webcast link is available on the Investors & Media section of the Zentalis website at www.zentalis.com.