Type C Meeting With FDA Requested by Allarity to Discuss Dovitinib in Third-Line RCC

Allarity Therapeutics Inc. (Allarity) has requested a Type C meeting with the FDA to discuss potential clinical paths to support approval of dovitinib as a potential option in the third-line treatment of patients with renal cell carcinoma (RCC), as well as its DRP-Dovitinib companion diagnostic.¹

This request follows the FDA providing Allarity with a refusal to file (RTF) letter for a marketing application for dovitinib in this setting.

“We look forward to working closely with the FDA and we remain highly confident in the clinical profile of dovitinib, together with the DRP-Dovitinib companion diagnostic. We are determined to further advance this product candidate as a potential new treatment option for cancer patients,” said Steve Carchedi, chief executive officer of Allarity, in a press release. “With clarification from the FDA following our requested Type C meeting, we hope to have a clinical path forward with the goal of refiling our NDA and PMA once additional clinical data are in hand.”

The RTF also covers a pre-market approval application for the DRP-Dovitinib companion diagnostic as the FDA determined the submitted applications not to be sufficiently complete to allow for substantive reviews upon their own preliminary review. Regarding the marketing application, the FDA said that the data demonstrated through the submitted clinical trial do not conclude efficacy based on non-inferiority data set.

In December, Allarity submitted its first regulatory application for marketing approval. This was supported by the company’s prior pre-market approval submission with the regulatory agency for use of the companion diagnostic Dovitinib-DRP as treatment to eligible patients with RCC.²

Dovitinib is ​​a pan-TKI developed to target FGFR, VEGFR, and other receptor tyrosine kinases (RTKs). It works by binding to and inhibiting the phosphorylation of type III-V RTKs that encourage tumor cell proliferation and survival in certain cancer cells.² The agent inhibits other members of the RTK superfamily which potentially allows dovitinib to reduce cellular proliferation and angiogenesis and induce tumor cell apoptosis.

The open-label, phase 3 GOLD trial (NCT01223027) which previously took place examined the safety and efficacy of dovitinib compared to sorafenib (Nexavar) in patients with metastatic RCC.³

Those with a clear cell or a component of clear cell histology and who previously had received 1 VEGF-targeted therapy plus 1 prior mTOR inhibitor in either sequence were eligible for enrollment in the study. Other inclusion criteria included being 18 years of age or older, had disease progression on, were within 6 months of receiving their last therapy, measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of 70 or higher, and acceptable hematologic, renal, and hepatic functions. Additionally, patients were allowed to have received prior anticancer agents, including cytokines and anticancer vaccines.

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

Progression-free survival (PFS) was the primary end point of the trial with a key secondary end point of overall survival (OS). Other secondary end points included overall response (OR), 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.

Within the randomized population, the most used prior VEGF inhibitor was sunitinib, and 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).

Findings revealed the median PFS per central radiologist review with dovitinib was 3.7 months (95% CI, 3.5-3.9) compared to 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). No subset of patients was found to have a clinically significant PFS benefit with dovitinib when assessed by patient demographics and disease characteristics.

Additionally, the best OR per central review was a partial response which occurred in 4% of patients who received dovitinib and 4% that 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 revealed tumor reductions in 51% of those who received dovitinib and 46% of those who were given sorafenib.

The median OS was 11.1 months with dovitinib (95% CI, 9.5-13.4) and 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).

Between each of the treatment arms, PROs proved to be comparable as 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).

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

Grade 3 or 4 treatment-emergent toxicities included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), anemia (5%), and increase in γ-glutamyltransferase levels (5%) with dovitinib. There were 85 patients given dovitinib who reported treatment-emergent acne-like rashes compared to 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).

In the investigative arm, 14% of patients died on the study or within 30 days of their last dose and 15% of those on the control arm, most commonly due to their RCC, at 12% and 13%, respectively. There were also 4 deaths suspected to be associated with study treatment, with 3 reported in the dovitinib group. These patients had large intestine perforation, pulmonary embolism, and death not otherwise specified. In the sorafenib group, the 1 reported was due to toxic epidermal necrolysis.

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

“I remain enthusiastic about dovitinib, together with its DRP-Dovitinib companion diagnostic, as a promising new treatment option for mRCC patients,” stated Professor Roberto Pili, MD, associate dean for Cancer Research and Integrative Oncology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, in the press release. “These patients, and their treating oncologists, are greatly in 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 later-stage mRCC is evolving to include combination therapies, I continue to see a potential place for dovitinib with its DRP companion diagnostic in the treatment of these patients.”

References:

1. Allarity Therapeutics provides update on dovitinib program. News Release. Allarity Therapeutics, Inc.; March 15, 2022. Accessed March 16, 2022. https://yhoo.it/3JoKDMg

2. 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

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, randomized phase 3 trial. Lancet Oncol. 2014;15(3):286-296. doi:10.1016/S1470-2045(1)70030-0