Sunvozertinib

The FDA confirmed the accelerated approval pathway for Dizal's sunvozertinib in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations The FDA in March converted Johnson & Johnson’s Rybrevant use in previously treated EGFR exon20 insertion-mutated non-small cell lung cancer into a full nod. But the door to an accelerated approval in the same indication remains open, according to Dizal Pharma. “The FDA actually encouraged us […] to submit as soon as possible,” Dizal CEO Xiaolin Zhang, Ph.D., told Fierce Pharma on the sidelines of the American Society of Clinical Oncology (ASCO) annual meeting in Chicago early June. Dizal is developing the EGFR tyrosine kinase inhibitor sunvozertinib, which was approved in China in August for pretreated NSCLC with EGFR exon 20 insertion mutations. After a positive global pivotal trial readout and what Zhang described as a successful pre-NDA meeting with the FDA, the AstraZeneca spinout is on the verge of filing for an accelerated approval in the U.S. The FDA confirmed the accelerated approval pathway and then granted breakthrough therapy designation to sunvozertinib as a frontline treatment after the agency had handed J&J’s Rybrevant its full nod, which came hand-in-hand with a first-line approval. “Clearly, the FDA views there are patients’ needs for alternative or better therapies for this disease,” Zhang said. The FDA has in the past turned away accelerated approval applications when a full approval was already in place. Back in 2021, Agenus was forced to pull a cervical cancer submission for balstilimab after the FDA granted full approval to Merck’s Keytruda in the same indication. While both balstilimab and Keytruda are PD-1 inhibitors, sunvozertinib and Rybrevant are different, as the J&J drug is an EGFR-MET bispecific antibody. With an FDA filing around the corner, Dizal has been in discussion with multiple larger pharma companies to team up on sunvozertinib, Zhang said. Many potential partners were waiting for results from the global WU-KONG1B trial presented at ASCO 2024 and were asking questions about the first-line setting, where the drug’s key opportunity lies. Dizal is open to all deal types, Zhang said. As to whether the biotech can take U.S. commercialization in its own hands, the CEO said he’s comfortable with the company’s cash flow, especially now that sunvozertinib has started generating revenue. “We’re going to do the best deal that maximizes that potential of sunvozertinib commercially and benefit our patients,” Zhang said. “We are not going to do a deal for the sake of it.” Sunvozertinib has proven its worth in the single-arm, pivotal WU-KONG1B trial, which enrolled more than 40% non-Asian patients. As of a data cut in March, investigators recorded a best overall response rate (ORR) of 53.3% and a confirmed ORR of 44.9%, including two confirmed complete responses, among 107 patients who received sunvozertinib at the recommended 300mg dose. Notably, the drug showed anti-tumor effect regardless of prior treatment with Rybrevant. The best ORRs for those with or without prior exposure to the J&J drug were similar at 50% and 53.8%, respectively. The median duration of response was not reached, and 57% of patients were in remission for at least nine months. Dizal can’t file just yet because the FDA wants at least six-month follow-up for the last responder. And Dizal could have that additional data late June, Zhang said.  When Rybrevant got its accelerated approval in 2021, the drug’s ORR was 40% with a median response duration of 11.1 months. Sunvozertinib’s tumor shrinkage data also appeared to be far better than Takeda’s disgraced small-molecule drug Exkivity, which got a conditional nod based on a 28% ORR. Takeda has decided to pull Exkivity off the market after failing a confirmatory phase 3 trial in the first-line setting. Dizal designed sunvozertinib in a flexible way to accommodate different types of EGFR exon 20 insertions, as well as some potency against wild-type EGFR, Zhang explained. Other drugs that focus on certain more sensitive insertions may have strong inhibition in those subtypes but may be too weak elsewhere. To shoot for an accelerated approval, the FDA has been requiring that a confirmatory trial be underway. The phase 3 WU-KONG28 trial could serve that purpose, and it’s already 70% enrolled, according to Zhang. The study is evaluating sunvozertinib monotherapy versus platinum-based doublet chemotherapy in first-line EGFR exon 20-mutated NSCLC. J&J’s Rybrevant succeeded in the first line as part of a combination with chemotherapy, while Takeda’s Exkivity flopped as a monotherapy. Still, Zhang believes single-agent sunvozertinib is the right approach because in newly diagnosed patients, quality of life is important. “Our view is that in the first line, the goal of treatment is different from later lines,” Zhang explained. “You want to keep the [progression-free survival] as long as you can, and the patient sill have very good quality of life because these are patients who generally have a reasonable daily life. So, we don’t think, if possible, that first-line combo with chemo is a desirable strategy. Once you have chemo, then that patient’s quality [of life] immediately goes down.” At last year’s European Society of Medical Oncology annual meeting, Dizal unveiled a pooled analysis of early-phase data for sunvozertinib monotherapy in first-line EGFR exon 20 NSCLC, showing a median progression-free survival of 12.4 months. The result compared favorable to Rybrevant-plus-chemo’s 11.4 months from J&J’s phase 3 PAPILLON trial. J&J is also angling Rybrevant for the more common EGFR mutations involving exon 19 and exon 21, which is currently dominated by AstraZeneca’s Tagrisso. Zhang, who previously led AZ’s China innovation center before its spinoff into Dizal, knows Tagrisso very well. Tagrisso has established itself very well in common EGFR mutations, Zhang said, “so we focus on second-line treatment after Tagrisso failure.” And that’s where Dizal will explore combinations with sunvozertinib. These include pairings with chemotherapy and with Dizal’s JAK1 inhibitor golidocitinib, which last week won Chinese approval for peripheral T-cell lymphoma. And the company has DZD6008, an EGFR inhibitor specifically designed for post-Tagrisso treatment.

Chinese regulators have approved Dizal's JAK1 inhibitor golidocitinib for adult patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).The decision makes it "the world's first JAK1-only inhibitor" for PTCL patients, noted CEO Xiaolin Zhang, as well as the second approved drug from Dizal after the AstraZeneca spinout's lung cancer treatment sunvozertinib was waved through in China last year.While a few drugs have been granted conditional regulatory approvals in the relapsed or refractory PTCL setting, Dizal noted that their single-agent activities have been "modest," with objective response rates (ORRs) below 30%.During an advisory panel meeting last November, the FDA raised questions about accelerated approvals for Acrotech Biopharma's folate analogue inhibitor Folotyn (pralatrexate) and HDAC inhibitor Beleodaq (belinostat) in relapsed/refractory PTCL after both their confirmatory trials experienced major delays.However, Dizal says its drug has demonstrated "superior and durable" clinical benefits in the pivotal JACKPOT8B study, compared with these existing treatment options. Data from the trial presented last year showed an ORR of 44.3% with golidocitinib, including a 23.9% complete response rate.Median duration of response was 20.7 months and 53.8% of patients were still responding. Moreover, tumour responses were observed across various PTCL subtypes. Results of the JACKPOT8 trial have been published in Annals of Oncology and The Lancet Oncology."With > 200 to 400-fold selectivity over other JAK family members and ideal pharmacokinetic properties, golidocitinib exerts potent antitumour efficacy with a favourable safety profile," the company said.