Allarity Therapeutics, Inc. has filed a formal request with the FDA to host a Type C meeting where they can discuss possible clinical pathways to support approval of dovitinib in renal cell carcinoma, as well as its companion diagnostic DRP- Dovitinib.
Allarity Therapeutics, Inc. has filed a formal request with the FDA to host a Type C meeting where they can discuss possible clinical pathways to support the approval of dovitinib in renal cell carcinoma (RCC), as well as its diagnosis DRP-Dovitinib companion.1
In December 2021, a new drug application (NDA) requesting marketing authorization for dovitinib as a potential third-line treatment option for patients with RCC has been submitted to the FDA.2 The application was supported by the diagnostics company’s pre-marketing approval (PMA) pre-submission to select eligible patients with RCC for treatment with this agent.
Two months later, in February 2022, the FDA issued denial letters regarding both applications. At the time, the late-stage precision medicine company shared its intention to seek additional guidance regarding the specific information, data and deliverables the regulator would need to resubmit applications and be considered complete. The initiation of a new prospective clinical trial evaluating the agent in this population was also planned.
Type C meetings are generally scheduled within 75 days of FDA’s receipt of the written meeting request. Allarity Therapeutics, Inc. announced its intention to provide an additional update on meeting results before the end of the third quarter.
“We look forward to working closely with the FDA and remain very confident in the clinical profile of dovitinib, as well as the DRP-Dovitinib companion diagnostic. We are committed to further advancing this product candidate as a potential new treatment option for cancer patients,” said Steve Carchedi, Chief Executive Officer of Allarity Therapeutics, Inc., in a press release. “With clarification from the FDA following our requested Type C meeting, we hope to have a clinical pathway forward with the goal of refiling our NDA and PMA once additional clinical data becomes available.”
In the Phase 3 GOLD trial (NCT01223027), the safety and efficacy of dovitinib was compared to that of sorafenib (Nexavar) in patients with metastatic RCC.3 To be eligible for enrollment, patients had to have clear cells or a component of clear cell histology and had received 1 prior VEGF-targeting therapy such as sunitinib (Sutent) or bevacizumab (Avastin) as well as an mTOR inhibitor such as everolimus (Afinitor) or temsirolimus (Torisel) in both sequences.
These patients were at least 18 years of age, had measurable disease by RECIST v1.1 criteria, a Karnofsky performance status of 70 or greater, and had experienced disease progression within 6 months of receiving their last treatment. Patients had to have acceptable hematological, renal and hepatic function. Notably, they were allowed to have previously received cancer drugs, including cytokines and cancer vaccines.
In the trial, 570 patients were randomized to receive oral dovitinib at a dose of 500 mg on a 5-day on and 2-day off schedule (n=284) or oral sorafenib at 400 mg twice daily (n=286) . Patients received treatment until disease progression, unacceptable toxicity, death, or withdrawal of consent. The trial did not allow switching from the control arm to the investigation arm.
The primary endpoint of the research was progression-free survival (PFS), and overall survival (OS) served as a key secondary endpoint. Other endpoints of interest included overall response rate, investigator-assessed PFS, time to definitive deterioration in performance status, patient-reported outcomes (PRO), and safety. . Investigators also performed biomarker analyses.
Patient characteristics were well balanced between the 2 treatment arms. The most commonly received VEGF inhibitor was sunitinib, and the most commonly used mTOR inhibitor was everolimus. The majority of patients (92%) first received a VEGF inhibitor and then an mTOR inhibitor.
The results of the trial indicated that the median PFS by central radiological examination with dovitinib versus sorafenib was 3.7 months (95% CI, 3.5-3.9) and 3.6 months (CI 95%, 3.5-3.7), respectively (RR, 0.86; 95% CI, 0.86; 95% CI, 0.71-1.04; P = 0.063). The median PFS by investigator assessment was 3.9 months in the dovitinib arm (95% CI, 3.7-5.1) and in the sorafenib arm (95% CI, 0.82-1, 21; RR, 1.00).
No subset of patients was found to experience a clinically meaningful benefit in PFS with dovitinib over sorafenib.
The best overall response by central review was a partial response, and this occurred in 4% of those who received dovitinib and 4% of those who received sorafenib. In both arms, 52% of patients achieved stable disease. Twenty-nine percent of patients in the experimental group experienced disease progression compared with 31% of those in the control group.
The median OS in the investigation and control arms was 11.1 months (95% CI, 9.5-13.4) and 11.0 months (95% CI, 8.6-13, 5), respectively (HR, 0.96; 95% CI, 0.75-1.22). Additionally, the median time to definitive worsening of Karnofsky performance status was 5.1 months (95% CI, 3.8-6.5) in the experimental group and 5.7 months (95% CI, 4.6-7.4) in the control group (RR, 1.12; 95% CI, 0.87-1.45).
PRO data was found to be comparable between the 2 arms. The median time to definitive deterioration of 10% in EORTC QLQ-C30 quality of life scores in the dovitinib and sorafenib arms was 4.1 months (95% CI, 3.2-5.3) and 4.7 months (95% CI, 3.8-5.6), respectively (HR, 1.08; 95% CI, 0.86-1.36).
Regarding safety, 280 patients in the dovitinib arm and 284 patients in the sorafenib arm were included in the analysis. At the data cutoff of January 25, 2013 and at a median follow-up of 11.3 months (range, 7.9-14.6), a total of 440 PFS events and 265 deaths were reported.
Grade 3 or 4 treatment-emergent adverse reactions observed with dovitinib included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6 %), anemia (5%) and increased γ-glutamyltransferase levels (5%). Eighty-five patients who received dovitinib had treatment-emergent acne-like rashes compared with 66 of those who received sorafenib.
Treatment-related serious events of any grade occurred in 48% of patients who received dovitinib versus 39% of those who received sorafenib, the most common being dyspnea (6% versus 5%, respectively).
In addition, 14% of people in the experimental group died during the study or within 30 days of their last dose compared to 15% of those in the control group; it was most often because of their CRC, at 12% and 13%, respectively. Four deaths were suspected to be potentially associated with the study treatment. Three cases were reported in the dovitinib group, and these patients had large bowel perforation, pulmonary embolism and unspecified death. The 1 reported in the sorafenib group was due to toxic epidermal necrolysis.
“I remain excited about dovitinib, along with its companion diagnostic DRP-Dovitinib, as a promising new treatment option for patients with mRCC,” said Professor Roberto Pili, MD, Associate Dean for Research on cancer and integrative oncology at the University at Buffalo Jacobs School of Medicine. and biomedical sciences, added in the press release. “These patients, and their treating oncologists, are in dire need of new precision medicines, coupled with validated companion diagnostics, to help select and treat the most likely responders. Although the landscape of treatment options for late-stage mRCC is evolving to include combination therapies, I continue to see a potential place for dovitinib with its companion diagnostic DRP in the treatment of these patients. »
- Allarity Therapeutics provides an update on the dovitinib program. Press release. Allarity Therapeutics, Inc.; March 15, 2022. Accessed March 15, 2022. https://yhoo.it/3qaIGvf
- Allarity Therapeutics submits a New Drug Application (NDA) to the US FDA for dovitinib for the third-line treatment of renal cell carcinoma (RCC). Press release. Allarity Therapeutics, Inc.; December 22, 2021. Accessed March 15, 2022. https://bit.ly/32qiAeA
- Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: a randomized open-label phase 3 trial. Lancet Oncol. 2014;15(3):286-296. doi:10.1016/S1470-2045(1)70030-0