NDA for the Dovitinib Submitted to FDA for Approval in RCC

Allarity Therapeutics, Inc has submitted a new drug application to the FDA for dovitinib as a potential option in the third-line treatment of patients with renal cell carcinoma (RCC), according to a press release by the company.¹

The application is supported by the company’s prior pre-market approval submission with the regulatory agency for use of the validated companion diagnostic Dovitinib-DRP, to select eligible patients with RCC for treatment with the agent.

“This NDA submission for dovitinib, in connection with the Dovitinib-DRP companion diagnostic, is a historic milestone for our Company and an important step for late-stage RCC patients awaiting new treatment options,” Steve Carchedi, chief executive officer of Allarity Therapeutics, Inc., stated in a press release. “Over the past decade, we have worked diligently to advance our novel oncology therapeutics pipeline together with our unique DRP diagnostic technology to realize the promise of personalized cancer care for patients.”

A pan-TKI that was developed to target FGFR, VEGFR, and other receptor tyrosine kinases (RTKs), dovitinib binds to and inhibits the phosphorylation of type III-V RTKs that encourage tumor cell proliferation and survival in certain cancer cells.²

Moreover, the agent inhibits other members of the RTK superfamily, such as FGFR1, FGFR3, FMS-like tyrosine kinase 3, c-KIT, and colony-stimulating factor receptor 1. By doing this, dovitinib can potentially reduce cellular proliferation and angiogenesis, and induce tumor cell apoptosis.

Previously, in the open-label, phase 3 GOLD trial (NCT01223027), investigators set out to compare the safety and efficacy of dovitinib with that of sorafenib (Nexavar) in patients with metastatic RCC.³

The trial enrolled those who had a clear cell or a component of clear cell histology and who had previously received 1 VEGF-targeted therapy like sunitinib (Sutent) or bevacizumab (Avastin) plus 1 prior mTOR inhibitor like everolimus (Afinitor) or temsirolimus (Torisel) in either sequence. To be eligible, patients needed to be at least 18 years of age and have had disease progression on, or within 6 months of receiving, their last therapy.

Other inclusion criteria included measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of 70 or higher, and acceptable hematologic, renal, and hepatic functions. Patients were allowed to have received prior anticancer agents, including cytokines and anticancer vaccines.

If patients received prior sorafenib or dovitinib, had brain metastases, clinically significant cardiac disease, or uncontrolled hypertension, they were excluded.

A total of 570 participants were randomized to receive oral dovitinib at a dose of 500 mg on a 5-days-on and 2-days-off schedule (n = 284) or oral sorafenib at a twice-daily dose of 400 mg (n = 286). Treatment was administered until progressive disease, intolerable toxicity, death, or withdrawn consent. Crossover was not permitted.

The primary end point of the trial was progression-free survival (PFS), and the key secondary end point was overall survival (OS). Additional secondary end points comprised overall response, PFS per investigator assessment, time to definitive worsening of Karnofsky performance status, patient-reported outcomes (PROs), and safety. Biomarker analyses served as an exploratory end point of the research.

Patient characteristics were noted to be well balanced between the treatment arms. Among the randomized population, sunitinib was the most used prior VEGF inhibitor; everolimus was the most frequently utilized mTOR inhibitor. Ninety-two percent of patients received a VEGF inhibitor followed by an mTOR inhibitor (n = 259, dovitinib arm; n = 265, sorafenib arm).

Data showed that the median PFS per central radiologist review with dovitinib was 3.7 months (95% CI, 3.5-3.9) vs 3.6 months (95% CI, 3.5-3.7) with sorafenib (HR, 0.86; 95% CI, 0.72-1.04; 1-sided P = .063). The median investigator-assessed PFS in the investigative (95% CI, 3.7-5.1) and control (95% CI, 3.7-5.0) arms was 3.9 months (HR, 1.00; 95% CI, 0.82-1.21).

When assessed by patient demographics and disease characteristics, no subset of patients was found to have a clinically significant PFS benefit with dovitinib.

Moreover, the best overall response per central review was a partial response; this occurred in 4% of those who received dovitinib and 4% who received sorafenib. In both the investigative and control arms, 52% of patients achieved stable disease; 29% and 31% of patients, respectively, experienced disease progression.

The best percentage change from baseline in sum of diameters per central review and by waterfall plot revealed tumor reductions in 51% of those who received dovitinib and 46% of those who were given sorafenib.

Additionally, the median OS with dovitinib was 11.1 months (95% CI, 9.5-13.4) vs 11.0 months (95% CI, 8.6-13.5) with sorafenib (HR, 0.96; 95% CI, 0.75-1.22). The median time to definitive worsening of Karnofsky performance status was 5.1 months (95% CI, 3.8-6.5) and 5.7 months (95% CI, 4.6-7.4) in the investigative and control arms, respectively (HR, 1.12; 95% CI, 0.87-1.45).

PROs proved to be comparable between the 2 treatment arms. For example, the median time to definitive deterioration by 10% in the quality-of-life scores of the EORTC QLQ-C30 in the investigative and control 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).

The safety analysis included all participants who received at least 1 dose of dovitinib (n = 280) or sorafenib (n = 284). At the time of the data cutoff, which was January 25, 2013, the median follow-up was 11.3 months (range, 7.9-14.6), 440 PFS events and 265 deaths were reported.

Treatment-emergent toxicities that were grade 3 or 4 in severity included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), anemia (5%), and increase in γ-glutamyltransferase levels (5%) with dovitinib. Eighty-five patients who received dovitinib reported treatment-emergent acne-like rashes vs 66 patients who received sorafenib.

Treatment-emergent serious effects of any grade were experienced by 48% of those who received dovitinib and 39% of those who were given sorafenib, the most common of which was dyspnea (6% vs 5%, respectively).

Fourteen percent of patients on the investigative arm died on the study or within 30 days of their last dose vs 15% of those on the control arm; this was most commonly because of their RCC, at 12% and 13%, respectively. Four deaths were suspected to potentially be associated with study treatment. Three were reported in the dovitinib group, and these patients had large intestine perforation, pulmonary embolism, and death not otherwise specified. The 1 reported in the sorafenib group was because of toxic epidermal necrolysis.

Dovitinib has also demonstrated activity in gastrointestinal stromal tumors, endometrial cancer, breast cancer, and hepatocellular carcinoma.

“We greatly look forward to the approval of dovitinib and to introducing the clinical value of DRP companion diagnostics to oncologists and their patients,” Carchedi said, in the press release.

_References

1. _{Allarity Therapeutics submits new drug application (NDA) to the US FDA for dovitinib for third-line treatment of renal cell carcinoma (RCC). News release. Allarity Therapeutics, Inc.; December 22, 2021. Accessed December 22, 2021. https://bit.ly/32qiAeA}
2. _{Pipeline: dovitinib. Allarity Therapeutics, Inc. website. Accessed December 22, 2021. https://bit.ly/32pMnEb}
3. _{Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286-296. doi:10.1016/S1470-2045(1)70030-0}