Allarity Therapeutics Requests Type C Meeting With FDA to Discuss Dovitinib in Third-Line RCC

US FDA

Allarity Therapeutics, Inc. has filed a formal request with the FDA to hold a Type C meeting where they can discuss possible clinical paths to support the approval of dovitinib in renal cell carcinoma (RCC), as well as its DRP-Dovitinib companion diagnostic.¹

In December 2021, a new drug application (NDA) seeking the marketing approval of dovitinib as a potential third-line treatment option for patients with RCC was submitted to the FDA.² The application was supported by the company’s prior pre-market approval (PMA) submission of the diagnostic to select eligible patients with RCC for treatment with this agent.

Two months later, in February 2022, the FDA issued Refusal to File letters regarding both applications. At the time, the late clinical-stage, precision medicine company shared plans to seek additional guidance regarding the information, data, and specific deliverables that the regulatory agency would need to resubmit the applications and be deemed complete. The launch of a new prospective clinical trial evaluating the agent in this population was also projected.

Type C meetings are typically scheduled within 75 days of receipt by the FDA of the written meeting request. Allarity Therapeutics, Inc. shared that they intend to provide an additional update on the outcome of the meeting before the third quarter comes to a close.

“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,” Steve Carchedi, chief executive officer of Allarity Therapeutics, Inc., stated 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.”

In the phase 3 GOLD trial (NCT01223027), the safety and efficacy of dovitinib was compared with sorafenib (Nexavar) in patients with metastatic RCC.³ To be eligible for enrollment, patients needed to have clear cell or a component of clear cell histology and received 1 prior VEGF-targeted therapy such as sunitinib (Sutent) or bevacizumab (Avastin) as well as 1 mTOR inhibitor such as everolimus (Afinitor) or temsirolimus (Torisel) in either sequence.

These patients were at least 18 years of age, had measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of 70 or higher, and had experienced disease progression on or within 6 months of receiving their last treatment. Patients needed to have acceptable hematologic, renal, and hepatic function. Notably, they were permitted to have previously received anticancer drugs, including cytokines and anticancer vaccines.

In the trial, 570 patients were randomized to receive dovitinib orally at a dose of 500 mg on a 5-days-on and 2-days-off schedule (n = 284) or sorafenib orally at 400 mg twice daily (n = 286). Patients received treatment until disease progression, unacceptable toxicity, death, or consent was withdrawn. The trial did not allow for crossover from the control arm to the investigative arm.

The primary end point of the research was progression-free survival (PFS), and overall survival (OS) served as a key secondary end point. Other end points of interest included overall response rate, investigator-assessed PFS, time to definitive worsening of performance status, patient-reported outcomes (PROs), and safety. Investigators also conducted 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%) received a VEGF inhibitor first, and then a mTOR inhibitor.

Findings from the trial indicated that the median PFS per central radiologist review with dovitinib vs sorafenib was 3.7 months (95% CI, 3.5-3.9) and 3.6 months (95% CI, 3.5-3.7), respectively (HR, 0.86; 95% CI, 0.86; 95% CI, 0.71-1.04; P = .063). The median PFS per investigator assessment was 3.9 months in both the dovitinib arm (95% CI, 3.7-5.1) and the sorafenib arm (95% CI, 0.82-1.21; HR, 1.00).

No patient subsets were found to derive a clinically significant PFS benefit with dovitinib over sorafenib.

The best overall response per central review was a partial response, and this occurred in 4% of those who received dovitinib and 4% of those given sorafenib. In both arms, 52% of patients achieved stable disease. Twenty-nine percent of patients in the investigative arm experienced disease progression vs 31% of those in the control arm.

The median OS in the investigative 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 investigative arm and 5.7 months (95% CI, 4.6-7.4) in the control arm (HR, 1.12; 95% CI, 0.87-1.45).

PRO data were found to be comparable between the 2 arms. The median time to definitive deterioration by 10% in the quality-of-life scores of the EORTC QLQ-C30 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 a data cutoff of January 25, 2013, and 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-related adverse effects experienced with dovitinib included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), anemia (5%), and increase in γ-glutamyltransferase levels (5%). Eighty-five patients who received dovitinib experienced treatment-emergent acne-like rashes vs 66 of those who received sorafenib.

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

Moreover, 14% of those 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.

“I remain enthusiastic about dovitinib, together with its DRP-Dovitinib companion diagnostic, as a promising new treatment option for mRCC patients,” Professor Roberto Pili, MD, associate dean for Cancer Research 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 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 15, 2022. https://yhoo.it/3qaIGvf
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 March 15, 2022. 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, randomised phase 3 trial. Lancet Oncol. 2014;15(3):286-296. doi:10.1016/S1470-2045(1)70030-0